diff --git "a/experimental_data/protein_retrieval_multiple_sources/omim_descriptions.csv" "b/experimental_data/protein_retrieval_multiple_sources/omim_descriptions.csv" new file mode 100644--- /dev/null +++ "b/experimental_data/protein_retrieval_multiple_sources/omim_descriptions.csv" @@ -0,0 +1,9765 @@ +efo,omim_def_curated +EFO_1000775,"Definition: Autosomal dominant vibratory urticaria is characterized by localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum (previous studies)." +EFO_0003888,"Definition: Attention deficit-hyperactivity disorder (ADHD) is the most common childhood-onset behavioral disorder, affecting approximately 5 to 10% of children and adolescents (previous studies). In this condition, persistent inattention and/or hyperactive-impulsive behavior results in impaired social and/or academic functioning. Boys are affected about 8 times more frequently than girls (previous studies). + + Genetic Heterogeneity of Attention Deficit-Hyperactivity Disorder + +Susceptibility to ADHD7 (previous studies) may be conferred by variation in the TPH2 gene (previous studies) on chromosome 12q21. ADHD8 (previous studies) is caused by mutation in the CDH2 gene (previous studies) on chromosome 18q12. + +Several loci for susceptibility to ADHD have been mapped, including ADHD1 (previous studies) on chromosome 16p13, ADHD2 (previous studies) on chromosome 17p11, ADHD3 (previous studies) on chromosome 6q12, ADHD4 (previous studies) on chromosome 5p13, ADHD5 (previous studies) on 2q21.1, and ADHD6 (previous studies) on 13q12.11. Also see MOLECULAR GENETICS." +EFO_1001978,"Definition: The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by previous studies). + + Genetic Heterogeneity of 3MC Syndrome + +Also see 3MC syndrome-2 (3MC2; previous studies), caused by mutation in the COLEC11 gene (previous studies), and 3MC syndrome-3 (3MC3; previous studies), caused by mutation in the COLEC1 gene (previous studies)." +EFO_0004562,"Definition: Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by previous studies)." +EFO_0004895,"Definition: Tourette syndrome is a neurobehavioral disorder manifest particularly by motor and vocal tics and associated with behavioral abnormalities. Tics are sudden, brief, intermittent, involuntary or semi-voluntary movements (motor tics) or sounds (phonic or vocal tics). They typically consist of simple, coordinated, repetitive movements, gestures, or utterances that mimic fragments of normal behavior. Motor tics may range from simple blinking, nose twitching, and head jerking to more complex throwing, hitting, or making rude gestures. Phonic tics include sniffling, throat clearing, blowing, coughing, echolalia, or coprolalia. Males are affected about 3 times more often than females, and onset usually occurs between 3 and 8 years of age. By age 18 years, more than half of affected individuals are free of tics, but they may persist into adulthood (review by previous studies)." +EFO_0009162,"Definition: Charcot-Marie-Tooth disease type 2T (CMT2T) is a slowly progressive autosomal recessive sensorimotor peripheral neuropathy with onset in middle age (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +EFO_1001333,"Definition: Danon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease; previous studies) with 'normal acid maltase' or alpha-glucosidase (GAA; previous studies) (previous studies). However, previous studies stated that Danon disease is not a glycogen storage disease because glycogen is not always increased. + +previous studies classified Danon disease as a form of autophagic vacuolar myopathy, characterized by intracytoplasmic autophagic vacuoles with sarcolemmal features. The characteristic vacuole is believed to be an autolysosome surrounded by secondarily-generated membranes containing sarcolemmal proteins, basal lamina, and acetylcholinesterase activity. + +X-linked myopathy with excessive autophagy (XMEA; previous studies) is a distinct disorder with similar pathologic features." +EFO_0009043,"Definition: Porphyria cutanea tarda (PCT) is characterized by light-sensitive dermatitis and the excretion of large amounts of uroporphyrin in urine (previous studies). + +previous studies and others classified porphyria cutanea tarda, the most common type of porphyria, into 2 types: type I (previous studies), or 'sporadic' type, associated with approximately 50% level of uroporphyrinogen decarboxylase (UROD) in liver (previous studies; previous studies), and type II, or 'familial' type, characterized by 50% deficient activity of the same enzyme in many tissues (previous studies; previous studies). + +PCT type II is an autosomal dominant disorder with low penetrance and constitutes about 20% of cases of PCT. Recognized exacerbating factors of PCT include iron overload, excessive use of alcohol, exposure to polyhalogenated aromatic chemicals, exposure to estrogens, chronic viral hepatitis C, HIV infections, and mutation in the HFE gene (previous studies) that are responsible for hereditary hemochromatosis (previous studies) (review by previous studies)." +EFO_0000174,"Definition: The Ewing sarcoma family of tumors (primitive neuroectodermal tumors; PNET) comprise morphologically heterogeneous tumors that are characterized by nonrandom chromosomal translocations involving the EWS gene on chromosome 22q12 and one of several members of the ETS family of transcription factors. The tumors include Ewing sarcoma, peripheral neuroepithelioma, and Askin tumor. In approximately 90% of cases of ESFT, the FLI1 gene (previous studies) on chromosome 11 is the fusion partner of EWS; in approximately 10%, the EWS fusion partner is the ERG gene (previous studies) on chromosome 22. Many other ETS family members have been identified as fusion partners of EWS, but these cases are rare (previous studies)." +EFO_0009646,"Definition: Macrothrombocytopenia with or without granulocyte inclusions, nephritis, or sensorineural hearing loss was previously thought to comprise 4 distinct entities with overlapping features: Fechtner syndrome, May-Hegglin anomaly, Epstein syndrome, and Sebastian syndrome. Fechtner syndrome was characterized by the triad of thrombocytopenia, giant platelets, and Dohle body-like inclusions in peripheral blood leukocytes, with the additional Alport syndrome (previous studies)-like features of nephritis, hearing loss, and eye abnormalities, predominantly cataracts (previous studies). May-Hegglin anomaly was characterized by the triad of thrombocytopenia, giant platelets, and Dohle body-like inclusions in peripheral blood leukocytes. Epstein syndrome was characterized by thrombocytopenia, deafness, and nephritis, and lacked leukocyte inclusion bodies on classic staining of peripheral blood smears. Sebastian syndrome was similar to May-Hegglin anomaly, but had a different ultrastructural appearance of the leukocyte inclusions. previous studies suggested that these 4 disorders were not distinct entities, but rather represented a single disorder with a continuous clinical spectrum because variable phenotypic expression is observed not only between families but also within families having the same MYH9 mutation. In addition, previous studies noted that all patients present leukocyte inclusion bodies, although of variable size. previous studies proposed the term 'MYH9-related disease' for the disorder; however, an isolated form of nonsyndromic deafness (DFNA17; previous studies) is also caused by mutation in the MYH9 gene." +EFO_0009028,Definition: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome is an autosomal recessive condition characterized by the association of congenital or early-onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions are found in some patients (summary by previous studies). +EFO_0005840,Definition: Elevation of red cell ATP levels is accompanied by elevated red cell pyruvate kinase activity and mild erythrocytosis. Red cell life span is slightly shortened. The patients in whom this trait was first described were asymptomatic (summary by previous studies). +EFO_1001977,"Definition: The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by previous studies). + +For a discussion of genetic heterogeneity of 3MC syndrome, see 3MC1 (previous studies)." +EFO_0009077,"Definition: Premature chromatid separation consists of separate and splayed chromatids with discernible centromeres and involves all or most chromosomes of a metaphase. It is found in up to 2% of metaphases in cultured lymphocytes from approximately 40% of normal individuals. When PCS is present in 5% or more of cells, it is known as the 'heterozygous PCS trait' and has no obvious phenotypic effect, although some have reported decreased fertility (previous studies). Inheritance is autosomal codominant (previous studies). + +See also previous studies for a possible inherited predisposition to nondisjunction, which may be a related phenomenon." +EFO_0000640,"Definition: Hereditary papillary renal cell carcinoma is characterized by the development of multiple, bilateral papillary renal tumors (previous studies). The transmission pattern is consistent with autosomal dominant inheritance with incomplete penetrance. + +Papillary renal cell carcinoma is histologically and genetically distinct from 2 other forms of inherited renal carcinoma, von Hippel Lindau disease (previous studies), caused by mutation in the VHL gene (previous studies) on chromosome 3, and a form associated with the chromosome translocation t(3;8), as described by previous studies. previous studies reviewed the molecular genetics of familial and nonfamilial cases of renal cell carcinoma, including the roles of VHL, MET, and translocations involving chromosomes 1, 3, and X. + +For background information and a discussion of genetic heterogeneity of nonpapillary renal cell carcinoma, see RCC (previous studies). + +See also a hereditary syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma (HLRCC; previous studies) caused by germline mutation in the FH gene (previous studies)." +EFO_1001501,"Definition: Shortened telomeres can cause a wide variety of clinical features that constitute a phenotypic spectrum. The most severe form is dyskeratosis congenita (see, e.g., previous studies), characterized by early childhood onset of skin abnormalities, bone marrow failure, predisposition to malignancy, and risk of pulmonary and hepatic fibrosis. Adult-onset pulmonary fibrosis is the most common manifestation of mutant telomerase genes, but hepatopulmonary syndrome may precede the pulmonary fibrosis. Other manifestations include aplastic anemia due to bone marrow failure, liver disease, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and squamous cell carcinoma. Phenotype, age at onset, and severity are determined by telomere length, not just telomerase mutation (previous studies; previous studies). + +The genetic diagnosis of telomere-related bone marrow failure and pulmonary fibrosis has implications for treatment because affected individuals generally do not respond to immunosuppression and may be at increased risk for fatal complications after bone marrow or lung transplantation (previous studies). + + Genetic Heterogeneity of Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndromes + +Also see PFBMFT2 (previous studies), caused by mutation in the TERC gene (previous studies) on chromosome 3q26; PFBMFT3 (previous studies), caused by mutation in the RTEL1 gene (previous studies) on chromosome 20q13; PFBMFT4 (previous studies), caused by mutation in the PARN gene (previous studies) on chromosome 16p13; PFBMFT5 (previous studies), caused by mutation in the ZCCHC8 gene (previous studies) on chromosome 12q24; PFBMFT6 (previous studies), caused by mutation in the RPA1 gene (previous studies) on chromosome 17p13; PFBMFT7 (previous studies), caused by mutation in the NAF1 gene (previous studies) on chromosome 4q32; PFBMFT8 (previous studies), caused by mutation in the POT1 gene (previous studies) on chromosome 7q31; and PFBMFT9 (previous studies), caused by mutation in the NOP10 gene (previous studies) on chromosome 15q14." +EFO_0009384,"Definition: Hyperphosphatemic familial tumoral calcinosis is a rare autosomal recessive metabolic disorder characterized by the progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone (previous studies). The biochemical hallmark of tumoral calcinosis is hyperphosphatemia caused by increased renal absorption of phosphate due to loss-of-function mutations in the FGF23 (previous studies) or GALNT3 (previous studies) gene. The term 'hyperostosis-hyperphosphatemia syndrome' is sometimes used when the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis. Although some have distinguished HHS from FTC by the presence of bone involvement and the absence of skin involvement (previous studies), previous studies concluded that the 2 entities represent a continuous spectrum of the same disease, best described as familial hyperphosphatemic tumoral calcinosis. + +HFTC is considered to be the clinical converse of autosomal dominant hypophosphatemic rickets (ADHR; previous studies), an allelic disorder caused by gain-of-function mutations in the FGF23 gene and associated with hypophosphatemia and decreased renal phosphate absorption (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HFTC, see previous studies." +EFO_0000198,"Definition: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematologic stem cell disorders characterized by ineffective hematopoiesis resulting in low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia (AML; previous studies). Blood smears and bone marrow biopsies show dysplastic changes in myeloid cells, with abnormal proliferation and differentiation of 1 or more lineages (erythroid, myeloid, megakaryocytic). MDS can be subdivided into several categories based on morphologic characteristics, such as low-grade refractory anemia (RA) or high-grade refractory anemia with excess blasts (RAEB). Bone marrow biopsies of some patients show ringed sideroblasts (RARS), which reflects abnormal iron staining in mitochondria surrounding the nucleus of erythrocyte progenitors (summary by previous studies and previous studies)." +EFO_0009153,"Definition: Lymphatic malformation-6 is a form of generalized lymphatic dysplasia (GLD), which is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. In LMPHM6, there is a high incidence of nonimmune hydrops fetalis (NIHF) with either death or complete resolution of the neonatal edema, but childhood onset of lymphedema with or without systemic involvement also occurs. Mild facial edema is often present. Patients have normal intelligence and no seizures (summary by previous studies). + +For a discussion of genetic heterogeneity of lymphatic malformation, see previous studies." +EFO_0005425,"Definition: Specific language impairment-5 (SLI5) is characterized by a delay in early speech acquisition and is usually associated with cerebral white matter abnormalities on brain MRI. Some individuals may show disorders in communication, consistent with autism spectrum disorder, or global developmental delay, although others ultimately show normal cognitive function. Penetrance is incomplete and expressivity is variable. This type of disorder is observed most commonly among individuals of East Asian descent (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of specific language impairment, see SLI1 (previous studies)." +EFO_0009071,"Definition: Susceptibility to malignant hyperthermia (MHS), a skeletal muscle disorder most often inherited as an autosomal dominant trait, is one of the main causes of death due to anesthesia. In susceptible people, a malignant hyperthermia episode is triggered by exposure to commonly used volatile anesthetic agents such as halothane or depolarizing muscle relaxants such as succinyl choline. A fulminant MH crisis is characterized by any combination of hyperthermia, skeletal muscle rigidity, tachycardia or arrhythmia, respiratory and metabolic acidosis, and rhabdomyolysis. Except for this susceptibility to triggering agents, MHS patients are not clinically distinguishable from the general population (summary by previous studies). + + Genetic Heterogeneity of Susceptibility to Malignant Hyperthermia + +Other MHS loci include MHS2 (previous studies) on chromosome 17q; MHS3 (previous studies) on chromosome 7q; MHS4 (previous studies) on chromosome 3q; MHS5 (previous studies), caused by mutation in the CACNA1S gene (previous studies) on chromosome 1q32; and MHS6 (previous studies) on chromosome 5p." +EFO_1000012,"Definition: Loeys-Dietz syndrome-5 (LDS5), also known as Rienhoff (pronounced REENhoff) syndrome, is characterized by syndromic presentation of aortic aneurysms involving the thoracic and/or abdominal aorta, with risk of dissection and rupture. Other systemic features include cleft palate, bifid uvula, mitral valve disease, skeletal overgrowth, cervical spine instability, and clubfoot deformity; however, not all clinical features occur in all patients. In contrast to other forms of LDS (see previous studies), no striking aortic or arterial tortuosity is present in these patients, and there is no strong evidence for early aortic dissection (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see LDS1 (previous studies)." +EFO_0000191,"Definition: The concept of mucosa-associated lymphoid tissue (MALT) lymphomas was introduced by previous studies. MALT lymphomas are now recognized as a distinct subtype of non-Hodgkin lymphoma (previous studies). B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) are the most common form of lymphoma arising in extranodal sites, in most cases arising in the gastric mucosa (previous studies)." +EFO_1000355,"Definition: Malignant mesothelioma is an aggressive neoplasm of the serosal lining of the chest etiologically linked to asbestos. It is diagnosed in approximately 2,000 to 3,000 individuals annually in the United States, most of whom die within 2 years of diagnosis (summary by previous studies). + +See also previous studies for a tumor predisposition syndrome that may contribute to the development of malignant mesothelioma upon asbestos exposure and is caused by germline mutation in the BAP1 gene (previous studies) on chromosome 3p21." +EFO_0009644,"Definition: Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA) is an autosomal recessive disorder characterized by severe global developmental delay with poor motor and intellectual function apparent soon after birth, as well as postnatal progressive microcephaly. Most patients develop early-onset, frequent, and often intractable seizures, compatible with an epileptic encephalopathy. Other features include poor feeding, poor overall growth, absent speech, poor or absent eye contact, inability to achieve walking, hypotonia, and peripheral spasticity. Brain imaging usually shows progressive cerebral atrophy, thin corpus callosum, and abnormalities in myelination. Death in childhood may occur (summary by previous studies)." +EFO_0009160,"Definition: Stromme syndrome is an autosomal recessive congenital disorder affecting multiple systems with features of a ciliopathy. Affected individuals typically have some type of intestinal atresia, variable ocular abnormalities, microcephaly, and sometimes involvement of other systems, including renal and cardiac. In some cases, the condition is lethal in early life, whereas other patients show normal survival with or without mild cognitive impairment (summary by previous studies)." +EFO_0000224,"Definition: Acute promyelocytic leukemia (APL) is associated with 2 cardinal features: a granulocytic differentiation block and reciprocal and balanced translocations that always involve rearrangement of the RARA gene (previous studies). The most frequent translocation is t(15,17)(q21;q22), which fuses the RARA gene with the PML gene (previous studies) and represents more than 98% of APL (previous studies)." +EFO_0003096,"Definition: Pick disease refers to the neuropathologic finding of 'Pick bodies,' which are argyrophilic, intraneuronal inclusions, and 'Pick cells,' which are enlarged neurons. The clinical correlates of Pick disease of brain include those of frontotemporal dementia, which encompass the behavioral variant of FTD, semantic dementia, and progressive nonfluent aphasia (summary by previous studies). + +previous studies suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), progressive supranuclear palsy (previous studies), and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease,' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies." +EFO_0000685,"Definition: Rheumatoid arthritis is an inflammatory disease, primarily of the joints, with autoimmune features and a complex genetic component." +EFO_0006792,"Definition: Dementia with Lewy bodies (DLB) is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease (see PD; previous studies). Alzheimer disease (AD; previous studies)-associated pathology and spongiform changes may also be seen (previous studies; previous studies; previous studies)." +EFO_0000182,"Definition: Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (previous studies)." +EFO_1001983,"Definition: Charcot-Marie-Tooth disease type 2X (CMT2X) is an autosomal recessive, slowly progressive, axonal peripheral sensorimotor neuropathy characterized by lower limb muscle weakness and atrophy associated with distal sensory impairment and gait difficulties. Some patients also have involvement of the upper limbs. Onset usually occurs in the first 2 decades of life, although later onset can also occur (summary by previous studies) + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +EFO_0009383,"Definition: Hyperphosphatemic familial tumoral calcinosis is a rare autosomal recessive metabolic disorder characterized by the progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone (previous studies). The biochemical hallmark of tumoral calcinosis is hyperphosphatemia caused by increased renal absorption of phosphate due to loss-of-function mutations in the FGF23 or GALNT3 (previous studies) gene. The term 'hyperostosis-hyperphosphatemia syndrome' is sometimes used when the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis. Although some have distinguished HHS from FTC by the presence of bone involvement and the absence of skin involvement (previous studies), previous studies concluded that the 2 entities represent a continuous spectrum of the same disease, best described as familial hyperphosphatemic tumoral calcinosis. + +HFTC is considered to be the clinical converse of autosomal dominant hypophosphatemic rickets (ADHR; previous studies), an allelic disorder caused by gain-of-function mutations in the FGF23 gene and associated with hypophosphatemia and decreased renal phosphate absorption (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HFTC, see previous studies." +EFO_1000063,"Definition: In humans, the activities of lactase and most of the other digestive hydrolases are maximal at birth. The majority of the world's human population experiences a decline in production of the digestive enzyme lactase-phlorizin hydrolase during maturation, with the age of onset ranging from the toddler years to young adulthood. Due to the reduced lactase level, lactose present in dairy products cannot be digested in the small intestine and instead is fermented by bacteria in the distal ileum and colon. The fermentative products result in symptoms of diarrhea, gas bloat, flatulence, and abdominal pain. However, in a minority of adults, high levels of lactase activity persist in adulthood. Lactase persistence is a heritable autosomal dominant condition that results in a sustained ability to digest the milk sugar lactose throughout adulthood (previous studies)." +EFO_0005556,"Definition: The hereditary hyperbilirubinemias (previous studies) include (1) those resulting in predominantly unconjugated hyperbilirubinemia: Gilbert or Arias syndrome, Crigler-Najjar syndrome type I (previous studies), and Crigler-Najjar syndrome type II (previous studies); and (2) those resulting in predominantly conjugated hyperbilirubinemia: Dubin-Johnson syndrome (previous studies), Rotor syndrome (previous studies), and several forms of intrahepatic cholestasis (previous studies, previous studies, previous studies, previous studies). Detailed studies show that patients with Gilbert syndrome have reduced activity of bilirubin glucuronosyltransferase (previous studies, previous studies). + + Genetic Heterogeneity of Hyperbilirubinemia + +See also Crigler-Najjar syndrome type I (HBLRCN1; previous studies), Crigler-Najjar syndrome type II (HBLRCN2; previous studies), and transient familial neonatal hyperbilirubinemia (HBLRTFN; previous studies), all caused by mutation in the UGT1A1 gene (previous studies) on chromosome 2q37; Dubin-Johnson syndrome (DJS, HBLRDJ; previous studies), caused by mutation in the ABCC2 gene (previous studies) on chromosome 10q24; and Rotor syndrome (HBLRR; previous studies), caused by digenic mutation in the SLCO1B1 (previous studies) and SLCOB3 (previous studies) genes, both on chromosome 12p." +EFO_0007143,"Definition: Alveolar soft part sarcoma is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior (previous studies; previous studies). The typical histology of ASPS shows well-defined nests of cells with abundant pink cytoplasm. The loss of central cohesion produces a pseudoalveolar appearance (previous studies)." +EFO_0009907,"Definition: Hereditary desmoid disease usually presents as an extraintestinal manifestation of familial adenomatous polyposis (FAP; previous studies), also known as Gardner syndrome, which is an autosomal dominant disorder caused by germline mutation in the APC gene. The desmoid tumors are usually intraabdominal and, although benign, can be locally aggressive and result in significant morbidity. Desmoid tumors can also arise sporadically (previous studies)." +EFO_1001979,"Definition: Congenital isolated adrenocorticotropic hormone deficiency is characterized by severe hypoglycemia in the neonatal period, associated with seizures in about half of cases; prolonged cholestatic jaundice; and very low plasma ACTH levels with no significant response to CRH (previous studies). Plasma cortisol levels are also extremely low (previous studies). TBX19 is required for initiation of transcription of the POMC gene (previous studies), which produces the precursor peptide from which ACTH is derived (previous studies)." +EFO_0006342,"Definition: Aggressive periodontitis, which may be generalized or localized, is characterized by severe and protracted gingival infections, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting (previous studies). The term 'aggressive periodontitis' replaced the terms 'early-onset,' 'prepubertal,' or 'juvenile periodontitis' at a 1999 International workshop for a classification of periodontal disease and conditions, where it was decided that the classification terminology should not be age dependent or require knowledge of rates of progression (previous studies). + + Genetic Heterogeneity of Aggressive Periodontitis + +Aggressive periodontitis-2 (previous studies) has been mapped to chromosome 1q25." +EFO_0004144,"Definition: Acatalasemia, also known as acatalasia, is a metabolic disorder characterized by a total or near total loss of catalase activity in erythrocytes. About half of cases originate from ulcerating oral gangrenes, and these cases are referred to as having Takahara disease. Half-normal levels of catalase in heterozygotes is referred to as hypocatalasemia or hypocatalasia (previous studies)." +EFO_1001186,"Definition: Sneddon syndrome is a noninflammatory arteriopathy characterized by onset of livedo reticularis in the second decade and onset of cerebrovascular disease in early adulthood (summary by previous studies). + +Livedo reticularis occurs also with polyarteritis nodosa, systemic lupus erythematosus, and central thrombocythemia, any one of which may be accompanied by cerebrovascular accidents (previous studies)." +EFO_0007193,"Definition: Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by previous studies). + +Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (previous studies), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (previous studies), argininosuccinate lyase deficiency (previous studies), and arginase deficiency (previous studies)." +EFO_0009645,"Definition: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart is an autosomal dominant syndrome characterized by onset in infancy of developmental delay, intellectual disability, and behavioral disorders, such as autism spectrum disorders. About half of patients have additional abnormalities, most commonly involving the eye, heart, and genitourinary system. The phenotype is reminiscent of that observed in patients with 1p36 deletion syndrome (previous studies); RERE is located in the proximal 1p36 critical region (summary by previous studies)." +EFO_0002939,"Definition: Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (previous studies), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (see previous studies). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (previous studies). + +previous studies reviewed the histopathologic variants and molecular subgroups of medulloblastoma. Pretreatment prognosis of medulloblastoma has been refined by histopathologic subclassification into the following variants: large-cell medulloblastoma, anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity (MBEN). The latter 2 groups have been shown to have a significantly superior prognosis as compared to the large cell and anaplastic groups in young children. At the molecular level, medulloblastomas have been categorized into the following subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. Each subgroup is characterized by a unique set of genetics and gene expression as well as demographic and clinical features." +EFO_0004242,"Definition: Obsessive-compulsive disorder (OCD) is characterized by recurring obsessions and/or compulsions and has been estimated to affect nearly 5 million people in the United States (previous studies). Evidence for a strong genetic component in OCD comes from twin studies, family genetics studies, and segregation analyses, as reviewed by previous studies. + +previous studies suggested that hoarding is likely to be an evolutionarily conserved trait that, in times of adversity, was associated with increased survival and reproductive fitness. However, extreme forms of this trait are associated with marked disability and poor response to treatment (previous studies; previous studies)." +EFO_0009302,"Definition: Amelogenesis imperfecta is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (previous studies)." +EFO_0009059,"Definition: Spinocerebellar ataxia-42 is an autosomal dominant neurologic disorder characterized predominantly by gait instability and additional cerebellar signs such as dysarthria, nystagmus, and saccadic pursuits. The age at onset and severity of the disorder is highly variable; it is slowly progressive (summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +EFO_1001981,"Definition: Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by previous studies)." +EFO_0005584,Definition: Seborrheic keratoses are common benign epidermal lesion that can develop on any part of the body. +EFO_0007409,"Definition: Ornithine transcarbamylase deficiency is an X-linked inborn error of metabolism of the urea cycle, which causes hyperammonemia. The disorder is treatable with supplemental dietary arginine and low protein diet. + +Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: OTC deficiency, carbamyl phosphate synthetase deficiency (previous studies), argininosuccinate synthetase deficiency, or citrullinemia (previous studies), argininosuccinate lyase deficiency (previous studies), and arginase deficiency (previous studies)." +Orphanet_2053,"Definition: Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (previous studies)." +EFO_0006513,"Definition: Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism wherein the body accumulates excess iron (summary by previous studies). Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. Removal of excess iron by therapeutic phlebotomy decreases morbidity and mortality if instituted early in the course of the disease. Classic hemochromatosis (HFE) is most often caused by mutation in a gene designated HFE on chromosome 6p21.3. + +previous studies reviewed the clinical features, pathophysiology, and management of hemochromatosis. + + Genetic Heterogeneity of Hemochromatosis + +At least 4 additional iron overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Juvenile hemochromatosis, or hemochromatosis type 2 (HFE2), is autosomal recessive and is divided into 2 forms: HFE2A (previous studies), caused by mutation in the HJV gene (previous studies) on chromosome 1q21, and HFE2B (previous studies), caused by mutation in the HAMP gene (previous studies) on chromosome 19q13. Hemochromatosis type 3 (HFE3; previous studies), an autosomal recessive disorder, is caused by mutation in the TFR2 gene (previous studies) on chromosome 7q22. Hemochromatosis type 4 (HFE4; previous studies), an autosomal dominant disorder, is caused by mutation in the SLC40A1 gene (previous studies) on chromosome 2q32. Hemochromatosis type 5 (HFE5; previous studies) is caused by mutation in the FTH1 gene (previous studies) on chromosome 11q12." +EFO_0009157,"Definition: Malaria, a major cause of child mortality worldwide, is caused by mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the 4 species that infect humans, P. falciparum causes the most severe forms of malaria and is the major cause of death and disease. Although less fatal, P. malariae, P. ovale, and, in particular, P. vivax infections are major causes of morbidity. The parasite cycle involves a first stage in liver cells and a subsequent stage at erythrocytes, when malaria symptoms occur. A wide spectrum of phenotypes are observed, from asymptomatic infection to mild disease, including fever and mild anemia, to severe disease, including cerebral malaria, profound anemia, and respiratory distress. Genetic factors influence the response to infection, as well as disease progression and severity. Malaria is the strongest known selective pressure in the recent history of the human genome, and it is the evolutionary driving force behind sickle-cell disease (previous studies), thalassemia (see previous studies), glucose-6-phosphatase deficiency (previous studies), and other erythrocyte defects that together constitute the most common mendelian diseases of humans (previous studies; previous studies)." +EFO_0001064,"Definition: Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21." +EFO_0009144,Definition: Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by previous studies). +EFO_0009052,"Definition: Pleuropulmonary blastoma (PPB) is a rare pediatric tumor of the lung that arises during fetal lung development and is often part of an inherited cancer syndrome (previous studies). PPBs contain both epithelial and mesenchymal cells. Early in tumorigenesis, cysts form in lung airspaces, and these cysts are lined with benign-appearing epithelium. Mesenchymal cells susceptible to malignant transformation reside within the cyst walls and form a dense 'cambium' layer beneath the epithelial lining. In a subset of patients, overgrowth of the mesenchymal cells produces a sarcoma, a transition that is associated with a poorer prognosis (previous studies). + +In approximately 35% of families in which a child has PPB, the patient or a family member manifests 1 or more additional conditions from an unusual array of dysontogenetic-dysplastic and malignant conditions, known as the 'PPB family tumor and dysplasia syndrome' (PPBFTDS). Cystic nephroma, which are benign lesions of the kidney, are found in 9 to 10% of family members affected by PPB (summary by previous studies). + +Larger studies have shown that DICER1 mutations are associated with a variety of tumor types, indicating that this disorder can be considered a tumor predisposition syndrome (summary by previous studies)." +EFO_1001065,"Definition: Normal-pressure hydrocephalus-1 (HYDNP1) is an autosomal dominant neurologic disorder characterized by the clinical triad of slowly progressive gait instability, urinary incontinence, and cognitive decline associated with ventricular enlargement on brain imaging with normal pressure of the cerebrospinal fluid (CSF). The onset of symptoms is usually in late adulthood; the symptoms are responsive to shunting. The disorder has been associated with recurrent respiratory infections and possible infertility issues, but the latter has not been confirmed (summary by previous studies and previous studies)." +EFO_0005581,"Definition: Normal color vision in humans is trichromatic, being based on 3 classes of cone that are maximally sensitive to light at approximately 420 nm (blue cones; previous studies), 530 nm (green cones; previous studies), and 560 nm (red cones; previous studies). Comparison by neural circuits of light absorption by the 3 classes of cone photoreceptors allows perception of red, yellow, green, and blue colors individually or in various combinations. Dichromatic color vision is severely defective color vision based on the use of only 2 types of photoreceptors, blue plus green (protanopia; see previous studies) or blue plus red (deuteranopia). Anomalous trichromacy is trichromatic color vision based on a blue, green, and an anomalous red-like photoreceptor (protanomaly), or a blue, red, and an anomalous green-like photoreceptor (deuteranomaly). The color vision defect is generally mild but may in certain cases be severe. Common variation in red-green color vision exists among both normal and color-deficient individuals (review by previous studies)." +EFO_0004129,"Definition: Hereditary amyloidoses are a clinically and genetically heterogeneous group of autosomal dominantly inherited diseases characterized by the deposit of unsoluble protein fibrils in the extracellular matrix (summary by previous studies). Patients with transthyretin amyloidosis typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. In later stages of the disease severe diarrhea with malabsorption, cachexia, incapacitating neuropathy, severe cardiac disturbances, and marked orthostatic hypotension dominate the clinical picture. Death usually occurs 5 to 15 years after onset of symptoms. + +Before the emergence of molecular genetics, hereditary amyloidoses were classified into 4 subtypes according to symptom constellation and ethnic origin (summary by previous studies). The course of disease beginning with sensorimotor polyneuropathy that starts in early adulthood symmetrically at the legs and progresses rather rapidly to incapacitate the patient within a few years has been labeled familial amyloid polyneuropathy type I (FAP I), also known as Portuguese, Portuguese-Swedish-Japanese, or Andrade type. FAP I can be considered the prototype of the manifestation of hereditary TTR amyloidosis. The overwhelming majority of cases of FAP I result from a val30-to-met (V30M; previous studies) substitution. A course of disease with neuropathy beginning at the hands and frequent carpal tunnel operations has been designated FAP II, also known as the Indiana/Swiss (previous studies) or Maryland/German (previous studies) type. Vitreous opacities occur early in the disease course, whereas impotence and renal insufficiency are rare. Amyloidosis due to mutations in the APOA1 gene (previous studies) has been referred to as FAP III or Iowa type (see previous studies and previous studies). The Finnish type of amyloidosis (previous studies) has been referred to as FAP IV and is caused by mutations in gelsolin (previous studies). + +Systems based on clinical phenotypes have historically been used to classify the amyloidoses, but emphasis on the characterization of the amyloid fibril protein has proved more useful (previous studies). In addition to hereditary amyloidosis, 2 other major forms of systemic amyloidosis exist. Immunoglobulin (AL) amyloidosis, formerly known as primary amyloidosis, is caused by the accumulation of monoclonal immunoglobulin (Ig) light chains as amyloid fibrils. Reactive (AA) amyloidosis, formerly known as secondary amyloidosis, is associated with chronic inflammatory diseases (e.g., rheumatoid arthritis, previous studies; familial Mediterranean fever, previous studies), and fibrils are derived from the circulating acute-phase reactant serum amyloid A protein (see previous studies). + +previous studies provided a review of transthyretin-related familial amyloid polyneuropathy. The authors stated that the phenotypes can be classified into neuropathic, oculoleptomeningeal, and cardiac." +EFO_0000280,"Definition: Barrett esophagus, or Barrett metaplasia, describes the phenotypic change of normal esophageal squamous epithelium to a columnar and intestinal-type epithelium. This metaplastic change is important because patients with Barrett esophagus have an increased risk of esophageal adenocarcinoma. The main cause of Barrett metaplasia is gastroesophageal reflux (GER; previous studies). The retrograde movement of acid and bile salts from the stomach into the esophagus in this disease causes prolonged injury to the esophageal epithelium and induces chronic esophagitis, which in turn is believed to trigger the pathologic changes (summary by previous studies)." +EFO_0009082,"Definition: Pilomatrixoma, also known as calcifying epithelioma of Malherbe, is a superficial benign skin tumor that arises from hair follicle matrix cells. The lesions occur most commonly in the first or second decades. They occur thoughout the body but most often in the head and neck region (review by previous studies)." +EFO_0009538,"Definition: Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy characterized most commonly by symmetric limb weakness and loss of tendon reflexes. It is a putative autoimmune disorder presenting after an infectious illness, most commonly Campylobacter jejuni, a gram-negative bacterium that causes acute enteritis (previous studies; previous studies). Approximately 1 in 1,000 individuals develops GBS after C. jejuni infection (previous studies). + +Although rare familial cases have been reported, GBS is considered to be a complex multifactorial disorder with both genetic and environmental factors rather than a disorder following simple mendelian inheritance (previous studies)." +EFO_0001376,"Definition: Synovial sarcomas, which represent approximately 10% of all soft tissue sarcomas, are aggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation. They consistently show a specific t(X;18)(p11.2;q11.2), which usually represents either of 2 gene fusions, SYT (previous studies)-SSX1 (previous studies) or SYT-SSX2 (previous studies), encoding putative transcriptional proteins differing at 13 amino acid positions (summary by previous studies). + +Synovial sarcoma, according to the experience of previous studies, is the fourth most common type of soft tissue sarcoma. It usually develops in adolescents and young adults, is more common in males than in females, and has no racial predilection." +EFO_0009301,"Definition: Dystonia-28 (DYT28) is an autosomal dominant neurologic disorder characterized by onset of progressive dystonia in the first decade of life. Dystonia typically begins focally in the lower limbs, resulting in gait difficulties, with later progression to other body regions, including the upper limbs, neck, and orofacial region. The severity is variable, and some patients may become wheelchair-bound. Many patients also have an elongated face with bulbous nose, and some have abnormal eye movements. About half of patients show delayed motor and/or cognitive development with mild intellectual disability (summary by previous studies and previous studies)." +EFO_0001378,"Definition: Multiple myeloma is a neoplastic plasma cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction (previous studies)." +EFO_0009155,"Definition: GRIDHH is an autosomal recessive multisystem disorder characterized by poor overall growth, impaired intellectual development, hypotonia, and variable liver dysfunction. Additional features, such as seizures and hearing loss, may also be present (summary by previous studies)." +EFO_0000309,"Definition: Burkitt lymphoma is a rare, aggressive B-cell lymphoma that accounts for 30 to 50% of lymphomas in children but only 1 to 2% of lymphomas in adults (previous studies). It results from chromosomal translocations that involve the MYC gene (previous studies) and either the lambda or the kappa light chain immunoglobulin genes (previous studies, previous studies). Burkitt lymphoma is causally related to the Epstein-Barr virus (EBV), although the pathogenetic mechanisms are not clear." +EFO_1001868,"Definition: CLIFAHDD is a congenital disorder characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, hypotonia, and variable degrees of developmental delay. All reported cases have occurred de novo (summary by previous studies)." +EFO_0004235,Definition: Exfoliation syndrome (XFS) is a common age-related disorder of the extracellular matrix that is frequently associated with severe chronic secondary open-angle glaucoma and cataract. XFS syndrome may affect up to 30% of people over 60 years of age worldwide and is biomicroscopically diagnosed by abnormal microfibrillar deposits on ocular structures that line the aqueous-bathed surfaces of the anterior segment (summary by previous studies). +EFO_0005580,"Definition: Normal color vision in humans is trichromatic, being based on 3 classes of cone that are maximally sensitive to light at approximately 420 nm (blue cones; previous studies), 530 nm (green cones; previous studies), and 560 nm (red cones; previous studies). Comparison by neural circuits of light absorption by the 3 classes of cone photoreceptors allows perception of red, yellow, green, and blue colors individually or in various combinations. Dichromatic color vision is severely defective color vision based on the use of only 2 types of photoreceptors, blue plus green (protanopia) or blue plus red (deuteranopia; see previous studies). Anomalous trichromacy is trichromatic color vision based on a blue, green, and an anomalous red-like photoreceptor (protanomaly), or a blue, red, and an anomalous green-like photoreceptor (deuteranomaly). The color vision defect is generally mild but may in certain cases be severe. Common variation in red-green color vision exists among both normal and color-deficient individuals (review by previous studies)." +EFO_1000566,"Definition: Testicular germ cell tumors (TGCTs) affect 1 in 500 men and are the most common cancer in males aged 15 to 40 in western European populations. The incidence of TGCT rose dramatically during the 20th century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT, and a family history of the disease. Brothers of men with TGCT have an 8- to 10-fold risk of developing TGCT, whereas the relative risk to fathers and sons is 4-fold. This familial relative risk is much higher than that for most other types of cancer (summary by previous studies). + + Genetic Heterogeneity of Testicular Germ Cell Tumors + +A locus for testicular germ cell tumors (TGCT1; previous studies) has been identified on chromosome Xq27." +EFO_1001010,"Definition: Focal epilepsy with speech disorder is a childhood-onset seizure disorder with a highly variable phenotype. Seizures typically occur in the temporal lobe, or rolandic brain region, which affects speech and language, and electroencephalogram (EEG) characteristically shows centrotemporal spike-wave discharges. EEG abnormalities often occur during sleep and may manifest as continuous spike-wave discharges during slow-wave sleep (CSWS or CSWSS). FESD represents an electroclinical spectrum that ranges from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and mental retardation to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. There is incomplete penetrance and intrafamilial variability, even among family members who carry the same GRIN2A mutation (summary by previous studies; previous studies; previous studies). + +The disorder represented here encompasses several clinical entities, including Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike and wave during slow-wave sleep (ECSWS; CSWSS), autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (ADRESD; RESDAD), and benign epilepsy with centrotemporal spikes (BECTS; see previous studies). LKS is classically described as a childhood-onset variant of epileptic aphasia. It is associated with EEG abnormalities occurring in the temporal lobe of the language-dominant hemisphere, even in the absence of overt clinical seizures. LKS is sometimes referred to as an 'acquired aphasia' because most affected children show normal psychomotor development until the onset of seizures, usually between 3 and 7 years, although some may have prior delayed development. A hallmark of the disorder is severe impairment in auditory language comprehension and speech. Some patients may also have persistent intellectual disability or behavioral abnormalities reminiscent of autism or attention deficit-hyperactivity disorder. EEG abnormalities typically include centrotemporal spikes suggestive of rolandic epilepsy or continuous spike and waves during slow-wave sleep. The presence of CSWS is associated with more widespread behavioral and cognitive regression than LKS, although the 2 disorders may be considered part of a spectrum. There is controversy about the precise definition of LKS and its relationship to CSWS that stems mainly from the phenotypic heterogeneity of the disorder (summary by previous studies)." +EFO_1000552,"Definition: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon form of T-cell non-Hodgkin lymphoma in which cytotoxic CD8 (see previous studies)+ T cells infiltrate adipose tissue forming subcutaneous nodules. Both children and adults can be affected, with a median age at diagnosis of 36 years and a female gender bias. Most patients have accompanying systemic features such as fever or flank pain. A subset (about 20%) of patients develop hemophagocytic lymphohistiocytosis (HLH), usually associated with CD8+ T cells rimming adipocytes in the bone marrow. An infectious agent is not identified, and the disorder is believed to result from improperly activated inflammation. Immunosuppressive therapy may be helpful; hematopoietic bone marrow transplantation is usually curative (summary by previous studies). + +For a general discussion of genetic heterogeneity of HLH, see HLH1 (previous studies)." +EFO_0009650,"Definition: Insulin (INS; previous studies) is produced posttranslationally from its precursor molecule, proinsulin, by site-directed proteolysis in beta-cell granules. Conversion involves cleavage at pairs of basic residues that link both the insulin A and B chains to C-peptide. Human proinsulin conversion has a preferred sequential route, such that cleavage at the B-chain/C-peptide junction occurs first, producing des-31,32 split proinsulin as the major conversion intermediate. Under normal circumstances, proinsulin conversion is largely completed before secretion, and low plasma levels of intact proinsulin and conversion intermediates are found. Structural abnormalities in the proinsulin molecule can impair conversion, leading to the accumulation of proinsulin-like material in the circulation. Such defects show an autosomal dominant mode of inheritance and are the main cause of familial hyperproinsulinemia (summary by previous studies)." +EFO_0009148,"Definition: ACTH-independent macronodular adrenal hyperplasia-2 is an autosomal dominant tumor susceptibility with syndromic incomplete penetrance, as a second hit to the ARMC5 gene is required to develop macronodular hyperplasia (previous studies)." +EFO_1001980,"Definition: AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (summary by previous studies)." +EFO_1000309,"Definition: Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (previous studies). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (previous studies). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (previous studies). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (previous studies) hyperphosphorylation (previous studies). + + Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia + +In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (previous studies), KRAS (previous studies), and NRAS (previous studies) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (previous studies). Somatic disruptions of the GRAF gene (ARHGAP26; previous studies) have also been found in patients with JMML. + +About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; previous studies) due to germline mutations in the NF1 gene (previous studies). In addition, patients with Noonan syndrome (NS1, previous studies; NS3, previous studies) or Noonan syndrome-like disorder (NSLL; previous studies) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. + + Genetic Heterogeneity of Chronic Myelomonocytic Leukemia + +Somatic mutations in the CBL, ASXL1 (previous studies), TET2 (previous studies), and SF3B1 (previous studies) genes have been found in patients with CMML." +EFO_0002429,"Definition: Polycythemia vera, the most common form of primary polycythemia, is caused by somatic mutation in a single hematopoietic stem cell leading to clonal hematopoiesis. PV is a myeloproliferative disorder characterized predominantly by erythroid hyperplasia, but also by myeloid leukocytosis, thrombocytosis, and splenomegaly. Familial cases of PV are very rare and usually manifest in elderly patients (previous studies). PV is distinct from the familial erythrocytoses (see, e.g., ECYT1, previous studies), which are caused by inherited mutations resulting in hypersensitivity of erythroid progenitors to hormonal influences or increased levels of circulating hormones, namely erythropoietin (EPO; previous studies) (previous studies)." +EFO_1000886,"Definition: Mastocytosis, or mast cell disease, is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells in various tissues, especially in the skin and hematopoietic organs. Mastocytosis usually appears in infancy or early adulthood. In most pediatric cases, the disease is limited to the skin, but it can be associated with systemic symptoms due to the release of mediators from mast cells, even when there is no systemic infiltration. It usually has a good prognosis, with substantial improvement or spontaneous resolution before puberty. In rare cases, the disease may remain active through adolescence as a systemic adult mastocytosis. Cutaneous mastocytosis is characterized by macules, papules, nodules, or diffuse infiltration of the skin, often associated with localized hyperpigmentation. Gentle rubbing of the lesions induces histamine release from mechanically activated mast cells, causing local wheals, erythema, and often pruritus, a phenomenon termed the 'Darier sign.' In contrast to childhood-onset mastocytosis, adult-onset mastocytosis often persists for the lifetime of the patient and is also more likely to be a severe and systemic disease involving numerous organs. In some cases, it is associated with a clonal hematologic non-mast-cell lineage disease, such as a myelodysplastic or myeloproliferative disorder. Adult-onset mastocytosis can also lead to the rare mast cell leukemia, which carries a high risk of mortality (summary by previous studies and previous studies)." +EFO_1000666,Definition: Acrokeratosis verruciformis of Hopf (AKV) is a localized disorder of keratinization affecting the distal extremities. Onset occurs early in life (previous studies). +EFO_1000855,"Definition: Congenital myopathy-1A (CMYP1A) with susceptibility to malignant hyperthermia is an autosomal dominant disorder of skeletal muscle characterized by muscle weakness primarily affecting the proximal muscles of the lower limbs beginning in infancy or early childhood, although later onset of symptoms has been reported. There is significant phenotypic variability, even within families, and the wide clinical diversity most likely depends on the severity of the RYR1 mutation. The disorder is static or slowly progressive; affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Some patients present with orthopedic deformities. Serum creatine kinase is usually not elevated. Respiratory involvement is rare and there is no central nervous system or cardiac involvement. Patients with dominant mutations in the RYR1 gene are at risk for malignant hyperthermia and both disorders may segregate in the same family. Historically, patients with congenital myopathy due to RYR1 mutations were diagnosed based on the finding of pathologic central cores (central core disease; CCD) on muscle biopsy, which represent areas that lack oxidative enzymes and mitochondrial activity in type 1 muscle fibers. However, additional pathologic findings may also be observed, including cores and rods, central nuclei, fiber type disproportion, multiminicores, and uniform type 1 fibers. These histopathologic features are not always specific to RYR1 myopathy and often change over time (previous studies; previous studies; previous studies; previous studies). Some patients with RYR1 mutations have pathologic findings on muscle biopsy, but are clinically asymptomatic (previous studies; previous studies). + +Rare patients with a more severe phenotype have been found to carry a heterozygous mutation in the RYR1 gene inherited from an unaffected parent. However, in these cases, there is a possibility of recessive inheritance (CMYP1B; previous studies) with either a missed second RYR1 mutation in trans or a genomic rearrangement on the other allele that is undetectable on routine genomic sequencing, since the RYR1 gene is very large and genetic analysis may be difficult (previous studies). + + Genetic Heterogeneity of Congenital Myopathy + +See also CMYP1B (previous studies), caused by mutation in the RYR1 gene (previous studies) on chromosome 19q13; CMYP2A (previous studies), CMYP2B (previous studies), and CMYP2C (previous studies), caused by mutation in the ACTA1 gene (previous studies) on chromosome 1q42; CMYP3 (previous studies), caused by mutation in the SELENON gene (previous studies) on chromosome 1p36; CMYP4A (previous studies) and CMYP4B (previous studies), caused by mutation in the TPM3 gene (previous studies) on chromosome 1q21; CMYP5 (previous studies), caused by mutation in the TTN gene (previous studies) on chromosome 2q31; CMYP6 (previous studies), caused by mutation in the MYH2 gene (previous studies) on chromosome 17p13; CMYP7A (previous studies) and CMYP7B (previous studies), caused by mutation in the MYH7 gene (previous studies) on chromosome 14q11; CMYP8 (previous studies), caused by mutation in the ACTN2 gene (previous studies) on chromosome 1q43; CMYP9A (previous studies) and CMYP9B (previous studies), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYP10A (previous studies) and CMYP10B (previous studies), caused by mutation in the MEGF10 gene (previous studies) on chromosome 5q23; CMYP11 (previous studies), caused by mutation in the HACD1 gene (previous studies) on chromosome 10p12; CMYP12 (previous studies), caused by mutation in the CNTN1 gene (previous studies) on chromosome 12q12; CMYP13 (previous studies), caused by mutation in the STAC3 gene (previous studies) on chromosome 12q13; CMYP14 (previous studies), caused by mutation in the MYL1 gene (previous studies) on chromosome 2q34; CMYP15 (previous studies), caused by mutation in the TNNC2 gene (previous studies) on chromosome 20q13; CMYP16 (previous studies), caused by mutation in the MYBPC1 gene (previous studies) on chromosome 12q23; CMYP17 (previous studies), caused by mutation in the MYOD1 gene (previous studies) on chromosome 11p15; CMYP18 (previous studies), caused by mutation in the CACNA1S gene (previous studies) on chromosome 1q32; CMYP19 (previous studies), caused by mutation in the PAX7 gene (previous studies) on chromosome 1p36; CMYP20 (previous studies), caused by mutation in the RYR3 gene (previous studies) on chromosome 15q13; CMYP21 (previous studies), caused by mutation in the DNAJB4 gene (previous studies) on chromosome 1p31; CMYP22A (previous studies) and CMYP22B (previous studies), both caused by mutation in the SCN4A gene (previous studies) on chromosome 17q23; CMYP23 (previous studies), caused by mutation in the TPM2 gene (previous studies) on chromosome 9p13; and CMYP24 (previous studies), caused by mutation in the MYPN gene (previous studies) on chromosome 10q21." +MONDO_0007915,"Definition: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by previous studies). + + Genetic Heterogeneity of Systemic Lupus Erythematosus + +An autosomal recessive form of systemic lupus erythematosus (SLEB16; previous studies) is caused by mutation in the DNASE1L3 gene (previous studies) on chromosome 3p14.3. An X-linked dominant form of SLE (SLEB17; previous studies) is caused by heterozygous mutation in the TLR7 gene (previous studies) on chromosome Xp22. + +See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE." +MONDO_0009785,"Definition: Opsismodysplasia (OPSMD) is a rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death in utero or secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges (summary by previous studies and previous studies)." +MONDO_0010355,"Definition: Claes-Jensen type of X-linked syndromic intellectual developmental disorder (MRXSCJ) is characterized by impaired intellectual development with substantial clinical heterogeneity in affected males. However, males are usually reported to have short stature, microcephaly, hyperreflexia, and aggressive behavior. In rare cases, female carriers exhibit mildly impaired intellectual development or learning difficulties (summary by previous studies)." +Orphanet_85279,"Definition: Claes-Jensen type of X-linked syndromic intellectual developmental disorder (MRXSCJ) is characterized by impaired intellectual development with substantial clinical heterogeneity in affected males. However, males are usually reported to have short stature, microcephaly, hyperreflexia, and aggressive behavior. In rare cases, female carriers exhibit mildly impaired intellectual development or learning difficulties (summary by previous studies)." +MONDO_0010613,"Definition: previous studies noted that there are 3 clinically distinct forms of glycerol kinase deficiency: infantile, juvenile, and adult. The infantile form is associated with severe developmental delay, and those with the adult form have no symptoms and are often detected fortuitously. + +The infantile form of GK deficiency, or the 'GK complex,' results from the Xp21 contiguous gene deletion syndrome (previous studies) with congenital adrenal hypoplasia (previous studies) and/or Duchenne muscular dystrophy (DMD; previous studies), whereas the juvenile and adult forms have isolated GK deficiency (previous studies)." +MONDO_0011411,"Definition: Chudley-McCullough syndrome is an autosomal recessive neurologic disorder characterized by early-onset sensorineural deafness and specific brain anomalies on MRI, including hypoplasia of the corpus callosum, enlarged cysterna magna with mild focal cerebellar dysplasia, and nodular heterotopia. Some patients have hydrocephalus. Psychomotor development is normal (summary by previous studies)." +MONDO_0011505,"Definition: Hypobetalipoproteinemia (HBL) is defined as permanently low levels, below the 5th percentile of sex- and age-matched individuals in the population, of apolipoprotein B (apoB), total cholesterol, and low-density lipoprotein (LDL) cholesterol; the lipid profile in FHBL2 includes low HDL cholesterol as well. HBL can result from environmental factors such as a strict vegetarian diet, or can be secondary to certain diseases such as intestinal fat malabsorption, chronic pancreatitis, severe liver disease, malnutrition, or hyperthyroidism. Heritable primary causes of HBL include chylomicron retention disease (CMRD; previous studies), abetalipoproteinemia (previous studies), and familial hypobetalipoproteinemia (FHBL) (summary by previous studies). + +For a discussion of genetic heterogeneity of familial hypobetalipoproteinemia, see FHBL1 (previous studies)." +MONDO_0031040,"Definition: Progressive familial intrahepatic cholestasis-12 (PFIC12) is characterized by neonatal-onset jaundice and conjugated hyperbilirubinemia, associated with intense pruritus. Transaminases are mildly elevated but GGT (see previous studies) is normal. Hepatosplenomegaly and mildly prolonged activated partial thromboplastin time (APTT) have been observed in some patients (previous studies)." +MONDO_0859151,"Definition: Multifocal fibromuscular dysplasia (FMDMF) is characterized histologically by medial fibroplasia and angiographically by multiple arterial stenoses with intervening mural dilations. Arterial tortuosity, macroaneurysms, dissections, and rupture may occur (summary by previous studies)." +MONDO_0859238,"Definition: Intermediate primary alphalipoproteinemia-2 is an autosomal dominant condition characterized by half-normal plasma levels of apoA-I and HDL-C (previous studies). Affected individuals may develop xanthomas and corneal opacities, but most do not have increased cardiovascular risk (summary by previous studies). + +For a discussion of genetic heterogeneity of hypoalphalipoproteinemia, see previous studies." +Orphanet_158684,"Definition: Epidermolysis bullosa simplex 5C with pyloric atresia (EBS5C) is an autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. In reports of 2 consensus meetings for EB, previous studies considered EBSPA to be a 'basal' form of simplex EB because the electron microscopy shows that skin cleavage occurs in the lower basal level of the keratinocyte, just above the hemidesmosome. There is often decreased integration of keratin filaments with hemidesmosomes. + +See also forms of junctional EB with pyloric atresia, JEB5B (previous studies) and JEB6 (previous studies), caused by mutation in the ITGB4 (previous studies) and ITGA6 (previous studies) genes, respectively. + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0012807,"Definition: Epidermolysis bullosa simplex 5C with pyloric atresia (EBS5C) is an autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. In reports of 2 consensus meetings for EB, previous studies considered EBSPA to be a 'basal' form of simplex EB because the electron microscopy shows that skin cleavage occurs in the lower basal level of the keratinocyte, just above the hemidesmosome. There is often decreased integration of keratin filaments with hemidesmosomes. + +See also forms of junctional EB with pyloric atresia, JEB5B (previous studies) and JEB6 (previous studies), caused by mutation in the ITGB4 (previous studies) and ITGA6 (previous studies) genes, respectively. + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +Orphanet_363429,Definition: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development beginning in infancy. Affected individuals show mildly to profoundly impaired intellectual development with poor or absent speech as well as gait and stance ataxia and hyperreflexia. Most individuals also have eye movement abnormalities. Brain MRI shows cerebellar atrophy and ventriculomegaly (previous studies). +MONDO_0013905,Definition: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development beginning in infancy. Affected individuals show mildly to profoundly impaired intellectual development with poor or absent speech as well as gait and stance ataxia and hyperreflexia. Most individuals also have eye movement abnormalities. Brain MRI shows cerebellar atrophy and ventriculomegaly (previous studies). +Orphanet_324262,Definition: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development beginning in infancy. Affected individuals show mildly to profoundly impaired intellectual development with poor or absent speech as well as gait and stance ataxia and hyperreflexia. Most individuals also have eye movement abnormalities. Brain MRI shows cerebellar atrophy and ventriculomegaly (previous studies). +Orphanet_79124,"Definition: Hepatic venoocclusive disease with immunodeficiency syndrome (VODI) is an autosomal recessive primary immunodeficiency associated with hepatic vascular occlusion and fibrosis. The immunodeficiency is characterized by severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, and absent tissue plasma cells (summary by previous studies)." +MONDO_0009338,"Definition: Hepatic venoocclusive disease with immunodeficiency syndrome (VODI) is an autosomal recessive primary immunodeficiency associated with hepatic vascular occlusion and fibrosis. The immunodeficiency is characterized by severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, and absent tissue plasma cells (summary by previous studies)." +EFO_0010630,"Definition: Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (IDNADFS) is characterized by mildly impaired global development, speech delay with nasal speech, and dysmorphic facial features, including high forehead, midface hypoplasia, micrognathia or high-arched palate, hypo/hypertelorism, upslanting palpebral fissures, and thin upper lip. Some patients may have skeletal anomalies, such as brachydactyly, 2-3 toe syndactyly, and flat feet (summary by previous studies and previous studies)." +MONDO_0007846,"Definition: KBG syndrome (KBGS) is characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement that includes global developmental delay, seizures, and intellectual disability (summary by previous studies). previous studies noted that it is likely that KBG syndrome is underdiagnosed, since many of the features, including intellectual disability, are mild, and none of the features is a prerequisite for diagnosis." +MONDO_0013951,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 14 (CG14, equivalent to CGJ) have mutations in the PEX19 gene. For information on the history of PBD complementation groups, see previous studies." +Orphanet_912,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 14 (CG14, equivalent to CGJ) have mutations in the PEX19 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0014142,"Definition: MDDGC14 is an autosomal recessive form of muscular dystrophy characterized by onset in early childhood of mild proximal muscle weakness. Some patients may have additional features, such as mild intellectual disability or seizures. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (summary by previous studies). Some patients with GMPPB mutations may show features consistent with a congenital myasthenic syndrome (see, e.g., CMS1A; previous studies), such as fatigability and decremental compound muscle action potential response to repetitive nerve stimulation; these patients may show a positive therapeutic response to treatment with pyridostigmine (previous studies). + +For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (previous studies)." +MONDO_0014450,"Definition: Congenital aplastic deformities of the breast include amastia (total absence of breasts and nipple), athelia (absence of the nipple), and amazia (absence of the mammary gland). Most common is amastia. Bilateral absence of the breasts may occur as an isolated anomaly or may be associated with a syndrome or a cluster of other anomalies, including anhidrotic ectodermal dysplasia (previous studies) or Poland syndrome (previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of aplasia or hypoplasia of the breasts and/or nipples, see previous studies." +MONDO_0032485,"Definition: Autosomal dominant intellectual developmental disorder-61 (MRD61) is characterized by global developmental delay apparent in infancy with mildly impaired intellectual development, expressive speech delay, and behavioral abnormalities, including autism spectrum disorder and attention deficit-hyperactivity disorder (ADHD). Most affected individuals learn to walk on time or with some mild delay. Additional features are highly variable and may include nonspecific dysmorphic features, obstipation, ocular anomalies, and poor overall growth (previous studies)." +MONDO_0032781,"Definition: Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) is a syndromic neurodevelopmental disorder characterized by severe global developmental delay, impaired intellectual development with poor or absent language, significant motor disability with inability to walk, dysmorphic facial features, skeletal anomalies, and variable congenital anomalies. Most patients also have seizures and structural brain abnormalities (summary by previous studies)." +MONDO_0044318,"Definition: Jansen-de Vries syndrome (JDVS) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with speech delay, and behavioral abnormalities. Most patients have variable additional features, including feeding and gastrointestinal difficulties, high pain threshold and/or hypersensitivity to sound, and dysmorphic features, including mild facial abnormalities, strabismus, and small hands and feet (summary by previous studies)." +Orphanet_2750,"Definition: Orofaciodigital syndrome type I (OFD1) is characterized by malformations of the face, oral cavity, and digits and is transmitted as an X-linked dominant condition with lethality in males. Thickened alveolar ridges and abnormal dentition, including absent lateral incisors, are additional characteristics of OFD1. The central nervous system may also be involved in as many as 40% of cases. Although these clinical features overlap those reported in other forms of orofaciodigital syndrome, OFD1 can be easily distinguished from among these by its X-linked dominant inheritance pattern and by polycystic kidney disease, which seems to be specific to type I (summary by previous studies). + +Since the CXORF5 gene localizes to the centrosome and basal body of primary cilia, OFD1 is considered to be a ciliopathy (previous studies)." +MONDO_0010702,"Definition: Orofaciodigital syndrome type I (OFD1) is characterized by malformations of the face, oral cavity, and digits and is transmitted as an X-linked dominant condition with lethality in males. Thickened alveolar ridges and abnormal dentition, including absent lateral incisors, are additional characteristics of OFD1. The central nervous system may also be involved in as many as 40% of cases. Although these clinical features overlap those reported in other forms of orofaciodigital syndrome, OFD1 can be easily distinguished from among these by its X-linked dominant inheritance pattern and by polycystic kidney disease, which seems to be specific to type I (summary by previous studies). + +Since the CXORF5 gene localizes to the centrosome and basal body of primary cilia, OFD1 is considered to be a ciliopathy (previous studies)." +Orphanet_320385,"Definition: Hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9) is an autosomal recessive neurodevelopmental and neurodegenerative disorder. Clinical features include global developmental delay and intellectual disability, axial and appendicular hypotonia, dysarthria, and an abnormal gait that is often described as ataxic. Other features may include peripheral neuropathy, hyporeflexia, and autonomic dysfunction (summary by previous studies). + +For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (previous studies)." +MONDO_0014016,"Definition: Hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9) is an autosomal recessive neurodevelopmental and neurodegenerative disorder. Clinical features include global developmental delay and intellectual disability, axial and appendicular hypotonia, dysarthria, and an abnormal gait that is often described as ataxic. Other features may include peripheral neuropathy, hyporeflexia, and autonomic dysfunction (summary by previous studies). + +For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (previous studies)." +Orphanet_352662,"Definition: Multiple self-healing palmoplantar carcinoma (MSPC) is characterized by recurrent keratoacanthomas in palmoplantar skin as well as in conjunctival and corneal epithelia. In addition, patients experience a high susceptibility to malignant squamous cell carcinoma (summary by previous studies)." +MONDO_0014089,"Definition: Multiple self-healing palmoplantar carcinoma (MSPC) is characterized by recurrent keratoacanthomas in palmoplantar skin as well as in conjunctival and corneal epithelia. In addition, patients experience a high susceptibility to malignant squamous cell carcinoma (summary by previous studies)." +Orphanet_36355,Definition: Platelet-type bleeding disorder-8 is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation (review by previous studies). +MONDO_0012354,Definition: Platelet-type bleeding disorder-8 is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation (review by previous studies). +Orphanet_401874,"Definition: Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; previous studies), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (previous studies)." +MONDO_0013675,"Definition: Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; previous studies), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (previous studies)." +Orphanet_75376,"Definition: Doyne honeycomb retinal dystrophy (DHRD) is characterized by drusen deposits at the level of the Bruck membrane in the macula and around the edge of the optic nerve head. The drusen are large, soft, external to the basement membrane of the retinal pigment epithelium (RPE), and occupy the entire thickness of the Bruch membrane. In contrast, in malattia leventinese (MLVT) small discrete drusen radiate into the peripheral retina, with the later development of confluent soft drusen in the macula. Radial drusen extending into the periphery had not been described in DHRD (summary by previous studies). + +previous studies noted that both DHRD and MLVT present with clinical and pathologic symptoms similar to age-related macular degeneration (ARMD), including soft drusen accumulation, loss of basolateral ruffling of the RPE, RPE vacuolization, and atrophy, with eventual neovascularization in an accelerated time frame, usually in the fourth decade of life." +MONDO_0007471,"Definition: Doyne honeycomb retinal dystrophy (DHRD) is characterized by drusen deposits at the level of the Bruck membrane in the macula and around the edge of the optic nerve head. The drusen are large, soft, external to the basement membrane of the retinal pigment epithelium (RPE), and occupy the entire thickness of the Bruch membrane. In contrast, in malattia leventinese (MLVT) small discrete drusen radiate into the peripheral retina, with the later development of confluent soft drusen in the macula. Radial drusen extending into the periphery had not been described in DHRD (summary by previous studies). + +previous studies noted that both DHRD and MLVT present with clinical and pathologic symptoms similar to age-related macular degeneration (ARMD), including soft drusen accumulation, loss of basolateral ruffling of the RPE, RPE vacuolization, and atrophy, with eventual neovascularization in an accelerated time frame, usually in the fourth decade of life." +Orphanet_98702,"Definition: Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (previous studies). It is classified as a form of Ehlers-Danlos syndrome (previous studies). + +For a discussion of genetic heterogeneity of brittle cornea syndrome, see BCS1 (previous studies)." +Orphanet_98885,Definition: Platelet-type bleeding disorder-11 is an autosomal recessive mild to moderate bleeding disorder caused by defective platelet activation and aggregation in response to collagen (summary by previous studies). +MONDO_0013623,Definition: Platelet-type bleeding disorder-11 is an autosomal recessive mild to moderate bleeding disorder caused by defective platelet activation and aggregation in response to collagen (summary by previous studies). +MONDO_0010907,"Definition: Congenital hypertryptophanemia, which is accompanied by hyperserotonemia, does not appear to have significant clinical consequences (previous studies)." +Orphanet_2224,"Definition: Congenital hypertryptophanemia, which is accompanied by hyperserotonemia, does not appear to have significant clinical consequences (previous studies)." +MONDO_0011922,Definition: Nonimmune chronic idiopathic neutropenia of adults (NI-CINA) is a relatively mild form of neutropenia diagnosed in adults but predisposing to leukemia in a subset of patients (previous studies). +MONDO_0012476,"Definition: Spastic paraplegia-30 (SPG30) is a neurologic disorder characterized by onset of slowly progressive spastic paraplegia in the first or second decades of life. Affected individuals have unsteady spastic gait and hyperreflexia of the lower limbs. Some patients have a 'pure' form of the disorder, limited to spastic paraplegia, whereas others may have a 'complicated' form that includes cognitive dysfunction, learning disabilities, or behavioral abnormalities, peripheral sensorimotor neuropathy, urinary sphincter problems, and/or cerebellar atrophy with thin corpus callosum on brain imaging. The phenotypic features represent a spectrum of abnormalities of the central, peripheral, and autonomic nervous system (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +Orphanet_101010,"Definition: Spastic paraplegia-30 (SPG30) is a neurologic disorder characterized by onset of slowly progressive spastic paraplegia in the first or second decades of life. Affected individuals have unsteady spastic gait and hyperreflexia of the lower limbs. Some patients have a 'pure' form of the disorder, limited to spastic paraplegia, whereas others may have a 'complicated' form that includes cognitive dysfunction, learning disabilities, or behavioral abnormalities, peripheral sensorimotor neuropathy, urinary sphincter problems, and/or cerebellar atrophy with thin corpus callosum on brain imaging. The phenotypic features represent a spectrum of abnormalities of the central, peripheral, and autonomic nervous system (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0013584,"Definition: Hereditary sensory neuropathy type IE is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia (summary by previous studies). + +For a discussion of genetic heterogeneity of HSN, see HSAN1A (previous studies)." +MONDO_0014536,"Definition: Thrombocytopenia-5 is an autosomal dominant disorder characterized by a decreased number of platelets and a bleeding tendency. Affected individuals have an increased susceptibility to the development of hematologic malignancies, and possibly to solid neoplasms. Thrombocytopenia is usually apparent in early childhood, whereas the development of malignancy can occur throughout life (summary by previous studies). + +For a discussion of genetic heterogeneity of thrombocytopenia, see previous studies." +MONDO_0016002,"Definition: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The major characteristics of kyphoscoliotic-type EDS are severe muscle hypotonia at birth, generalized joint laxity, scoliosis at birth, and scleral fragility and rupture of the ocular globe (previous studies). + +Nevo syndrome, previously thought to be a distinct entity, is identical to EDS type VI (previous studies). + + Genetic Heterogeneity of Ehlers-Danlos Syndrome, Kyphoscoliotic Type + +See EDSSKCL2 (previous studies), caused by mutation in the FKBP14 gene (previous studies). + + Classification of Ehlers-Danlos Syndromes + +The current classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by previous studies, which recognizes 13 EDS subtypes. This classification revised the 'Villefranche classification' reported by previous studies. + +previous studies reported on a revised nosology of the Ehlers-Danlos syndromes, designated the Villefranche classification. Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. Six main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of 'unspecified forms.'" +Orphanet_1900,"Definition: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The major characteristics of kyphoscoliotic-type EDS are severe muscle hypotonia at birth, generalized joint laxity, scoliosis at birth, and scleral fragility and rupture of the ocular globe (previous studies). + +Nevo syndrome, previously thought to be a distinct entity, is identical to EDS type VI (previous studies). + + Genetic Heterogeneity of Ehlers-Danlos Syndrome, Kyphoscoliotic Type + +See EDSSKCL2 (previous studies), caused by mutation in the FKBP14 gene (previous studies). + + Classification of Ehlers-Danlos Syndromes + +The current classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by previous studies, which recognizes 13 EDS subtypes. This classification revised the 'Villefranche classification' reported by previous studies. + +previous studies reported on a revised nosology of the Ehlers-Danlos syndromes, designated the Villefranche classification. Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. Six main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of 'unspecified forms.'" +MONDO_0030781,"Definition: Restrictive dermopathy is a rare genodermatosis characterized mainly by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial dysmorphism (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures, and an early neonatal lethal course. Liveborn children usually die within the first week of life (summary by previous studies). + +For a discussion of genetic heterogeneity of restrictive dermopathy, see RSDM1 (previous studies)." +MONDO_0030992,"Definition: SOFM is characterized by marked short stature, oligodontia, mild facial dysmorphism, and motor delay. Endosteal hyperostosis has also been observed, and patients may exhibit some features of progeria (previous studies; previous studies)." +MONDO_0033649,"Definition: Mitochondrial complex IV deficiency nuclear type 14 (MC4DN14) is an autosomal recessive metabolic disorder characterized by global developmental delay, exercise intolerance, walking difficulties, impaired intellectual development, short stature, mild dysmorphic features, and sensorimotor peripheral neuropathy. Patient skeletal muscle tissue shows decreased levels and activity of mitochondrial respiratory complex IV (previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0060578,"Definition: NEMMLAS is an autosomal recessive multisystemic disorder characterized by delayed psychomotor development, intellectual disability, and abnormal motor function, including hypotonia, dystonia, ataxia, and spasticity. Patient tissues may show deficiencies in one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes, but this is not a constant finding (summary by previous studies)." +Orphanet_369837,"Definition: Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by previous studies). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. + +For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (previous studies). + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +Orphanet_99943,"Definition: For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0011903,"Definition: For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +EFO_0000756,"Definition: Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by previous studies). + + Genetic Heterogeneity of Susceptibility to Cutaneous Malignant Melanoma + +The locus for susceptibility to familial cutaneous malignant melanoma-1 (CMM1) has been mapped to chromosome 1p36. Other CMM susceptibility loci include CMM2 (previous studies), caused by variation in the CDKN2A gene (previous studies) on chromosome 9p21; CMM3 (previous studies), caused by variation in the CDK4 gene (previous studies) on chromosome 12q14; CMM4 (previous studies), mapped to chromosome 1p22; CMM5 (previous studies), caused by variation in the MC1R gene (previous studies) on chromosome 16q24; CMM6 (previous studies), caused by variation in the XRCC3 gene (previous studies) on chromosome 14q32; CMM7 (previous studies), mapped to chromosome 20q11; CMM8 (previous studies), caused by variation in the MITF gene (previous studies) on chromosome 3p13; CMM9 (previous studies), caused by variation in the TERT gene (previous studies) on chromosome 5p15; and CMM10 (previous studies), caused by mutation in the POT1 gene (previous studies) on chromosome 7q31. + +Somatic mutations causing malignant melanoma have also been identified in several genes, including BRAF (previous studies), STK11 (previous studies), PTEN (previous studies), TRRAP (previous studies), DCC (previous studies), GRIN2A (previous studies), ZNF831, BAP1 (previous studies), and RASA2 (previous studies). A large percentage of melanomas (40-60%) carry an activating somatic mutation in the BRAF gene, most often V600E (previous studies) (previous studies; previous studies)." +EFO_0000389,"Definition: Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by previous studies). + + Genetic Heterogeneity of Susceptibility to Cutaneous Malignant Melanoma + +The locus for susceptibility to familial cutaneous malignant melanoma-1 (CMM1) has been mapped to chromosome 1p36. Other CMM susceptibility loci include CMM2 (previous studies), caused by variation in the CDKN2A gene (previous studies) on chromosome 9p21; CMM3 (previous studies), caused by variation in the CDK4 gene (previous studies) on chromosome 12q14; CMM4 (previous studies), mapped to chromosome 1p22; CMM5 (previous studies), caused by variation in the MC1R gene (previous studies) on chromosome 16q24; CMM6 (previous studies), caused by variation in the XRCC3 gene (previous studies) on chromosome 14q32; CMM7 (previous studies), mapped to chromosome 20q11; CMM8 (previous studies), caused by variation in the MITF gene (previous studies) on chromosome 3p13; CMM9 (previous studies), caused by variation in the TERT gene (previous studies) on chromosome 5p15; and CMM10 (previous studies), caused by mutation in the POT1 gene (previous studies) on chromosome 7q31. + +Somatic mutations causing malignant melanoma have also been identified in several genes, including BRAF (previous studies), STK11 (previous studies), PTEN (previous studies), TRRAP (previous studies), DCC (previous studies), GRIN2A (previous studies), ZNF831, BAP1 (previous studies), and RASA2 (previous studies). A large percentage of melanomas (40-60%) carry an activating somatic mutation in the BRAF gene, most often V600E (previous studies) (previous studies; previous studies)." +MONDO_0007686,"Definition: The gray platelet syndrome (GPS) is a rare inherited disorder characterized by mild to moderate bleeding tendency, moderate thrombocytopenia, and a marked decrease or absence of platelet alpha-granules and of the proteins contained in alpha-granules. The platelets are enlarged, but not giant, and have a gray appearance on light microscopy of Wright-stained peripheral blood smears due to decreased granules. Many patients with gray platelet syndrome develop a stable myelofibrosis (summary by previous studies). + +Cases suggesting autosomal dominant and autosomal recessive inheritance have been described, indicating that GPS is probably a genetically heterogeneous disorder with more than one molecular cause." +MONDO_0009258,"Definition: Galactosemia I (GALAC1), or classic galactosemia, is an autosomal recessive disorder of galactose metabolism. Most patients present in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycemia, renal tubular dysfunction, muscle hypotonia, sepsis, and cataract. Long-term complications include mental retardation, verbal dyspraxia, motor abnormalities, and hypergonadotropic hypogonadism (summary by previous studies). + + Genetic Heterogeneity of Galactosemia + +Also see galactosemia II (GALAC2; previous studies), caused by mutation in the GALK1 gene (previous studies), which encodes the first enzyme in the Leloir pathway, and galactosemia III (GALAC3; previous studies), caused by mutation in the GALE gene (previous studies), which encodes the third enzyme in the Leloir pathway." +MONDO_0009324,"Definition: Hartnup disorder (HND) is characterized by transient manifestations of pellagra, cerebellar ataxia, and psychosis. It is caused by impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa (summary by previous studies)." +MONDO_0010164,Definition: The Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome (AARRS) is a rare autosomal recessive disorder characterized by severe malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. The disorder is believed to represent a defect of dorsoventral patterning and outgrowth of limbs (summary by previous studies). +MONDO_0010233,"Definition: Periventricular nodular heterotopia is a disorder of neuronal migration in which neurons fail to migrate appropriately from the ventricular zone to the cortex during development, resulting in the formation of nodular brain tissue lining the ventricles. Most affected individuals with the X-linked form are female, while hemizygous males tend to die in utero. Affected females usually present with epilepsy, but have normal intelligence. Additional features include defects of the cardiovascular system, such as patent ductus arteriosus, bicuspid aortic valve, and dilation of the sinuses of Valsalva or the thoracic aorta (summary by previous studies). Several patients with PVNH and mutations in the FLNA gene have been reported with a spectrum of connective tissue abnormalities characterized by combinations of vascular, cardiac, cutaneous, and joint-related symptoms (summary by previous studies). + + Genetic Heterogeneity of Periventricular Nodular Heterotopia + +Periventricular nodular heterotopia is a genetically heterogeneous condition: see also PVNH2 (previous studies), caused by mutation in the ARFGEF2 gene (previous studies) on chromosome 20q13; PVNH3 (previous studies), associated with anomalies of 5p; PVNH5 (previous studies), associated with deletions of chromosome 5q; PVNH6 (previous studies), caused by mutation in the ERMARD gene (previous studies) on chromosome 6q27; PVNH7 (previous studies), caused by mutation in the NEDD4L gene (previous studies) on chromosome 18q21; PVNH8 (previous studies), caused by mutation in the ARF1 gene (previous studies) on chromosome 1q42; and PVNH9 (previous studies), caused by mutation in the MAP1B gene (previous studies) on chromosome 5q13. + +The form of PVNH that was previously designated the Ehlers-Danlos variant (PVNH4) is now considered to be the same as X-linked PVNH1." +MONDO_0011240,"Definition: Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria (summary by previous studies). This disorder is also known as the macrocephaly-capillary malformation (MCM) syndrome (previous studies). previous studies suggested use of the term MCAP rather than MCM to reflect the very large brain size, rather than simply large head size, that characterizes this syndrome, and the importance and high frequency of perisylvian polymicrogyria." +MONDO_0013784,Definition: Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by previous studies). +MONDO_0014555,"Definition: Peeling skin syndrome-3 is characterized by asymptomatic lifelong and continuous shedding of the stratum corneum of the epidermis. Symptoms start during the second half of the first decade of life and consist of generalized white scaling occurring over the upper and lower extremities (previous studies). + +For a discussion of genetic heterogeneity of peeling skin syndrome, see PSS1 (previous studies)." +MONDO_0018160,Definition: Retinoblastoma (RB) is an embryonic malignant neoplasm of retinal origin. It almost always presents in early childhood and is often bilateral. Spontaneous regression ('cure') occurs in some cases. The retinoblastoma gene (RB1) was the first tumor suppressor gene cloned. It is a negative regulator of the cell cycle through its ability to bind the transcription factor E2F (previous studies) and repress transcription of genes required for S phase (previous studies). +EFO_0005717,Definition: Retinoblastoma (RB) is an embryonic malignant neoplasm of retinal origin. It almost always presents in early childhood and is often bilateral. Spontaneous regression ('cure') occurs in some cases. The retinoblastoma gene (RB1) was the first tumor suppressor gene cloned. It is a negative regulator of the cell cycle through its ability to bind the transcription factor E2F (previous studies) and repress transcription of genes required for S phase (previous studies). +MONDO_0020740,"Definition: Ectodermal dysplasia with immunodeficiency-1 (EDAID1) is an X-linked recessive disorder that characteristically affects only males. Affected individuals have onset of recurrent severe infections due to immunodeficiency in early infancy or in the first years of life. There is increased susceptibility to bacterial, pneumococcal, mycobacterial, and fungal infections. Laboratory studies usually show dysgammaglobulinemia with low IgG subsets and normal or increased IgA and IgM, consistent with impaired 'class-switching' of B cells, although immunologic abnormalities may be subtle compared to the clinical picture, and B- and T-cell numbers are usually normal. There is a poor antibody response to polysaccharide vaccinations, particularly pneumococcus; response to other vaccinations is variable. Patients also have features of ectodermal dysplasia, including conical incisors, hypo/anhidrosis, and thin skin or hair. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, likely due to different hypomorphic mutations, and may be fatal in childhood. Intravenous immunoglobulins and prophylactic antibiotics are used as treatment; some patients may benefit from bone marrow transplantation. Although only males tend to be affected with immunodeficiency, many patients inherit a mutation from a mother who has mild features of IP or conical teeth (summary by previous studies, previous studies, previous studies, previous studies). + + Genetic Heterogeneity of Ectodermal Dysplasia and Immune Deficiency + +Also see EDAID2 (previous studies), caused by mutation in the NFKBIA gene (previous studies)." +Orphanet_98813,"Definition: Ectodermal dysplasia with immunodeficiency-1 (EDAID1) is an X-linked recessive disorder that characteristically affects only males. Affected individuals have onset of recurrent severe infections due to immunodeficiency in early infancy or in the first years of life. There is increased susceptibility to bacterial, pneumococcal, mycobacterial, and fungal infections. Laboratory studies usually show dysgammaglobulinemia with low IgG subsets and normal or increased IgA and IgM, consistent with impaired 'class-switching' of B cells, although immunologic abnormalities may be subtle compared to the clinical picture, and B- and T-cell numbers are usually normal. There is a poor antibody response to polysaccharide vaccinations, particularly pneumococcus; response to other vaccinations is variable. Patients also have features of ectodermal dysplasia, including conical incisors, hypo/anhidrosis, and thin skin or hair. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, likely due to different hypomorphic mutations, and may be fatal in childhood. Intravenous immunoglobulins and prophylactic antibiotics are used as treatment; some patients may benefit from bone marrow transplantation. Although only males tend to be affected with immunodeficiency, many patients inherit a mutation from a mother who has mild features of IP or conical teeth (summary by previous studies, previous studies, previous studies, previous studies). + + Genetic Heterogeneity of Ectodermal Dysplasia and Immune Deficiency + +Also see EDAID2 (previous studies), caused by mutation in the NFKBIA gene (previous studies)." +MONDO_0030937,"Definition: Mitochondrial complex II deficiency nuclear type 3 (MC2DN3) is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients may have an encephalomyopathic picture with episodic developmental regression, loss of motor skills, hypotonia, ataxia, dystonia, and seizures or myoclonus. Other patients present in infancy with hypertrophic cardiomyopathy, which may be fatal. Laboratory studies show increased serum lactate and mitochondrial complex II deficiency in muscle and fibroblasts (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (previous studies)." +MONDO_0100213,"Definition: The IFAP/BRESHECK syndrome is an X-linked multiple congenital anomaly disorder with variable severity. The classic triad, which defines IFAP, is ichthyosis follicularis, atrichia, and photophobia. Some patients have additional features, including mental retardation, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, particularly of the vertebrae, which constitutes BRESHECK syndrome (summary by previous studies). + + Genetic Heterogeneity of IFAP Syndrome + +IFAP syndrome-2 (IFAP2; previous studies) is caused by heterozygous mutation in the SREBF1 gene (previous studies) on chromosome 17p11." +Orphanet_238455,"Definition: Infantile-onset parkinsonism-dystonia-1 (PKDYS1), also known as dopamine transporter deficiency syndrome (DTDS), is an autosomal recessive complex motor neurologic disorder with onset in infancy. Affected individuals show hyperkinesia with orolingual and limb dyskinesia, dystonia, and chorea, or hypokinesia with parkinsonian features, such as bradykinesia, rigidity, and tremor. Other features may include axial hypotonia, pyramidal tract signs, and eye movement abnormalities. Many patients are misdiagnosed as having cerebral palsy. Cognitive function appears to be less severely affected, but most patients die in the teenage years. There is no effective treatment. Laboratory studies show an increased ratio of homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF), which represents an increased ratio of dopamine to serotonin metabolites (review by previous studies). + + Genetic Heterogeneity of Infantile- or Childhood-Onset Parkinsonism-Dystonia + +See also PKDYS2 (previous studies), caused by mutation in the SLC18A2 gene (previous studies) on chromosome 10q25, and PKDYS3 (previous studies), caused by mutation in the WARS2 gene (previous studies) on chromosome 1p12. + +For an overlapping phenotype, see tyrosine hydroxylase deficiency (previous studies), also known as autosomal recessive Segawa syndrome." +MONDO_0054835,"Definition: Infantile-onset parkinsonism-dystonia-1 (PKDYS1), also known as dopamine transporter deficiency syndrome (DTDS), is an autosomal recessive complex motor neurologic disorder with onset in infancy. Affected individuals show hyperkinesia with orolingual and limb dyskinesia, dystonia, and chorea, or hypokinesia with parkinsonian features, such as bradykinesia, rigidity, and tremor. Other features may include axial hypotonia, pyramidal tract signs, and eye movement abnormalities. Many patients are misdiagnosed as having cerebral palsy. Cognitive function appears to be less severely affected, but most patients die in the teenage years. There is no effective treatment. Laboratory studies show an increased ratio of homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF), which represents an increased ratio of dopamine to serotonin metabolites (review by previous studies). + + Genetic Heterogeneity of Infantile- or Childhood-Onset Parkinsonism-Dystonia + +See also PKDYS2 (previous studies), caused by mutation in the SLC18A2 gene (previous studies) on chromosome 10q25, and PKDYS3 (previous studies), caused by mutation in the WARS2 gene (previous studies) on chromosome 1p12. + +For an overlapping phenotype, see tyrosine hydroxylase deficiency (previous studies), also known as autosomal recessive Segawa syndrome." +Orphanet_245,"Definition: Nager syndrome is the prototype for a group of disorders collectively referred to as the acrofacial dysostoses (AFDs), which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of Nager syndrome include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The presence of anterior upper-limb defects and the typical lack of lower-limb involvement distinguishes Nager syndrome from Miller syndrome (previous studies), another rare AFD; however, distinguishing Nager syndrome from other AFDs, including Miller syndrome, can be challenging (summary by previous studies)." +MONDO_0007943,"Definition: Nager syndrome is the prototype for a group of disorders collectively referred to as the acrofacial dysostoses (AFDs), which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of Nager syndrome include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The presence of anterior upper-limb defects and the typical lack of lower-limb involvement distinguishes Nager syndrome from Miller syndrome (previous studies), another rare AFD; however, distinguishing Nager syndrome from other AFDs, including Miller syndrome, can be challenging (summary by previous studies)." +Orphanet_2686,"Definition: Cyclic neutropenia is a rare disease characterized by regular 21-day cyclic fluctuations in the number of blood neutrophils, monocytes, eosinophils, lymphocytes, platelets, and reticulocytes. The recurrent severe neutropenia causes patients to experience periodic symptoms of fever, malaise, mucosal ulcers, and, rarely, life-threatening infections. The disease occurs both as a congenital disorder and in an acquired form, with essentially identical phenotypic presentations (summary by previous studies)." +MONDO_0008090,"Definition: Cyclic neutropenia is a rare disease characterized by regular 21-day cyclic fluctuations in the number of blood neutrophils, monocytes, eosinophils, lymphocytes, platelets, and reticulocytes. The recurrent severe neutropenia causes patients to experience periodic symptoms of fever, malaise, mucosal ulcers, and, rarely, life-threatening infections. The disease occurs both as a congenital disorder and in an acquired form, with essentially identical phenotypic presentations (summary by previous studies)." +Orphanet_79369,"Definition: This form of isolated toenail dystrophy has been found to segregate as an autosomal dominant trait in families in which another member has the autosomal recessive skin disorder dystrophic epidermolysis bullosa (previous studies) or transient bullous dermolysis of the newborn (previous studies), the features of which include dystrophic nails. The nail changes in isolated toenail dystrophy are most severe in the great toes and consist of the nail plate being buried in the nail bed with a deformed and narrow free edge (summary by previous studies). This form of toenail dystrophy is referred to here as nonsyndromic congenital nail disorder-8 (NDNC8). + +For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (previous studies)." +EFO_0010632,"Definition: Lessel-Kubisch syndrome (LSKB) is characterized by short stature and progeroid features, including prematurely gray hair, pinched facies, and scleroderma-like skin changes. Renal failure-associated hypertension and hypogonadism have also been observed (previous studies)." +MONDO_0007841,"Definition: Ischiocoxopodopatellar syndrome (ICPPS) is a rare autosomal dominant disorder characterized by a/hypoplasia of the patellas and various anomalies of the pelvis and feet. Pelvic anomalies include bilateral absent or delayed ossification of the ischiopubic junction and infraacetabular axe cut notches. Other major signs are a wide gap between the first and second toes, short fourth and fifth rays of the feet, and pes planus (summary by previous studies). Pediatric-onset pulmonary arterial hypertension may be seen in association with ICPPS (previous studies and previous studies)." +MONDO_0008017,"Definition: Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant genodermatosis characterized by onset in infancy of a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Patients develop cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses (previous studies). Although 1 family was reported to have progressive severe interstitial lung disease (previous studies), this feature has not been reported in other families and is not considered a criterion for diagnosis. However, the clinical triad of nonscarring alopecia, well-demarcated fiery red mucosa, and psoriasiform perineal involvement has been consistently observed (review by previous studies)." +MONDO_0009020,"Definition: Macular corneal dystrophy (MCD) is an autosomal recessive disorder in which progressive punctate opacities in the cornea result in bilateral loss of vision, eventually necessitating corneal transplantation. MCD is classified into 2 subtypes, type I and type II, defined by the respective absence and presence of sulfated keratan sulfate in the patient serum, although both types have clinically indistinguishable phenotypes (summary by previous studies)." +MONDO_0010318,"Definition: FG syndrome-4 (FGS4) is an X-linked recessive intellectual developmental disorder characterized by congenital hypotonia, constipation, behavioral disturbances, and dysmorphic features (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of FG syndrome, see FGS1 (previous studies)." +MONDO_0010615,"Definition: IGHD3 is characterized by agammaglobulinemia and markedly reduced numbers of B cells, short stature, delayed bone age, and good response to treatment with growth hormone (summary by previous studies). + +For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see previous studies." +MONDO_0011382,"Definition: Sickle cell disease is a multisystem disease associated with episodes of acute illness and progressive organ damage. Hemoglobin polymerization, leading to erythrocyte rigidity and vasoocclusion, is central to the pathophysiology of the disease, but the importance of chronic anemia, hemolysis, and vasculopathy has been established. The most common cause of sickle cell anemia is the HbS variant (previous studies), with hemoglobin SS disease being most prevalent in Africans (review by previous studies). + +See review of infection in sickle cell disease by previous studies. + +previous studies reviewed the genetic and nongenetic modifiers of the severity of sickle cell disease." +MONDO_0013761,"Definition: Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (previous studies). + +For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (previous studies)." +MONDO_0031057,"Definition: Digenic dyskeratosis congenita (DKCD) is characterized clinically by a combination of mucocutaneous features including abnormal skin pigmentation, nail dystrophy, thin hair, and oral leukoplakia. Some patients may have evidence of bone marrow failure, manifest as immune defects such as recurrent infections or hypogammaglobulinemia. Telomeres are shortened in patient cells. Individuals with DKCD may show severe adverse reactions to treatment with 5-FU (previous studies). + +For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (previous studies)." +MONDO_0100221,"Definition: Follicular ichthyosis, atrichia, and photophobia syndrome-2 (IFAP2) is characterized by ichthyosis follicularis or follicular hyperkeratosis, sparse to no body hair, and photophobia with corneal lesions. Ultrastructural hair analysis shows trichorrhexis nodosa (previous studies). + +For a discussion of genetic heterogeneity of IFAP syndrome, see IFAP1 (previous studies)." +MONDO_0859517,"Definition: Autosomal recessive congenital myopathy-2B (CMYP2B) is a disorder of the skeletal muscle characterized by severe hypotonia with lack of spontaneous movements and respiratory insufficiency, usually leading to death in infancy or early childhood (previous studies). However, longer survival has also been reported, likely due to the type of mutation and extent of its impact (previous studies). + +Mutations in the ACTA1 gene can cause a range of skeletal muscle diseases. About 90% of patients with ACTA1 mutations carry heterozygous mutations, usually de novo (CMYP2A; previous studies), whereas 10% of patients carry biallelic ACTA1 mutations (CMYP2B) (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +Orphanet_241,"Definition: Dyschromatosis universalis hereditaria (DUH) is a rare autosomal dominant genodermatosis characterized by irregularly shaped, asymptomatic hyper- and hypopigmented macules that appear in infancy or early childhood and occur in a generalized distribution over the trunk, limbs, and sometimes the face. Involvement of the palms or soles is unusual. Abnormalities of hair and nails have been reported, and DUH may be associated with abnormalities of dermal connective tissue, nerve tissue, or other systemic complications (summary by previous studies). + +The autosomal dominant SASH1-associated DUH1 phenotype is characterized by generalized lentigines accompanied by mottled hyper- and hypopigmentation (previous studies). + +DUH is distinct from dyschromatosis symmetrica hereditaria (DSH; previous studies), which also occurs particularly in Japanese and Korean individuals, but shows a characteristic mixture of hyper- and hypopigmented macules limited largely to the dorsal aspects of the hands and feet (previous studies). previous studies noted that lesions associated with DUH appear within the first year of life predominantly on the trunk, whereas the age of onset of DSH is approximately 6 years and lesions appear predominantly on the extremities. + + Genetic Heterogeneity of Dyschromatosis Universalis Hereditaria + +Dyschromatosis universalis hereditaria-2 (DUH2; previous studies) maps to chromosome 12q21-q23. DUH3 (previous studies) is caused by mutation in the ABCB6 gene (previous studies) on chromosome 2q35." +EFO_0010249,"Definition: Spinocerebellar ataxia with axonal neuropathy-3 (SCAN3) is an autosomal recessive neuromuscular disorder characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy and distal sensory impairment due to an axonal peripheral neuropathy. Affected individuals have gait disturbances and sometimes manual dexterity difficulties, as well as cerebellar ataxia associated with cerebellar atrophy on brain imaging. Additional features usually include dysarthria, hyporeflexia, and increased serum creatine kinase. Some patients may have impaired intellectual development (summary by previous studies). + +For a discussion of genetic heterogeneity of SCAN, see SCAN1 (previous studies)." +HP_0004936,"Definition: Thrombophilia due to activated protein C resistance is due to a mutation in the F5 gene that renders factor V resistant to cleavage and inactivation by activated protein C (PROC; previous studies) and results in a tendency to thrombosis. + +See also factor V deficiency (previous studies), an allelic disorder resulting in a hemorrhagic diathesis due to lack of factor V. + +The most common mutation that causes this disorder is referred to as factor V Leiden (R506Q; previous studies), named after the town in the Netherlands where previous studies discovered the defect. Homozygosity increases the risk of thrombotic complications to a greater extent than heterozygosity. However, heterozygous presence of the mutation may be combined with defects in other genes in the clotting pathway to contribute to the disorder. Expressivity is variable and influenced by environment." +MONDO_0008560,"Definition: Thrombophilia due to activated protein C resistance is due to a mutation in the F5 gene that renders factor V resistant to cleavage and inactivation by activated protein C (PROC; previous studies) and results in a tendency to thrombosis. + +See also factor V deficiency (previous studies), an allelic disorder resulting in a hemorrhagic diathesis due to lack of factor V. + +The most common mutation that causes this disorder is referred to as factor V Leiden (R506Q; previous studies), named after the town in the Netherlands where previous studies discovered the defect. Homozygosity increases the risk of thrombotic complications to a greater extent than heterozygosity. However, heterozygous presence of the mutation may be combined with defects in other genes in the clotting pathway to contribute to the disorder. Expressivity is variable and influenced by environment." +MONDO_0007496,"Definition: Dystonia-12 (DYT12), also known as rapid-onset dystonia-parkinsonism, is an autosomal dominant disorder characterized by abrupt onset of asymmetric dystonia and parkinsonism in young adulthood, often after a trigger such as physical overexertion, trauma, heat, or fever. Affected individuals also show slowly progressive nonparoxysmal neurologic deterioration in a rostrocaudal gradient with prominent bulbar dysfunction (summary by previous studies)." +Orphanet_71517,"Definition: Dystonia-12 (DYT12), also known as rapid-onset dystonia-parkinsonism, is an autosomal dominant disorder characterized by abrupt onset of asymmetric dystonia and parkinsonism in young adulthood, often after a trigger such as physical overexertion, trauma, heat, or fever. Affected individuals also show slowly progressive nonparoxysmal neurologic deterioration in a rostrocaudal gradient with prominent bulbar dysfunction (summary by previous studies)." +MONDO_0008290,"Definition: Porokeratosis is a rare skin disorder characterized by one or more annular plaques with a surrounding raised horny border that spreads centrifugally. Variants of porokeratosis have been described that differ in morphologic shapes, distribution, and clinical course (previous studies). However, as noted by previous studies, several families with expression of more than one variant of porokeratosis among members, and several individuals expressing more than one variant, have been reported, suggesting that the distinctions among these variants may be artificial. + +Mutations in the MVK gene have been found to cause multiple types of porokeratosis, which have been described as porokeratosis of Mibelli, porokeratoma, genital porokeratosis, hyperkeratotic porokeratosis, and linear porokeratosis. + +The preferred title of this entry was formerly 'Porokeratosis 1, Mibelli Type; POROK1.' + + Genetic Heterogeneity of Porokeratosis + +Also see porokeratosis-2 (POROK2; previous studies), mapped to chromosome 12q24; POROK3 (previous studies), caused by mutation in the MVK gene (previous studies) on chromosome 12q24; POROK4 (previous studies), mapped to chromosome 15q25-q26; POROK5 (previous studies), mapped to chromosome 1p31; POROK6 (previous studies), mapped to chromosome 1p31; POROK7 (previous studies), caused by mutation in the MVD gene (previous studies) on chromosome 16q24; POROK8 (previous studies), caused by mutation in the SLC17A9 gene (previous studies) on chromosome 20q13; and POROK9 (previous studies), caused by mutation in the FDPS gene (previous studies) on chromosome 1q22. + +A palmoplantar form of punctate porokeratosis has also been described (PPKP2; previous studies). + + Genotype/Phenotype Correlations + +previous studies screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified mutations in the MVK, MVD, PMVK, and FDPS genes in 113 patients. The authors noted that giant plaque-type porokeratosis ptychotropica with lesion diameters of at least 5 cm appeared to be uniquely associated with mutation in MVK; it was observed in 19 (50%) of 38 MVK probands, but not in patients with mutations in any of the other 3 genes or in the 21 probands in whom no mutation was found. MVK patients also showed the widest range in terms of the number and size of lesions, as well as presence of porokeratosis subtypes. In patients with MVD mutations, the age of onset ranged from 5 to 70 years, and lesion diameters were generally less than 2 cm. In addition, 6 of the 62 MVD probands exhibited solar facial porokeratosis, which was not seen in any other patients. Localized genital porokeratosis and porokeratoma appeared to be uniquely associated with mutation in the PMVK gene, whereas patients with mutations in the FDPS gene had more than 500 lesions, all with diameters of 1 cm or less." +MONDO_0009249,"Definition: Hereditary fructose intolerance (HFI) becomes apparent in infancy at the time of weaning, when fructose or sucrose is added to the diet. Clinical features include recurrent vomiting, abdominal pain, and hypoglycemia that may be fatal. Long-term exposure to fructose can result in liver failure, renal tubulopathy, and growth retardation. Older patients who survive infancy develop a natural avoidance of sweets and fruits. previous studies provided a detailed review of the biochemical, genetic, and molecular basis of aldolase B deficiency in hereditary fructose intolerance." +MONDO_0009520,"Definition: 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by previous studies)." +MONDO_0010134,"Definition: Pendred syndrome, the most common syndromal form of deafness, is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter) (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of thyroid dyshormonogenesis, see TDH1 (previous studies)." +MONDO_0010976,"Definition: Autosomal recessive generalized intermediate or severe epidermolysis bullosa simplex-1D (EBS1D) is a skin disorder characterized by blistering elicited by minor trauma that usually heals without scarring. Severity is variable; in some patients hands and feet are primarily affected, and in others blistering anywhere on the body may occur. In some patients the condition improves with age. Histology shows cleavage at the level of basal keratinocytes (previous studies; previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies reviewed the classification of inherited epidermolysis bullosa." +Orphanet_89838,"Definition: Autosomal recessive generalized intermediate or severe epidermolysis bullosa simplex-1D (EBS1D) is a skin disorder characterized by blistering elicited by minor trauma that usually heals without scarring. Severity is variable; in some patients hands and feet are primarily affected, and in others blistering anywhere on the body may occur. In some patients the condition improves with age. Histology shows cleavage at the level of basal keratinocytes (previous studies; previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies reviewed the classification of inherited epidermolysis bullosa." +MONDO_0011217,"Definition: Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (summary by previous studies)." +MONDO_0013760,"Definition: ISQMR is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (summary by previous studies)." +Orphanet_352333,"Definition: ISQMR is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (summary by previous studies)." +MONDO_0026730,"Definition: Basilicata-Akhtar syndrome (MRXSBA) is characterized by global developmental delay apparent from infancy, feeding difficulties, hypotonia, and poor or absent speech. Most patients are able to walk, although they may have an unsteady gait or spasticity. Additional findings include dysmorphic facial features and mild distal skeletal anomalies. Males and females are similarly affected (summary by previous studies)." +MONDO_0030376,"Definition: Martsolf syndrome-2 (MARTS2) is an autosomal recessive disorder with the main features of congenital cataracts, mildly to severely impaired intellectual development, and facial dysmorphism. Other features include brain malformations, microcephaly, and hypogonadism-hypogenitalism (summary by previous studies)." +MONDO_0032942,"Definition: Nabais Sa-de Vries syndrome type 1 (NSDVS1) is characterized by global developmental delay apparent from infancy, variable behavioral abnormalities, microcephaly, and dysmorphic facial features, including round face, small palpebral fissures, highly arched eyebrows, and short nose. The severity is variable (summary by previous studies)." +MONDO_0100211,"Definition: Autosomal recessive growth hormone insensitivity syndrome with immune dysregulation-1 (GHISID1) is a congenital disorder characterized by short stature due to insensitivity to growth hormone (GH1; previous studies). Affected individuals usually have failure to thrive, delayed bone age, and delayed puberty associated with decreased serum IGF1 (previous studies), IGFBP3 (previous studies), and ALS (previous studies). Some patients may have dysmorphic features. Most, but not all, patients have features of immune dysregulation, including chronic pulmonary disease, interstitial pneumonitis, recurrent or severe infections, eczema, and autoimmune arthritis. The immune features are highly variable (summary by previous studies; previous studies). + +See previous studies for a form of growth hormone insensitivity caused by mutation in the growth hormone receptor gene (GHR; previous studies)." +Orphanet_79478,"Definition: Griscelli syndrome type 3 (GS3) is a rare autosomal recessive disorder that results in a characteristic pigmentary dilution of the skin and hair, which shows a silvery-gray sheen associated with large clumps of pigment in hair shafts and an abnormal accumulation of end-stage melanosomes in the center of melanocytes. There are no immunologic or neurologic manifestations (summary by previous studies). + +For a discussion of phenotypic and genetic heterogeneity in Griscelli syndrome, see GS1 (previous studies)." +MONDO_0012220,"Definition: Griscelli syndrome type 3 (GS3) is a rare autosomal recessive disorder that results in a characteristic pigmentary dilution of the skin and hair, which shows a silvery-gray sheen associated with large clumps of pigment in hair shafts and an abnormal accumulation of end-stage melanosomes in the center of melanocytes. There are no immunologic or neurologic manifestations (summary by previous studies). + +For a discussion of phenotypic and genetic heterogeneity in Griscelli syndrome, see GS1 (previous studies)." +MONDO_0007813,"Definition: Ichthyosis bullosa of Siemens (IBS) is an autosomal dominant congenital bullous ichthyosis without erythroderma. Blistering occurs in response to mild physical trauma and results in superficial erosion ('molting') of the outer skin, particularly on flexures, shins, and the periumbilical region. Keratin filament aggregates are seen by electron microscopy in the granular and upper spinous layers of the epidermis (summary by previous studies)." +MONDO_0008061,"Definition: Nail-patella syndrome (NPS) is an autosomal dominant disorder characterized by developmental defects of dorsal limb structures, the kidney, and the eye, manifested by nail dysplasia, patellar abnormalities, elbow dysplasia, iliac horns, nephropathy, and glaucoma, respectively (summary by previous studies)." +MONDO_0009182,"Definition: Severe junctional epidermolysis bullosa 1B (JEB1B) is an autosomal recessive skin blistering disorder characterized by extreme fragility of the skin and epithelia of various extracutaneous tissues. Blisters and erosions are present at birth. Blister formation occurs within the dermal-epidermal basement membrane zone. Patients usually die before 1 year of age (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the pathophysiology and phenotypic and genetic heterogeneity of the various forms of epidermolysis bullosa." +Orphanet_79404,"Definition: Severe junctional epidermolysis bullosa 1B (JEB1B) is an autosomal recessive skin blistering disorder characterized by extreme fragility of the skin and epithelia of various extracutaneous tissues. Blisters and erosions are present at birth. Blister formation occurs within the dermal-epidermal basement membrane zone. Patients usually die before 1 year of age (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the pathophysiology and phenotypic and genetic heterogeneity of the various forms of epidermolysis bullosa." +MONDO_0012495,"Definition: Spondyloepiphyseal dysplasia of the Genevieve type (SEMDG) is characterized by infantile-onset severe developmental delay and skeletal dysplasia, including short stature, premature carpal ossification, platyspondyly, longitudinal metaphyseal striations, and small epiphyses (summary by previous studies)." +MONDO_0013461,Definition: Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes (previous studies). +MONDO_0020746,"Definition: Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1B (CPSFS1B) is characterized by contractures of proximal and distal joints, pterygia involving the neck, elbows, fingers, and/or knees, and variable vertebral, carpal, and tarsal fusions. Inter- and intrafamilial variability has been observed (previous studies). + +An autosomal dominant form of contractures, pterygia, and spondylocarpotarsal fusion syndrome (CPSFS1A; previous studies) is caused by heterozygous mutation in the MYH3 gene." +MONDO_0029140,"Definition: DEE95 is a severe autosomal recessive developmental disorder characterized by severely impaired global development, hypotonia, weakness, ataxia, coarse facial features, and intractable seizures. More variable features may include abnormalities of the hands and feet, inguinal hernia, and feeding difficulties. The disorder is part of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies. + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +MONDO_0031446,"Definition: Familial hypercholanemia-1 (FHCA1) is an autosomal recessive disorder characterized by elevated concentrations of bile acids (usually conjugated), itching, and fat malabsorption, leading to poor overall growth and deficiencies of fat-soluble vitamins. Vitamin D deficiency results in rickets, and vitamin K deficiency results in a coagulopathy (previous studies; previous studies; summary by previous studies). + +See also bile acid conjugation defect-1 (BACD1; previous studies), which can also show increased bile acid levels, although the bile acids in BACD1 are unconjugated. + + Genetic Heterogeneity of FHCA + +See FHCA2 (previous studies), caused by mutation in the SLC10A1 gene (previous studies) on chromosome 14q24." +MONDO_0035133,"Definition: Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioral abnormalities, dysmorphic features, and obesity. The severity of the phenotype and additional features are variable (summary by previous studies)." +Orphanet_766,Definition: Red cell pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. PK deficiency is also the most frequent enzyme abnormality of the glycolytic pathway (previous studies). +MONDO_0009950,Definition: Red cell pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. PK deficiency is also the most frequent enzyme abnormality of the glycolytic pathway (previous studies). +MONDO_0009970,"Definition: Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype) (previous studies). Absence or paucity of differentiated proximal tubules is the histopathologic hallmark of the disorder and may be associated with skull ossification defects." +MONDO_0011451,"Definition: Mitochondrial complex IV deficiency nuclear type 2 (MC4DN2) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms at birth or in the first weeks or months of life. Affected individuals have severe hypotonia, often associated with feeding difficulties and respiratory insufficiency necessitating tube feeding and mechanical ventilation. The vast majority of patients develop hypertrophic cardiomyopathy in the first days or weeks of life, which usually leads to death in infancy or early childhood. Patients also show neurologic abnormalities, including developmental delay, nystagmus, fasciculations, dystonia, EEG changes, and brain imaging abnormalities compatible with a diagnosis of Leigh syndrome (see previous studies). There may also be evidence of systemic involvement with hepatomegaly and myopathy, although neurogenic muscle atrophy is more common and may resemble spinal muscular atrophy type I (SMA1; previous studies). Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0012099,"Definition: AICA-ribosuria is characterized by severe to profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante-postnatal growth impairment, and severe scoliosis. Dysmorphic features include coarse facies and upturned nose. Early-onset epilepsy may occur. Less common features may include aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis (previous studies)." +MONDO_0014227,"Definition: Cole disease is a rare autosomal dominant disorder characterized by congenital or early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show nonspecific changes including hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer (summary by previous studies). Some patients also exhibit calcinosis cutis or early-onset calcific tendinopathy (previous studies)." +MONDO_0014620,"Definition: Myoclonic dystonia-26 (DYT26) is an autosomal dominant neurologic disorder characterized by onset of myoclonic jerks affecting the upper limbs in the first or second decade of life. The disorder is progressive, and patients later develop dystonia with predominant involvement of the craniocervical regions and sometimes the trunk and/or lower limbs. Dystonia dominates the clinical picture (summary by previous studies)." +MONDO_0014656,"Definition: Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-2 is a mitochondrial disorder characterized by adult onset of progressive external ophthalmoplegia, exercise intolerance, muscle weakness, and signs and symptoms of spinocerebellar ataxia, such as impaired gait and dysarthria. Some patients may have respiratory insufficiency. Laboratory studies are consistent with a defect in mtDNA replication (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (previous studies)." +MONDO_0014809,"Definition: Familial myeloproliferative/lymphoproliferative neoplasms (MPLPF) is an autosomal dominant cancer predisposition syndrome characterized by adult-onset of hematologic malignancies mainly affecting the myeloid line. Most patients present with myelodysplastic syndrome (MDS; previous studies) and/or acute myeloid leukemia (AML; previous studies). Rare lymphoid malignancies, including lymphoma, can also occur. Some mutation carriers, even if unaffected by a hematologic malignancy, may have evidence of immune dysregulation disorders, including asthma, eczema, or juvenile arthritis. The disorder shows incomplete penetrance (summary by previous studies). Patients may show a favorable response to treatment with lenalidomide (summary by previous studies)." +MONDO_0030309,Definition: Autosomal recessive Leber hereditary optic neuropathy (LHONAR) is characterized by bilateral synchronous or asynchronous vision loss with variable recovery of visual acuity. The visual field defect is typically in the central visual field. The disorder shows incomplete penetrance and male predominance (previous studies). +MONDO_0030341,"Definition: Autosomal recessive presynaptic congenital myasthenic syndrome-7B (CMS7B) is characterized by severe generalized muscle weakness apparent from birth; decreased fetal movements may be apparent in utero. Affected infants have generalized hypotonia with poor cry and feeding, head lag, and facial muscle weakness with ptosis. Some patients may have respiratory involvement. Electrophysiologic studies show decreased compound muscle action potentials (CMAPs) and a decremental response to repetitive nerve stimulation. Treatment with 3,4-diaminopyridine and pyridostigmine may result in clinical improvement (summary by previous studies)." +MONDO_0030756,"Definition: Stuve-Wiedemann syndrome-2 (STWS2) is an autosomal recessive lethal skeletal dysplasia characterized by short stature, small chest, bowing of the long bones, and neonatal cardiopulmonary and autonomous dysfunction. Additional variable features include congenital thrombocytopenia, eczematoid dermatitis, renal anomalies, and defective acute-phase response (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of Stuve-Wiedemann syndrome, see STWS1 (previous studies)." +MONDO_0033664,"Definition: Kilquist syndrome (KILQS) is an autosomal recessive multisystem disorder characterized by neurologic, gastrointestinal, and secretory dysfunction. Affected individuals present at birth with hypotonia, feeding difficulties, mild dysmorphic features, and sensorineural hearing loss. They show poor overall growth associated with gastrointestinal anomalies such as gastroesophageal reflux or midgut malrotation, as well as profound global developmental delay with inability to sit or speak. Tear, sweat, and saliva production is also impaired, causing dry mouth and recurrent bronchial mucus plugging. Some of the clinical features are reminiscent of cystic fibrosis (CF; previous studies) (summary by previous studies)." +Orphanet_1299,"Definition: The core phenotype of Elsahy-Waters syndrome consists of brachycephaly, facial asymmetry, marked hypertelorism, proptosis, blepharochalasis, midface hypoplasia, broad nose with concave nasal ridge, and prognathism; radicular dentin dysplasia with consequent obliterated pulp chambers, apical translucent cysts, recurrent infections, and early loss of teeth; vertebral fusions, particularly at C2-C3; and moderate mental retardation. Skin wrinkling over the glabellar region seems common, and in males, hypospadias has always been present. Inter- and intrafamilial variability has been reported regarding the presence of vertebral fusions, hearing loss, and dentigerous cysts. Midface hypoplasia, facial asymmetry, progressive dental anomalies, and impaired cognitive development become more evident in adulthood (summary by previous studies)." +Orphanet_357329,"Definition: Immunodeficiency-56 is an autosomal recessive primary immunodeficiency characterized by B- and T-cell defects and variable dysfunction of NK cells. Patients tend to have normal numbers of lymphocytes, but show defective class-switched B cells, low IgG, defective antibody response, and defective T-cell responses to certain antigens (summary by previous studies)." +MONDO_0014082,"Definition: Immunodeficiency-56 is an autosomal recessive primary immunodeficiency characterized by B- and T-cell defects and variable dysfunction of NK cells. Patients tend to have normal numbers of lymphocytes, but show defective class-switched B cells, low IgG, defective antibody response, and defective T-cell responses to certain antigens (summary by previous studies)." +EFO_1000359,"Definition: Susceptibility to pancreatic ductal adenocarcinoma (PDAC) may be conferred by mutation in RABL3. Other cancers, including melanoma, breast cancer, and colon cancer, have been reported in RABL3 mutation-carrying individuals, with or without PDAC (previous studies). + +For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see previous studies." +MONDO_0007888,"Definition: Hereditary leiomyomatosis and renal cell cancer is an autosomal dominant tumor predisposition syndrome characterized by the variable development of 3 tumors: cutaneous piloleiomyomata that develop in essentially all patients by age 40 years; leiomyomata (fibroids) of the uterus, and rarely leiomyosarcomas, at a mean age of 30 years (range, 18 to 52 years); and type 2 papillary renal cell carcinoma at a mean age of 46 years (range, 17 to 75 years), which occurs in about 20% of patients. Type 2 papillary renal cell carcinoma is a pathologic subtype characterized by large tumor cells with eosinophilic cytoplasm and pseudostratified nuclei; it shows an aggressive clinical course. Some patients with FH mutations may develop collecting duct renal cell carcinoma. The main focus of management in HLRCC is prevention of disease and death due to renal cancer (summary by previous studies; previous studies; and previous studies). + +For a general discussion of papillary renal cell carcinoma, see RCCP1 (previous studies)." +MONDO_0009295,"Definition: Glycogen storage disease VII is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and partial loss of muscle and red cell PFK activity, respectively. previous studies noted that not all patients with GSD VII seek medical care because in some cases it is a relatively mild disorder." +MONDO_0010664,"Definition: Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR) is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthric speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia (summary by previous studies)." +Orphanet_3063,"Definition: Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR) is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthric speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia (summary by previous studies)." +MONDO_0013327,"Definition: Primary hyperoxaluria is an autosomal recessive disorder of glyoxylate metabolism that results in excessive endogenous oxalate synthesis and the formation of calcium oxalate kidney stones. Progressive renal inflammation and interstitial fibrosis from advanced nephrocalcinosis, recurrent urolithiasis, and urinary tract infections can cause reduced renal function, systemic oxalate deposition, and end-stage renal failure. Compared to hyperoxaluria type I (HP1; previous studies) and type II (HP2; previous studies), HP3 appears to be the least severe, with good preservation of kidney function in most patients. The typical clinical characteristic is early onset of recurrent urolithiasis, but less active stone formation later (summary by previous studies). + +For a discussion of genetic heterogeneity of primary hyperoxaluria, see previous studies." +MONDO_0013885,"Definition: Malan syndrome (MALNS) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present (summary by previous studies)." +MONDO_0013948,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 12 (CG12, equivalent to CGG) have mutations in the PEX3 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0019149,"Definition: Deficiency of lysosomal acid lipase causes 2 distinct phenotypes in humans: Wolman disease (WOLD; previous studies) and cholesteryl ester storage disease (CESD). WOLD is an early-onset fulminant disorder of infancy with massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides. Death occurs early in life. CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters. This slowly progressive visceral disease has a wide spectrum of involvement ranging from early onset with severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood (summary by previous studies)." +EFO_0700022,"Definition: Deficiency of lysosomal acid lipase causes 2 distinct phenotypes in humans: Wolman disease (WOLD; previous studies) and cholesteryl ester storage disease (CESD). WOLD is an early-onset fulminant disorder of infancy with massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides. Death occurs early in life. CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters. This slowly progressive visceral disease has a wide spectrum of involvement ranging from early onset with severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood (summary by previous studies)." +MONDO_0020788,"Definition: HOMGSMR2 is characterized by generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persist despite magnesium supplementation, and are associated with significantly impaired intellectual development (previous studies). + +For a discussion of genetic heterogeneity of HOMGSMR, see previous studies." +MONDO_0033546,"Definition: Sodium-dependent multivitamin transporter deficiency (SMVTD) is an autosomal recessive multisystemic metabolic disorder with highly variable manifestations. Affected individuals usually present at birth or in infancy with severe feeding problems, gastrointestinal reflux, cyclic vomiting, and diarrhea associated with failure to thrive. Gastrointestinal hemorrhage may occur; tube-feeding is often required for a short time. The course and severity of the disease varies: some patients have episodes of acute metabolic decompensation during infection that respond well to treatment, whereas others show more permanent neurologic regression with loss of early motor and cognitive milestones in the first year or so of life. Less severely affected patients have normal development or mild growth and motor delays, whereas more severely affected individuals may have seizures, ataxia, spasticity, peripheral neuropathy, immune defects, and osteopenia. In severely affected patients, brain imaging shows cerebral, cerebellar, and brainstem atrophy and thin corpus callosum. Treatment with biotin, pantothenic acid, and alpha-lipoic acid has been shown to result in significant clinical improvement (previous studies; previous studies)." +MONDO_0044725,"Definition: Immunodeficiency-55 is an autosomal recessive primary immunodeficiency characterized by intrauterine growth retardation, natural killer (NK) cell deficiency, and chronic neutropenia. Most patients also have postnatal growth retardation. Other clinical manifestations include mild facial dysmorphism, dry or eczematous skin, and recurrent infections with both viruses and bacteria. The disorder appears to result from a defect in DNA replication causing blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells (summary by previous studies)." +MONDO_0100348,"Definition: Neurodevelopmental disorder with microcephaly, language delay, and gait abnormalities (NEDMILG) is an autosomal recessive disorder characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. More variable features include hypotonia, early-onset seizures, and a peripheral demyelinating or axonal peripheral sensorimotor neuropathy. The disease follows a neurodegenerative course in many patients; clinical features suggest involvement of both the central and peripheral nervous systems (previous studies)." +Orphanet_171723,"Definition: White sponge nevus is a rare autosomal dominant disorder of noncornifying squamous epithelial differentiation that presents clinically as white, soft, thick plaques of the oral mucosa. Less frequently, the mucous membranes of the nose, esophagus, genitalia, and rectum are involved. Histopathologic features, including epithelial thickening, parakeratosis, extensive vacuolization of the suprabasal keratinocytes, and compact aggregates of keratin intermediate filaments in the upper spinus layers resemble those found in epidermal disorders shown to be associated with keratin defects (summary by previous studies). + + Genetic Heterogeneity of White Sponge Nevus + +White sponge nevus-2 (WSN2; previous studies) is caused by mutation in the KRT13 gene (previous studies) on chromosome 17q21." +MONDO_0008676,"Definition: White sponge nevus is a rare autosomal dominant disorder of noncornifying squamous epithelial differentiation that presents clinically as white, soft, thick plaques of the oral mucosa. Less frequently, the mucous membranes of the nose, esophagus, genitalia, and rectum are involved. Histopathologic features, including epithelial thickening, parakeratosis, extensive vacuolization of the suprabasal keratinocytes, and compact aggregates of keratin intermediate filaments in the upper spinus layers resemble those found in epidermal disorders shown to be associated with keratin defects (summary by previous studies). + + Genetic Heterogeneity of White Sponge Nevus + +White sponge nevus-2 (WSN2; previous studies) is caused by mutation in the KRT13 gene (previous studies) on chromosome 17q21." +Orphanet_415,"Definition: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) is an autosomal recessive, chronic and progressive disorder of the urea cycle with typical age of onset in early life. The acute phase is characterized by hyperammonemia accompanied by vomiting, ataxia, lethargy, confusion, and coma. Chronically, aversion to protein-rich foods, coagulation abnormalities, hypotonia, developmental delay, progressive encephalopathy with mental regression, and signs of motor dysfunction are present. About 95% of patients survive after diagnosis and therapy is established. However, in early adulthood most patients develop signs of pyramidal tract dysfunction (summary by previous studies)." +MONDO_0009393,"Definition: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) is an autosomal recessive, chronic and progressive disorder of the urea cycle with typical age of onset in early life. The acute phase is characterized by hyperammonemia accompanied by vomiting, ataxia, lethargy, confusion, and coma. Chronically, aversion to protein-rich foods, coagulation abnormalities, hypotonia, developmental delay, progressive encephalopathy with mental regression, and signs of motor dysfunction are present. About 95% of patients survive after diagnosis and therapy is established. However, in early adulthood most patients develop signs of pyramidal tract dysfunction (summary by previous studies)." +EFO_0010256,"Definition: Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is a severe autosomal recessive neurodevelopmental disorder affecting the central and peripheral nervous system. Patients present in the first year of life with global developmental delay, impaired intellectual development, poor or absent speech, and motor abnormalities. Brain imaging shows cerebellar atrophy. The severity is variable, but death in childhood may occur (previous studies)." +EFO_0010646,"Definition: Premature ovarian failure-16 (POF16) is characterized by onset of amenorrhea early in the fourth decade of life, accompanied by elevated follicle-stimulating hormone (FSH; see previous studies) levels and low estradiol levels. Ovaries are smaller than normal and show a solid echo pattern with no antral follicle (previous studies)." +MONDO_0009652,"Definition: Mucolipidosis type III gamma is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates (summary by previous studies)." +MONDO_0011074,"Definition: Autosomal dominant deafness-7 (DFNA7) is a form of progressive sensorineural hearing loss with highly variable age at onset and severity, even within families. The age at onset ranges from congenital to mid-adulthood. Some patients may have associated vertigo (summary by previous studies)." +MONDO_0011628,"Definition: Propionic acidemia is an autosomal recessive metabolic disorder caused by defective functioning in the mitochondrial enzyme propionyl CoA carboxylase (PCC), resulting in the accumulation of propionic acid metabolites, and dysfunction in the respiratory chain and urea cycle pathways. The disorder is clinically heterogeneous. A neonatal-onset form is characterized by poor feeding, vomiting, and fatigue in the first days of life in a previously healthy infant, and if untreated, may be followed by lethargy, seizures, coma, and death. The neonatal form is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenia. A late-onset form in older children and adults has a milder phenotype, is less common, and may present with developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction, which may result in dystonia and choreoathetosis, and cardiomyopathy. Metabolically unstable individuals can have an acute decompensation that resembles the neonatal presentation, often precipitated by a catabolic stress such as infection, injury, or surgery, or an excessive intake of intact (i.e., complete, dietary, or natural) protein. Long-term manifestations of neonatal and late onset of propionic acidemia can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other less common manifestations include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure (summary by previous studies)." +MONDO_0011633,"Definition: HMSN2C, also known as Charcot-Marie-Tooth disease type 2C (CMT2C), is an autosomal dominant form of peripheral axonal neuropathy with diaphragmatic and vocal cord paresis. Age at onset and severity is variable (previous studies; summary by previous studies)." +Orphanet_99937,"Definition: HMSN2C, also known as Charcot-Marie-Tooth disease type 2C (CMT2C), is an autosomal dominant form of peripheral axonal neuropathy with diaphragmatic and vocal cord paresis. Age at onset and severity is variable (previous studies; summary by previous studies)." +MONDO_0012301,"Definition: Mitochondrial DNA depletion syndrome-2 is an autosomal recessive disorder characterized primarily by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later childhood onset of a slowly progressive myopathy (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0012414,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (previous studies)." +Orphanet_228337,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (previous studies)." +Orphanet_168486,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (previous studies)." +MONDO_0013526,"Definition: Progressive myoclonic epilepsy-6 is an autosomal recessive neurologic disorder characterized by onset of ataxia in the first years of life, followed by action myoclonus and seizures later in childhood, and loss of independent ambulation in the second decade. Cognition is not usually affected, although mild memory difficulties may occur in the third decade (summary by previous studies). + +For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (previous studies)." +MONDO_0013585,"Definition: Hydrolethalus syndrome is an autosomal recessive embryonic lethal disorder characterized by hydrocephaly or anencephaly, postaxial polydactyly of the upper limbs, and pre- or postaxial polydactyly of the lower limbs. Duplication of the hallux is a common finding. HLS2 is considered a ciliopathy (summary by previous studies). + +Acrocallosal syndrome (ACLS; previous studies) is an allelic disorder with a less severe phenotype. + +For a discussion of genetic heterogeneity of hydrolethalus syndrome, see previous studies." +Orphanet_2189,"Definition: Hydrolethalus syndrome is an autosomal recessive embryonic lethal disorder characterized by hydrocephaly or anencephaly, postaxial polydactyly of the upper limbs, and pre- or postaxial polydactyly of the lower limbs. Duplication of the hallux is a common finding. HLS2 is considered a ciliopathy (summary by previous studies). + +Acrocallosal syndrome (ACLS; previous studies) is an allelic disorder with a less severe phenotype. + +For a discussion of genetic heterogeneity of hydrolethalus syndrome, see previous studies." +MONDO_0013626,"Definition: Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein (previous studies) (summary by previous studies). GPP often presents in patients with existing or prior psoriasis vulgaris (PV; see previous studies); however, GPP can develop without a history of PV (previous studies). Palmoplantar pustulosis and acrodermatitis continua of Hallopeau represent acral forms of pustular psoriasis that have historically been grouped with GPP (summary by previous studies). + +GPP in association with sterile multifocal osteomyelitis and periostitis (previous studies) is caused by mutation in the IL1RN gene (previous studies). + +previous studies noted that the percentage of GPP patients reported to be negative for mutation in IL36RN ranges from 51 to 84%, indicative of genetic heterogeneity in the generalized pustular form of psoriasis. + +For a discussion of genetic heterogeneity of psoriasis, see PSORS1 (previous studies)." +MONDO_0013938,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 8 (CG8, equivalent to CGA) have mutations in the PEX26 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0013959,"Definition: Charcot-Marie-Tooth disease type 4F is an autosomal recessive demyelinating neuropathy characterized by distal sensory impairment and distal muscle weakness and atrophy affecting the lower more than the upper limbs. Nerve conduction velocities are decreased and sural nerve biopsy shows loss of myelinated fibers. The age at onset is variable and can range from childhood to adult years. When the onset is in infancy, the phenotype is characterized as Dejerine-Sottas syndrome (DSS; previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (previous studies)." +MONDO_0014628,"Definition: Idiopathic basal ganglia calcification is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive neuropsychiatric and movement disorders, although some patients remain asymptomatic. Clinical features can include dystonia, parkinsonism, gait abnormalities, psychosis, dementia, and chorea. Brain imaging shows calcifications of the basal ganglia and other brain regions (summary by previous studies). + +For a detailed phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (previous studies)." +MONDO_0014643,"Definition: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities (summary by previous studies)." +MONDO_0014946,"Definition: Sifrim-Hitz-Weiss syndrome is an autosomal dominant intellectual developmental disorder with variable congenital defects affecting other systems, including cardiac, skeletal, and urogenital. Some patients may have short stature, enlarged head circumference, hearing loss, and nonspecific dysmorphic facial features (summary by previous studies and previous studies)." +MONDO_0019154,"Definition: The androgen insensitivity syndrome is an X-linked recessive disorder in which affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal male 46,XY karyotype. Partial androgen insensitivity (PAIS; previous studies), also called Reifenstein syndrome, results in hypospadias and micropenis with gynecomastia." +MONDO_0030308,"Definition: Immunodeficiency-82 with systemic inflammation (IMD82) is a complex autosomal dominant immunologic disorder characterized by recurrent infections with various organisms, as well as noninfectious inflammation manifest as lymphocytic organ infiltration with gastritis, colitis, and lung, liver, CNS, or skin disease. One of the more common features is inflammation of the stomach and bowel. Most patients develop symptoms in infancy or early childhood; the severity is variable. There may be accompanying fever, elevated white blood cell count, decreased B cells, hypogammaglobulinemia, increased C-reactive protein (CRP; previous studies), and a generalized hyperinflammatory state. Immunologic workup shows variable B- and T-cell abnormalities such as skewed subgroups. Patients have a propensity for the development of lymphoma, usually in adulthood. At the molecular level, the disorder results from a gain-of-function mutation that leads to constitutive and enhanced activation of the intracellular inflammatory signaling pathway. Treatment with SYK inhibitors rescued human cell abnormalities and resulted in clinical improvement in mice (previous studies)." +MONDO_0030543,"Definition: Combined oxidative phosphorylation deficiency-54 (COXPD54) is an autosomal recessive disorder with pleiotropic multisystem presentations resulting from a disruption in mitochondrial transcription and translation. The phenotype is highly variable. Many patients have early-onset sensorineural hearing loss, sometimes in isolation, and sometimes associated with global developmental delay or primary ovarian failure. Other features may include peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0030726,"Definition: Autosomal dominant severe congenital neutropenia-9 (SCN9) is characterized by onset of neutropenia in the first years of life. Most patients have recurrent infections; bone marrow examination shows a myeloid maturation arrest. Rare patients may exhibit additional features such as seizures, learning difficulties, or cataracts, which are more commonly observed in patients with MGCA7 (previous studies). However, patients with SCN9 do not have 3-methylglutaconic aciduria, and most have normal neurologic function (previous studies). + +For a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (previous studies)." +MONDO_0030880,"Definition: Mandibuloacral dysplasia progeroid syndrome (MDPS) is an autosomal recessive severe laminopathy-like disorder characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis, and hypertension (previous studies)." +MONDO_0032698,"Definition: Neurodevelopmental disorder with central and peripheral motor dysfunction (NEDCPMD) is an autosomal recessive neurologic disorder with a highly variable phenotype. At the severe end of the spectrum, patients may have hypotonia apparent from birth, necessitating mechanical respiration and tube-feeding, and global developmental delay with absence of reaction to touch and no eye contact. At the mild end of the spectrum, patients may present with infantile-onset progressive ataxia and demyelinating peripheral neuropathy. The disorder is caused by mutation in the NFASC gene, which has several neuronal- and glial-specific transcripts. The variable clinical phenotype may be caused by several factors, including the severity of the mutation, the selective involvement of distinct isoforms by pathogenic variants, and the presence of genetic modifiers (summary by previous studies)." +MONDO_0032912,"Definition: Coffin-Siris syndrome-11 (CSS11) is a syndromic neurodevelopmental disorder characterized by global developmental delay and impaired intellectual development associated with hypotonia, feeding difficulties, and variable dysmorphic features. Most patients have distal anomalies, such as small hands and feet and hypoplastic fifth toenails (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (previous studies)." +MONDO_0060532,"Definition: Congenital heart defects and skeletal malformations syndrome (CHDSKM) is characterized by atrial and ventricular septal defects, with aortic root dilation in adulthood. Skeletal defects are variable and include pectus excavatum, scoliosis, and finger contractures, and some patients exhibit joint laxity. Failure to thrive is observed during infancy and early childhood (previous studies)." +Orphanet_101003,"Definition: Spastic paraplegia-23 (SPG23) is an autosomal recessive neurologic disorder characterized by childhood-onset spastic paraplegia resulting in gait difficulties and associated with pigmentary abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions. Some patients may also have a peripheral neuropathy (summary by previous studies)." +MONDO_0010046,"Definition: Spastic paraplegia-23 (SPG23) is an autosomal recessive neurologic disorder characterized by childhood-onset spastic paraplegia resulting in gait difficulties and associated with pigmentary abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions. Some patients may also have a peripheral neuropathy (summary by previous studies)." +Orphanet_163721,"Definition: Focal epilepsy with speech disorder is a childhood-onset seizure disorder with a highly variable phenotype. Seizures typically occur in the temporal lobe, or rolandic brain region, which affects speech and language, and electroencephalogram (EEG) characteristically shows centrotemporal spike-wave discharges. EEG abnormalities often occur during sleep and may manifest as continuous spike-wave discharges during slow-wave sleep (CSWS or CSWSS). FESD represents an electroclinical spectrum that ranges from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and mental retardation to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. There is incomplete penetrance and intrafamilial variability, even among family members who carry the same GRIN2A mutation (summary by previous studies; previous studies; previous studies). + +The disorder represented here encompasses several clinical entities, including Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike and wave during slow-wave sleep (ECSWS; CSWSS), autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (ADRESD; RESDAD), and benign epilepsy with centrotemporal spikes (BECTS; see previous studies). LKS is classically described as a childhood-onset variant of epileptic aphasia. It is associated with EEG abnormalities occurring in the temporal lobe of the language-dominant hemisphere, even in the absence of overt clinical seizures. LKS is sometimes referred to as an 'acquired aphasia' because most affected children show normal psychomotor development until the onset of seizures, usually between 3 and 7 years, although some may have prior delayed development. A hallmark of the disorder is severe impairment in auditory language comprehension and speech. Some patients may also have persistent intellectual disability or behavioral abnormalities reminiscent of autism or attention deficit-hyperactivity disorder. EEG abnormalities typically include centrotemporal spikes suggestive of rolandic epilepsy or continuous spike and waves during slow-wave sleep. The presence of CSWS is associated with more widespread behavioral and cognitive regression than LKS, although the 2 disorders may be considered part of a spectrum. There is controversy about the precise definition of LKS and its relationship to CSWS that stems mainly from the phenotypic heterogeneity of the disorder (summary by previous studies)." +Orphanet_183518,"Definition: Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by previous studies). + +For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (previous studies)." +Orphanet_199348,"Definition: Thiamine metabolism dysfunction syndrome-2 is an autosomal recessive metabolic disorder characterized by episodic encephalopathy, often triggered by febrile illness, presenting as confusion, seizures, external ophthalmoplegia, dysphagia, and sometimes coma and death. Administration of high doses of biotin, and sometimes thiamine, during these crises results in partial or complete improvement within days. If untreated, encephalopathies can result in permanent dystonia. Brain imaging may show characteristic bilateral lesions of the basal ganglia. It is not known why biotin administration results in clinical improvement, as the molecular basis of the disorder is mutation in a gene encoding a thiamine transporter. However, biotin may increase the gene expression of SLC19A3 (summary by previous studies). + +For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (previous studies)." +MONDO_0011841,"Definition: Thiamine metabolism dysfunction syndrome-2 is an autosomal recessive metabolic disorder characterized by episodic encephalopathy, often triggered by febrile illness, presenting as confusion, seizures, external ophthalmoplegia, dysphagia, and sometimes coma and death. Administration of high doses of biotin, and sometimes thiamine, during these crises results in partial or complete improvement within days. If untreated, encephalopathies can result in permanent dystonia. Brain imaging may show characteristic bilateral lesions of the basal ganglia. It is not known why biotin administration results in clinical improvement, as the molecular basis of the disorder is mutation in a gene encoding a thiamine transporter. However, biotin may increase the gene expression of SLC19A3 (summary by previous studies). + +For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (previous studies)." +Orphanet_848,"Definition: Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The disorder is clinically heterogeneous (summary by previous studies). + +Absence of beta globin causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic, carrier state). The molecular and clinical aspects of the beta-thalassemias were reviewed by previous studies. + +The remarkable phenotypic diversity of the beta-thalassemias reflects the heterogeneity of mutations at the HBB locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors (previous studies). + +For a review of beta-thalassemia, see previous studies." +MONDO_0013517,"Definition: Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The disorder is clinically heterogeneous (summary by previous studies). + +Absence of beta globin causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic, carrier state). The molecular and clinical aspects of the beta-thalassemias were reviewed by previous studies. + +The remarkable phenotypic diversity of the beta-thalassemias reflects the heterogeneity of mutations at the HBB locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors (previous studies). + +For a review of beta-thalassemia, see previous studies." +EFO_1000954,"Definition: Miscarriage, the commonest complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation. Recurrent miscarriage, defined as 3 or more consecutive pregnancy losses, affects about 1% of couples; when defined as 2 or more losses, the scale of the problem increases to 5% of all couples trying to conceive (summary by previous studies). + +Pregnancy losses have traditionally been designated 'spontaneous abortions' if they occur before 20 weeks gestation and 'stillbirths' if they occur after 20 weeks. Subtypes of spontaneous abortions can be further distinguished on the basis of embryonic development and include anembryonic loss in the first 5 weeks after conception (so-called 'blighted ovum'), embryonic loss from 6 to 9 weeks' gestation, and fetal loss from 10 weeks' gestation through the remainder of the pregnancy. These distinctions are important because the causes of pregnancy loss vary over gestational ages, with anembryonic losses being more likely to be associated with chromosomal abnormalities, for example. Possible etiologies for RPRGL include uterine anatomic abnormalities, cytogenetic abnormalities in the parents or fetus, single gene disorders, thrombophilic conditions, and immunologic or endocrine factors as well as environmental or infectious agents (summary by previous studies). + + Genetic Heterogeneity of Recurrent Pregnancy Loss + +Susceptibility to RPRGL2 (previous studies) is conferred by mutation in the coagulation factor II gene (previous studies) on chromosome 11p11; RPRGL3 (previous studies) by mutation in the ANXA5 gene (previous studies) on chromosome 4q27; and RPRGL4 (see previous studies) by mutation in the SYCP3 gene (previous studies) on chromosome 12q23. + +Genetic variation in the conceptus itself that results in decreased viability of the embryo or fetus is discussed in the respective gene and/or phenotype entry (see, e.g., MTHFR, previous studies; NLRP7, previous studies; hydatidiform mole, previous studies)." +MONDO_0008752,"Definition: In decreasing order of frequency, 3 forms of Alexander disease (ALXDRD) are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset. Imaging studies of the brain typically show cerebral white matter abnormalities, preferentially affecting the frontal region (previous studies). All 3 forms have been shown to be caused by mutations in the GFAP gene." +MONDO_0009033,"Definition: Temtamy syndrome is a mental retardation/multiple congenital anomaly syndrome characterized by variable craniofacial dysmorphism, ocular coloboma, seizures, and brain abnormalities, including abnormalities of the corpus callosum and thalamus (summary by previous studies)." +MONDO_0009916,"Definition: HSD17B3 deficiency is an autosomal recessive disorder that manifests, in males, as undermasculinization characterized by hypoplastic-to-normal internal genitalia (epididymis, vas deferens, seminal vesicles, and ejaculatory ducts) but female external genitalia and the absence of a prostate. This phenotype is caused by inadequate testicular synthesis of testosterone, which, in turn, results in insufficient formation of dihydrotestosterone in the anlage of the external genitalia and prostate during fetal development. At the expected time of puberty, there is a marked increase in plasma leuteinizing hormone and, consequently, in testicular secretion of androstenedione. Hence, a diagnostic hallmark of this disorder is a decreased plasma testosterone-to-androstenedione ratio. Significant amounts of the circulating androstenedione are, however, converted to testosterone, in peripheral tissues, thereby causing virilization (summary by previous studies)." +MONDO_0010214,"Definition: Xeroderma pigmentosum is an autosomal recessive disorder characterized by increased sensitivity to sunlight and defects in DNA repair. For a general overview of the disorder, see XPA (previous studies). + +Some patients with xeroderma pigmentosum have been found to have normal DNA excision repair, but defective postreplication repair (previous studies). This XP 'variant' class is characterized by a defect in conversion of newly synthesized DNA from low to high molecular weight after UV irradiation (previous studies). + +So-called 'pigmentary xerodermoid' is apparently identical to the XP variant, which is characterized by loss of a gene product that permits normal cells to replicate DNA without interruption at UV-damaged sites (previous studies)." +Orphanet_90342,"Definition: Xeroderma pigmentosum is an autosomal recessive disorder characterized by increased sensitivity to sunlight and defects in DNA repair. For a general overview of the disorder, see XPA (previous studies). + +Some patients with xeroderma pigmentosum have been found to have normal DNA excision repair, but defective postreplication repair (previous studies). This XP 'variant' class is characterized by a defect in conversion of newly synthesized DNA from low to high molecular weight after UV irradiation (previous studies). + +So-called 'pigmentary xerodermoid' is apparently identical to the XP variant, which is characterized by loss of a gene product that permits normal cells to replicate DNA without interruption at UV-damaged sites (previous studies)." +MONDO_0012456,"Definition: Anterior segment dysgeneses are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by previous studies). + +Anterior segment dysgenesis is sometimes divided into subtypes, including aniridia (see previous studies), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (previous studies). + +Some patients with ASGD2 have been reported with a congenital primary aphakia subtype. + +Congenital primary aphakia is a rare developmental disorder characterized by absence of the lens, the development of which is normally induced during the fourth to fifth week of human embryogenesis. This original failure leads, in turn, to complete aplasia of the anterior segment of the eye, which is the diagnostic histologic criterion for CPAK. In contrast, in secondary aphakia, lens induction occurs and the lens vesicle develops to some degree, but is progressively resorbed perinatally, resulting in less severe ocular defects (summary by previous studies)." +MONDO_0012557,"Definition: Mitochondrial phosphate carrier deficiency (MPCD) is an autosomal recessive disorder characterized by onset of cardiorespiratory insufficiency soon after birth. Patients usually require intervention in the neonatal period. The disorder may result in death in infancy, although those that survive have stabilization or amelioration of symptoms with age. Most affected individuals have hypotonia, delayed motor development, and exercise intolerance, but cognitive development is normal. Laboratory studies typically show increased serum lactate, although this may not be present. Muscle biopsy shows abnormal mitochondria and lipid accumulation. There is phenotypic variability likely depending on the location of the mutation (summary by previous studies)." +Orphanet_91130,"Definition: Mitochondrial phosphate carrier deficiency (MPCD) is an autosomal recessive disorder characterized by onset of cardiorespiratory insufficiency soon after birth. Patients usually require intervention in the neonatal period. The disorder may result in death in infancy, although those that survive have stabilization or amelioration of symptoms with age. Most affected individuals have hypotonia, delayed motor development, and exercise intolerance, but cognitive development is normal. Laboratory studies typically show increased serum lactate, although this may not be present. Muscle biopsy shows abnormal mitochondria and lipid accumulation. There is phenotypic variability likely depending on the location of the mutation (summary by previous studies)." +MONDO_0012856,"Definition: Birk-Barel syndrome (BIBARS) is a paternally imprinted, autosomal dominant disorder characterized by motor and speech delay, impaired intellectual development, early feeding difficulties, muscular hypotonia, and behavioral abnormalities, including hyperactivity and aggression (summary by previous studies)." +MONDO_0014052,"Definition: Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction (NMJ) that are classified by the site of the transmission defect: presynaptic, synaptic, and postsynaptic. CMS8 is an autosomal recessive disorder characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable (summary by previous studies). + +For a discussion of genetic heterogeneity of CMS, see CMS1A (previous studies)." +Orphanet_98913,"Definition: Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction (NMJ) that are classified by the site of the transmission defect: presynaptic, synaptic, and postsynaptic. CMS8 is an autosomal recessive disorder characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable (summary by previous studies). + +For a discussion of genetic heterogeneity of CMS, see CMS1A (previous studies)." +MONDO_0014101,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as dystroglycanopathies (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0014271,"Definition: Congenital disorder of glycosylation type Ix (CDG1X) is a rare autosomal recessive disorder of protein glycosylation. Clinical features include hypotonia, developmental delay, seizures and respiratory difficulties (previous studies; previous studies)." +MONDO_0014639,"Definition: Familial temporal lobe epilepsy-7 is a form of autosomal dominant lateral temporal lobe epilepsy characterized by focal seizures with prominent auditory symptoms (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of familial temporal lobe epilepsy, see previous studies." +MONDO_0014831,"Definition: The marfanoid-progeroid-lipodystrophy syndrome (MFLS) is characterized by congenital lipodystrophy, premature birth with an accelerated linear growth disproportionate to weight gain, and progeroid appearance with distinct facial features, including proptosis, downslanting palpebral fissures, and retrognathia. Other characteristic features include arachnodactyly, digital hyperextensibility, myopia, dural ectasia, and normal psychomotor development (previous studies). + +previous studies noted phenotypic overlap with Marfan syndrome (previous studies) and Shprintzen-Goldberg craniosynostosis syndrome (previous studies)." +MONDO_0020485,"Definition: King-Denborough syndrome (KDS) is an autosomal dominant disorder characterized by the triad of congenital myopathy, dysmorphic features, and susceptibility to malignant hyperthermia (summary by previous studies)." +MONDO_0025356,"Definition: Obstructive azoospermia with nephrolithiasis (OAZON) is characterized by male infertility due to obstruction at the head of the epididymis, as well as hypercalciuria and kidney stones (previous studies)." +MONDO_0030423,Definition: Congenital disorder of glycosylation type 2v (CDG2V) is an autosomal recessive disorder characterized by neurodevelopmental delay and variable facial dysmorphisms (previous studies). +Orphanet_1187,"Definition: Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy (previous studies). Susceptibility to infections, especially of the upper respiratory tract, can result in early death." +MONDO_0010533,"Definition: Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy (previous studies). Susceptibility to infections, especially of the upper respiratory tract, can result in early death." +Orphanet_123,"Definition: Bjornstad syndrome (BJS) is an autosomal recessive disorder characterized by sensorineural hearing loss and pili torti. The hearing loss is congenital and of variable severity. Pili torti (twisted hairs), a condition in which the hair shafts are flattened at irregular intervals and twisted 180 degrees from the normal axis, making the hair very brittle, is usually recognized early in childhood (previous studies)." +MONDO_0009872,"Definition: Bjornstad syndrome (BJS) is an autosomal recessive disorder characterized by sensorineural hearing loss and pili torti. The hearing loss is congenital and of variable severity. Pili torti (twisted hairs), a condition in which the hair shafts are flattened at irregular intervals and twisted 180 degrees from the normal axis, making the hair very brittle, is usually recognized early in childhood (previous studies)." +Orphanet_275517,"Definition: Caspase 8 deficiency is a syndrome of lymphadenopathy and splenomegaly, marginal elevation of 'double-negative T cells' (DNT; T-cell receptor alpha/beta+, CD4-/CD8-), defective FAS-induced apoptosis, and defective T-, B-, and natural killer (NK)-cell activation, with recurrent bacterial and viral infections (summary by previous studies)." +MONDO_0011804,"Definition: Caspase 8 deficiency is a syndrome of lymphadenopathy and splenomegaly, marginal elevation of 'double-negative T cells' (DNT; T-cell receptor alpha/beta+, CD4-/CD8-), defective FAS-induced apoptosis, and defective T-, B-, and natural killer (NK)-cell activation, with recurrent bacterial and viral infections (summary by previous studies)." +Orphanet_289494,"Definition: Hypomyelinating leukodystrophy-9 is an autosomal recessive neurologic disorder characterized by onset of delayed psychomotor development, spasticity, and nystagmus in the first year of life. Additional neurologic features such as ataxia and abnormal movements may also occur. Brain imaging shows diffuse hypomyelination affecting all regions of the brain (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see previous studies." +MONDO_0014506,"Definition: Hypomyelinating leukodystrophy-9 is an autosomal recessive neurologic disorder characterized by onset of delayed psychomotor development, spasticity, and nystagmus in the first year of life. Additional neurologic features such as ataxia and abnormal movements may also occur. Brain imaging shows diffuse hypomyelination affecting all regions of the brain (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see previous studies." +Orphanet_726,"Definition: Mitochondrial DNA depletion syndrome-4A, also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in the cerebral gray matter with reactive astrocytosis and liver cirrhosis. The disorder is progressive and often leads to death from hepatic failure or status epilepticus before age 3 years (review by previous studies). + +Some affected individuals may show mild intermittent 3-methylglutaconic aciduria and defects in mitochondrial oxidative phosphorylation (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies). + +Neuropathologic changes characteristic of Alpers syndrome, namely laminar cortical necrosis, may also be seen in some patients with combined oxidative phosphorylation deficiency-14 (COXPD14; previous studies), caused by mutation in the FARS2 gene (previous studies), and COXPD24 (previous studies), caused by mutation in the NARS2 gene (previous studies)." +MONDO_0008758,"Definition: Mitochondrial DNA depletion syndrome-4A, also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in the cerebral gray matter with reactive astrocytosis and liver cirrhosis. The disorder is progressive and often leads to death from hepatic failure or status epilepticus before age 3 years (review by previous studies). + +Some affected individuals may show mild intermittent 3-methylglutaconic aciduria and defects in mitochondrial oxidative phosphorylation (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies). + +Neuropathologic changes characteristic of Alpers syndrome, namely laminar cortical necrosis, may also be seen in some patients with combined oxidative phosphorylation deficiency-14 (COXPD14; previous studies), caused by mutation in the FARS2 gene (previous studies), and COXPD24 (previous studies), caused by mutation in the NARS2 gene (previous studies)." +EFO_0009034,"Definition: Combined oxidative phosphorylation deficiency-24 (COXPD24) is an autosomal recessive mitochondrial disorder with wide phenotypic variability. Most patients present in infancy with delayed neurodevelopment, refractory seizures, hypotonia, and hearing impairment due to auditory neuropathy. Less common features may include cortical blindness, renal dysfunction, and/or liver involvement, suggestive of Alpers syndrome (MTDPS4A; previous studies). Patients with the severe phenotype tend to have brain abnormalities on imaging, including cerebral atrophy and hyperintensities in the basal ganglia and brainstem, consistent with Leigh syndrome. Laboratory values may be normal or show increased lactate and evidence of mitochondrial respiratory chain defects, particularly in muscle. Some patients achieve little developmental milestones and may die in infancy or early childhood. However, some patients have a less severe phenotype manifest only by myopathy (summary by previous studies, previous studies, and previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +EFO_0010253,"Definition: Menke-Hennekam syndrome-2 (MKHK2) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, and hearing impairment are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-2 (RSTS2; previous studies), patients with MKHK1 do not resemble the striking phenotype of RSTS2. + +For a discussion of genetic heterogeneity of Menke-Hennekam syndrome, see MKHK1 (previous studies)." +MONDO_0009658,"Definition: The mucopolysaccharidoses are a family of lysosomal storage diseases caused by deficiencies of enzymes required for the catabolism of glycosaminoglycans. The defects result in accumulation of excessive intralysosomal glycosoaminoglycans (mucopolysaccharides) in various tissues, causing distended lysosomes to accumulate in the cell and interfere with cell function. Multiple types have been described (previous studies)." +MONDO_0009787,"Definition: 3-Methylglutaconic aciduria type III (MGCA3) is a neuroophthalmologic syndrome consisting of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is increased (previous studies). The phenotype is similar to Behr syndrome (previous studies) and may in some cases represent the same disorder (previous studies; previous studies). + +For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +MONDO_0010504,"Definition: Immunodeficiency-47 (IMD47) is an X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Some patients also have neurologic abnormalities (summary by previous studies)." +MONDO_0013572,"Definition: Keppen-Lubinsky syndrome is a very rare disorder characterized by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth (summary by previous studies)." +MONDO_0014561,"Definition: 3-Methylglutaconic aciduria (MGCA7) is an inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with variable neurologic deficits and neutropenia. The phenotype is highly variable: most patients have infantile onset of a severe progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common variable features include cataracts, seizures, recurrent infections due to neutropenia, and brain imaging abnormalities (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (previous studies)." +MONDO_0030066,"Definition: Autosomal recessive chronic granulomatous disease-5 (CGD5) is a primary immunodeficiency characterized by onset of recurrent infections and severe colitis in the first decade of life. Patients often present with features of inflammatory bowel disease and may show granulomata on biopsy. Patients are particularly susceptible to catalase-positive organisms, including Burkholderia cepacia, Legionella, and Candida albicans. Some patients may develop autoinflammatory symptoms, including recurrent fever in the absence of infection, hemolytic anemia, and lymphopenia. Additional features may include short stature, viral infections, cutaneous abscesses, pulmonary infections, and lymphadenitis. Hematopoietic bone marrow transplant is curative. The disorder results from impaired oxidative burst via the NAPDH oxidative complex in macrophages and neutrophils (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of CGD, see the X-linked form (CGDX; previous studies)." +MONDO_0030607,"Definition: Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by previous studies). + +For a discussion of genetic heterogeneity of Bryant-Li-Bhoj neurodevelopmental syndrome, see BRYLIB1 (previous studies)." +MONDO_0033559,"Definition: Intellectual developmental disorder with seizures and language delay (IDDSELD) is characterized by global developmental delay with speech and language impairment and onset of seizures usually in the first few years of life. Seizures tend to be myoclonic, although variable types have been reported. Many patients have accompanying behavioral abnormalities, most commonly autism spectrum disorder and anxiety. Additional features, such as facial dysmorphism, tapering fingers, and pigmentary skin changes may also be observed (summary by previous studies)." +MONDO_0033657,"Definition: Hypomyelinating leukodystrophy-20 (HLD20) is an autosomal recessive neurodegenerative disorder characterized by the loss of developmental milestones at about 12 to 16 months of age after normal early development. Patients lose motor, language, and cognitive skills and show poor overall growth with microcephaly. The disorder is progressive, resulting in feeding difficulties and spastic quadriplegia. Some patients may have seizures. Brain imaging shows subcortical white matter abnormalities and a thin corpus callosum, suggesting a myelination defect. Death usually occurs in childhood (previous studies). + +For a discussion of genetic heterogeneity of HLD, see previous studies." +MONDO_0044726,"Definition: Birk-Landau-Perez syndrome (BILAPES) is an autosomal recessive syndromic developmental disorder characterized by global developmental delay apparent from infancy or early childhood. Some patients have developmental regression with loss of speech and motor skills, whereas other patients never achieve these milestones. More variable features may include hypotonia, poor overall growth, ataxia, dystonia, abnormal eye movements, and renal insufficiency (previous studies; previous studies)." +Orphanet_2250,"Definition: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence (summary by previous studies). + +Also see absence of nasal bones (previous studies)." +MONDO_0011323,"Definition: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence (summary by previous studies). + +Also see absence of nasal bones (previous studies)." +Orphanet_1135,"Definition: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence (summary by previous studies). + +Also see absence of nasal bones (previous studies)." +Orphanet_35704,"Definition: Cerebral creatine deficiency syndrome-3 (CCDS3) is an autosomal recessive disorder characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain (previous studies). Most patients develop a myopathy characterized by muscle weakness and atrophy later in life. Oral creatine supplementation can offer symptom improvement (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of cerebral creatine deficiency syndrome, see CCDS1 (previous studies)." +MONDO_0012996,"Definition: Cerebral creatine deficiency syndrome-3 (CCDS3) is an autosomal recessive disorder characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain (previous studies). Most patients develop a myopathy characterized by muscle weakness and atrophy later in life. Oral creatine supplementation can offer symptom improvement (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of cerebral creatine deficiency syndrome, see CCDS1 (previous studies)." +MONDO_0007866,"Definition: Bart-Pumphrey syndrome (BAPS) is an autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, which shows considerable phenotypic variability (summary by previous studies)." +Orphanet_2698,"Definition: Bart-Pumphrey syndrome (BAPS) is an autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, which shows considerable phenotypic variability (summary by previous studies)." +MONDO_0007982,"Definition: The Murk Jansen type of metaphyseal chondrodysplasia is characterized by severe short stature, short bowed limbs, clinodactyly, prominent upper face, and small mandible. Hypercalcemia and hypophosphatemia occur despite the lack of parathyroid abnormalities (summary by previous studies)." +MONDO_0008943,"Definition: Autosomal recessive spinocerebellar ataxia-2 is an neurologic disorder characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. Brain imaging shows cerebellar atrophy. Overall, the disorder is non- or slowly progressive, with survival into adulthood (summary by previous studies)." +Orphanet_1170,"Definition: Autosomal recessive spinocerebellar ataxia-2 is an neurologic disorder characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. Brain imaging shows cerebellar atrophy. Overall, the disorder is non- or slowly progressive, with survival into adulthood (summary by previous studies)." +MONDO_0010031,"Definition: Sjogren-Larsson syndrome is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (summary by previous studies)." +Orphanet_816,"Definition: Sjogren-Larsson syndrome is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (summary by previous studies)." +MONDO_0010339,"Definition: X-linked epilepsy-1 with variable learning disabilities and behavior disorders (EPILX1) is an X-linked neurologic disorder characterized by the onset of complex partial seizures in the first or second decades. The seizures are often triggered by showering or water-related hygiene activities, consistent with reflex bathing epilepsy. Additional spontaneous seizures and secondary generalization may also occur. Most patients have associated developmental defects, including learning disabilities, behavioral problems, or autistic features. The pathophysiology of the reflex seizures is thought to be hyperexcitability of the cortical or subcortical neuronal areas that respond to physiologic stimulus in an exaggerated manner, possibly due to aberrant synaptic maturation (summary by previous studies; previous studies; previous studies)." +Orphanet_85294,"Definition: X-linked epilepsy-1 with variable learning disabilities and behavior disorders (EPILX1) is an X-linked neurologic disorder characterized by the onset of complex partial seizures in the first or second decades. The seizures are often triggered by showering or water-related hygiene activities, consistent with reflex bathing epilepsy. Additional spontaneous seizures and secondary generalization may also occur. Most patients have associated developmental defects, including learning disabilities, behavioral problems, or autistic features. The pathophysiology of the reflex seizures is thought to be hyperexcitability of the cortical or subcortical neuronal areas that respond to physiologic stimulus in an exaggerated manner, possibly due to aberrant synaptic maturation (summary by previous studies; previous studies; previous studies)." +MONDO_0013755,"Definition: De Barsy syndrome, also known as autosomal recessive cutis laxa type III (ARCL3), is a rare autosomal recessive disorder characterized by an aged appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities, intrauterine growth retardation (IUGR), and cutis laxa (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of de Barsy syndrome, see previous studies. + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see previous studies." +MONDO_0014320,"Definition: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal dominant disorder characterized by delayed development, moderately impaired intellectual development, and optic atrophy. Most patients also have evidence of cerebral visual impairment. Dysmorphic facial features are variable and nonspecific (summary by previous studies)." +Orphanet_401777,"Definition: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal dominant disorder characterized by delayed development, moderately impaired intellectual development, and optic atrophy. Most patients also have evidence of cerebral visual impairment. Dysmorphic facial features are variable and nonspecific (summary by previous studies)." +MONDO_0015007,"Definition: Spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) is an autosomal dominant neurologic disorder characterized by rapid growth in infancy, global developmental delay, spastic paraplegia, variable ophthalmologic defects, and dysmorphic facial features (summary by previous studies)." +MONDO_0015010,"Definition: Glycine encephalopathy with normal serum glycine is a severe metabolic disorder characterized by arthrogryposis multiplex congenita, joint hyperlaxity, lack of neonatal respiratory effort, axial hypotonia, hypertonia with pronounced clonus, and delayed psychomotor development. Some patients may have dysmorphic facial features and/or brain imaging abnormalities. Laboratory studies show increased CSF glycine and normal or only mildly increased serum glycine. Most patients die in infancy. The disorder is similar to, but distinct from, glycine encephalopathy (GCE; previous studies) due to mutations in genes encoding the glycine cleavage system (summary by previous studies)." +MONDO_0015397,"Definition: Craniofacial microsomia (CFM) is an autosomal dominant disorder characterized by mandibular hypoplasia, microtia, facial and preauricular skin tags, epibulbar dermoids, and lateral oral clefts, in addition to skeletal and cardiac abnormalities. Inter- and intrafamilial variability has been observed (previous studies). + +Hemifacial microsomia is a common birth defect involving the first and second branchial arch derivatives. It typically affects the external ear, middle ear, mandible and temporomandibular joint, muscles of mastication and facial muscles, and other facial soft tissues on the affected side. In some cases, other facial structures, such as the orbit, eye, nose, cranium, or neck, may be involved. Involvement is usually limited to one side, but bilateral involvement is known. In addition to craniofacial anomalies, there may be cardiac, vertebral, and central nervous system defects. The phenotype is highly variable. Most cases are sporadic, but there are rare familial cases that exhibit autosomal dominant inheritance (summary by previous studies and previous studies). + +See also hemifacial microsomia with radial defects (previous studies) and oculoauriculofrontonasal dysplasia (OAFNS; previous studies), which may be part of the OAV spectrum. + +Another disorder that overlaps clinically with CFM is Townes-Brocks syndrome (TBS; previous studies)." +MONDO_0026767,"Definition: Immunodeficiency-74 (IMD74) is an X-linked recessive specific immunologic disorder characterized by the development of severe respiratory insufficiency in response to infection with the COVID-19 coronavirus, also known as SARS-CoV-2 ssRNA coronavirus. Affected individuals usually require mechanical ventilation in the ICU in order to survive. Laboratory studies show activation of the immune response and may show perturbation of some values, such as increased D-dimers and fibrinogen. In vitro functional studies of patient immune cells show impaired signaling through the TLR7 pathway, resulting in defective type I and type II interferon (IFN) responses. The patients reported to date did not have a history of immunodeficiency or chronic disease (summary by previous studies)." +MONDO_0032874,"Definition: Primary ciliary dyskinesia-43 (CILD43) is a disorder characterized by a defect in motile cilia and ciliary clearance resulting in the onset of respiratory insufficiency soon after birth, and associated with recurrent upper and lower respiratory infections with chronic progressive lung disease. Patients with this disorder also develop significant obstructive hydrocephalus requiring shunting in infancy, although adult onset of neurologic symptoms may occur. Other more variable features include infertility and about a 50% chance of situs inversus or other left-right asymmetry defects. The disorder is considered to be a type of ciliopathy known as 'reduced generation of multiple motile cilia' (RGMC) (summary by previous studies). + +For a discussion of genetic heterogeneity of primary ciliary dyskinesia, CILD1 (previous studies)." +MONDO_0043364,Definition: Eosinophil peroxidase deficiency is a rare abnormality of eosinophil granulocytes characterized by decreased or absent peroxidase activity and decreased volume of the granule matrix (summary by previous studies). previous studies noted that there are no clinical symptoms and the diagnosis is made solely by cytochemical analysis. +MONDO_0060733,Definition: Humerofemoral hypoplasia with radiotibial ray deficiency (HHRRD) is a severe dysostosis characterized by reduction of all 4 limbs as well as hypoplasia of the upper limb girdle and pelvis. Rudimentary finger- or toe-like appendages may be present (previous studies). +Orphanet_137893,"Definition: Spermatogenic failure-5 (SPGF5) is a form of male infertility associated with large-headed, multiflagellar, polyploid spermatozoa (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0009461,"Definition: Spermatogenic failure-5 (SPGF5) is a form of male infertility associated with large-headed, multiflagellar, polyploid spermatozoa (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +Orphanet_414,"Definition: Gyrate atrophy of the choroid and retina (GACR) due to deficiency of ornithine aminotransferase is clinically characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. Characteristic chorioretinal atrophy with progressive constriction of the visual fields leads to blindness at the latest during the sixth decade of life. Patients generally have normal intelligence (summary by previous studies). + +See previous studies for another hyperornithinemia syndrome." +MONDO_0009796,"Definition: Gyrate atrophy of the choroid and retina (GACR) due to deficiency of ornithine aminotransferase is clinically characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. Characteristic chorioretinal atrophy with progressive constriction of the visual fields leads to blindness at the latest during the sixth decade of life. Patients generally have normal intelligence (summary by previous studies). + +See previous studies for another hyperornithinemia syndrome." +Orphanet_678,"Definition: Papillion-Lefevre syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition (summary by previous studies)." +MONDO_0009490,"Definition: Papillion-Lefevre syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition (summary by previous studies)." +EFO_0021801,"Definition: Warfarin is a widely prescribed anticoagulant for the prevention of thromboembolic diseases for subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement. The dose requirement is highly variable, both interindividually and interethnically (previous studies)." +MONDO_0007399,"Definition: Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by previous studies). Mutation in the TWIST1 has been found to cause coronal and sagittal forms of craniosynostosis. + + Genetic Heterogeneity of Craniosynostosis + +Craniosynostosis-2 (CRS2; previous studies) is caused by mutation in the MSX2 gene (previous studies) on chromosome 5q35. Craniosynostosis-3 (CRS3; previous studies) is caused by mutation in the TCF12 gene (previous studies) on chromosome 15q21. Craniosynostosis-4 (CRS4; previous studies) is caused by mutation in the ERF gene (previous studies) on chromosome 19q13. Susceptibility to craniosynostosis-5 (CRS5; previous studies) is conferred by variation in the ALX4 gene (previous studies) on chromosome 11p11. Craniosynostosis-6 (CRS6; previous studies) is caused by mutation in the ZIC1 gene (previous studies) on chromosome 3q24. Susceptibility to craniosynostosis-7 (CRS7; previous studies) is conferred by variation in the SMAD6 gene (previous studies) on chromosome 15q22." +MONDO_0009643,"Definition: Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; previous studies) and sulfite oxidase (SUOX; previous studies), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by previous studies; previous studies). + + Genetic Heterogeneity of Molybdenum Cofactor Deficiency + +See also MOCOD, complementation group B (MOCODB; previous studies), caused by mutation in the MOCS2 gene (previous studies) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; previous studies), caused by mutation in the GPHN gene (previous studies) on chromosome 14q24." +MONDO_0010645,"Definition: Lowe oculocerebrorenal syndrome (OCRL) is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, severely impaired intellectual development, and renal tubular dysfunction with slowly progressive renal failure. Other features include postnatal growth retardation independent of kidney function, areflexia, nontender joint swelling, subcutaneous nodules, and arthropathy, which can be observed in about 50% of adult patients (review by previous studies)." +MONDO_0010657,"Definition: Methylmalonic aciduria and homocystinemia of the cblX type (MAHCX) is an X-linked recessive metabolic disorder characterized by severely delayed psychomotor development apparent in infancy. It is associated with failure to thrive, impaired intellectual development, and intractable epilepsy. Additional features may include microcephaly and choreoathetosis (summary by previous studies)." +MONDO_0014659,"Definition: Infantile liver failure syndrome-2 is an autosomal recessive disorder characterized by recurrent episodes of acute liver failure during intercurrent febrile illness. Patients first present in infancy or early childhood, and there is complete recovery between episodes with conservative treatment (summary by previous studies). + +For a discussion of genetic heterogeneity of infantile liver failure syndrome, see ILFS1 (previous studies)." +MONDO_0030326,"Definition: Mitochondrial DNA depletion syndrome-16B (MTDPS16B) is an autosomal recessive childhood-onset and progressive neuroophthalmic mtDNA depletion disorder characterized by optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia, and generalized chorea (previous studies)." +MONDO_0030977,"Definition: Hereditary motor neuropathy with myopathic features (HMNMYO) is an autosomal recessive disorder with both myopathic and neurogenic features. Affected individuals usually present in the first decade with lower leg weakness resulting in difficulty climbing stairs and problems standing on the heels. Some patients have later onset well into the adult years. Most patients have foot deformities, and some may have leg muscle atrophy. The disorder is slowly progressive and often involves the upper limbs. Muscle biopsy and electrophysiologic studies are consistent with both a myopathic process and an axonal motor neuropathy. Sensory abnormalities are not typically present, and patients remain ambulatory. The phenotype shows some phenotypic overlap with distal hereditary motor neuropathy (see, e.g., previous studies), but is distinguished by the presence of myopathic features (summary by previous studies and previous studies)." +MONDO_0032642,"Definition: ACCIID is characterized by arthrogryposis, cleft palate, craniosynostosis, micrognathia, short stature, and impaired intellectual development. Seizures and bony abnormalities (severe slenderness of the ribs and tubular bones and perinatal fractures) have been observed (previous studies)." +MONDO_0060549,"Definition: CAKUTHED is an autosomal dominant highly pleiotropic developmental disorder characterized mainly by variable congenital anomalies of the kidney and urinary tract, sometimes resulting in renal dysfunction or failure, dysmorphic facial features, and abnormalities of the outer ear, often with hearing loss. Most patients have global developmental delay (summary by previous studies and previous studies)." +Orphanet_100032,"Definition: Hypocalcified amelogenesis imperfecta is characterized by enamel of normal thickness on newly erupted and unerupted and unresolved teeth. The enamel is soft and may be lost soon after eruption leaving the crown composed only of dentin. The enamel has a cheesy consistency and can be scraped from the dentin. An anterior open bite has been recorded in over 60% of the cases observed. The hypocalcification type is the most frequent type of enamel dysplasia, occurring in about 1 in 20,000 individuals (previous studies). Large masses of supragingival calculus become deposited on the teeth, and this is frequently associated with severe gingivitis or periodontitis (previous studies)." +MONDO_0007538,"Definition: Hypocalcified amelogenesis imperfecta is characterized by enamel of normal thickness on newly erupted and unerupted and unresolved teeth. The enamel is soft and may be lost soon after eruption leaving the crown composed only of dentin. The enamel has a cheesy consistency and can be scraped from the dentin. An anterior open bite has been recorded in over 60% of the cases observed. The hypocalcification type is the most frequent type of enamel dysplasia, occurring in about 1 in 20,000 individuals (previous studies). Large masses of supragingival calculus become deposited on the teeth, and this is frequently associated with severe gingivitis or periodontitis (previous studies)." +Orphanet_168593,"Definition: Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is characterized by sudden cardiac or respiratory arrest, disordered testicular development, and neurologic dysfunction, and is uniformly fatal before 1 year of age (previous studies)." +MONDO_0012124,"Definition: Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is characterized by sudden cardiac or respiratory arrest, disordered testicular development, and neurologic dysfunction, and is uniformly fatal before 1 year of age (previous studies)." +Orphanet_2504,"Definition: Metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB) is an autosomal dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth (summary by previous studies)." +MONDO_0007984,"Definition: Metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly (MDMHB) is an autosomal dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth (summary by previous studies)." +Orphanet_52503,"Definition: Cerebral creatine deficiency syndrome-1 (CCDS1) is an X-linked disorder of creatine (Cr) transport characterized by mental retardation, severe speech delay, behavioral abnormalities, and seizures. It has a prevalence of 0.3 to 3.5% in males. Carrier females may show mild neuropsychologic impairment (summary by previous studies). + + Genetic Heterogeneity of Cerebral Creatine Deficiency Syndrome + +See also CCDS2 (previous studies), caused by mutation in the GAMT gene (previous studies) on chromosome 19p13, and CCDS3 (previous studies), caused by mutation in the AGAT gene (GATM; previous studies) on chromosome 15q21." +MONDO_0010305,"Definition: Cerebral creatine deficiency syndrome-1 (CCDS1) is an X-linked disorder of creatine (Cr) transport characterized by mental retardation, severe speech delay, behavioral abnormalities, and seizures. It has a prevalence of 0.3 to 3.5% in males. Carrier females may show mild neuropsychologic impairment (summary by previous studies). + + Genetic Heterogeneity of Cerebral Creatine Deficiency Syndrome + +See also CCDS2 (previous studies), caused by mutation in the GAMT gene (previous studies) on chromosome 19p13, and CCDS3 (previous studies), caused by mutation in the AGAT gene (GATM; previous studies) on chromosome 15q21." +Orphanet_83419,"Definition: SMA is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; previous studies), II (SMA2; previous studies), III (SMA3), and IV (previous studies), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by previous studies)." +MONDO_0009672,"Definition: SMA is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; previous studies), II (SMA2; previous studies), III (SMA3), and IV (previous studies), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by previous studies)." +Orphanet_93271,"Definition: Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by previous studies and previous studies). + +There is phenotypic overlap with the cranioectodermal dysplasias (see CED1, previous studies). + +For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (previous studies)." +MONDO_0007377,"Definition: Groenouw type I, or granular type I, corneal dystrophy (CDGG1) is an autosomal dominant disorder characterized by irregular aggregates of hyaline material in the corneal stroma. These aggregates can cause significant visual disturbance and may require corneal transplantation for restoration of visual acuity or for relief from recurrent corneal erosions (summary by previous studies)." +MONDO_0009857,"Definition: The persistent mullerian duct syndrome is characterized by the persistence of mullerian derivatives, uterus and tubes, in otherwise normally virilized males (summary by previous studies)." +Orphanet_2856,"Definition: The persistent mullerian duct syndrome is characterized by the persistence of mullerian derivatives, uterus and tubes, in otherwise normally virilized males (summary by previous studies)." +MONDO_0010028,"Definition: Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by previous studies)." +MONDO_0010663,"Definition: The term 'X-linked intellectual disability-hypotonic facies syndrome' comprises several syndromes previously reported separately. These include Carpenter-Waziri, Holmes-Gang, and Smith-Fineman-Myers syndromes as well as 1 family with X-linked mental retardation with spastic paraplegia. All these syndromes were found to be caused by mutation in the XH2 gene and are characterized primarily by severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women (previous studies). Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects. + +X-linked alpha-thalassemia/mental retardation syndrome (ATR-X; previous studies) is an allelic disorder with a similar phenotype with the addition of alpha-thalassemia and Hb H inclusion bodies in erythrocytes." +Orphanet_73220,"Definition: The term 'X-linked intellectual disability-hypotonic facies syndrome' comprises several syndromes previously reported separately. These include Carpenter-Waziri, Holmes-Gang, and Smith-Fineman-Myers syndromes as well as 1 family with X-linked mental retardation with spastic paraplegia. All these syndromes were found to be caused by mutation in the XH2 gene and are characterized primarily by severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women (previous studies). Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects. + +X-linked alpha-thalassemia/mental retardation syndrome (ATR-X; previous studies) is an allelic disorder with a similar phenotype with the addition of alpha-thalassemia and Hb H inclusion bodies in erythrocytes." +MONDO_0011772,"Definition: Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem disorders that are commonly associated with severe psychomotor and mental retardation. The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans (summary by previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies)." +MONDO_0012138,"Definition: MDDGB6 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and structural brain abnormalities (previous studies). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (previous studies)." +MONDO_0012400,"Definition: Pitt-Hopkins-like syndrome-1 (PTHSL1) is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (summary by previous studies)." +Orphanet_163681,"Definition: Pitt-Hopkins-like syndrome-1 (PTHSL1) is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (summary by previous studies)." +MONDO_0012640,"Definition: Charcot-Marie-Tooth disease type 4J is an autosomal recessive progressive neurologic disorder with a highly variable phenotype and onset ranging from early childhood to adulthood. Most patients have both proximal and distal asymmetric muscle weakness of the upper and lower limbs. There is significant motor dysfunction, followed by variably progressive sensory loss, which may be mild. Nerve conduction studies and nerve biopsies indicate demyelination as well as axonal loss (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (previous studies)." +MONDO_0030035,"Definition: Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) is characterized by global developmental delay apparent in early childhood, followed by episodic neurologic regression or decompensation associated with systemic stress, such as febrile infection. Affected individuals have hypotonia, gait difficulties or ataxia, poor or absent speech with dysarthria, and variable motor abnormalities, including spasticity, dystonia, extrapyramidal signs, and tremor. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities, poor myelination, thin corpus callosum, and generalized cerebral atrophy with enlarged ventricles. The clinical features of the disorder and the abnormal brain imaging findings are progressive (summary by previous studies)." +MONDO_0030055,"Definition: Sorbitol dehydrogenase deficiency with peripheral neuropathy (SORDD) is an autosomal recessive disorder characterized by onset of distal muscle weakness mainly affecting the lower limbs and resulting in difficulty walking. Onset of symptoms is usually in the first or second decades of life, although later adult onset has been reported; the disorder is slowly progressive. Nerve conduction velocities are most consistent with an axonal process. More variable features include distal sensory impairment, upper limb tremor, and scoliosis. Laboratory studies show increased serum sorbitol (summary by previous studies)." +MONDO_0030489,"Definition: Generalized severe epidermolysis bullosa simplex-2A (EBS2A) is an autosomal dominant skin disorder characterized by extensive intraepidermal blistering after minor mechanical stress from the time of birth with herpetiform marginal spreading and central healing. Oral mucosal involvement, nail dystrophy, onychogryposis, formation of milia, and palmoplantar hyperkeratosis are common features. Blistering is more frequent in warm weather and generally improves with advancing age. The 'severe' subtype of EBS was previously known as the Dowling-Meara type (EBSDM). In addition to the intraepidermal blister formation after minor mechanical stress common to all forms of EBS, skin biopsies from patients with the severe EBS subtype show aggregation and clumping of basal keratins on electron microscopy, resulting in a total collapse of the keratin cytoskeleton of basal keratinocytes (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0700112,"Definition: Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (previous studies). Heterotaxy is a clinically and genetically heterogeneous disorder. + +For a discussion of genetic heterogeneity of visceral heterotaxy, see HTX1 (previous studies)." +Orphanet_2585,"Definition: Ataxia-pancytopenia syndrome (ATXPC) is an autosomal dominant disorder characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to bone marrow failure and myeloid leukemia. The germline genetic defect is associated with somatic loss of chromosome 7 (monosomy 7) resulting in the deletion of several genes on chromosome 7 that may predispose to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) (summary by previous studies and previous studies)." +MONDO_0008038,"Definition: Ataxia-pancytopenia syndrome (ATXPC) is an autosomal dominant disorder characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to bone marrow failure and myeloid leukemia. The germline genetic defect is associated with somatic loss of chromosome 7 (monosomy 7) resulting in the deletion of several genes on chromosome 7 that may predispose to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) (summary by previous studies and previous studies)." +Orphanet_79477,"Definition: Griscelli syndrome type 2 (GS2) is an autosomal recessive disorder characterized by pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. Patients also have immunologic abnormalities with or without neurologic impairment (summary by previous studies). Some GS2 patients have been reported in whom central nervous system manifestations are the first presentation (previous studies, previous studies; previous studies; previous studies). + +For a discussion of phenotypic and genetic heterogeneity of Griscelli syndrome, see Griscelli syndrome type 1 (GS1; previous studies)." +MONDO_0011872,"Definition: Griscelli syndrome type 2 (GS2) is an autosomal recessive disorder characterized by pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. Patients also have immunologic abnormalities with or without neurologic impairment (summary by previous studies). Some GS2 patients have been reported in whom central nervous system manifestations are the first presentation (previous studies, previous studies; previous studies; previous studies). + +For a discussion of phenotypic and genetic heterogeneity of Griscelli syndrome, see Griscelli syndrome type 1 (GS1; previous studies)." +Orphanet_381,"Definition: Griscelli syndrome type 2 (GS2) is an autosomal recessive disorder characterized by pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. Patients also have immunologic abnormalities with or without neurologic impairment (summary by previous studies). Some GS2 patients have been reported in whom central nervous system manifestations are the first presentation (previous studies, previous studies; previous studies; previous studies). + +For a discussion of phenotypic and genetic heterogeneity of Griscelli syndrome, see Griscelli syndrome type 1 (GS1; previous studies)." +MONDO_0007555,"Definition: Epidermolysis bullosa simplex, Ogna type (EBS5A) is an autosomal dominant skin disorder characterized by onset at birth of skin blistering, mainly acral but occasionally widespread. The course tends to be mild, with postlesional violaceous and hypopigmented macules (summary by previous studies). Electron microscopy reveals aberrant ultrastructure of hemidesmosomal attachment plates that is not seen in classic forms of EBS (see, e.g., EBS1A, previous studies) caused by mutation in keratin-5 (previous studies) or -14 (previous studies) (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +Orphanet_79401,"Definition: Epidermolysis bullosa simplex, Ogna type (EBS5A) is an autosomal dominant skin disorder characterized by onset at birth of skin blistering, mainly acral but occasionally widespread. The course tends to be mild, with postlesional violaceous and hypopigmented macules (summary by previous studies). Electron microscopy reveals aberrant ultrastructure of hemidesmosomal attachment plates that is not seen in classic forms of EBS (see, e.g., EBS1A, previous studies) caused by mutation in keratin-5 (previous studies) or -14 (previous studies) (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0008005,"Definition: Cardiospondylocarpofacial syndrome (CSCF) is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion, extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations (summary by previous studies)." +MONDO_0009097,"Definition: Persistent hyperplastic primary vitreous (PHPV), also termed 'persistent fetal vasculature,' is a developmental malformation of the eye in which the primary vitreous fails to regress in utero, resulting in the presence of a retrolental fibrovascular membrane with persistence of the posterior portion of the tunica vasculosa lentis and hyaloid artery. This abnormality is usually unilateral and associated with microphthalmia, cataract, glaucoma, and congenital retinal nonattachment (see previous studies; previous studies; previous studies). + +PHPV shares phenotypic overlap with Norrie disease (previous studies). + + Genetic Heterogeneity of Persistent Hyperplastic Primary Vitreous + +A dominant form of PHPV has been described (PHPVAD; previous studies)." +MONDO_0010094,"Definition: Spondylocarpotarsal synostosis syndrome (SCT) is characterized by disproportionate short stature and spinal deformity. Clinical features include clubfeet, facial dysmorphism, dental enamel hypoplasia, cleft palate, joint laxity, and conductive hearing loss. Characteristic radiologic findings include block vertebrae and carpal and tarsal fusion. Delay in ossification of the epiphyses of carpal bones and epiphyseal dysplasia of the femur have been observed (previous studies). + +Spondylocarpotarsal fusions in association with contractures and pterygia (see CPSKF1A, previous studies and CPSKF1B, previous studies) can be caused by mutation in the MYH3 gene (previous studies)." +Orphanet_3275,"Definition: Spondylocarpotarsal synostosis syndrome (SCT) is characterized by disproportionate short stature and spinal deformity. Clinical features include clubfeet, facial dysmorphism, dental enamel hypoplasia, cleft palate, joint laxity, and conductive hearing loss. Characteristic radiologic findings include block vertebrae and carpal and tarsal fusion. Delay in ossification of the epiphyses of carpal bones and epiphyseal dysplasia of the femur have been observed (previous studies). + +Spondylocarpotarsal fusions in association with contractures and pterygia (see CPSKF1A, previous studies and CPSKF1B, previous studies) can be caused by mutation in the MYH3 gene (previous studies)." +MONDO_0012399,"Definition: Complex cortical dysplasia with other brain malformations-7 is an autosomal dominant, clinically heterogeneous disorder showing a wide spectrum of abnormalities of cortical brain development. The most severely affected patients are fetuses with microlissencephaly, absence of the cortical plate, agenesis of the corpus callosum, and severely hypoplastic brainstem and cerebellum. Other patients have lissencephaly, polymicrogyria, cortical dysplasia, or neuronal heterotopia. Those with less severe malformations can survive, but usually have some degree of neurologic impairment, such as mental retardation, seizures, and movement abnormalities (summary by previous studies; previous studies). + +For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (previous studies)." +Orphanet_300573,"Definition: Complex cortical dysplasia with other brain malformations-7 is an autosomal dominant, clinically heterogeneous disorder showing a wide spectrum of abnormalities of cortical brain development. The most severely affected patients are fetuses with microlissencephaly, absence of the cortical plate, agenesis of the corpus callosum, and severely hypoplastic brainstem and cerebellum. Other patients have lissencephaly, polymicrogyria, cortical dysplasia, or neuronal heterotopia. Those with less severe malformations can survive, but usually have some degree of neurologic impairment, such as mental retardation, seizures, and movement abnormalities (summary by previous studies; previous studies). + +For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (previous studies)." +MONDO_0012589,"Definition: The Pitt-Hopkins syndrome is characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea (previous studies). + +See also Pitt-Hopkins-like syndrome-1 (previous studies), caused by mutation in the CNTNAP2 gene (previous studies) on chromosome 7q35, and Pitt-Hopkins-like syndrome-2 (previous studies), caused by mutation in the NRXN1 gene (previous studies) on chromosome 2p16.3." +MONDO_0013154,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0013308,"Definition: Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; previous studies) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by previous studies). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; previous studies), as also seen in patients with Noonan syndrome (summary by previous studies)." +Orphanet_363972,"Definition: Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; previous studies) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by previous studies). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; previous studies), as also seen in patients with Noonan syndrome (summary by previous studies)." +MONDO_0014120,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is a autosomal recessive disorder associated with severe neurologic defects and resulting in early infantile death. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as dystroglycanopathies (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0014865,"Definition: Severe congenital neutropenia-7 is an autosomal recessive immunodeficiency characterized by onset of recurrent infections in infancy or early childhood. Patients have peripheral neutropenia, although bone marrow biopsy shows normal granulocyte maturation. The neutropenia is not responsive to treatment with G-CSF, but may be responsive to GM-CSF (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (previous studies)." +MONDO_0033618,"Definition: Vissers-Bodmer syndrome (VIBOS) is characterized by global developmental delay with variably impaired intellectual development, speech delay, motor delay, and behavioral abnormalities apparent from infancy. The phenotype is highly variable: some individuals have only mild learning difficulties, whereas others have severe cognitive impairment with IQ in the 50s. Many patients have behavioral abnormalities, including autism spectrum disorder, ADD, ADHD, obsessive-compulsive disorder, and impulsivity. Other common features include growth impairment abnormalities, hypotonia, and distal skeletal defects, such as foot and hand deformities. Less common features include seizures, brain abnormalities on MRI, feeding problems, and joint hypermobility. Most individuals have dysmorphic facial features, but there is no recognizable gestalt (summary by previous studies)." +MONDO_0044326,"Definition: DEDSM is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability, and early-onset seizures with a myoclonic component. Most patients have delayed motor development and show abnormal movements, including ataxia, dystonia, and tremor (summary by previous studies)." +Orphanet_332,"Definition: Congenital pernicious anemia (PA), or intrinsic factor deficiency, is a rare disorder characterized by the lack of gastric intrinsic factor in the presence of normal acid secretion and mucosal cytology and the absence of GIF antibodies that are found in the acquired form of pernicious anemia (previous studies). + +See also pernicious anemia due to defect in the receptor for vitamin B12/intrinsic factor (previous studies)." +MONDO_0009852,"Definition: Congenital pernicious anemia (PA), or intrinsic factor deficiency, is a rare disorder characterized by the lack of gastric intrinsic factor in the presence of normal acid secretion and mucosal cytology and the absence of GIF antibodies that are found in the acquired form of pernicious anemia (previous studies). + +See also pernicious anemia due to defect in the receptor for vitamin B12/intrinsic factor (previous studies)." +Orphanet_79258,"Definition: Glycogen storage disease type I, also known as von Gierke disease, typically manifests during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of glycogen. Affected individuals exhibit growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia, and in adults a high incidence of hepatic adenomas (summary by previous studies)." +MONDO_0009287,"Definition: Glycogen storage disease type I, also known as von Gierke disease, typically manifests during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of glycogen. Affected individuals exhibit growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia, and in adults a high incidence of hepatic adenomas (summary by previous studies)." +Orphanet_364,"Definition: Glycogen storage disease type I, also known as von Gierke disease, typically manifests during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of glycogen. Affected individuals exhibit growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia, and in adults a high incidence of hepatic adenomas (summary by previous studies)." +EFO_1000643,"Definition: Developmental and epileptic encephalopathy-91 (DEE91) is characterized by delayed psychomotor development apparent in infancy and resulting in severely to profoundly impaired intellectual development with poor or absent speech. Most patients never achieve independent walking. Patients typically have onset of refractory multifocal seizures between the first weeks and years of life, and some may show developmental regression. Additional features, such as hypotonia and cortical visual impairment, are more variable (summary by previous studies). + +For a discussion of genetic heterogeneity of DEE, see 308350." +MONDO_0020630,"Definition: Developmental and epileptic encephalopathy-91 (DEE91) is characterized by delayed psychomotor development apparent in infancy and resulting in severely to profoundly impaired intellectual development with poor or absent speech. Most patients never achieve independent walking. Patients typically have onset of refractory multifocal seizures between the first weeks and years of life, and some may show developmental regression. Additional features, such as hypotonia and cortical visual impairment, are more variable (summary by previous studies). + +For a discussion of genetic heterogeneity of DEE, see 308350." +MONDO_0007167,"Definition: Atelosteogenesis is the name given by previous studies to a lethal chondrodysplasia characterized by distal hypoplasia of the humeri and femurs, hypoplasia of the midthoracic spine, occasionally complete lack of ossification of single hand bones, and the finding in cartilage of multiple degenerated chondrocytes encapsulated in fibrous tissue. previous studies termed it 'giant cell chondrodysplasia.' Patients with AO1 exhibit severe short-limbed dwarfism and dislocated elbows, hips, and knees (previous studies). + + Genetic Heterogeneity of Atelosteogenesis + +Atelosteogenesis type II (AO2; previous studies) is caused by mutation in the SLC26A2 gene (previous studies) on chromosome 5q32. AO3 (previous studies) is also caused by mutation in the FLNB gene (previous studies)." +MONDO_0007308,"Definition: Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (previous studies) and CMT1A (previous studies) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (previous studies) and CMTX1 (previous studies) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively. + + Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 2 + +Several forms of axonal CMT neuropathies caused by mutations in different genes or at different loci have been described, including CMT2B (previous studies), CMT2B1 (previous studies), CMT2B2 (previous studies), CMT2C (previous studies), CMT2D (previous studies), CMT2E (previous studies), CMT2F (previous studies), CMT2H (previous studies), CMT2I (previous studies), CMT2J (previous studies), CMT2K (previous studies), CMT2L (previous studies), CMT2M (see previous studies), CMT2N (previous studies), CMT2O (previous studies), CMT2P (previous studies), CMT2Q (previous studies), CMT2R (previous studies), CMT2S (previous studies), CMT2T (previous studies), CMT2U (previous studies), CMT2V (previous studies), CMT2W (previous studies), CMT2X (previous studies), CMT2Y (previous studies), CMT2Z (previous studies), CMT2CC (previous studies), CMT2DD (previous studies), CMT2EE (previous studies), CMT2FF (previous studies), CMT2GG (previous studies), CMT2HH (previous studies), and CMT2II (previous studies). + +A form of axonal CMT that was previously designated CMT2G was found to be the same as CMT2P (previous studies)." +Orphanet_99946,"Definition: Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (previous studies) and CMT1A (previous studies) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (previous studies) and CMTX1 (previous studies) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively. + + Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 2 + +Several forms of axonal CMT neuropathies caused by mutations in different genes or at different loci have been described, including CMT2B (previous studies), CMT2B1 (previous studies), CMT2B2 (previous studies), CMT2C (previous studies), CMT2D (previous studies), CMT2E (previous studies), CMT2F (previous studies), CMT2H (previous studies), CMT2I (previous studies), CMT2J (previous studies), CMT2K (previous studies), CMT2L (previous studies), CMT2M (see previous studies), CMT2N (previous studies), CMT2O (previous studies), CMT2P (previous studies), CMT2Q (previous studies), CMT2R (previous studies), CMT2S (previous studies), CMT2T (previous studies), CMT2U (previous studies), CMT2V (previous studies), CMT2W (previous studies), CMT2X (previous studies), CMT2Y (previous studies), CMT2Z (previous studies), CMT2CC (previous studies), CMT2DD (previous studies), CMT2EE (previous studies), CMT2FF (previous studies), CMT2GG (previous studies), CMT2HH (previous studies), and CMT2II (previous studies). + +A form of axonal CMT that was previously designated CMT2G was found to be the same as CMT2P (previous studies)." +MONDO_0007478,"Definition: Kenny-Caffey syndrome is characterized by severe proportionate short stature, cortical thickening and medullary stenosis of the tubular bones, delayed closure of the anterior fontanel, eye abnormalities, and transient hypocalcemia. Patients with autosomal dominant KCS type 2 have normal intelligence (previous studies; previous studies; summary by previous studies). + +See KCS1 (previous studies) for a discussion of an autosomal recessive form of Kenny-Caffey syndrome." +MONDO_0008221,"Definition: Prolidase deficiency is a rare autosomal recessive multisystem disorder associated with massive imidodipeptiduria and lack of or reduced prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts. The disorder is clinically heterogeneous and severity varies widely. Features include chronic, slowly healing ulcerations, mainly on the legs and feet. The ulcers are often preceded by other dermatologic manifestations that may occur anywhere and include erythematous papular eruptions, telangiectases with pruritus and photosensitivity, impetigo-like eruptions, pruritic eczematous lesions, and necrotic papules. Mild to severe mental retardation is often a feature, and recurrent respiratory tract infections, sometimes fatal, are common. Facial dysmorphism may include low hairline and hirsutism, saddle nose, ocular hypertelorism, micrognathia, a high-arched palate, mandibular protrusion, and exophthalmos. Clinical manifestations are usually detectable after birth or in early childhood, but late-onset cases have been reported (summary by previous studies)." +MONDO_0009724,"Definition: Focal segmental glomerulosclerosis-10 (FSGS10) is an autosomal dominant kidney disease characterized by isolated glomerulopathy without extrarenal manifestations. In particular, affected individuals do not have other signs of NPS. The renal disease is highly variable in severity and pathology, even within the same family. Most patients present in the first decades of life with proteinuria and hematuria, although onset of symptoms can manifest at any age, including late adulthood. Some patients progress to end-stage renal disease, whereas others have a stable disease course. Light microscopic analysis of renal biopsies shows a constellation of glomerular abnormalities, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and, rarely, immune complex nephropathy. Electron microscopy characteristically shows an irregular thickening of the glomerular basement membrane (GBM) with electron-lucent areas containing accumulated bundles of type III collagen fibrils. The collagen deposition usually occurs in endothelial cells of the GBM; partial effacement of podocyte foot processes may also be present. These specific pathologic findings are similar to those observed in NPS patients with nephropathy. However, these findings may not always be present, which may make the diagnosis challenging (summary by previous studies, previous studies; review by previous studies). + +For a discussion of genetic heterogeneity of FSGS, see FSGS1 (previous studies)." +MONDO_0010298,"Definition: The features of Lesch-Nyhan syndrome (LNS) are intellectual disability, spastic cerebral palsy, choreoathetosis, uric acid urinary stones, and self-destructive biting of fingers and lips. Megaloblastic anemia has been found in some patients (summary by previous studies, previous studies)." +MONDO_0011576,"Definition: Familial hyperaldosteronism type II is an autosomal dominant disorder characterized by hypertension due to increased aldosterone, often with hypokalemia. Patients usually present before age 20 years, although some may present in infancy. The disorder shows incomplete penetrance and variable expressivity; some patients may have normal blood pressure but have an increased aldosterone:renin ratio (ARR) on laboratory testing. Spironolactone is an effective treatment (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (previous studies)." +MONDO_0018931,"Definition: Mucolipidosis type III alpha/beta is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. It is phenotypically less severe than the allelic disorder mucolipidosis type II alpha/beta (summary by previous studies)." +MONDO_0020721,"Definition: The essential features of X-linked sideroblastic anemia include the following: (1) a hypochromic microcytic anemia and 2 discrete populations of red blood cells, one microcytic and the other normocytic; (2) marrow ringed sideroblasts, particularly prominent in the late erythroid precursors; (3) a variable hematologic response to pharmacologic doses of pyridoxine; and (4) systemic iron overload secondary to chronic ineffective erythropoiesis. The age of clinical onset of the disorder can vary from in utero to the ninth decade. Whereas males are preferentially affected, females may present with clinically severe anemia. More commonly, female carriers of the disease have an increased red blood cell distribution width and sometimes erythrocyte dimorphism (previous studies). + + Genetic Heterogeneity of Sideroblastic Anemia + +See also SIDBA2 (previous studies), caused by mutation in the SLC25A38 gene (previous studies) on chromosome 3p22; SIDBA3 (previous studies), caused by mutation in the GLRX5 gene (previous studies) on chromosome 14q32; SIDBA4 (previous studies), caused by mutation in the HSPA9 gene (previous studies) on chromosome 5q31; and SIDBA5 (previous studies), caused by mutation in the HSCB gene (previous studies) on chromosome 22q12." +MONDO_0030058,Definition: Autosomal dominant deafness-77 (DFNA77) is characterized by progressive hearing loss affecting high frequencies beginning in the second to third decades of life and affecting all frequencies by the fourth or fifth decades (previous studies). +MONDO_0030876,"Definition: Cardioacrofacial dysplasia-1 (CAFD1) is characterized by congenital cardiac defects, primarily common atrium or atrioventricular septal defect; limb anomalies, including short limbs, brachydactyly, and postaxial polydactyly; and dysmorphic facial features (previous studies). + + Genetic Heterogeneity of Cardioacrofacial Dysplasia + +CAFD2 (previous studies) is caused by mutation in the PRKACB gene (previous studies) on chromosome 1p31." +MONDO_0060457,"Definition: Autoinflammation with arthritis and dyskeratosis is characterized by recurrent fever, widespread skin dyskeratosis, arthritis, elevated biologic markers of inflammation, and mild autoimmunity with a high transitional B-cell level (summary by previous studies)." +MONDO_0100101,"Definition: The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (previous studies). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome (see previous studies). + + Genetic Heterogeneity of Fetal Akinesia Deformation Sequence + +FADS2 (previous studies) is caused by mutation in the RAPSN gene (previous studies), FADS3 (previous studies) is caused by mutation in the DOK7 gene (previous studies), and FADS4 (previous studies) is caused by mutation in the NUP88 gene (previous studies). + +As mutations in the MUSK, RAPSN, and DOK7 genes have been associated with congenital myasthenic syndromes (see, e.g., CMS1A, previous studies), the disorders in these patients likely represent extreme phenotypes of CMS (previous studies)." +MONDO_0859300,"Definition: Distal hereditary motor neuropathy-10 (HMN10) is an autosomal dominant neurologic disorder of the peripheral nerves characterized clinically by length-dependent motor neuropathy primarily affecting the lower limbs. Affected individuals have onset of distal muscle weakness and atrophy in early childhood that results in walking difficulties and gait abnormalities. Some have pyramidal signs, including hyperreflexia, suggesting the involvement of upper motor neurons. Electrophysiologic studies are consistent with a neurogenic process. More variable features may include mild intellectual disability, minor gyration defects on brain imaging, foot deformities, and connective tissue defects (1 family) (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMN1 (previous studies)." +Orphanet_16,"Definition: Blue cone (OPN1SW; previous studies) monochromatism is a rare X-linked congenital stationary cone dysfunction syndrome characterized by the absence of functional long wavelength-sensitive and medium wavelength-sensitive cones in the retina. Color discrimination is severely impaired from birth, and vision is derived from the remaining preserved blue (S) cones and rod photoreceptors. BCM typically presents with reduced visual acuity, pendular nystagmus, and photophobia. Patients often have myopia (review by previous studies). There is evidence for progression of disease in some BCM families (previous studies; previous studies; previous studies)." +MONDO_0010563,"Definition: Blue cone (OPN1SW; previous studies) monochromatism is a rare X-linked congenital stationary cone dysfunction syndrome characterized by the absence of functional long wavelength-sensitive and medium wavelength-sensitive cones in the retina. Color discrimination is severely impaired from birth, and vision is derived from the remaining preserved blue (S) cones and rod photoreceptors. BCM typically presents with reduced visual acuity, pendular nystagmus, and photophobia. Patients often have myopia (review by previous studies). There is evidence for progression of disease in some BCM families (previous studies; previous studies; previous studies)." +Orphanet_276258,Definition: Xeroderma pigmentosum is a rare autosomal recessive disorder characterized by acute photosensitivity and a predisposition to skin cancer on sun-exposed areas of the body. The primary defect in XP involves nucleotide excision repair (NER) (summary by previous studies). +MONDO_0010212,Definition: Xeroderma pigmentosum is a rare autosomal recessive disorder characterized by acute photosensitivity and a predisposition to skin cancer on sun-exposed areas of the body. The primary defect in XP involves nucleotide excision repair (NER) (summary by previous studies). +Orphanet_77258,"Definition: Trichorhinophalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Craniofacial features include sparse, slowly growing scalp hair, laterally sparse eyebrows, a bulbous tip of the nose, protruding ears, long flat philtrum, and thin upper vermillion border. The most typical radiographic findings in TRPS are cone-shaped epiphyses, predominantly at the middle phalanges. Hip malformations such as coxa plana, coxa magna, or coxa vara are present in over 70% of patients. In older patients, the hip abnormalities resemble degenerative arthrosis. TRPS3 differs from TRPS1 by the presence of severe brachydactyly, due to short metacarpals, and severe short stature (summary by previous studies)." +MONDO_0008597,"Definition: Trichorhinophalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Craniofacial features include sparse, slowly growing scalp hair, laterally sparse eyebrows, a bulbous tip of the nose, protruding ears, long flat philtrum, and thin upper vermillion border. The most typical radiographic findings in TRPS are cone-shaped epiphyses, predominantly at the middle phalanges. Hip malformations such as coxa plana, coxa magna, or coxa vara are present in over 70% of patients. In older patients, the hip abnormalities resemble degenerative arthrosis. TRPS3 differs from TRPS1 by the presence of severe brachydactyly, due to short metacarpals, and severe short stature (summary by previous studies)." +EFO_0009172,"Definition: Inherited abnormalities in the level of serum TBG have been classified as complete deficiency (TBG-CD), partial deficiency (TBG-PD), and excess (TBG-E). Patients are euthyroid (summary by previous studies)." +EFO_0020000,"Definition: Developmental and epileptic encephalopathy-94 (DEE94) is a severe form of epilepsy characterized by onset of multiple seizure types in the first few years of life and associated with poor prognosis. Affected individuals have cognitive regression and impaired intellectual development (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0008409,"Definition: Autosomal dominant myosin storage congenital myopathy-7A (CMYP7A) is a skeletal muscle disorder with wide phenotypic variability. The age at symptom onset can range from early childhood to late adulthood. Affected individuals have proximal muscle weakness affecting the upper and lower limbs and distal muscle weakness of the lower limbs, resulting in gait difficulties and scapular winging (scapuloperoneal myopathy). Additional features may include thin habitus, high-arched palate, foot drop, pes cavus, calf pseudohypertrophy, and decreased reflexes. The severity is also variable: some patients develop respiratory insufficiency, joint contractures, and scoliosis in the first decades, whereas others are clinically unaffected, but show subtle signs of the disorder on examination. Serum creatine kinase may be normal or elevated. The disease is usually slowly progressive and most patients remain ambulatory. Skeletal muscle biopsy can show different abnormalities, including hyaline bodies, type 1 fiber predominance, congenital fiber-type disproportion (CFTD), and nonspecific myopathic changes with myofibrillar disarray. Intrafamilial variability is common (previous studies; previous studies; review by previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0008667,"Definition: Von Hippel-Lindau syndrome (VHLS) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. + +previous studies classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). previous studies further subdivided VHL type 2 into type 2A (with pheochromocytoma) and type 2B (with pheochromocytoma and renal cell carcinoma). previous studies noted that VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. previous studies proposed that patients with VHL syndrome caused by large VHL deletions that include the HSPC300 gene (C3ORF10; previous studies) have a specific subtype of VHL syndrome characterized by protection from renal cell carcinoma, which the authors proposed be named VHL type 1B. + +previous studies provided a review of the genetics of von Hippel-Lindau disease." +MONDO_0008769,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure. The lipopigment pattern seen most often in CLN2 consists of 'curvilinear' profiles (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_228349,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure. The lipopigment pattern seen most often in CLN2 consists of 'curvilinear' profiles (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0010814,"Definition: Nivelon-Nivelon-Mabille syndrome (NNMS) is characterized by progressive microcephaly, vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia (previous studies)." +Orphanet_1422,"Definition: Nivelon-Nivelon-Mabille syndrome (NNMS) is characterized by progressive microcephaly, vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia (previous studies)." +MONDO_0010831,"Definition: Sacral defect with anterior meningocele (SDAM) is a form of caudal dysgenesis. It is present at birth and becomes symptomatic later in life, usually because of obstructive labor in females, chronic constipation, or meningitis. Inheritance is autosomal dominant (previous studies). previous studies gave a population frequency of 0.14%. + +Caudal dysgenesis syndrome and caudal regression syndrome are broad terms that refer to a heterogeneous constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. Approximately 15 to 25% of mothers of children with caudal dysgenesis have insulin-dependent diabetes mellitus (previous studies) (previous studies). + +See also Currarino syndrome (previous studies), a similar disorder caused by mutation in the HLXB9 gene (previous studies) on chromosome 7q36. Currarino syndrome classically comprises the triad of hemisacrum, anorectal malformation, and presacral mass. However, Currarino syndrome also shows phenotypic variability: previous studies stated that there is variable expressivity of clinical features and that some patients with Currarino syndrome are asymptomatic. previous studies found the complete triad of Currarino syndrome in only 8 of 23 patients with mutations in the HLXB9 gene, These reports suggest that some patients previously reported as having forms of sacral agenesis, including SDAM, may have had Currarino syndrome and vice versa. + +See also spina bifida (previous studies), which can be seen in some patients with sacral agenesis or caudal regression syndrome and may be etiologically related." +MONDO_0012211,"Definition: Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (previous studies) and CDG Ib (previous studies)." +MONDO_0012569,"Definition: Patients with mitral valve prolapse-3 (MVP3) have nonsyndromic MVP of variable severity with an autosomal dominant pattern of inheritance. + +For a general phenotypic description and discussion of genetic heterogeneity of mitral valve prolapse, see MVP1 (previous studies)." +MONDO_0014198,"Definition: Mitochondrial DNA depletion syndrome-13 is an autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Cells derived from patient tissues show defects in mitochondrial oxidative phosphorylation and decreased mtDNA content (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +Orphanet_369897,"Definition: Mitochondrial DNA depletion syndrome-13 is an autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Cells derived from patient tissues show defects in mitochondrial oxidative phosphorylation and decreased mtDNA content (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0014418,"Definition: Centronuclear myopathy-5 (CNM5) is an autosomal recessive congenital myopathy characterized by severe neonatal hypotonia with respiratory insufficiency and difficulty feeding. Some patients die in infancy, and some develop dilated cardiomyopathy. Children show severely delayed motor development (summary by previous studies). + +For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (previous studies)." +MONDO_0014803,"Definition: Childhood-onset spasticity with hyperglycinemia is an autosomal recessive disorder characterized by onset of slowly progressive spasticity that results in impaired gait in the first decade of life. Imaging of the central nervous system shows leukodystrophy and/or lesions in the upper spinal cord. More variable features include visual defects and mild learning disabilities. Serum glycine is increased, but CSF glycine is only mildly increased or normal; serum lactate is normal. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; previous studies), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including SPAHGC, appear to result from defects of mitochondrial lipoate biosynthesis (summary by previous studies)." +MONDO_0030894,"Definition: AMED syndrome (AMEDS) is an autosomal recessive digenic multisystem disorder characterized by global developmental delay with impaired intellectual development, onset of bone marrow failure and myelodysplastic syndrome (MDS) in childhood, and poor overall growth with short stature (summary by previous studies). + +For a discussion of genetic heterogeneity of bone marrow failure syndrome (BMFS), see BMFS1 (previous studies)." +MONDO_0030935,"Definition: Mitochondrial complex II deficiency nuclear type 2 (MC2DN2) is an autosomal recessive multisystemic metabolic disorder with variable severity and features. Most patients present with neurologic deterioration in infancy or early childhood after normal early development. Features include loss of motor skills, spastic paresis, dystonia, and loss of speech associated with increased serum and CSF lactate. Some patients may have mental decline or visual loss. Skeletal muscle samples show isolated complex II deficiency, and proton MRS shows increased succinate levels in the CSF and brain white matter. Brain imaging usually shows progressive leukoencephalopathy. Although the pattern of brain involvement may not be characteristic of Leigh syndrome (see previous studies), postmortem examination in 1 patient showed multifocal spongiform encephalomyelopathy consistent with a diagnosis of Leigh syndrome. The most severely affected patients die of multiorgan failure and lactic acidosis, whereas others who survive may stabilize and regain some skills. Treatment with riboflavin may offer clinical improvement (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (previous studies)." +MONDO_0032807,"Definition: Neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA) is characterized by global developmental delay with impaired intellectual development and speech delay, variable visual defects, including retinitis pigmentosa and optic atrophy, hypotonia or hypertonia, and variable structural brain abnormalities. Other nonspecific features may be found (summary by previous studies)." +MONDO_0036484,"Definition: CMTDIG is an autosomal dominant neurologic disorder with a highly variable phenotype. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. More severely affected individuals may have pes cavus and claw hands and become wheelchair-bound, whereas other affected individuals have later onset with a milder disease course. Electrophysiologic studies tend to show median motor nerve conduction velocities (NCV) in the 'intermediate' range, between 25 and 45 m/s (summary by previous studies). + +In a review of intermediate CMT, previous studies noted that advanced axonal degeneration may induce secondary demyelinating changes resulting in decreased NCV and attenuated compound muscle action potential (CMAP) in median nerve conduction studies. They thus suggested that testing the upper arm, axilla to elbow, may provide more accurate assessment of NCV and CMAP and reveal an intermediate phenotype (review by previous studies). + +For a discussion of genetic heterogeneity of CMTDI, see previous studies." +EFO_0010267,"Definition: CMTDIG is an autosomal dominant neurologic disorder with a highly variable phenotype. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. More severely affected individuals may have pes cavus and claw hands and become wheelchair-bound, whereas other affected individuals have later onset with a milder disease course. Electrophysiologic studies tend to show median motor nerve conduction velocities (NCV) in the 'intermediate' range, between 25 and 45 m/s (summary by previous studies). + +In a review of intermediate CMT, previous studies noted that advanced axonal degeneration may induce secondary demyelinating changes resulting in decreased NCV and attenuated compound muscle action potential (CMAP) in median nerve conduction studies. They thus suggested that testing the upper arm, axilla to elbow, may provide more accurate assessment of NCV and CMAP and reveal an intermediate phenotype (review by previous studies). + +For a discussion of genetic heterogeneity of CMTDI, see previous studies." +Orphanet_170,"Definition: Woolly hair (WH) refers to a group of hair shaft disorders that are characterized by fine and tightly curled hair. Compared to normal curly hair that is observed in some populations, WH grows slowly and stops growing after a few inches. Under light microscopy, WH shows some structural anomalies, including trichorrhexis nodosa and tapered ends. WH can appear as part of several syndromes, such as Naxos disease (previous studies) and cardiofaciocutaneous syndrome (previous studies) (summary by previous studies). + +See previous studies for a discussion of genetic heterogeneity of autosomal recessive woolly hair." +Orphanet_91132,"Definition: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by previous studies). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (previous studies). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; previous studies) (previous studies). + +NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by previous studies). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to reduced barrier function and defects of lipid composition in the stratum corneum (summary by previous studies). + +In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (previous studies)." +MONDO_0011218,"Definition: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by previous studies). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (previous studies). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; previous studies) (previous studies). + +NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by previous studies). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to reduced barrier function and defects of lipid composition in the stratum corneum (summary by previous studies). + +In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (previous studies)." +Orphanet_99947,"Definition: Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (previous studies) and CMT1A (previous studies) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (previous studies) and CMTX1 (previous studies) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively. + +For a discussion of genetic heterogeneity of CMT type 2, see previous studies." +MONDO_0012231,"Definition: Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (previous studies) and CMT1A (previous studies) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (previous studies) and CMTX1 (previous studies) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively. + +For a discussion of genetic heterogeneity of CMT type 2, see previous studies." +EFO_0000588,"Definition: Malignant mesothelioma is an aggressive neoplasm of the serosal lining of the chest etiologically linked to asbestos. It is diagnosed in approximately 2,000 to 3,000 individuals annually in the United States, most of whom die within 2 years of diagnosis (summary by previous studies). + +See also previous studies for a tumor predisposition syndrome that may contribute to the development of malignant mesothelioma upon asbestos exposure and is caused by germline mutation in the BAP1 gene (previous studies) on chromosome 3p21." +MONDO_0007078,"Definition: Pseudohypoparathyroidism is a term applied to a heterogeneous group of disorders whose common feature is end-organ resistance to parathyroid hormone (PTH; previous studies). In addition to PTH resistance, PHP Ia is characterized by resistance to other hormones, including thyroid-stimulating hormone (TSH; see TSHB, previous studies) and gonadotropins. PHP Ia is associated with a constellation of clinical features referred to as Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation (previous studies). + +In contrast, pseudopseudohypoparathyroidism (PPHP; previous studies) is characterized by the physical findings of AHO but without hormone resistance (previous studies; previous studies; previous studies). + +PHP1A occurs only after maternal inheritance of the molecular defect, whereas PPHP occurs only after paternal inheritance of the molecular defect (previous studies; previous studies). This is an example of imprinting, with differential gene expression depending on the parent of origin of the allele. See INHERITANCE and PATHOGENESIS sections." +MONDO_0007290,"Definition: Congenital cataracts cause 10 to 30% of all blindness in children, with one-third of cases estimated to have a genetic cause (summary by previous studies). Mutations in the HSF4 gene have been found to cause multiple types of cataract, which have been described as infantile, lamellar, zonular, nuclear, anterior polar, stellate, and Marner-type. + +The preferred title for this entry was formerly 'Lamellar Cataract,' with 'Cataract, Marner Type; CAM; CTM' an included title." +MONDO_0007301,"Definition: Cerebrocostomandibular syndrome (CCMS) is characterized mainly by severe micrognathia, rib defects, and mental retardation. A spectrum of rib gap defects have been reported ranging from a few dorsal rib segments to complete absence of ossification. In about half of the 65 reported cases to date, there is cerebral involvement including mental retardation, microcephaly, and histologic anomalies. Both autosomal dominant and autosomal recessive forms of the disorder have been described (previous studies). + +See CDG2G (previous studies) for a cerebrocostomandibular-like syndrome." +Orphanet_1393,"Definition: Cerebrocostomandibular syndrome (CCMS) is characterized mainly by severe micrognathia, rib defects, and mental retardation. A spectrum of rib gap defects have been reported ranging from a few dorsal rib segments to complete absence of ossification. In about half of the 65 reported cases to date, there is cerebral involvement including mental retardation, microcephaly, and histologic anomalies. Both autosomal dominant and autosomal recessive forms of the disorder have been described (previous studies). + +See CDG2G (previous studies) for a cerebrocostomandibular-like syndrome." +MONDO_0007871,"Definition: Congenital nasolacrimal drainage system impatency is relatively common, occurring in approximately 20% of children within the first year of life. Such infants typically manifest persistent epiphora and/or recurrent infections of the lacrimal pathway such as conjunctivitis. The most frequent site of such obstruction occurs at the distal intranasal segment of the nasolacrimal drainage system at the valve of Hasner (summary by previous studies). + +Congenital dacryocystocele, an uncommon variant of nasolacrimal duct obstruction, characterized by the appearance of a cystic blue mass over the area of the lacrimal duct soon after birth. Dacryocystoceles are thought to result from a persistent membrane at the valve of Hasner and a functional obstruction of the common canaliculus or valve of Rosenmuller. The resulting lacrimal sac distention has been reported to be more common in female and non-Hispanic white patients, and familial cases have been described only sporadically. Common presenting signs include dacryocystitis, facial cellulitis, and respiratory distress; the development of astigmatism in association with dacryocystocele has only rarely been observed (summary by previous studies)." +MONDO_0008297,"Definition: Variegate porphyria is characterized by cutaneous manifestations, including increased photosensitivity, blistering, skin fragility with chronic scarring of sun-exposed areas, and postinflammatory hyperpigmentation. Acute exacerbations of VP include abdominal pain, the passage of dark urine, and neuropsychiatric symptoms that characterize the acute hepatic porphyrias, such as bulbar paralysis, quadriplegia, motor neuropathy, and weakness of the limbs. In heterozygotes, PPOX activity is decreased by about 50% (summary by previous studies)." +Orphanet_79473,"Definition: Variegate porphyria is characterized by cutaneous manifestations, including increased photosensitivity, blistering, skin fragility with chronic scarring of sun-exposed areas, and postinflammatory hyperpigmentation. Acute exacerbations of VP include abdominal pain, the passage of dark urine, and neuropsychiatric symptoms that characterize the acute hepatic porphyrias, such as bulbar paralysis, quadriplegia, motor neuropathy, and weakness of the limbs. In heterozygotes, PPOX activity is decreased by about 50% (summary by previous studies)." +MONDO_0008832,"Definition: Right atrial isomerism (RAI) is a severe complex congenital heart defect resulting from embryonic disruption of proper left-right axis determination. RAI is usually characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous pulmonary drainage, and transposition or malposition of the great arteries. Affected individuals present at birth with severe cardiac failure. Other associated abnormalities include bilateral trilobed lungs, midline liver, and asplenia, as well as situs inversus affecting other organs. Left atrial isomerism (LAI) is a related disorder with a somewhat better prognosis. LAI is characterized by bilateral superior vena cava, interruption of the intrahepatic portion of the inferior vena cava, partial anomalous pulmonary venous drainage, and ventricular septal defect. Patients with LAI may have polysplenia and bilateral bilobed lungs, as well as situs inversus affecting other organs. Both RAI and LAI malformation complexes have classically been referred to as Ivemark syndrome (summary by previous studies and previous studies)." +Orphanet_97548,"Definition: Right atrial isomerism (RAI) is a severe complex congenital heart defect resulting from embryonic disruption of proper left-right axis determination. RAI is usually characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous pulmonary drainage, and transposition or malposition of the great arteries. Affected individuals present at birth with severe cardiac failure. Other associated abnormalities include bilateral trilobed lungs, midline liver, and asplenia, as well as situs inversus affecting other organs. Left atrial isomerism (LAI) is a related disorder with a somewhat better prognosis. LAI is characterized by bilateral superior vena cava, interruption of the intrahepatic portion of the inferior vena cava, partial anomalous pulmonary venous drainage, and ventricular septal defect. Patients with LAI may have polysplenia and bilateral bilobed lungs, as well as situs inversus affecting other organs. Both RAI and LAI malformation complexes have classically been referred to as Ivemark syndrome (summary by previous studies and previous studies)." +MONDO_0010752,"Definition: VACTERL is an acronym for vertebral anomalies (similar to those of spondylocostal dysplasia), anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb; see previous studies). Some patients may have hydrocephalus, which is referred to as VACTERL-H (previous studies)." +MONDO_0010995,"Definition: For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (previous studies)." +MONDO_0012186,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0013687,"Definition: Autosomal recessive spinocerebellar ataxia-12 is a neurologic disorder characterized by onset of generalized seizures in infancy, delayed psychomotor development with mental retardation, and cerebellar ataxia. Some patients may also show spasticity (summary by previous studies)." +MONDO_0014121,"Definition: SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by previous studies). + +For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (previous studies)." +MONDO_0014137,"Definition: Early activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty, which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The timing of puberty is associated with risks of subsequent disease: earlier age of menarche in girls is associated with increased risk of breast cancer, endometrial cancer, obesity, type 2 diabetes, and cardiovascular disease. Central precocious puberty has also been associated with an increased incidence of conduct and behavior disorders during adolescence (summary by previous studies). + +For discussion of genetic heterogeneity of central precocious puberty, see CPPB1 (previous studies)." +MONDO_0014258,"Definition: ASNS deficiency (ASNSD) is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder may show onset in utero or at birth and may result in early death (summary by previous studies); it may also present with early normal development followed by infantile-onset seizures and neurodevelopmental delays (previous studies)." +Orphanet_391376,"Definition: ASNS deficiency (ASNSD) is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder may show onset in utero or at birth and may result in early death (summary by previous studies); it may also present with early normal development followed by infantile-onset seizures and neurodevelopmental delays (previous studies)." +MONDO_0014503,Definition: Autosomal recessive spinocerebellar ataxia-17 (SCAR17) is a neurologic disorder characterized by onset of gait ataxia and cerebellar signs in early childhood. Patients also have variably impaired intellectual development (summary by previous studies). +MONDO_0014892,"Definition: Autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44) is characterized by mildly delayed global development resulting in variable intellectual deficits or learning difficulties, distinctive facial features, and abnormalities of the fingers, particularly brachydactyly, tapering fingers, and broad interphalangeal joints. Additional features are highly variable (summary by previous studies)." +MONDO_0032926,"Definition: Sandestig-Stefanova syndrome (SANDSTEF) is an autosomal recessive developmental syndrome characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataract, microphthalmia, facial gestalt, camptodactyly, loss of periventricular white matter, thin corpus callosum, delayed myelinization, and poor prognosis (previous studies)." +Orphanet_101049,"Definition: Familial hypocalciuric hypercalcemia type II (HHC2) is an autosomal dominant disorder characterized by lifelong elevations of serum calcium concentrations with low urinary calcium excretion and normal circulating parathyroid hormone concentrations in most patients. Patients are generally asymptomatic (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of hypocalciuric hypercalcemia, see HHC1 (previous studies)." +MONDO_0007792,"Definition: Familial hypocalciuric hypercalcemia type II (HHC2) is an autosomal dominant disorder characterized by lifelong elevations of serum calcium concentrations with low urinary calcium excretion and normal circulating parathyroid hormone concentrations in most patients. Patients are generally asymptomatic (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of hypocalciuric hypercalcemia, see HHC1 (previous studies)." +Orphanet_163937,"Definition: Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder affecting females and characterized by severely impaired intellectual development and variable degrees of pontocerebellar hypoplasia. Affected individuals have very poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss or eye anomalies. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (summary by previous studies)." +MONDO_0010417,"Definition: Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder affecting females and characterized by severely impaired intellectual development and variable degrees of pontocerebellar hypoplasia. Affected individuals have very poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss or eye anomalies. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (summary by previous studies)." +Orphanet_258,"Definition: Merosin-deficient congenital muscular dystrophy is an autosomal recessive form of muscular dystrophy characterized by muscle weakness apparent at birth or in the first 6 months of life. Patients show hypotonia, poor suck and cry, and delayed motor development; most never achieve independent ambulation. Most patients also have periventricular white matter abnormalities on brain imaging, but mental retardation and/or seizures occur only rarely (summary by previous studies)." +MONDO_0011925,"Definition: Merosin-deficient congenital muscular dystrophy is an autosomal recessive form of muscular dystrophy characterized by muscle weakness apparent at birth or in the first 6 months of life. Patients show hypotonia, poor suck and cry, and delayed motor development; most never achieve independent ambulation. Most patients also have periventricular white matter abnormalities on brain imaging, but mental retardation and/or seizures occur only rarely (summary by previous studies)." +Orphanet_280293,"Definition: Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (summary by previous studies). + +The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; previous studies), which is caused by mutation in the PLP1 gene (previous studies). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see previous studies." +MONDO_0009843,"Definition: Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (summary by previous studies). + +The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; previous studies), which is caused by mutation in the PLP1 gene (previous studies). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see previous studies." +Orphanet_65743,"Definition: Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1A (CPSFS1) is characterized by contractures of proximal and distal joints, pterygia involving the neck, axillae, elbows, and/or knees, as well as variable vertebral, carpal, and tarsal fusions and short stature. Progression of vertebral fusions has been observed, and inter- and intrafamilial variability has been reported (previous studies; previous studies; previous studies). + +An autosomal recessive form of CPSFS (CPSFS1B; previous studies) is caused by compound heterozygous mutation in the MYH3 gene." +MONDO_0008338,"Definition: Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1A (CPSFS1) is characterized by contractures of proximal and distal joints, pterygia involving the neck, axillae, elbows, and/or knees, as well as variable vertebral, carpal, and tarsal fusions and short stature. Progression of vertebral fusions has been observed, and inter- and intrafamilial variability has been reported (previous studies; previous studies; previous studies). + +An autosomal recessive form of CPSFS (CPSFS1B; previous studies) is caused by compound heterozygous mutation in the MYH3 gene." +Orphanet_79,"Definition: Alpha-2-plasmin inhibitor deficiency is a rare autosomal recessive hemorrhagic diathesis. Most bleeds are severe, appear during childhood, and, in a few cases, umbilical bleeding is the first manifestation. Some homozygous patients present only moderate bleeding (previous studies)." +MONDO_0009883,"Definition: Alpha-2-plasmin inhibitor deficiency is a rare autosomal recessive hemorrhagic diathesis. Most bleeds are severe, appear during childhood, and, in a few cases, umbilical bleeding is the first manifestation. Some homozygous patients present only moderate bleeding (previous studies)." +EFO_0010268,"Definition: Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) is an autosomal recessive disorder characterized by brain abnormalities, progressive neurologic deterioration, and sclerotic bone dysplasia similar to dysosteosclerosis (DOS). The age at onset is highly variable: some patients may present in infancy with hydrocephalus, global developmental delay, and hypotonia, whereas others may have onset of symptoms in the late teens or early twenties after normal development. Neurologic features include loss of previous motor and language skills, cognitive impairment, spasticity, and focal seizures. Brain imaging shows periventricular white matter abnormalities and calcifications, large cisterna magna or Dandy-Walker malformation, and sometimes agenesis of the corpus callosum (summary by previous studies)." +EFO_0010660,"Definition: Patients with intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS) have impaired intellectual development or developmental delay of varying severity with impaired motor skills and language delay. Macrocephaly, obesity, and overgrowth are frequently seen. Approximately half of patients experience seizures, and neurobehavioral disorders including autism are usually present (previous studies; previous studies)." +MONDO_0007892,"Definition: Lenz-Majewski hyperostotic dwarfism is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, distinct craniofacial and dental anomalies, loose skin, and distal limb anomalies, particularly brachydactyly and symphalangism. Patients have multiple radiographic abnormalities due to progressive generalized hyperostosis that affects the cranium, vertebrae, and diaphyses of tubular bones, leading to severe growth retardation (summary by previous studies)." +MONDO_0009340,Definition: Hexokinase deficiency is an autosomal recessive disorder characterized by early-onset severe hemolytic anemia (summary by previous studies). +MONDO_0009443,"Definition: Harlequin ichthyosis is a rare severe form of congenital ichthyosis, which may be fatal. The neonate is encased in an 'armor' of thick scale plates separated by deep fissures. There is bilateral ectropion and eclabium, and the nose and ears are flattened and appear rudimentary. Constricting bands around the extremities can restrict movement and cause digital necrosis. As the skin barrier is severely compromised, neonates are more prone to sepsis, dehydration, and impaired thermoregulation. Treatment with oral retinoids encourages shedding of the grossly thickened skin. Babies who survive into infancy and beyond develop skin changes resembling severe nonbullous congenital ichthyosiform erythroderma (see previous studies) (summary by previous studies). + +At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass lamellar ichthyosis (LI), nonbullous congenital ichthyosis erythroderma (NCIE), and harlequin ichthyosis (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (previous studies)." +Orphanet_457,"Definition: Harlequin ichthyosis is a rare severe form of congenital ichthyosis, which may be fatal. The neonate is encased in an 'armor' of thick scale plates separated by deep fissures. There is bilateral ectropion and eclabium, and the nose and ears are flattened and appear rudimentary. Constricting bands around the extremities can restrict movement and cause digital necrosis. As the skin barrier is severely compromised, neonates are more prone to sepsis, dehydration, and impaired thermoregulation. Treatment with oral retinoids encourages shedding of the grossly thickened skin. Babies who survive into infancy and beyond develop skin changes resembling severe nonbullous congenital ichthyosiform erythroderma (see previous studies) (summary by previous studies). + +At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass lamellar ichthyosis (LI), nonbullous congenital ichthyosis erythroderma (NCIE), and harlequin ichthyosis (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (previous studies)." +MONDO_0009552,"Definition: Mal de Meleda (MDM) is a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities (summary by previous studies)." +MONDO_0009926,"Definition: Multiple pterygium syndromes comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (previous studies). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal (previous studies) and nonlethal (Escobar) types." +MONDO_0010456,"Definition: Xp11 translocation renal cell carcinomas (RCCX1) are a group of neoplasms distinguished by chromosomal translocations with breakpoints involving the TFE3 gene within tumor cells. The result is a TFE3 transcription factor gene fusion with 1 of multiple reported genes including ASPRCR1 (previous studies) on chromosome 17q25 and PRCC (previous studies) on 1q21, and more rarely, NONO (previous studies) on Xq13, SFPQ (previous studies) on 1p34, CLTC (previous studies) on 17q23, and unknown genes on chromosomes 3 and 10. Xp11 translocations are often found in pediatric tumors and less commonly in adults. However, adult cases may outnumber pediatric cases since renal cell carcinoma is more common in the adult population. Prior chemotherapy is a known risk factor for Xp11 translocations. Histology shows both clear cells and papillary architecture, often with abundant psammoma bodies, although variable histologic features have been observed (review by previous studies). + +For a discussion of genetic heterogeneity of renal cell carcinoma, see RCC (previous studies)." +MONDO_0011185,"Definition: Thiel-Behnke corneal dystrophy (CDTB) is characterized by progressive honeycomb-like, subepithelial corneal opacities with recurrent erosions (previous studies)." +MONDO_0011244,"Definition: The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (previous studies)." +MONDO_0011398,"Definition: Dystrophic epidermolysis bullosa is an inherited skin fragility disorder associated with anchoring fibril abnormalities and sublamina densa blistering. + +EB pruriginosa is a rare distinct clinical subtype of dystrophic EB in which skin fragility, blistering, and scar formation are associated with intense pruritus, nodular prurigo-like lichenified lesions, nail dystrophy, and variable presence of albopapuloid lesions (previous studies; previous studies). The onset of these clinical features may be evident in early childhood, but in some cases is delayed until the second or third decade of life. Autosomal dominant, autosomal recessive, and sporadic inheritance patterns have all been described in this disorder." +MONDO_0012725,"Definition: Lipoprotein glomerulopathy is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries (previous studies). It mainly affects people of Japanese and Chinese origin; in these populations, it is associated with mutations in the gene that encodes apolipoprotein E (APOE; previous studies). The disorder had rarely been described in Caucasians." +MONDO_0013870,"Definition: CDG2K is an autosomal recessive disorder with a variable phenotype. Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern (summary by previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies) and CDG2A (previous studies)." +MONDO_0030837,"Definition: Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) is characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, including ataxia and spasticity, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. Dysmorphic facial features may also be observed. Most patients have early-onset seizures; some may develop a demyelinating peripheral neuropathy. The clinical features suggest involvement of both the central and peripheral nervous systems (previous studies)." +MONDO_0033554,"Definition: Immunodeficiency-73B with defective neutrophil chemotaxis (IMD73B) is an autosomal dominant immunologic disorder characterized by onset of recurrent infections in infancy or early childhood. Affected individuals develop respiratory infections, cellulitis, and severe invasive infections or sepsis; organisms include bacteria such as Staphylococcus, as well as viruses, fungi, and mycobacterial species. Laboratory studies show variable abnormalities, including B- and T-cell lymphopenia, decreased immunoglobulin subsets, decreased TRECs and dysfunctional T cells, decreased NK cells, neutropenia, and impaired neutrophil chemotaxis. Hematopoietic stem cell transplantation is curative (summary by previous studies; review by previous studies). + +In a review of autosomal forms of chronic granulomatous disease (see previous studies for genetic heterogeneity of CGD), previous studies noted that patients with RAC2 mutations may manifest CGD-like symptoms due to defects in neutrophil NADPH oxidase activity." +Orphanet_158665,"Definition: Generalized epidermolysis bullosa simplex-6 with scarring and hair loss, with or without dilated cardiomyopathy (EBS6) is characterized by extensive skin erosions present at birth that heal with pigmentation defects and atrophy. Skin fragility improves with age, with progressive alopecia developing by adulthood (previous studies, previous studies). In addition, patients are at risk for the development of severe dilated cardiomyopathy in young adulthood, with some requiring cardiac transplantation (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0015006,"Definition: Generalized epidermolysis bullosa simplex-6 with scarring and hair loss, with or without dilated cardiomyopathy (EBS6) is characterized by extensive skin erosions present at birth that heal with pigmentation defects and atrophy. Skin fragility improves with age, with progressive alopecia developing by adulthood (previous studies, previous studies). In addition, patients are at risk for the development of severe dilated cardiomyopathy in young adulthood, with some requiring cardiac transplantation (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +Orphanet_749,Definition: Prekallikrein deficiency (PKKD) is a rare asymptomatic clotting defect characterized by prolongation of activated partial thromboplastin time (summary by previous studies). +MONDO_0012901,Definition: Prekallikrein deficiency (PKKD) is a rare asymptomatic clotting defect characterized by prolongation of activated partial thromboplastin time (summary by previous studies). +EFO_0009026,"Definition: Bardet-Biedl syndrome-7 (BBS7) is an autosomal recessive disorder characterized by retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity, renal anomalies, and hypogenitalism (previous studies). previous studies estimated the contribution of BBS7 gene mutations to the total BBS mutational load to be 1.50%. + +For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +MONDO_0008713,"Definition: Acrodermatitis enteropathica of the zinc deficiency type (AEZ) is characterized by intermittent simultaneous occurrence of diarrhea and dermatitis with failure to thrive. Alopecia of the scalp, eyebrows, and eyelashes is a usual feature. The skin lesions are bullous. Noteworthy is the cure by diodoquin, or diiodohydroxyquinoline (previous studies; previous studies). previous studies described autopsy findings, including pancreatic islet hyperplasia, absence of the thymus and of germinal centers, and plasmocytosis of lymph nodes and spleen." +MONDO_0010122,"Definition: Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome (USS), is a rare autosomal recessive thrombotic microangiopathy (TMA). Clinically, acute phases of TTP are defined by microangiopathic mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia. Hereditary TTP makes up 5% of TTP cases and is caused mostly by biallelic mutation in the ADAMTS13 gene, or in very rare cases, by monoallelic ADAMTS13 mutation associated with a cluster of single-nucleotide polymorphisms (SNPs); most cases of all TTP (95%) are acquired via an autoimmune mechanism (see previous studies). Hereditary TTP is more frequent among child-onset TTP compared with adult-onset TTP, and its clinical presentation is significantly different as a function of its age of onset. Child-onset TTP usually starts in the neonatal period with hematological features and severe jaundice. In contrast, almost all cases of adult-onset hereditary TTP are unmasked during the first pregnancy of a woman whose disease was silent during childhood (summary by previous studies)." +MONDO_0012511,"Definition: Preterm premature rupture of the membranes (PPROM) is defined as rupture of membranes before 37 weeks of gestation, which occurs in approximately 3% of all pregnancies and accounts for about one-third of spontaneous preterm births (previous studies). previous studies reviewed the pathophysiology of PPROM and noted that familial clustering and ethnic differences in the incidence of PPROM suggest possible genetic influences." +MONDO_0012596,"Definition: Deficiency of phosphoserine aminotransferase (PSAT) is characterized biochemically by low plasma and cerebrospinal fluid (CSF) concentrations of serine and glycine and clinically by intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation. Outcome is poor once the individual becomes symptomatic, but treatment with serine and glycine supplementation from birth can lead to a normal outcome (previous studies)." +Orphanet_284417,"Definition: Deficiency of phosphoserine aminotransferase (PSAT) is characterized biochemically by low plasma and cerebrospinal fluid (CSF) concentrations of serine and glycine and clinically by intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation. Outcome is poor once the individual becomes symptomatic, but treatment with serine and glycine supplementation from birth can lead to a normal outcome (previous studies)." +MONDO_0014034,"Definition: GAND syndrome is a neurodevelopmental syndrome characterized by global developmental delay apparent from infancy, with motor delay and moderate to severely impaired intellectual development. Most patients have poor speech acquisition, especially expressive language development, and may manifest signs of speech apraxia. Affected individuals have hypotonia and feeding difficulties in infancy, as well as common dysmorphic features, such as macrocephaly, frontal bossing, hypertelorism, deep-set eyes, posteriorly rotated ears, and elongated wide nose with prominent nasal tip. More variable features may include seizures, cardiac abnormalities, and nonspecific findings on brain imaging (summary by previous studies)." +MONDO_0014641,"Definition: Frontotemporal dementia and/or amyotrophic lateral sclerosis-4 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. The phenotype is highly variable (summary by previous studies). + +For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (previous studies)." +MONDO_0024777,"Definition: X-linked immunodeficiency-98 with autoinflammation (IMD98) is characterized by onset of recurrent infections associated with lymphoproliferation and autoinflammation in the first decade of life. Mostly males are affected; carrier females may have mild symptoms. Laboratory studies show evidence of immune dysregulation, including hypogammaglobulinemia with reduced memory B cells, skewed T-cell subsets, increased levels of proinflammatory cytokines, activated T cells and monocytes, and autoimmune cytopenias, including neutropenia (previous studies; previous studies)." +MONDO_0030975,"Definition: Premature ovarian failure-20 (POF20) is characterized by female infertility due to secondary amenorrhea. Some patients exhibit atrophic ovaries lacking follicles (previous studies; previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of POF, see POF1 (previous studies)." +MONDO_0033639,"Definition: Mitochondrial complex IV deficiency nuclear type 10 (MC4DN10) is an autosomal recessive multisystem metabolic disorder characterized by the onset of severe symptoms soon after birth. Affected infants have respiratory and neurologic distress, metabolic lactic acidosis, and dysmorphic features, including microphthalmia. Death occurs in early infancy. Postmortem examination has demonstrated systemic involvement with hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. There is also abnormal brain myelination and cavitating brain lesions. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +Orphanet_300751,"Definition: Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years of age. A heritable pattern is present in 20 to 30% of cases. Most familial CMD pedigrees show an autosomal dominant pattern of inheritance, usually presenting in the second or third decade of life (summary by previous studies). + + Genetic Heterogeneity of Dilated Cardiomyopathy + +Mutations in many other genes have been found to cause different forms of autosomal dominant dilated cardiomyopathy. These include CMD1C (previous studies), with or without left ventricular noncompaction, caused by mutation in the LDB3 gene (previous studies) on 10q23; CMD1D (previous studies), caused by mutation in the TNNT2 gene (previous studies) on 1q32; CMD1E (previous studies), caused by mutation in the SCN5A gene (previous studies) on 3p22; CMD1G (previous studies), caused by mutation in the TTN gene (previous studies) on 2q31; CMD1I (previous studies), caused by mutation in the DES gene (previous studies) on 2q35; CMD1J (previous studies), caused by mutation in the EYA4 gene (previous studies) on 6q23; CMD1L (previous studies), caused by mutation in the SGCD gene (previous studies) on 5q33; CMD1M (previous studies), caused by mutation in the CSRP3 gene (previous studies) on 11p15; CMD1O (previous studies), caused by mutation in the ABCC9 gene (previous studies) on 12p12; CMD1P (previous studies), caused by mutation in the PLN gene (previous studies) on 6q22; CMD1R (previous studies), caused by mutation in the ACTC gene (previous studies) on 15q14; CMD1S (previous studies), caused by mutation in the MYH7 gene (previous studies) on 14q12; CMD1U (previous studies), caused by mutation in the PSEN1 gene (previous studies) on 14q24; CMD1V (previous studies), caused by mutation in the PSEN2 gene (previous studies) on 1q42; CMD1W (previous studies), caused by mutation in the gene encoding metavinculin (VCL; previous studies) on 10q22; CMD1X (previous studies), caused by mutation in the gene encoding fukutin (FKTN; previous studies) on 9q31; CMD1Y (previous studies), caused by mutation in the TPM1 gene (previous studies) on 15q22; CMD1Z (previous studies), caused by mutation in the TNNC1 gene (previous studies) on 3p21; CMD1AA (previous studies), caused by mutation in the ACTN2 gene (previous studies) on 1q43; CMD1BB (previous studies), caused by mutation in the DSG2 gene (previous studies) on 18q12; CMD1CC (previous studies), caused by mutation in the NEXN gene (previous studies) on 1p31; CMD1DD (previous studies), caused by mutation in the RBM20 gene (previous studies) on 10q25; CMD1EE (previous studies), caused by mutation in the MYH6 gene (previous studies) on 14q12; CMD1FF (previous studies), caused by mutation in the TNNI3 gene (previous studies) on 19q13; CMD1GG (previous studies), caused by mutation in the SDHA gene (previous studies) on 5p15; CMD1HH (previous studies), caused by mutation in the BAG3 gene (previous studies) on 10q26; CMD1II (previous studies), caused by mutation in the CRYAB gene (previous studies) on 6q21; CMD1JJ (previous studies), caused by mutation in the LAMA4 gene (previous studies) on 6q21; CMD1KK (previous studies), caused by mutation in the MYPN gene (previous studies) on 10q21; CMD1LL (previous studies), caused by mutation in the PRDM16 gene (previous studies) on 1p36; CMD1MM (see previous studies), caused by mutation in the MYBPC3 gene (previous studies) on 11p11; CMD1NN (previous studies), caused by mutation in the RAF1 gene (previous studies) on 3p25; CMD1OO (previous studies), caused by mutation in the VEZF1 gene (previous studies) on chromosome 17q22; and CMD1PP (see previous studies), caused by mutation in the FLNC gene (previous studies) on chromosome 7q32. + +Several additional loci for autosomal dominant familial dilated cardiomyopathy have been mapped: CMD1B (previous studies) on 9q13; CMD1H (previous studies) on 2q14-q22; CMD1K (previous studies) on 6q12-q16; and CMD1Q (previous studies) on 7q22.3-q31.1. + +Autosomal recessive CMD includes CMD2A (previous studies), caused by mutation in the TNNI3 gene (previous studies) on 19q13; CMD2B (previous studies), caused by mutation in the GATAD1 gene (previous studies) on 7q21; CMD2C (previous studies), caused by mutation in the PPCS gene (previous studies) on 1p34; CMD2D (previous studies), caused by mutation in the RPL3L gene (previous studies) on 16p13; CMD2E (previous studies), caused by mutation in the JPH2 gene (previous studies) on chromosome 20q13; CMD2F (previous studies), caused by mutation in the BAG5 gene (previous studies) on chromosome 14q32; CMD2G (previous studies), caused by mutation in the LMOD2 gene (previous studies) on chromosome 7q31; and CMD2H (previous studies), caused by mutation in the GET3 gene (previous studies) on chromosome 19p13. + +An X-linked form of CMD (CMD3B; previous studies) is caused by mutation in the DMD gene (previous studies). An X-linked form previously designated CMD3A was found to be the same as Barth syndrome (previous studies). + + Reclassified CMD Symbols + +The symbol CMD1F was formerly used for a disorder later found to be the same as desmin-related myopathy (previous studies). + +The symbol CMD1N (see previous studies) was previously used for a form of dilated cardiomyopathy reported to be caused by a mutation in the TCAP gene (previous studies); this variant has been reclassified as a variant of unknown significance. + +The symbol CMD1T was previously used for a form of dilated cardiomyopathy reported to be caused by a mutation in the TMPO gene (previous studies); this variant has been reclassified as a variant of unknown significance." +EFO_0002945,"Definition: Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years of age. A heritable pattern is present in 20 to 30% of cases. Most familial CMD pedigrees show an autosomal dominant pattern of inheritance, usually presenting in the second or third decade of life (summary by previous studies). + + Genetic Heterogeneity of Dilated Cardiomyopathy + +Mutations in many other genes have been found to cause different forms of autosomal dominant dilated cardiomyopathy. These include CMD1C (previous studies), with or without left ventricular noncompaction, caused by mutation in the LDB3 gene (previous studies) on 10q23; CMD1D (previous studies), caused by mutation in the TNNT2 gene (previous studies) on 1q32; CMD1E (previous studies), caused by mutation in the SCN5A gene (previous studies) on 3p22; CMD1G (previous studies), caused by mutation in the TTN gene (previous studies) on 2q31; CMD1I (previous studies), caused by mutation in the DES gene (previous studies) on 2q35; CMD1J (previous studies), caused by mutation in the EYA4 gene (previous studies) on 6q23; CMD1L (previous studies), caused by mutation in the SGCD gene (previous studies) on 5q33; CMD1M (previous studies), caused by mutation in the CSRP3 gene (previous studies) on 11p15; CMD1O (previous studies), caused by mutation in the ABCC9 gene (previous studies) on 12p12; CMD1P (previous studies), caused by mutation in the PLN gene (previous studies) on 6q22; CMD1R (previous studies), caused by mutation in the ACTC gene (previous studies) on 15q14; CMD1S (previous studies), caused by mutation in the MYH7 gene (previous studies) on 14q12; CMD1U (previous studies), caused by mutation in the PSEN1 gene (previous studies) on 14q24; CMD1V (previous studies), caused by mutation in the PSEN2 gene (previous studies) on 1q42; CMD1W (previous studies), caused by mutation in the gene encoding metavinculin (VCL; previous studies) on 10q22; CMD1X (previous studies), caused by mutation in the gene encoding fukutin (FKTN; previous studies) on 9q31; CMD1Y (previous studies), caused by mutation in the TPM1 gene (previous studies) on 15q22; CMD1Z (previous studies), caused by mutation in the TNNC1 gene (previous studies) on 3p21; CMD1AA (previous studies), caused by mutation in the ACTN2 gene (previous studies) on 1q43; CMD1BB (previous studies), caused by mutation in the DSG2 gene (previous studies) on 18q12; CMD1CC (previous studies), caused by mutation in the NEXN gene (previous studies) on 1p31; CMD1DD (previous studies), caused by mutation in the RBM20 gene (previous studies) on 10q25; CMD1EE (previous studies), caused by mutation in the MYH6 gene (previous studies) on 14q12; CMD1FF (previous studies), caused by mutation in the TNNI3 gene (previous studies) on 19q13; CMD1GG (previous studies), caused by mutation in the SDHA gene (previous studies) on 5p15; CMD1HH (previous studies), caused by mutation in the BAG3 gene (previous studies) on 10q26; CMD1II (previous studies), caused by mutation in the CRYAB gene (previous studies) on 6q21; CMD1JJ (previous studies), caused by mutation in the LAMA4 gene (previous studies) on 6q21; CMD1KK (previous studies), caused by mutation in the MYPN gene (previous studies) on 10q21; CMD1LL (previous studies), caused by mutation in the PRDM16 gene (previous studies) on 1p36; CMD1MM (see previous studies), caused by mutation in the MYBPC3 gene (previous studies) on 11p11; CMD1NN (previous studies), caused by mutation in the RAF1 gene (previous studies) on 3p25; CMD1OO (previous studies), caused by mutation in the VEZF1 gene (previous studies) on chromosome 17q22; and CMD1PP (see previous studies), caused by mutation in the FLNC gene (previous studies) on chromosome 7q32. + +Several additional loci for autosomal dominant familial dilated cardiomyopathy have been mapped: CMD1B (previous studies) on 9q13; CMD1H (previous studies) on 2q14-q22; CMD1K (previous studies) on 6q12-q16; and CMD1Q (previous studies) on 7q22.3-q31.1. + +Autosomal recessive CMD includes CMD2A (previous studies), caused by mutation in the TNNI3 gene (previous studies) on 19q13; CMD2B (previous studies), caused by mutation in the GATAD1 gene (previous studies) on 7q21; CMD2C (previous studies), caused by mutation in the PPCS gene (previous studies) on 1p34; CMD2D (previous studies), caused by mutation in the RPL3L gene (previous studies) on 16p13; CMD2E (previous studies), caused by mutation in the JPH2 gene (previous studies) on chromosome 20q13; CMD2F (previous studies), caused by mutation in the BAG5 gene (previous studies) on chromosome 14q32; CMD2G (previous studies), caused by mutation in the LMOD2 gene (previous studies) on chromosome 7q31; and CMD2H (previous studies), caused by mutation in the GET3 gene (previous studies) on chromosome 19p13. + +An X-linked form of CMD (CMD3B; previous studies) is caused by mutation in the DMD gene (previous studies). An X-linked form previously designated CMD3A was found to be the same as Barth syndrome (previous studies). + + Reclassified CMD Symbols + +The symbol CMD1F was formerly used for a disorder later found to be the same as desmin-related myopathy (previous studies). + +The symbol CMD1N (see previous studies) was previously used for a form of dilated cardiomyopathy reported to be caused by a mutation in the TCAP gene (previous studies); this variant has been reclassified as a variant of unknown significance. + +The symbol CMD1T was previously used for a form of dilated cardiomyopathy reported to be caused by a mutation in the TMPO gene (previous studies); this variant has been reclassified as a variant of unknown significance." +MONDO_0007269,"Definition: Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years of age. A heritable pattern is present in 20 to 30% of cases. Most familial CMD pedigrees show an autosomal dominant pattern of inheritance, usually presenting in the second or third decade of life (summary by previous studies). + + Genetic Heterogeneity of Dilated Cardiomyopathy + +Mutations in many other genes have been found to cause different forms of autosomal dominant dilated cardiomyopathy. These include CMD1C (previous studies), with or without left ventricular noncompaction, caused by mutation in the LDB3 gene (previous studies) on 10q23; CMD1D (previous studies), caused by mutation in the TNNT2 gene (previous studies) on 1q32; CMD1E (previous studies), caused by mutation in the SCN5A gene (previous studies) on 3p22; CMD1G (previous studies), caused by mutation in the TTN gene (previous studies) on 2q31; CMD1I (previous studies), caused by mutation in the DES gene (previous studies) on 2q35; CMD1J (previous studies), caused by mutation in the EYA4 gene (previous studies) on 6q23; CMD1L (previous studies), caused by mutation in the SGCD gene (previous studies) on 5q33; CMD1M (previous studies), caused by mutation in the CSRP3 gene (previous studies) on 11p15; CMD1O (previous studies), caused by mutation in the ABCC9 gene (previous studies) on 12p12; CMD1P (previous studies), caused by mutation in the PLN gene (previous studies) on 6q22; CMD1R (previous studies), caused by mutation in the ACTC gene (previous studies) on 15q14; CMD1S (previous studies), caused by mutation in the MYH7 gene (previous studies) on 14q12; CMD1U (previous studies), caused by mutation in the PSEN1 gene (previous studies) on 14q24; CMD1V (previous studies), caused by mutation in the PSEN2 gene (previous studies) on 1q42; CMD1W (previous studies), caused by mutation in the gene encoding metavinculin (VCL; previous studies) on 10q22; CMD1X (previous studies), caused by mutation in the gene encoding fukutin (FKTN; previous studies) on 9q31; CMD1Y (previous studies), caused by mutation in the TPM1 gene (previous studies) on 15q22; CMD1Z (previous studies), caused by mutation in the TNNC1 gene (previous studies) on 3p21; CMD1AA (previous studies), caused by mutation in the ACTN2 gene (previous studies) on 1q43; CMD1BB (previous studies), caused by mutation in the DSG2 gene (previous studies) on 18q12; CMD1CC (previous studies), caused by mutation in the NEXN gene (previous studies) on 1p31; CMD1DD (previous studies), caused by mutation in the RBM20 gene (previous studies) on 10q25; CMD1EE (previous studies), caused by mutation in the MYH6 gene (previous studies) on 14q12; CMD1FF (previous studies), caused by mutation in the TNNI3 gene (previous studies) on 19q13; CMD1GG (previous studies), caused by mutation in the SDHA gene (previous studies) on 5p15; CMD1HH (previous studies), caused by mutation in the BAG3 gene (previous studies) on 10q26; CMD1II (previous studies), caused by mutation in the CRYAB gene (previous studies) on 6q21; CMD1JJ (previous studies), caused by mutation in the LAMA4 gene (previous studies) on 6q21; CMD1KK (previous studies), caused by mutation in the MYPN gene (previous studies) on 10q21; CMD1LL (previous studies), caused by mutation in the PRDM16 gene (previous studies) on 1p36; CMD1MM (see previous studies), caused by mutation in the MYBPC3 gene (previous studies) on 11p11; CMD1NN (previous studies), caused by mutation in the RAF1 gene (previous studies) on 3p25; CMD1OO (previous studies), caused by mutation in the VEZF1 gene (previous studies) on chromosome 17q22; and CMD1PP (see previous studies), caused by mutation in the FLNC gene (previous studies) on chromosome 7q32. + +Several additional loci for autosomal dominant familial dilated cardiomyopathy have been mapped: CMD1B (previous studies) on 9q13; CMD1H (previous studies) on 2q14-q22; CMD1K (previous studies) on 6q12-q16; and CMD1Q (previous studies) on 7q22.3-q31.1. + +Autosomal recessive CMD includes CMD2A (previous studies), caused by mutation in the TNNI3 gene (previous studies) on 19q13; CMD2B (previous studies), caused by mutation in the GATAD1 gene (previous studies) on 7q21; CMD2C (previous studies), caused by mutation in the PPCS gene (previous studies) on 1p34; CMD2D (previous studies), caused by mutation in the RPL3L gene (previous studies) on 16p13; CMD2E (previous studies), caused by mutation in the JPH2 gene (previous studies) on chromosome 20q13; CMD2F (previous studies), caused by mutation in the BAG5 gene (previous studies) on chromosome 14q32; CMD2G (previous studies), caused by mutation in the LMOD2 gene (previous studies) on chromosome 7q31; and CMD2H (previous studies), caused by mutation in the GET3 gene (previous studies) on chromosome 19p13. + +An X-linked form of CMD (CMD3B; previous studies) is caused by mutation in the DMD gene (previous studies). An X-linked form previously designated CMD3A was found to be the same as Barth syndrome (previous studies). + + Reclassified CMD Symbols + +The symbol CMD1F was formerly used for a disorder later found to be the same as desmin-related myopathy (previous studies). + +The symbol CMD1N (see previous studies) was previously used for a form of dilated cardiomyopathy reported to be caused by a mutation in the TCAP gene (previous studies); this variant has been reclassified as a variant of unknown significance. + +The symbol CMD1T was previously used for a form of dilated cardiomyopathy reported to be caused by a mutation in the TMPO gene (previous studies); this variant has been reclassified as a variant of unknown significance." +Orphanet_85165,"Definition: Thanatophoric dysplasia is a severe short-limb dwarfism syndrome that is usually lethal in the perinatal period. previous studies classified cases of TD into subtypes based on the presence of curved as opposed to straight femurs; patients with straight, relatively long femurs always had associated severe cloverleaf skull and were designated TD type II (TD2), while TD cases with curved, short femurs with or without cloverleaf skull were designated TD type I (TD1) (previous studies)." +MONDO_0008546,"Definition: Thanatophoric dysplasia is a severe short-limb dwarfism syndrome that is usually lethal in the perinatal period. previous studies classified cases of TD into subtypes based on the presence of curved as opposed to straight femurs; patients with straight, relatively long femurs always had associated severe cloverleaf skull and were designated TD type II (TD2), while TD cases with curved, short femurs with or without cloverleaf skull were designated TD type I (TD1) (previous studies)." +Orphanet_98811,"Definition: GLUT1 deficiency syndrome-2 is an autosomal dominant disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have epilepsy, most commonly childhood absence epilepsy, with an average onset of about 2 to 3 years. Mild mental retardation may also occur. One family has been reported with the additional feature of hemolytic anemia (previous studies). GLUT1 deficiency syndrome-2 shows wide clinical variability both within and between affected families. The disorder, which results from a defect in the GLUT1 glucose transporter causing decreased glucose concentration in the central nervous system, is part of a spectrum of neurologic phenotypes resulting from GLUT1 deficiency. GLUT1 deficiency syndrome-1 (previous studies) represents the more severe end of the phenotypic spectrum. Correct diagnosis of GLUT1 deficiency is important because a ketogenic diet often results in marked clinical improvement in motor and seizure symptoms (reviews by previous studies and previous studies)." +MONDO_0012805,"Definition: GLUT1 deficiency syndrome-2 is an autosomal dominant disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have epilepsy, most commonly childhood absence epilepsy, with an average onset of about 2 to 3 years. Mild mental retardation may also occur. One family has been reported with the additional feature of hemolytic anemia (previous studies). GLUT1 deficiency syndrome-2 shows wide clinical variability both within and between affected families. The disorder, which results from a defect in the GLUT1 glucose transporter causing decreased glucose concentration in the central nervous system, is part of a spectrum of neurologic phenotypes resulting from GLUT1 deficiency. GLUT1 deficiency syndrome-1 (previous studies) represents the more severe end of the phenotypic spectrum. Correct diagnosis of GLUT1 deficiency is important because a ketogenic diet often results in marked clinical improvement in motor and seizure symptoms (reviews by previous studies and previous studies)." +MONDO_0007215,"Definition: In the classification of the brachydactylies, the analysis by previous studies proved highly useful. The type A brachydactylies of Bell have the shortening confined mainly to the middle phalanges. In the A1 type, the middle phalanges of all the digits are rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. + + Genetic Heterogeneity of Brachydactyly Type A1 + +BDA1B (previous studies) has been mapped to chromosome 5. BDA1C (previous studies) is caused by mutation in the GDF5 gene (previous studies) on chromosome 20q11. BDA1D (previous studies) is caused by mutation in the BMPR1B gene (previous studies) on chromosome 4q22." +MONDO_0009603,"Definition: 3-Hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by previous studies)." +Orphanet_88639,"Definition: 3-Hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by previous studies)." +MONDO_0009703,"Definition: Lipid storage myopathy due to FLAD1 deficiency is an autosomal recessive inborn error of metabolism that includes variable mitochondrial dysfunction. The phenotype is extremely heterogeneous: some patients have a severe disorder with onset in infancy and cardiac and respiratory insufficiency resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Some patients show significant improvement with riboflavin treatment (summary by previous studies)." +MONDO_0009855,"Definition: D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (previous studies), caused by mutation in the ACOX1 gene (previous studies) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; previous studies), Zellweger cerebrohepatorenal syndrome (see previous studies) and neonatal adrenoleukodystrophy (NALD; see previous studies) (previous studies). + +DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. previous studies proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; previous studies). previous studies noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed." +MONDO_0011811,"Definition: SCAR4 is an autosomal recessive neurologic disorder characterized by abnormal movements. Most patients have ataxic gait with spasticity and hyperreflexia of the lower limbs resulting in difficulty walking. The age at onset is highly variable: some have onset in early childhood with delayed walking, whereas others have onset of gait difficulties in adulthood. Additional features may include dysarthria, oculomotor abnormalities, distal sensory impairment, dystonia, chorea, hypotonia, pyramidal signs, and cerebellar atrophy on brain imaging. The disorder is slowly progressive. Some patients with onset in childhood may have global developmental delay with mild intellectual disability (summary by previous studies)." +Orphanet_95434,"Definition: SCAR4 is an autosomal recessive neurologic disorder characterized by abnormal movements. Most patients have ataxic gait with spasticity and hyperreflexia of the lower limbs resulting in difficulty walking. The age at onset is highly variable: some have onset in early childhood with delayed walking, whereas others have onset of gait difficulties in adulthood. Additional features may include dysarthria, oculomotor abnormalities, distal sensory impairment, dystonia, chorea, hypotonia, pyramidal signs, and cerebellar atrophy on brain imaging. The disorder is slowly progressive. Some patients with onset in childhood may have global developmental delay with mild intellectual disability (summary by previous studies)." +MONDO_0014873,"Definition: Nevus comedonicus (NC) is a rare type of epidermal nevus with predilection for the face and neck area. The condition develops within the first decade of life in most patients. NC is characterized by dilated, plugged follicular ostia containing lamellar keratinaceous material and grouped in a honeycomb pattern; the distribution of lesions may be unilateral, bilateral, linear, interrupted, segmental, or along the lines of Blaschko. NC may be nonpyogenic with an acne-like appearance or associated with the formation of cysts, papules, pustules, and abscesses. Histologically, the lesions are large, grouped, dilated follicular ostia devoid of hair shafts but filled with keratin layers (summary by previous studies)." +MONDO_0030065,"Definition: Agenesis of corpus callosum, cardiac, ocular, and genital syndrome (ACOGS) is a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, craniofacial dysmorphisms, and ocular, cardiac, and genital anomalies (previous studies)." +MONDO_0032690,"Definition: Microcephaly, growth deficiency, seizures, and brain malformations (MIGSB) is a severe autosomal recessive disorder characterized by intrauterine growth retardation, postnatal growth deficiency with severe microcephaly, and poor or absent psychomotor development. Additional features include optic atrophy, early-onset seizures, dysmorphic facial features, and brain malformations, such as partial agenesis of the corpus callosum and simplified gyration (summary by previous studies)." +MONDO_0800042,"Definition: Restrictive dermopathy is a rare, lethal genodermatosis with characteristic manifestations that are easily recognizable at birth: thin, tightly adherent translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, and generalized joint ankylosis. Prenatal signs can include intrauterine growth retardation, reduced fetal movements, polyhydramnios, and premature rupture of the membranes. Most infants die within the first week of life (summary by previous studies). + + Genetic Heterogeneity of Restrictive Dermopathy + +See also RSMD2 (previous studies), caused by mutation in the LMNA gene (previous studies) on chromosome 1q22." +Orphanet_1662,"Definition: Restrictive dermopathy is a rare, lethal genodermatosis with characteristic manifestations that are easily recognizable at birth: thin, tightly adherent translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, and generalized joint ankylosis. Prenatal signs can include intrauterine growth retardation, reduced fetal movements, polyhydramnios, and premature rupture of the membranes. Most infants die within the first week of life (summary by previous studies). + + Genetic Heterogeneity of Restrictive Dermopathy + +See also RSMD2 (previous studies), caused by mutation in the LMNA gene (previous studies) on chromosome 1q22." +Orphanet_2407,"Definition: Junctional epidermolysis bullosa 2C (JEB2C), also known as laryngoonychocutaneous syndrome (LOCS), is an autosomal recessive disorder characterized by skin erosions, nail dystrophy, dental anomalies, and excessive vascular granulation tissue of the conjunctiva and larynx. Onset is characterized by a hoarse cry soon after birth. Beginning in infancy, chronic skin ulcers and conjunctival lesions appear. Patients may die in childhood secondary to acute or chronic respiratory obstruction. Long-term survivors have visual loss and often require tracheostomy (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +MONDO_0009513,"Definition: Junctional epidermolysis bullosa 2C (JEB2C), also known as laryngoonychocutaneous syndrome (LOCS), is an autosomal recessive disorder characterized by skin erosions, nail dystrophy, dental anomalies, and excessive vascular granulation tissue of the conjunctiva and larynx. Onset is characterized by a hoarse cry soon after birth. Beginning in infancy, chronic skin ulcers and conjunctival lesions appear. Patients may die in childhood secondary to acute or chronic respiratory obstruction. Long-term survivors have visual loss and often require tracheostomy (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +Orphanet_93299,"Definition: The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (previous studies; previous studies). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. + + Classification of Achondrogenesis + +Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). previous studies suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by previous studies and previous studies, and type IB (previous studies), corresponding to the case originally published by previous studies. Analysis of the case reported by previous studies by previous studies suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (previous studies). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. previous studies suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. + + Genetic Heterogeneity of Achondrogenesis + +Achondrogenesis type IB (ACG1B; previous studies) is caused by mutation in the DTDST gene (previous studies), and achondrogenesis type II (ACG2; previous studies) is caused by mutation in the COL2A1 gene (previous studies)." +MONDO_0008701,"Definition: The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (previous studies; previous studies). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. + + Classification of Achondrogenesis + +Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). previous studies suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by previous studies and previous studies, and type IB (previous studies), corresponding to the case originally published by previous studies. Analysis of the case reported by previous studies by previous studies suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (previous studies). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. previous studies suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. + + Genetic Heterogeneity of Achondrogenesis + +Achondrogenesis type IB (ACG1B; previous studies) is caused by mutation in the DTDST gene (previous studies), and achondrogenesis type II (ACG2; previous studies) is caused by mutation in the COL2A1 gene (previous studies)." +EFO_0022192,Definition: Approximately 16% of the world population is predicted to have congenital deficiency of alpha-actinin-3 based on a common nonsense polymorphism in the ACTN3 gene. Expression of alpha-actinin-3 is limited to a subset of type 2 (fast) fibers. No disease phenotype is associated with this deficiency (previous studies). +MONDO_0007646,"Definition: NMAN is an autosomal recessive neurologic disorder characterized by onset in the first or second decade of a peripheral axonal neuropathy predominantly affecting motor more than sensory nerves. The axonal neuropathy is reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A1, previous studies) and distal hereditary motor neuropathy (see, e.g., HMN1, previous studies). Individuals with NMAN also have delayed muscle relaxation and action myotonia associated with neuromyotonic discharges on needle EMG resulting from hyperexcitability of the peripheral nerves (summary by previous studies)." +Orphanet_324442,"Definition: NMAN is an autosomal recessive neurologic disorder characterized by onset in the first or second decade of a peripheral axonal neuropathy predominantly affecting motor more than sensory nerves. The axonal neuropathy is reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A1, previous studies) and distal hereditary motor neuropathy (see, e.g., HMN1, previous studies). Individuals with NMAN also have delayed muscle relaxation and action myotonia associated with neuromyotonic discharges on needle EMG resulting from hyperexcitability of the peripheral nerves (summary by previous studies)." +MONDO_0008582,"Definition: Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. + +Witkop syndrome is a rare autosomal dominant ectodermal dysplasia involving the teeth and nails. Although a few reported cases have sparse or fine hair, almost all affected individuals have normal hair, sweat glands, and ability to tolerate heat. Affected individuals have a variable number and variable types of congenitally missing permanent and/or primary teeth, which frequently results in lip eversion due to loss of occlusion in the vertical dimension. Nails are generally thin, slow-growing, brittle, and spoon-shaped (koilonychia). Toenails are usually more severely affected than fingernails. The nail defects are alleviated with age and may not be easily detectable during adulthood (summary by previous studies)." +Orphanet_2228,"Definition: Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. + +Witkop syndrome is a rare autosomal dominant ectodermal dysplasia involving the teeth and nails. Although a few reported cases have sparse or fine hair, almost all affected individuals have normal hair, sweat glands, and ability to tolerate heat. Affected individuals have a variable number and variable types of congenitally missing permanent and/or primary teeth, which frequently results in lip eversion due to loss of occlusion in the vertical dimension. Nails are generally thin, slow-growing, brittle, and spoon-shaped (koilonychia). Toenails are usually more severely affected than fingernails. The nail defects are alleviated with age and may not be easily detectable during adulthood (summary by previous studies)." +MONDO_0008703,"Definition: Acromesomelic dysplasia-2A (AMD2A), or Grebe chondrodysplasia, is an autosomal recessive disorder characterized by severe abnormality of the limbs and limb joints. The severity of limb shortening progresses in a proximal-distal gradient, with the hands and feet being most affected. The fingers and toes lack articulation and appear as skin appendages. In contrast, axial skeletal structures and the craniofacial skeleton are not affected. Heterozygous individuals are of average stature and have mild skeletal abnormalities (summary by previous studies). Because Grebe syndrome exhibits increasing severity in a proximal-distal gradient, it is classified as a form of acromesomelic dysplasia (previous studies). + +For discussion of the genetic heterogeneity of acromesomelic dysplasia, see AMD1 (previous studies)." +Orphanet_2098,"Definition: Acromesomelic dysplasia-2A (AMD2A), or Grebe chondrodysplasia, is an autosomal recessive disorder characterized by severe abnormality of the limbs and limb joints. The severity of limb shortening progresses in a proximal-distal gradient, with the hands and feet being most affected. The fingers and toes lack articulation and appear as skin appendages. In contrast, axial skeletal structures and the craniofacial skeleton are not affected. Heterozygous individuals are of average stature and have mild skeletal abnormalities (summary by previous studies). Because Grebe syndrome exhibits increasing severity in a proximal-distal gradient, it is classified as a form of acromesomelic dysplasia (previous studies). + +For discussion of the genetic heterogeneity of acromesomelic dysplasia, see AMD1 (previous studies)." +MONDO_0011150,"Definition: Penttinen syndrome is characterized by a prematurely aged appearance involving lipoatrophy and epidermal and dermal atrophy, as well as hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acroosteolysis (previous studies)." +MONDO_0011911,"Definition: Craniolenticulosutural dysplasia is characterized by facial dysmorphism, late-closing fontanels, cataract, and skeletal defects (summary by previous studies)." +MONDO_0013570,"Definition: COXPD8 is an autosomal recessive disorder due to dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0014290,"Definition: Neurodegeneration with brain iron accumulation refers to a group of neurodegenerative disorders characterized by progressive motor and cognitive dysfunction beginning in childhood or young adulthood. Patients show extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism. Brain imaging shows iron accumulation in the basal ganglia (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (previous studies)." +Orphanet_397725,"Definition: Neurodegeneration with brain iron accumulation refers to a group of neurodegenerative disorders characterized by progressive motor and cognitive dysfunction beginning in childhood or young adulthood. Patients show extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism. Brain imaging shows iron accumulation in the basal ganglia (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (previous studies)." +MONDO_0014725,"Definition: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures (summary by previous studies and previous studies)." +MONDO_0030905,"Definition: Autosomal recessive deafness-117 (DFNB117) is characterized by nonsyndromic bilateral moderate-to-profound sensorineural deafness, with onset in early childhood (previous studies)." +MONDO_0033548,"Definition: Congenital myopathy-17 (CMYP17) is an autosomal recessive muscle disorder. Affected individuals present at birth with hypotonia and respiratory insufficiency associated with high diaphragmatic dome on imaging. Other features include poor overall growth, pectus excavatum, dysmorphic facies, and renal anomalies in some. The severity of the disorder is highly variable: some patients may have delayed motor development with mildly decreased endurance, whereas others have more severe hypotonia associated with distal arthrogryposis and lung hypoplasia, resulting in early death (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0054695,"Definition: Centronuclear myopathy-6 with fiber-type disproportion (CNM6) is an autosomal recessive, slowly progressive congenital myopathy with onset in infancy or early childhood. Patients may be hypotonic at birth, but all show delayed motor development and walking difficulties due to muscle weakness mainly affecting the proximal lower and upper limbs. Other features include scapular winging, scoliosis, and mildly decreased respiratory vital capacity. The phenotype and muscle biopsy abnormalities are variable, although centralized nuclei and fiber-type disproportion appear to be a common finding on muscle biopsy (summary by previous studies). + +For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (previous studies)." +Orphanet_1173,"Definition: Gordon Holmes syndrome (GDHS) is an autosomal recessive adult-onset neurodegenerative disorder characterized by progressive cognitive decline, dementia, and variable movement disorders, such as ataxia and chorea. The neurologic phenotype is associated with hypogonadotropic hypogonadism (summary by previous studies)." +MONDO_0008935,"Definition: Gordon Holmes syndrome (GDHS) is an autosomal recessive adult-onset neurodegenerative disorder characterized by progressive cognitive decline, dementia, and variable movement disorders, such as ataxia and chorea. The neurologic phenotype is associated with hypogonadotropic hypogonadism (summary by previous studies)." +Orphanet_391311,"Definition: IMD31B results from autosomal recessive (AR) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (previous studies)/IFNB (previous studies) (type I interferon) and IFNG (previous studies) (type III interferon). AR STAT1 deficiency affects both the IFNA/IFNB and the IFNG pathways, resulting in susceptibility to mycobacteria, Salmonella, and viruses, with a severe disease course and often fatal outcome (review by previous studies)." +Orphanet_79399,"Definition: Generalized intermediate epidermolysis bullosa simplex-1B (EBS1B) is an autosomal dominant disorder of skin in which intraepidermal blistering occurs after minor mechanical trauma. Skin blistering is generalized, begins at birth, and is worsened by heat, humidity, and sweating. The tendency to blistering diminishes in adolescence, when it may become localized to hands and feet. Intermediate EBS has previously been known as the Koebner type (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies provided a revised classification of the subtypes of inherited epidermolysis bullosa based on clinical and laboratory criteria. + +previous studies reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system. + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility." +MONDO_0007554,"Definition: Generalized intermediate epidermolysis bullosa simplex-1B (EBS1B) is an autosomal dominant disorder of skin in which intraepidermal blistering occurs after minor mechanical trauma. Skin blistering is generalized, begins at birth, and is worsened by heat, humidity, and sweating. The tendency to blistering diminishes in adolescence, when it may become localized to hands and feet. Intermediate EBS has previously been known as the Koebner type (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies provided a revised classification of the subtypes of inherited epidermolysis bullosa based on clinical and laboratory criteria. + +previous studies reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system. + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility." +EFO_0010659,"Definition: Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by previous studies)." +HP_0002110,"Definition: Patients with bronchiectasis with or without elevated sweat chloride-2 (BESC2) have bronchiectasis and chronic bronchitis of varying severity. Pancreatic insufficiency may be present (previous studies). + +For discussion of genetic heterogeneity in bronchiectasis with or without elevated sweat chloride, see BESC1 (previous studies)." +MONDO_0007154,"Definition: Arteriovenous malformations of the brain are tortuous, morphologically abnormal vascular channels between arteries and veins that lack an intervening capillary network, allowing high-pressure arterial blood from feeding arteries to shunt directly into the venous outflow system. These vascular malformations occur in approximately 15 per 100,000 persons and are a leading cause of hemorrhagic stroke in young adults and children (summary by previous studies)." +Orphanet_46724,"Definition: Arteriovenous malformations of the brain are tortuous, morphologically abnormal vascular channels between arteries and veins that lack an intervening capillary network, allowing high-pressure arterial blood from feeding arteries to shunt directly into the venous outflow system. These vascular malformations occur in approximately 15 per 100,000 persons and are a leading cause of hemorrhagic stroke in young adults and children (summary by previous studies)." +MONDO_0007424,"Definition: DFNA1 is an autosomal dominant form of progressive hearing loss with onset in the first decade. Some patients have mild thrombocytopenia and enlarged platelets, although most of these individuals do not have significant bleeding tendencies (summary by previous studies)." +MONDO_0008999,"Definition: Cohen syndrome is an autosomal recessive multisystem disorder characterized by many clinical features, including facial dysmorphism, microcephaly, truncal obesity, impaired intellectual development, progressive retinopathy, and intermittent congenital neutropenia (summary by previous studies)." +MONDO_0010006,"Definition: Sandhoff disease is a progressive neurodegenerative disorder characterized by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease (previous studies)." +MONDO_0010099,"Definition: The GM2-gangliosidoses are a group of disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes, mainly of neuronal cells. GM2-gangliosidosis AB variant is characterized by normal hexosaminidase A (HEXA; previous studies) and hexosaminidase B (HEXB; previous studies) but the inability to form a functional GM2 activator complex. The clinical and biochemical phenotype of the AB variant is very similar to that of classic Tay-Sachs disease (see previous studies) (previous studies)." +Orphanet_309246,"Definition: The GM2-gangliosidoses are a group of disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes, mainly of neuronal cells. GM2-gangliosidosis AB variant is characterized by normal hexosaminidase A (HEXA; previous studies) and hexosaminidase B (HEXB; previous studies) but the inability to form a functional GM2 activator complex. The clinical and biochemical phenotype of the AB variant is very similar to that of classic Tay-Sachs disease (see previous studies) (previous studies)." +MONDO_0010444,"Definition: XLANP is an X-linked recessive hematologic disorder characterized by early-onset anemia and bone marrow erythroid hypoplasia with variable neutropenia. Some patients may have low platelets or platelet abnormalities. The severity is variable. Some patients have shown a favorable response to corticosteroid treatment (summary by previous studies and previous studies). + +In some cases, the disorder may resemble Diamond-Blackfan anemia (see, e.g., DBA1; previous studies) (previous studies; previous studies; previous studies)." +MONDO_0012538,"Definition: Nemaline myopathy-7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (summary by previous studies). + +For a discussion of genetic heterogeneity of nemaline myopathy, see previous studies." +MONDO_0012912,"Definition: Patients with pseudopseudohypoparathyroidism do not show resistance to parathyroid hormone (PTH; previous studies) or other hormones, as is the case with PHP1A (previous studies), but do manifest the constellation of clinical features referred to as Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation (previous studies; previous studies; previous studies). + +PPHP occurs only after paternal inheritance of the molecular defect, whereas PHP1A occurs only after maternal inheritance of the molecular defect (see Inheritance and Pathogenesis below). This is an example of imprinting, with differential gene expression depending on the parent of origin of the allele (previous studies; previous studies). + +For a general phenotypic description, classification, and a discussion of molecular genetics of pseudohypoparathyroidism, see PHP1A (previous studies)." +Orphanet_665,"Definition: Patients with pseudopseudohypoparathyroidism do not show resistance to parathyroid hormone (PTH; previous studies) or other hormones, as is the case with PHP1A (previous studies), but do manifest the constellation of clinical features referred to as Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation (previous studies; previous studies; previous studies). + +PPHP occurs only after paternal inheritance of the molecular defect, whereas PHP1A occurs only after maternal inheritance of the molecular defect (see Inheritance and Pathogenesis below). This is an example of imprinting, with differential gene expression depending on the parent of origin of the allele (previous studies; previous studies). + +For a general phenotypic description, classification, and a discussion of molecular genetics of pseudohypoparathyroidism, see PHP1A (previous studies)." +MONDO_0014058,"Definition: FILS syndrome is characterized by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, immunodeficiency resulting in recurrent infections, and short stature (summary by previous studies)." +Orphanet_352712,"Definition: FILS syndrome is characterized by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, immunodeficiency resulting in recurrent infections, and short stature (summary by previous studies)." +MONDO_0030827,"Definition: Autosomal dominant isolated macrothrombocytopenia-2 (MACTHC2) is characterized by the finding of low platelet numbers and abnormally large platelets with irregular shapes. Affected individuals do not have increased bleeding episodes; macrothrombocytopenia is usually an incidental laboratory finding (previous studies) + +For a discussion of genetic heterogeneity of MACTHC, see MACTHC1 (previous studies)." +Orphanet_3115,"Definition: Roussy-Levy syndrome is an autosomal dominant disorder characterized by early onset of prominent ataxia followed by late onset of mild motor involvement. Symptoms progress very slowly, and affected individuals may remain ambulatory throughout life (previous studies; previous studies)." +MONDO_0008392,"Definition: Roussy-Levy syndrome is an autosomal dominant disorder characterized by early onset of prominent ataxia followed by late onset of mild motor involvement. Symptoms progress very slowly, and affected individuals may remain ambulatory throughout life (previous studies; previous studies)." +MONDO_0008992,"Definition: Juberg-Hayward syndrome (JHS) is characterized by cleft lip and palate, rhizomelia of the upper limbs with limited elbow extension due to humeroradial synostosis or dislocation of the radial head, and digital anomalies, including shortened thumbs and index and fifth fingers. Microcephaly has been observed in some patients (previous studies)." +MONDO_0010027,"Definition: Sialic acid storage diseases are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or as a slowly progressive adult form that is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia, and mental retardation; visceromegaly and coarse features are also present in the infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by MRI. Enlarged lysosomes are seen on electron microscopic studies, and patients excrete large amounts of free sialic acid in the urine (previous studies)." +MONDO_0012783,"Definition: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (previous studies). + +For a discussion of the classification of CDGs, see CDG1A (previous studies)." +MONDO_0012868,"Definition: Heterozygous protein S deficiency, like protein C deficiency (previous studies), is characterized by recurrent venous thrombosis. previous studies classified protein S deficiency into 3 clinical subtypes based on laboratory findings. Type I refers to deficiency of both free and total protein S as well as decreased protein S activity; type II shows normal plasma values, but decreased protein S activity; and type III shows decreased free protein S levels and activity, but normal total protein S levels. Approximately 40% of protein S circulates as a free active form, whereas the remaining 60% circulates as an inactive form bound to C4BPA (previous studies). + +previous studies observed coexistence of type I and type III PROS1-deficient phenotypes within a single family and determined that the subtypes are allelic. Under normal conditions, the concentration of protein S exceeds that of C4BPA by approximately 30 to 40%. Thus, free protein S is the molar surplus of protein S over C4BPA. Mild protein S deficiency will thus present with selective deficiency of free protein S, whereas more pronounced protein S deficiency will also decrease the complexed protein S and consequently the total protein S level. These findings explained why assays for free protein S have a higher predictive value for protein S deficiency. + +See also autosomal recessive thrombophilia due to protein S deficiency (THPH6; previous studies), which is a more severe disorder." +MONDO_0054730,"Definition: Spermatogenic failure-26 is characterized by acephalic spermatozoa, due to breakage that occurs in the midpiece of the sperm (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +Orphanet_2598,"Definition: Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow (previous studies). + + Genetic Heterogeneity of Myopathy, Lactic Acidosis, and Sideroblastic Anemia + +MLASA2 (previous studies) is caused by mutation in the YARS2 gene (previous studies) on chromosome 12p11. MLASA3 (previous studies) is caused by heteroplasmic mutation in the mitochondrially-encoded MTATP6 gene (previous studies)." +EFO_0004149,"Definition: Congenital hypomyelinating neuropathy-2 is an autosomal dominant neurologic disorder characterized by early-onset hypotonia, severely delayed motor development, muscle weakness with areflexia, and severely decreased nerve conduction velocities (NCV) resulting from improper myelination of axons. The severity is variable: some patients may present at birth with contractures and respiratory insufficiency, whereas others may achieve walking (summary by previous studies). + +CHN shows significant phenotypic overlap with Dejerine-Sottas syndrome (DSS; previous studies), which is also a neuropathy with early onset. Some classify the disorders differently, noting that CHN is characterized by hypo- or amyelination resulting from a congenital defect in myelin formation, whereas DSS has features of continuous myelin breakdown, with demyelination and remyelination (summary by previous studies). + +For a discussion of genetic heterogeneity of CHN, see CHN1 (previous studies)." +MONDO_0008471,"Definition: Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by previous studies)." +MONDO_0009026,"Definition: Costello syndrome is a rare multiple congenital anomaly syndrome associated in all cases with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood (previous studies). + +In patients with a clinical diagnosis of Costello syndrome, previous studies identified mutations in the KRAS gene, but noted that these patients may later develop features of CFC syndrome. In either case, the findings underscore the central role of Ras in the pathogenesis of these phenotypically related disorders (previous studies). However, previous studies commented that the diagnosis of Costello syndrome should only be used to refer to patients with mutations in the HRAS gene." +MONDO_0009141,"Definition: Torsion dystonia-2 is an autosomal recessive neurologic disorder characterized by onset of symptoms in childhood or adolescence. 'Dystonia' is characterized by involuntary, sustained muscle contractions affecting 1 or more sites of the body; 'torsion' refers to the twisting nature of body movements observed in dystonia. DYT2 first affects distal limbs and later involves the neck, orofacial, and craniocervical regions. DYT2 is slowly progressive but mild overall (summary by previous studies; previous studies; previous studies)." +MONDO_0009262,"Definition: GM1-gangliosidosis type III (GM1G3) is an autosomal recessive lysosomal storage disorder characterized by neurodegeneration and mild skeletal changes. Age at onset ranges from 3 to 30 years. The disorder is less severe than GM1-gangliosidosis types I and II (previous studies). Type III shows extreme clinical variability, with some patients having only focal neurologic signs, such as dystonia, and others having more severe involvement with extrapyramidal signs and mental retardation. GLB1 enzymatic activity usually ranges from approximately 4 to 10% of control values (previous studies)." +MONDO_0010068,"Definition: Sponastrime dysplasia is an autosomal recessive spondyloepimetaphyseal dysplasia (SEMD) named for characteristic clinical and radiographic findings, including spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, and striation of the metaphyses. Additional features include disproportionate short stature with exaggerated lumbar lordosis, scoliosis, coxa vara, limited elbow extension, small dysplastic epiphyses, childhood cataracts, short dental roots, and hypogammaglobulinemia. Radiographically, the abnormalities of the lumbar vertebral bodies are suggested to be the most specific finding because the characteristic metaphyseal striations may not be apparent at young ages. Striking clinical variability in presentation, severity, and associated features has been observed (summary by previous studies)." +Orphanet_93357,"Definition: Sponastrime dysplasia is an autosomal recessive spondyloepimetaphyseal dysplasia (SEMD) named for characteristic clinical and radiographic findings, including spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, and striation of the metaphyses. Additional features include disproportionate short stature with exaggerated lumbar lordosis, scoliosis, coxa vara, limited elbow extension, small dysplastic epiphyses, childhood cataracts, short dental roots, and hypogammaglobulinemia. Radiographically, the abnormalities of the lumbar vertebral bodies are suggested to be the most specific finding because the characteristic metaphyseal striations may not be apparent at young ages. Striking clinical variability in presentation, severity, and associated features has been observed (summary by previous studies)." +MONDO_0010598,"Definition: Glycogen storage disease type IX is a metabolic disorder resulting from a deficiency of hepatic phosphorylase kinase, a hexadecameric enzyme comprising 4 copies each of 4 unique subunits encoded by 4 different genes: alpha (PHKA2), beta (PHKB; previous studies), gamma (PHKG2; previous studies), and delta (CALM1; previous studies). Mutations within the PHKA2, PHKB, and PHKG2 genes result in GSD9A, GSD9B (previous studies), and GSD9C (previous studies), respectively. GSD IXa is an X-linked recessive disorder, whereas the others are autosomal recessive. + +GSD IXa has been further divided into types IXa1 (GSD9A1), with no PHK activity in liver or erythrocytes, and IXa2 (GSD9A2), with no PHK in liver, but normal activity in erythrocytes. The clinical presentation of both subtypes is the same, and both are caused by mutations in the PHKA2 gene. However, mutations that result in IXa2 are either missense or small in-frame deletions or insertions enabling residual enzyme expression in erythrocytes (previous studies; previous studies; previous studies). + +See also X-linked muscle PHK deficiency (GSD9D; previous studies), caused by mutation in the gene encoding the muscle-specific alpha PHK subunit (PHKA1; previous studies)." +MONDO_0012173,"Definition: Isolated deficiency of long-chain 3-hydroxyl-CoA dehydrogenase (LCHAD) is an autosomal recessive disorder characterized by early-onset cardiomyopathy, hypoglycemia, neuropathy, and pigmentary retinopathy, and sudden death (previous studies)." +MONDO_0012238,"Definition: Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe (previous studies; previous studies). + +PEO caused by mutations in the POLG gene are associated with more complicated phenotypes than those forms caused by mutations in the ANT1 or C10ORF2 genes (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (previous studies)." +MONDO_0013161,"Definition: MDDGC3 is a rare form of autosomal recessive limb-girdle muscular dystrophy with normal cognition (previous studies). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (previous studies)." +MONDO_0014014,"Definition: Autosomal recessive localized or generalized intermediate epidermolysis bullosa simplex-4 (EBS4) is a rare disorder characterized by mild skin fragility with onset at birth or in early childhood, associated with acral blistering with hemorrhagic crusts. Skin fragility improves with age in most patients, although mottled pigmentation may later develop on the trunk and proximal limbs. Histology shows intrabasal cleavage (previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0017380,"Definition: Juvenile polyposis syndrome is an autosomal dominant condition that predisposes gene carriers to various types of tumors. The diagnosis is based on the occurrence of hamartomatous gastrointestinal polyps that turn into malignant lesions in approximately 20% of cases (previous studies). + +It had been suggested that juvenile polyposis can be caused by mutations in the PTEN gene (previous studies), the same gene that is mutant in Cowden syndrome-1 (previous studies). In a comprehensive review of PTEN, previous studies concluded that juvenile intestinal polyposis is not a so-called PTEN hamartoma-tumor syndrome (PHTS). They suggested that the discovery of the germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect and that such an individual should be managed medically in the same manner as all patients with PHTS." +MONDO_0024522,"Definition: Primary localized cutaneous amyloidosis is characterized clinically by pruritus and skin scratching and histologically by the finding of deposits of amyloid staining on keratinous debris in the papillary dermis (summary by previous studies). + + Genetic Heterogeneity of Primary Localized Cutaneous Amyloidosis + +Primary localized cutaneous amyloidosis-2 (PLCA2; previous studies) is caused by heterozygous mutation in the IL31RA gene (previous studies) on chromosome 5q11. Primary localized cutaneous amyloidosis-3 (PLCA3; previous studies) is caused by mutation in the GPNMB gene (previous studies) on chromosome 7p15." +EFO_1001882,"Definition: Primary localized cutaneous amyloidosis is characterized clinically by pruritus and skin scratching and histologically by the finding of deposits of amyloid staining on keratinous debris in the papillary dermis (summary by previous studies). + + Genetic Heterogeneity of Primary Localized Cutaneous Amyloidosis + +Primary localized cutaneous amyloidosis-2 (PLCA2; previous studies) is caused by heterozygous mutation in the IL31RA gene (previous studies) on chromosome 5q11. Primary localized cutaneous amyloidosis-3 (PLCA3; previous studies) is caused by mutation in the GPNMB gene (previous studies) on chromosome 7p15." +MONDO_0031061,"Definition: Nephrotic syndrome type 26 (NPHS26) is an autosomal recessive renal disorder characterized by onset of proteinuria in the first months or years of life. Other features may include edema and hypoalbuminemia. Renal biopsy shows focal segmental glomerulosclerosis (FSGS), diffuse mesangial sclerosis (DMS), abnormalities of the glomerular basement membrane, and effacement of podocyte foot processes. There is variability in disease progression and response to treatment: some patients respond to steroids, whereas others show steroid resistance and progression to end-stage renal disease (ESRD) (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (previous studies)." +MONDO_0032903,"Definition: Neurogenic arthrogryposis multiplex congenita-4 with agenesis of the corpus callosum (AMC4) is a severe neurologic disorder with onset in utero. Affected individuals show little or no fetal movements and are born with significant contractures affecting the upper and lower limbs, as well as dysmorphic facial features. Other abnormalities include globally impaired development, optic atrophy, agenesis of the corpus callosum, seizures, and peripheral neuropathy. Many patients die in early childhood (summary by previous studies)." +MONDO_0060555,"Definition: VCRL2 is an autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal, and distal mild limb defects. Additional features are variable (summary by previous studies). + +For a discussion of genetic heterogeneity of VCRL, see VCRL1 (previous studies)." +Orphanet_100031,Definition: Hypoplastic amelogenesis imperfecta IA is characterized by enamel that may not develop to normal thickness. The enamel may have pits on the labial or buccal surfaces that are often arranged in rows and columns (see previous studies). +Orphanet_199241,"Definition: Pulmonary venoocclusive disease-2 is an autosomal recessive subtype of primary pulmonary hypertension (PPH; see previous studies). It is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules, and is frequently associated with pulmonary capillary dilatation and proliferation. The disorder can cause occult alveolar hemorrhage. High-resolution CT imaging of the chest shows patchy centrilobular ground-glass opacities, septal lines, and lymph node enlargement (summary by previous studies). + +For a discussion of genetic heterogeneity of pulmonary venoocclusive disease, see PVOD1 (previous studies)." +MONDO_0009329,"Definition: Pulmonary venoocclusive disease-2 is an autosomal recessive subtype of primary pulmonary hypertension (PPH; see previous studies). It is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules, and is frequently associated with pulmonary capillary dilatation and proliferation. The disorder can cause occult alveolar hemorrhage. High-resolution CT imaging of the chest shows patchy centrilobular ground-glass opacities, septal lines, and lymph node enlargement (summary by previous studies). + +For a discussion of genetic heterogeneity of pulmonary venoocclusive disease, see PVOD1 (previous studies)." +Orphanet_306511,"Definition: Spastic paraplegia-48 (SPG48) is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +MONDO_0013342,"Definition: Spastic paraplegia-48 (SPG48) is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +Orphanet_314629,"Definition: Neuronal ceroid lipofuscinosis-11 is an autosomal recessive neurologic disorder characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0013866,"Definition: Neuronal ceroid lipofuscinosis-11 is an autosomal recessive neurologic disorder characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_90309,"Definition: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (previous studies). + + Genetic Heterogeneity of Classic Ehlers-Danlos Syndrome + +See EDSCL2 (previous studies), caused by mutation in the COL5A2 gene (previous studies) on chromosome 2q32. + + Classification of Ehlers-Danlos Syndrome + +The current OMIM classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by previous studies, which recognizes 13 EDS subtypes: classic, classic-like (previous studies, previous studies), cardiac-valvular (previous studies), vascular (previous studies), hypermobile (previous studies), arthrochalasia (previous studies, previous studies), dermatosparaxis (previous studies), kyphoscoliotic (previous studies, previous studies), spondylodysplastic (previous studies, previous studies), musculocontractural (previous studies, previous studies), myopathic (previous studies), periodontal (previous studies, previous studies), and brittle cornea syndrome (previous studies, previous studies). This classification is a revision of the 'Villefranche classification' reported by previous studies, which was widely used in the literature and in OMIM. For a description of the Villefranche classification, see HISTORY. + +In an early classification of EDS, the designations EDS I and EDS II were used for severe and mild forms of classic EDS, respectively. EDS I was characterized by marked skin involvement and generalized, gross joint laxity, with musculoskeletal deformity and diverse orthopedic complications. Prematurity occurred in approximately 50% of cases. Internal complications such as aortic and bowel rupture were occasionally present. EDS II had all the stigmata of EDS I, but to a minor degree (summary by previous studies). Both were considered to be forms of classic EDS." +MONDO_0019567,"Definition: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (previous studies). + + Genetic Heterogeneity of Classic Ehlers-Danlos Syndrome + +See EDSCL2 (previous studies), caused by mutation in the COL5A2 gene (previous studies) on chromosome 2q32. + + Classification of Ehlers-Danlos Syndrome + +The current OMIM classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by previous studies, which recognizes 13 EDS subtypes: classic, classic-like (previous studies, previous studies), cardiac-valvular (previous studies), vascular (previous studies), hypermobile (previous studies), arthrochalasia (previous studies, previous studies), dermatosparaxis (previous studies), kyphoscoliotic (previous studies, previous studies), spondylodysplastic (previous studies, previous studies), musculocontractural (previous studies, previous studies), myopathic (previous studies), periodontal (previous studies, previous studies), and brittle cornea syndrome (previous studies, previous studies). This classification is a revision of the 'Villefranche classification' reported by previous studies, which was widely used in the literature and in OMIM. For a description of the Villefranche classification, see HISTORY. + +In an early classification of EDS, the designations EDS I and EDS II were used for severe and mild forms of classic EDS, respectively. EDS I was characterized by marked skin involvement and generalized, gross joint laxity, with musculoskeletal deformity and diverse orthopedic complications. Prematurity occurred in approximately 50% of cases. Internal complications such as aortic and bowel rupture were occasionally present. EDS II had all the stigmata of EDS I, but to a minor degree (summary by previous studies). Both were considered to be forms of classic EDS." +Orphanet_931,"Definition: Acheiropody is characterized by bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. Specific patterns of malformations consist of a complete amputation of the distal epiphysis of the humerus, amputation of the distal part of the tibial diaphysis, and aplasia of the radius, ulna, fibula, and of the carpal, metacarpal, tarsal, metatarsal, and phalangeal bones (summary by previous studies)." +MONDO_0008700,"Definition: Acheiropody is characterized by bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. Specific patterns of malformations consist of a complete amputation of the distal epiphysis of the humerus, amputation of the distal part of the tibial diaphysis, and aplasia of the radius, ulna, fibula, and of the carpal, metacarpal, tarsal, metatarsal, and phalangeal bones (summary by previous studies)." +EFO_0000218,"Definition: Familial erythroleukemia is a leukemic or preleukemic state in which red cell proliferation is the predominant feature. Hematologic characteristics include particularly ineffective and hyperplastic erythropoiesis with megaloblastic components accompanied by myeloblastic proliferation of varying degree (previous studies). + +previous studies discussed the evolution of the definition of 'erythroleukemia,' which is considered by most to be a subtype of acute myelogenous leukemia (AML; previous studies). Controversy about the precise definition of erythroleukemia revolves around the number or percentage of erythroblasts and myeloblasts found in the bone marrow and peripheral circulation. In the French-American-British (FAB) classification system (previous studies), it is known as AML-M6, whereas in the revised World Health Organization (WHO) classification system (previous studies), it is known as 'AML, not otherwise categorized' (previous studies)." +MONDO_0007636,"Definition: The term frontonasal dysplasia was coined by previous studies to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see previous studies); and (7) a V-shaped or widow's peak frontal hairline (previous studies). Most reported cases are sporadic, but a few familial cases have been reported. + +previous studies characterized frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features. + +Also see acromelic frontonasal dysplasia (AFND; previous studies), frontofacionasal dysplasia (FFND; previous studies), oculoauriculofrontonasal syndrome (OAFNS; previous studies), the acrofrontofacionasal dysostosis syndromes (previous studies, previous studies), and craniofrontonasal syndrome (previous studies). + + Genetic Heterogeneity of Frontonasal Dysplasia + +Frontonasal dysplasia-2 (FND2; previous studies) is caused by mutation in the ALX4 gene (previous studies) on chromosome 11p11. Frontonasal dysplasia-3 (FND3; previous studies) is caused by mutation in the ALX1 gene (previous studies) on chromosome 12q21." +MONDO_0008746,"Definition: Tyrosinase-positive oculocutaneous albinism (OCA, type II; OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Although affected infants may appear at birth to have OCA type I, or complete absence of melanin pigment, most patients with OCA type II acquire small amounts of pigment with age. Individuals with OCA type II have the characteristic visual anomalies associated with albinism, including decreased acuity and nystagmus, which are usually less severe than in OCA type I (previous studies; previous studies). + +OCA type II has a highly variable phenotype. The hair of affected individuals may turn darker with age, and pigmented nevi or freckles may be seen. African and African American individuals may have yellow hair and blue-gray or hazel irides. One phenotypic variant, 'brown OCA,' has been described in African and African American populations and is characterized by light brown hair and skin color and gray to tan irides. The hair and irides may turn darker with time and the skin may tan with sun exposure; the ocular features of albinism are present in all variants (previous studies). In addition, previous reports of so-called 'autosomal recessive ocular albinism,' (see, e.g., previous studies and previous studies) with little or no obvious skin involvement, are now considered most likely to be part of the phenotypic spectrum of OCA1 or OCA2 (previous studies; previous studies)." +MONDO_0009902,"Definition: The porphyrias are diseases caused by defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver (previous studies). + +previous studies provided a comprehensive review of congenital erythropoietic porphyria pathogenesis and treatment. + +One patient with a phenotype suggestive of congenital erythropoietic anemia was found to have a mutation in the GATA1 gene (previous studies) that affected UROS expression (see XLTT, previous studies)." +Orphanet_79277,"Definition: The porphyrias are diseases caused by defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver (previous studies). + +previous studies provided a comprehensive review of congenital erythropoietic porphyria pathogenesis and treatment. + +One patient with a phenotype suggestive of congenital erythropoietic anemia was found to have a mutation in the GATA1 gene (previous studies) that affected UROS expression (see XLTT, previous studies)." +MONDO_0010130,"Definition: Dihyropyrimidine dehydrogenase deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation in homozygous patients. In addition, homozygous and heterozygous mutation carriers can develop severe toxicity after the administration of the antineoplastic drug 5-fluorouracil (5FU), which is also catabolized by the DPYD enzyme. This is an example of a pharmacogenetic disorder (previous studies). + +Since there is no correlation between genotype and phenotype in DPD deficiency, it appears that the deficiency is a necessary, but not sufficient, prerequisite for the development of clinical abnormalities (previous studies; previous studies)." +MONDO_0010476,"Definition: NBIA5, sometimes referred to as 'static encephalopathy of childhood with neurodegeneration in adulthood (SENDA),' is an X-linked neurodegenerative disorder characterized by global developmental delay in early childhood that is essentially static, with slow motor and cognitive gains until adolescence or early adulthood. In young adulthood, affected individuals develop progressive dystonia, parkinsonism, extrapyramidal signs, and dementia resulting in severe disability. Brain MRI shows iron accumulation in the globus pallidus and substantia nigra. A characteristic finding is T1-weighted hyperintensity surrounding a central band of hypointensity in the substantia nigra. Cerebral and cerebellar atrophy are also observed (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (previous studies)." +MONDO_0011837,"Definition: Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of combined deficiency of vitamin K-dependent clotting factors, see VKCFD1 (previous studies)." +MONDO_0013220,"Definition: Juvenile, or type 2, hemochromatosis is an autosomal recessive inborn error of iron metabolism that leads to severe iron loading and organ failure before 30 years of age (summary by previous studies). HFE2B is caused by mutation in the HAMP gene (previous studies). HFE2 is genetically heterogeneous (see HFE2A, previous studies)." +MONDO_0013997,"Definition: The focal dermal dysplasias (FFDDs) are a group of related developmental defects characterized by bitemporal or preauricular skin lesions resembling aplasia cutis congenita. FFDD4 is characterized by isolated, preauricular skin lesions (summary by previous studies). + +For a classification and a discussion of genetic heterogeneity of FFDD, see FFDD1 (previous studies)." +MONDO_0018945,"Definition: Hematologically, McLeod syndrome is characterized by the absence of red blood cell Kx antigen, weak expression of Kell red blood cell antigens, acanthocytosis, and compensated hemolysis. Most carriers of this McLeod blood group phenotype have acanthocytosis and elevated serum creatine kinase levels and are prone to develop a severe neurologic disorder resembling Huntington disease (previous studies). Onset of neurologic symptoms ranges between 25 and 60 years (mean onset 30-40 years), and penetrance appears to be high. Additional symptoms include generalized seizures, neuromuscular symptoms leading to weakness and atrophy, and cardiomyopathy mainly manifesting with atrial fibrillation, malignant arrhythmias, and dilated cardiomyopathy (summary by previous studies). + +The cooccurrence of McLeod syndrome and chronic granulomatous disease (CGD; previous studies) results from a contiguous gene deletion (previous studies)." +MONDO_0030008,"Definition: Combined oxidative phosphorylation deficiency-42 (COXPD42) is an autosomal recessive metabolic disorder characterized by onset of cardiomyopathy, respiratory insufficiency, lactic metabolic acidosis, and anemia in the first months of life. Patient tissue shows variable impairment of mitochondrial oxidative phosphorylation affecting mtDNA-encoded subunits I, III, and IV. All reported affected infants have died in the first year of life (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0031332,"Definition: Glanzmann thrombasthenia-1 (GT1) is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb/IIIa (ITGB3; previous studies) platelet surface fibrinogen receptor complex resulting from mutations in the GPIIb gene (previous studies). + + Genetic Heterogeneity of Glanzmann Thrombasthenia + +See Glanzmann thrombasthenia-2 (GT2; previous studies), caused by mutation the ITGB3 gene (previous studies) on chromosome 17q21.32. + +See review by previous studies." +MONDO_0033946,"Definition: Hereditary angioedema-1 and -2 (HAE1 and HAE2) refer to disorders caused by mutation in the SERPING1 (C1HN) gene. The disorders are clinically indistinguishable: both are characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE1, representing 85% of patients, is characterized by serum levels of C1NH less than 35% of normal (previous studies; previous studies). HAE2 is characterized by normal or even elevated C1NH levels, but the protein is nonfunctional. + + Genetic Heterogeneity of Hereditary Angioedema + +See also HAE3 (previous studies), caused by mutation in the F12 gene (previous studies) on chromosome 5q35; HAE4 (previous studies), caused by mutation in the PLG gene (previous studies) on chromosome 6q26; HAE5 (previous studies), caused by mutation in the ANGPT1 gene (previous studies) on chromosome 8q23; HAE6 (previous studies), caused by mutation in the KNG1 gene (previous studies) on chromosome 3q27; HAE7 (previous studies), caused by mutation in the myoferlin gene (MYOF; previous studies) on chromosome 10q23; and HAE8 (previous studies), caused by mutation in the HS3ST6 gene (previous studies) on chromosome 16p13. + +See also previous studies for a discussion of angioedema induced by ACE inhibitors. + +previous studies, previous studies, and previous studies provided detailed reviews of the clinical features, management, and pathogenesis of the different genetic forms of hereditary angioedema. The pathogenesis is complex and is related to excessive production of bradykinin, which causes dilation, as well as to other signaling pathways that regulate vascular permeability." +MONDO_0044660,"Definition: Women show menstrual cycle-dependent physiologic changes in relation to sex hormone levels. Because ovulation triggers a significant change in the hormonal milieu that is similar to local inflammation, a 0.5 to 1.0 degree Celsius increase in basal body temperature after ovulation is commonly associated with progesterone secretion and is believed to be triggered by the induction of several inflammatory cytokines. Rare menstrual cycle-dependent febrile episodes have been reported, some of which have shown a luteal-phase-dependent pattern (summary by previous studies)." +MONDO_0044714,"Definition: Mitochondrial myopathy and ataxia (MMYAT) is an autosomal recessive mtDNA depletion disorder characterized by cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic, and pigmentary retinopathy (summary by previous studies)." +Orphanet_206966,"Definition: Mitochondrial myopathy and ataxia (MMYAT) is an autosomal recessive mtDNA depletion disorder characterized by cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic, and pigmentary retinopathy (summary by previous studies)." +Orphanet_139583,Definition: X-linked deafness-5 is a neurologic disorder characterized by childhood onset of auditory neuropathy and later onset of distal sensory impairment affecting the peripheral nervous system (summary by previous studies). +MONDO_0010378,Definition: X-linked deafness-5 is a neurologic disorder characterized by childhood onset of auditory neuropathy and later onset of distal sensory impairment affecting the peripheral nervous system (summary by previous studies). +Orphanet_1519,"Definition: Teebi hypertelorism syndrome-1 (TBHS1) is an autosomal dominant disorder characterized by hypertelorism with upslanting palpebral fissures, prominent forehead, broad and depressed nasal bridge with short nose, thick eyebrows, and widow's peak. Additional features include small broad hands with mild interdigital webbing and shawl scrotum. Umbilical malformations, cardiac defects, natal teeth, cleft lip/palate, congenital diaphragmatic hernia, and malformations of the central nervous system (ventriculomegaly, abnormal corpus callosum) have also been reported. Development is typically normal, although some patients with developmental delays have been reported (summary by previous studies). + + Genetic Heterogeneity of Teebi Hypertelorism Syndrome + +Teebi hypertelorism syndrome-2 (TBHS2; previous studies) is caused by mutation in the CDH11 gene (previous studies) on chromosome 16q21." +MONDO_0800025,"Definition: Teebi hypertelorism syndrome-1 (TBHS1) is an autosomal dominant disorder characterized by hypertelorism with upslanting palpebral fissures, prominent forehead, broad and depressed nasal bridge with short nose, thick eyebrows, and widow's peak. Additional features include small broad hands with mild interdigital webbing and shawl scrotum. Umbilical malformations, cardiac defects, natal teeth, cleft lip/palate, congenital diaphragmatic hernia, and malformations of the central nervous system (ventriculomegaly, abnormal corpus callosum) have also been reported. Development is typically normal, although some patients with developmental delays have been reported (summary by previous studies). + + Genetic Heterogeneity of Teebi Hypertelorism Syndrome + +Teebi hypertelorism syndrome-2 (TBHS2; previous studies) is caused by mutation in the CDH11 gene (previous studies) on chromosome 16q21." +Orphanet_2388,"Definition: Choreoacanthocytosis (CHAC) is a rare disorder characterized by progressive neurodegeneration and red cell acanthocytosis, with onset in the third to fifth decade of life (previous studies). + +See also McLeod syndrome (previous studies) for a phenotypically similar disorder." +MONDO_0008695,"Definition: Choreoacanthocytosis (CHAC) is a rare disorder characterized by progressive neurodegeneration and red cell acanthocytosis, with onset in the third to fifth decade of life (previous studies). + +See also McLeod syndrome (previous studies) for a phenotypically similar disorder." +Orphanet_255132,"Definition: Sideroblastic anemia-3 is an autosomal recessive hematologic disorder characterized by onset of anemia in adulthood. Affected individuals show signs of systemic iron overload, and iron chelation therapy may be of clinical benefit (summary by previous studies). + +For a discussion of genetic heterogeneity of sideroblastic anemia, see SIDBA1 (previous studies)." +MONDO_0014804,"Definition: Sideroblastic anemia-3 is an autosomal recessive hematologic disorder characterized by onset of anemia in adulthood. Affected individuals show signs of systemic iron overload, and iron chelation therapy may be of clinical benefit (summary by previous studies). + +For a discussion of genetic heterogeneity of sideroblastic anemia, see SIDBA1 (previous studies)." +Orphanet_272,"Definition: MDDGA4 is a severe autosomal recessive muscular dystrophy-dystroglycanopathy with characteristic brain and eye malformations, seizures, and mental retardation. Cardiac involvement in FCMD/MEB occurs in the second decade of life in those who survive. FKTN-related Walker-Warburg syndrome is a more severe manifestation of the disorder, with death usually in the first year of life. These entities are part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies; previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0009678,"Definition: MDDGA4 is a severe autosomal recessive muscular dystrophy-dystroglycanopathy with characteristic brain and eye malformations, seizures, and mental retardation. Cardiac involvement in FCMD/MEB occurs in the second decade of life in those who survive. FKTN-related Walker-Warburg syndrome is a more severe manifestation of the disorder, with death usually in the first year of life. These entities are part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies; previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +Orphanet_320411,"Definition: Spastic paraplegia-56 with or without pseudoxanthoma elasticum (SPG56) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy (summary by previous studies). Some patients also have pseudoxanthoma elasticum (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +MONDO_0014015,"Definition: Spastic paraplegia-56 with or without pseudoxanthoma elasticum (SPG56) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy (summary by previous studies). Some patients also have pseudoxanthoma elasticum (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +Orphanet_503,"Definition: Larsen syndrome is an osteochondrodysplasia characterized by large-joint dislocations and characteristic craniofacial abnormalities. The cardinal features of the condition are dislocations of the hip, knee and elbow joints, with equinovarus or equinovalgus foot deformities. Spatula-shaped fingers, most marked in the thumb, are also present. Craniofacial anomalies include hypertelorism, prominence of the forehead, a depressed nasal bridge, and a flattened midface. Cleft palate and short stature are often associated features. Spinal anomalies include scoliosis and cervical kyphosis. Hearing loss is a well-recognized complication (summary by previous studies)." +MONDO_0007875,"Definition: Larsen syndrome is an osteochondrodysplasia characterized by large-joint dislocations and characteristic craniofacial abnormalities. The cardinal features of the condition are dislocations of the hip, knee and elbow joints, with equinovarus or equinovalgus foot deformities. Spatula-shaped fingers, most marked in the thumb, are also present. Craniofacial anomalies include hypertelorism, prominence of the forehead, a depressed nasal bridge, and a flattened midface. Cleft palate and short stature are often associated features. Spinal anomalies include scoliosis and cervical kyphosis. Hearing loss is a well-recognized complication (summary by previous studies)." +MONDO_0008178,"Definition: IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by previous studies). + + Genetic Heterogeneity of IBMPFD + +IBMPFD2 (previous studies) is caused by mutation in the HNRNPA2B1 gene (previous studies) on chromosome 7p15. IBMPFD3 (previous studies) is caused by mutation in the HNRNPA1 gene (previous studies) on chromosome 12q13." +MONDO_0012013,"Definition: Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of WMS, see previous studies." +Orphanet_2084,"Definition: Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of WMS, see previous studies." +MONDO_0012724,"Definition: Familial cold autoinflammatory syndrome-2 (FCAS2) is an autosomal dominant autoinflammatory disorder characterized by episodic and recurrent rash, urticaria, arthralgia, myalgia, and headache. In most patients, these episodes are accompanied by fever and serologic evidence of inflammation. Most, but not all, patients report exposure to cold as a trigger for the episodes. Additional features may include abdominal pain, thoracic pain, and sensorineural deafness. The age at onset is variable, ranging from the first year of life to middle age, and the severity and clinical manifestations are heterogeneous (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of familial cold autoinflammatory syndrome, see FCAS1 (previous studies)." +Orphanet_247868,"Definition: Familial cold autoinflammatory syndrome-2 (FCAS2) is an autosomal dominant autoinflammatory disorder characterized by episodic and recurrent rash, urticaria, arthralgia, myalgia, and headache. In most patients, these episodes are accompanied by fever and serologic evidence of inflammation. Most, but not all, patients report exposure to cold as a trigger for the episodes. Additional features may include abdominal pain, thoracic pain, and sensorineural deafness. The age at onset is variable, ranging from the first year of life to middle age, and the severity and clinical manifestations are heterogeneous (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of familial cold autoinflammatory syndrome, see FCAS1 (previous studies)." +MONDO_0013316,"Definition: Occult macular dystrophy is characterized by progressive decline of visual acuity in both eyes, associated with a normal fundus and normal fluorescein angiography. Patients have normal full-field electroretinograms (ERGs) but severely reduced focal macular ERGs, as recorded by conventional techniques using small stimuli under background illumination. OCMD patients are believed to have localized retinal dysfunction distal to the ganglion cells in the central retina (summary by previous studies)." +MONDO_0013949,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 13 (CG13, equivalent to CGH) have mutations in the PEX13 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0014550,"Definition: LQT15 is a cardiac arrhythmia disorder characterized by ventricular arrhythmias, often life-threatening, occurring very early in life, frequent episodes of T-wave alternans, markedly prolonged QTc intervals, and intermittent 2:1 atrioventricular block (previous studies). + +Patients with LQT14 (previous studies), LQT15, or LQT16 (previous studies), resulting from mutation in calmodulin genes CALM1 (previous studies), CALM2, or CALM3 (previous studies), respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (previous studies)." +MONDO_0030515,"Definition: Spermatogenic failure-63 (SPGF63) is characterized by male infertility due to severe oligozoospermia with markedly reduced progressive motility (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0032745,"Definition: Developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA) is an autosomal dominant neurodevelopmental disorder. Most patients have impaired intellectual development with speech difficulties, and many have behavioral abnormalities, most commonly autism spectrum disorder (ASD), defects in attention, and/or hyperactivity. Many patients have dysmorphic features, although there is not a consistent gestalt. Additional more variable features may include hypotonia, somatic overgrowth with macrocephaly, mild distal skeletal anomalies, sleep disturbances, movement disorders, and gastrointestinal issues, such as constipation. The phenotype is highly variable (summary by previous studies and previous studies)." +EFO_0010644,"Definition: Developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA) is an autosomal dominant neurodevelopmental disorder. Most patients have impaired intellectual development with speech difficulties, and many have behavioral abnormalities, most commonly autism spectrum disorder (ASD), defects in attention, and/or hyperactivity. Many patients have dysmorphic features, although there is not a consistent gestalt. Additional more variable features may include hypotonia, somatic overgrowth with macrocephaly, mild distal skeletal anomalies, sleep disturbances, movement disorders, and gastrointestinal issues, such as constipation. The phenotype is highly variable (summary by previous studies and previous studies)." +Orphanet_1387,"Definition: Martsolf syndrome (MARTS) is characterized by congenital cataracts, hypogonadism, and impaired intellectual development (previous studies). + + Genetic Heterogeneity of Martsolf Syndrome + +Martsolf syndrome-2 (MARTS2; previous studies) is caused by mutation in the RAB3GAP1 gene (previous studies) on chromosome 2q21." +Orphanet_171876,"Definition: Autosomal recessive pseudohypoaldosteronism type I, including PHA1B1, is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Laboratory evaluation shows hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. Respiratory tract infections are common in affected children and may be mistaken for cystic fibrosis (CF; previous studies). Aggressive salt replacement and control of hyperkalemia results in survival, and the disorder appears to become less severe with age (review by previous studies). + +A milder, autosomal dominant form of type I pseudohypoaldosteronism (PHA1A; previous studies) is caused by mutations in the mineralocorticoid receptor gene (MCR, NR3C2; previous studies). + +Gitelman syndrome (previous studies), another example of primary renal tubular salt wasting, is due to mutation in the thiazide-sensitive sodium-chloride cotransporter (SLC12A3; previous studies). + +previous studies provided a detailed review of the ENaC gene family, including structure, function, tissue distribution, and associated inherited diseases." +MONDO_0009917,"Definition: Autosomal recessive pseudohypoaldosteronism type I, including PHA1B1, is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Laboratory evaluation shows hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. Respiratory tract infections are common in affected children and may be mistaken for cystic fibrosis (CF; previous studies). Aggressive salt replacement and control of hyperkalemia results in survival, and the disorder appears to become less severe with age (review by previous studies). + +A milder, autosomal dominant form of type I pseudohypoaldosteronism (PHA1A; previous studies) is caused by mutations in the mineralocorticoid receptor gene (MCR, NR3C2; previous studies). + +Gitelman syndrome (previous studies), another example of primary renal tubular salt wasting, is due to mutation in the thiazide-sensitive sodium-chloride cotransporter (SLC12A3; previous studies). + +previous studies provided a detailed review of the ENaC gene family, including structure, function, tissue distribution, and associated inherited diseases." +Orphanet_2796,"Definition: Autosomal recessive primary hypertrophic osteoarthropathy-1 (PHOAR1) is a rare familial disorder characterized by digital clubbing, osteoarthropathy, and acroosteolysis, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease (summary by previous studies; previous studies). + +Secondary hypertrophic osteoarthropathy, or pulmonary hypertrophic osteoarthropathy, is a different disorder characterized by digital clubbing secondary to acquired diseases, most commonly intrathoracic neoplasm (previous studies). + +previous studies recognized pachydermoperiostosis as a familial disorder with 3 clinical presentations or forms: a complete form characterized by periostosis and pachydermia; an incomplete form with bone changes but without pachydermia; and a 'forme fruste' with pachydermia and minimal skeletal changes. + + Genetic Heterogeneity + +PHOAR2 (previous studies) is caused by mutation in the SLCO2A1 gene (previous studies) on chromosome 3q22. + +Families with an autosomal dominant form of primary hypertrophic osteoarthropathy have also been reported (PHOAD; previous studies)." +MONDO_0024546,"Definition: Autosomal recessive primary hypertrophic osteoarthropathy-1 (PHOAR1) is a rare familial disorder characterized by digital clubbing, osteoarthropathy, and acroosteolysis, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease (summary by previous studies; previous studies). + +Secondary hypertrophic osteoarthropathy, or pulmonary hypertrophic osteoarthropathy, is a different disorder characterized by digital clubbing secondary to acquired diseases, most commonly intrathoracic neoplasm (previous studies). + +previous studies recognized pachydermoperiostosis as a familial disorder with 3 clinical presentations or forms: a complete form characterized by periostosis and pachydermia; an incomplete form with bone changes but without pachydermia; and a 'forme fruste' with pachydermia and minimal skeletal changes. + + Genetic Heterogeneity + +PHOAR2 (previous studies) is caused by mutation in the SLCO2A1 gene (previous studies) on chromosome 3q22. + +Families with an autosomal dominant form of primary hypertrophic osteoarthropathy have also been reported (PHOAD; previous studies)." +EFO_0004261,"Definition: Paget disease is a metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. See reviews by previous studies and previous studies. + +For a discussion of genetic heterogeneity of Paget disease of bone, see previous studies." +MONDO_0009998,"Definition: Patients with Richieri-Costa-Pereira syndrome display a pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of the mandible, cleft palate/Robin sequence, absence of lower central incisors, minor ear anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability is also a common finding (summary by previous studies)." +MONDO_0011106,"Definition: Traboulsi syndrome is characterized by dislocated crystalline lenses and anterior segment abnormalities in association with a distinctive facies involving flat cheeks and a beaked nose. Some affected individuals develop highly unusual nontraumatic conjunctival cysts (filtering blebs), presumably caused by abnormal thinning of the sclera (previous studies)." +MONDO_0011778,"Definition: Al-Gazali-Bakalinova syndrome (AGBK) is characterized by multiple epiphyseal dysplasia, macrocephaly, and distinctive facial features including frontal bossing, hypertelorism, flat malar regions, low-set ears, and short neck. Other features include pectus excavatum, spindle-shaped fingers, clinodactyly, prominent joints, and genu valgum (summary by previous studies)." +MONDO_0012825,"Definition: Extraskeletal myxoid chondrosarcoma is a rare soft tissue neoplasm of chondroblastic origin. The tumors are most commonly found in middle-aged and elderly individuals, are more common among men, and are often detected as deep-seated lesions in the extremities. Despite their relatively low-grade malignancy, recurrence and metastasis may appear many years after the initial diagnosis. Histologic tissue section examination reveals a mixture of cellular and myxoid stromal components (previous studies)." +MONDO_0013162,"Definition: MDDGC2 is an autosomal recessive muscular dystrophy with onset after ambulation is achieved. Cognition is normal (previous studies). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (previous studies)." +MONDO_0013372,"Definition: Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (previous studies). + +For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (previous studies)." +MONDO_0013925,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, the defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; previous studies) (summary by previous studies)." +MONDO_0014078,"Definition: Platelet-type bleeding disorder-15 is an autosomal dominant form of macrothrombocytopenia. Affected individuals usually have no or only mild bleeding tendency, such as epistaxis. Laboratory studies show decreased numbers of large platelets and anisocytosis, but the platelets show no in vitro functional abnormalities (summary by previous studies)." +MONDO_0014138,"Definition: Nemaline myopathy-8 is a severe autosomal recessive muscle disorder characterized by fetal akinesia or hypokinesia, followed by contractures, fractures, respiratory failure, and swallowing difficulties apparent at birth. Most patients die in infancy. Skeletal muscle biopsy shows numerous small nemaline bodies, often with no normal myofibrils (summary by previous studies). + +For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (previous studies)." +MONDO_0014558,"Definition: Arboleda-Tham syndrome (ARTHS) is an autosomal dominant disorder with the core features of impaired intellectual development, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications (summary by previous studies)." +MONDO_0018959,"Definition: In a report on the 37th ENMC Workshop, previous studies stated that the sodium channelopathies can be divided into 3 different forms: paramyotonia, potassium-aggravated myotonia, and periodic paralysis. Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia." +MONDO_0030037,"Definition: Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures (NEDHCAS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, delayed motor skills, and poor or absent speech. Most patients develop early-onset seizures and demonstrate cerebellar ataxia or dysmetria associated with progressive cerebellar atrophy on brain imaging. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by previous studies). + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +MONDO_0054813,"Definition: Ehlers-Danlos syndrome classic-like-2 (EDSCLL2) is characterized by severe joint and skin laxity, osteoporosis involving the hips and spine, osteoarthritis, soft redundant skin that can be acrogeria-like, delayed wound healing with abnormal atrophic scarring, and shoulder, hip, knee, and ankle dislocations. Variable features include gastrointestinal and genitourinary manifestations, such as bowel rupture, gut dysmotility, cryptorchidism, and hernias; vascular complications, such as mitral valve prolapse and aortic root dilation; and skeletal anomalies (previous studies). + +See previous studies for another classic-like EDS syndrome. For a discussion of the classification of EDS, see previous studies." +MONDO_0060491,"Definition: NEDIM is a neurodevelopmental and neurodegenerative disorder characterized by delayed psychomotor development and infantile or childhood onset of hyperkinetic involuntary movements, including chorea and athetosis. The abnormal movements can be severe, sometimes resulting in inability to sit, walk, speak, or eat. Hyperkinetic movements can be exacerbated by specific triggers, such as stress, illness, or high temperature. Some patients have brain abnormalities, such as cerebral atrophy or thin corpus callosum, and some patients may develop seizures (summary by previous studies and previous studies)." +MONDO_8000012,"Definition: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-1 (IMNEPD1) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy. However, some patients may not display all features (summary by previous studies, previous studies). + + Genetic Heterogeneity of Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease + +See also IMNEPD2 (previous studies), caused by mutation in the YARS1 gene (previous studies) on chromosome 1p35." +Orphanet_79310,"Definition: Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Different forms of isolated methylmalonic aciduria have been classified according to complementation groups of cells in vitro. Patients with defects in the synthesis of AdoCbl are usually responsive to vitamin B12 therapy and are classified as 'cbl' type: these include cblA and cblB (previous studies), which is caused by mutation in the MMAB gene (previous studies) on 12q24. See also cblH (previous studies), which may be a subset of cblA. The 'mut' form of MMA (previous studies) is caused by mutation in the MUT gene on chromosome 6p. In general, the mut form of MMA is unresponsive to vitamin B12 therapy. + +Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (previous studies), cblD (previous studies), cblF (previous studies), and cblJ (previous studies)." +MONDO_0009613,"Definition: Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Different forms of isolated methylmalonic aciduria have been classified according to complementation groups of cells in vitro. Patients with defects in the synthesis of AdoCbl are usually responsive to vitamin B12 therapy and are classified as 'cbl' type: these include cblA and cblB (previous studies), which is caused by mutation in the MMAB gene (previous studies) on 12q24. See also cblH (previous studies), which may be a subset of cblA. The 'mut' form of MMA (previous studies) is caused by mutation in the MUT gene on chromosome 6p. In general, the mut form of MMA is unresponsive to vitamin B12 therapy. + +Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (previous studies), cblD (previous studies), cblF (previous studies), and cblJ (previous studies)." +Orphanet_85458,"Definition: Cerebral amyloid angiopathy (CAA), defined by the deposition of congophilic material in the vessels of the cortex and leptomeninges, is a major cause of intracerebral hemorrhage in the elderly (previous studies, previous studies). previous studies referred to the disorder in Icelandic patients as hereditary cystatin C amyloid angiopathy (HCCAA)." +MONDO_0007098,"Definition: Cerebral amyloid angiopathy (CAA), defined by the deposition of congophilic material in the vessels of the cortex and leptomeninges, is a major cause of intracerebral hemorrhage in the elderly (previous studies, previous studies). previous studies referred to the disorder in Icelandic patients as hereditary cystatin C amyloid angiopathy (HCCAA)." +Orphanet_100008,"Definition: Cerebral amyloid angiopathy (CAA), defined by the deposition of congophilic material in the vessels of the cortex and leptomeninges, is a major cause of intracerebral hemorrhage in the elderly (previous studies, previous studies). previous studies referred to the disorder in Icelandic patients as hereditary cystatin C amyloid angiopathy (HCCAA)." +EFO_0000180,"Definition: The pathogenesis of HIV infection and the progression from infection to AIDS vary significantly between exposed individuals. Infection occurs after the virus, which has macrophage (M)- and T lymphocyte (T)-tropic strains and more than 12 subtypes, survives an array of nonspecific, nongenetic environmental and host factors." +MONDO_0007208,Definition: Boomerang dysplasia (BOOMD) is a perinatal lethal osteochondrodysplasia characterized by absence or underossification of the limb bones and vertebrae (summary by previous studies). +MONDO_0008148,"Definition: Osteogenesis imperfecta (OI) is a connective tissue disorder that is caused by an abnormality of type I collagen in over 90% of cases. Due to considerable phenotypic variability, previous studies developed a classification of OI subtypes: OI type I with blue sclerae (previous studies); perinatal lethal OI type II, also known as congenital OI (previous studies); OI type III, a progressively deforming form with normal sclera (previous studies); and OI type IV, with normal sclerae. previous studies suggested that OI subtypes could be further divided into types A and B based on the absence or presence of dentinogenesis imperfecta." +MONDO_0008494,"Definition: Cryohydrocytosis is an exceedingly rare condition characterized by a mild stomatocytic hemolytic state with hyperbilirubinemia. A hallmark of this condition is that red blood cells (RBCs) lyse on storage at 4 degrees centigrade. RBC cation permeability is increased at 37 degrees centigrade, and the cells also accumulate sodium in the cold (summary by previous studies). Patients present with fatigue, mild anemia, and pseudohyperkalemia due to a potassium leak from the RBCs (summary by previous studies). + +For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see previous studies." +Orphanet_398088,"Definition: Cryohydrocytosis is an exceedingly rare condition characterized by a mild stomatocytic hemolytic state with hyperbilirubinemia. A hallmark of this condition is that red blood cells (RBCs) lyse on storage at 4 degrees centigrade. RBC cation permeability is increased at 37 degrees centigrade, and the cells also accumulate sodium in the cold (summary by previous studies). Patients present with fatigue, mild anemia, and pseudohyperkalemia due to a potassium leak from the RBCs (summary by previous studies). + +For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see previous studies." +MONDO_0008948,"Definition: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Cholestanol, the 5-alpha-dihydro derivative of cholesterol, is enriched relative to cholesterol in all tissues. The diagnosis can be made by demonstrating cholestanol in abnormal amounts in the serum and tendon of persons suspected of being affected. Plasma cholesterol concentrations are low normal in CTX patients. + +previous studies examined the ophthalmologic findings of 13 CTX patients. In addition to cataracts, which were found in all cases, optic disc pallor was identified in 6 of the patients. Premature retinal senescence was also observed. + +In a tabular presentation, previous studies compared and contrasted CTX with 2 other lipid disorders with certain similarities and clinical course: familial hypercholesterolemia (see previous studies) and sitosterolemia (see previous studies)." +MONDO_0010602,"Definition: Hemophilia A (HEMA) is an X-linked recessive bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. The disorder is clinically heterogeneous with variable severity, depending on the plasma levels of coagulation factor VIII: mild, with levels 6 to 30% of normal; moderate, with levels 2 to 5% of normal; and severe, with levels less than 1% of normal. Patients with mild hemophilia usually bleed excessively only after trauma or surgery, whereas those with severe hemophilia have an annual average of 20 to 30 episodes of spontaneous or excessive bleeding after minor trauma, particularly into joints and muscles. These symptoms differ substantially from those of bleeding disorders due to platelet defects or von Willebrand disease (previous studies), in which mucosal bleeding predominates (review by previous studies)." +MONDO_0011946,"Definition: Diaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (summary by previous studies)." +MONDO_0012241,"Definition: Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (previous studies). + +PEO caused by mutations in the POLG gene (previous studies) are associated with more complicated phenotypes than those forms caused by mutations in the SLC25A4 (previous studies) or C10ORF2 genes (previous studies)." +MONDO_0013208,"Definition: Hypermanganesemia with dystonia-1 (HMNDYT1) is an autosomal recessive metabolic disorder characterized by increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, which leads to cirrhosis in some cases. Intellectual function is preserved (summary by previous studies and previous studies). + + Genetic Heterogeneity of Hypermanganesemia With Dystonia + +See also HMNDYT2 (previous studies), caused by mutation in the SLC39A14 gene (previous studies) on chromosome 8p21." +Orphanet_309854,"Definition: Hypermanganesemia with dystonia-1 (HMNDYT1) is an autosomal recessive metabolic disorder characterized by increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, which leads to cirrhosis in some cases. Intellectual function is preserved (summary by previous studies and previous studies). + + Genetic Heterogeneity of Hypermanganesemia With Dystonia + +See also HMNDYT2 (previous studies), caused by mutation in the SLC39A14 gene (previous studies) on chromosome 8p21." +MONDO_0014234,"Definition: Reticulate acropigmentation of Kitamura (RAK) is a rare pigmentary disorder that usually shows an autosomal dominant pattern of inheritance with high penetrance. Typical features include reticulate, slightly depressed, sharply demarcated brown macules without hypopigmentation, affecting the dorsa of the hands and feet in the first or second decade of life. The macules gradually darken and extend to the proximal regions of the extremities; progression of the eruptions stops in middle age. The increased pigmentation is found on the flexor aspects of the wrists, neck, patella, and olecranon. Other features include breaks in the epidermal ridges on the palms and fingers, palmoplantar pits, partial alopecia, and occasionally plantar keratoderma. Histopathologically, the brown macules show pigmentation in the tip of rete ridges with thinning of the epidermis, elongation and thinning of the rete ridges, and slight hyperkeratosis without parakeratosis. Only a few inflammatory cell infiltrates and no incontinentia pigmenti are seen in the dermis (summary by previous studies). + + Review of Reticulate Pigment Disorders + +previous studies reviewed the spectrum of reticulate pigment disorders of the skin, tabulating all reported cases of patients with Dowling-Degos disease (see DDD1; previous studies), reticulate acropigmentation of Kitamura (RAK), reticulate acropigmentation of Dohi (DSH, RAD; previous studies), Galli-Galli disease (GGD), and Haber syndrome (HS). Of 82 cases, 26 (31.7%) were clinically diagnosed as DDD, 13 (15.9%) as RAD, 11 (13.4%) as GGD, 8 (9.8%) as RAK, and 8 (9.8%) as HS; in addition, 16 (19.5%) of the cases showed overlap between DDD and RAK. previous studies also published photographs of an affected individual exhibiting an overlap of clinical features of DDD, GGD, RAD, and RAK. The authors noted that in reticulate disorders of the skin, the main disease entity is DDD, with a subset of cases exhibiting acantholysis (GGD), facial erythema (HS), or an acral distribution (RAD; RAK). previous studies concluded that all reticulate pigment diseases of the skin are varying manifestations of a single entity. + +For a discussion of genetic heterogeneity of reticulate pigment disorders, see previous studies." +MONDO_0014619,"Definition: Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by previous studies). + +For a discussion of genetic heterogeneity of TTD, see previous studies." +MONDO_0017400,"Definition: Mitchell-Riley syndrome is characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia. There is considerable phenotypic overlap between Mitchell-Riley syndrome and Martinez-Frias syndrome (previous studies), the latter being characterized by the features of the Mitchell-Riley syndrome except for neonatal diabetes, and including tracheoesophageal fistula in some patients (previous studies)." +MONDO_0020724,"Definition: Cerebral cavernous angiomas are relatively rare vascular malformations that may involve any part of the central nervous system. Cerebral cavernous angiomas are to be distinguished from cerebral arteriovenous malformations (previous studies, previous studies). CCMs are venous and not demonstrable by arteriography; hence they are referred to as angiographically silent. + +Capillary hemangiomas (previous studies) are classified as distinct from vascular malformations in that hemangiomas are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. Hemangiomas develop shortly after birth. In contrast, vascular malformations are present from birth, tend to grow with the individual, do not regress, and show normal rates of endothelial cell turnover (previous studies). + + Genetic Heterogeneity of CCM + +CCM2 (previous studies) is caused by germline mutation in the CCM2 gene (previous studies); CCM3 (previous studies) is caused by germline mutation in the PDCD10 gene (previous studies); and CCM4 (previous studies) is caused by somatic mutation in the PIK3CA gene (previous studies). + +Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM1 pathogenesis; see PATHOGENESIS and MOLECULAR GENETICS sections." +MONDO_0030071,"Definition: Retinitis pigmentosa-89 (RP89) is characterized by classic features of RP as well as features of ciliopathy, including postaxial polydactyly and renal and hepatic disease. Onset of symptoms is within the first decade of life (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of RP, see previous studies." +MONDO_0030073,"Definition: Mitchell syndrome (MITCH) is a progressive disorder characterized by episodic demyelination, sensorimotor polyneuropathy, and hearing loss (previous studies)." +MONDO_0033014,"Definition: Erythrokeratodermia variabilis et progressiva-4 is characterized by severe lesions of thick scaly skin on the face and genitals, as well as thickened, red, and scaly skin on the hands and feet (summary by previous studies). + +For a discussion of genetic heterogeneity of EKVP, see EKVP1 (previous studies)." +MONDO_0060624,"Definition: NDAGSCW is a neurodevelopmental disorder characterized by severely delayed psychomotor development apparent from infancy. Affected individuals have delayed and difficulty walking, intellectual disability, absent speech, and variable additional features, including hip dysplasia, tapering fingers, and seizures. Brain imaging shows decreased cortical white matter, often with decreased cerebellar white matter, thin corpus callosum, and thin brainstem (summary by previous studies)." +MONDO_0060650,Definition: Leber congenital amaurosis with early-onset deafness is an autosomal dominant syndrome manifesting as early-onset and severe photoreceptor and cochlear cell loss. Some patients show extinguished responses on electroretinography and moderate to severe hearing loss at birth (previous studies). +MONDO_0100215,"Definition: Rajab interstitial lung disease with brain calcifications-1 (RILCBC1) is an autosomal recessive multisystem disorder with a highly variable phenotype. Most patients present in infancy or early childhood with poor growth and interstitial lung disease, which may lead to death. Some may also have liver, skeletal, and renal abnormalities, and most have intracranial calcifications on brain imaging. Some may have early impaired motor development, but most have normal cognitive development (summary by previous studies). + + Genetic Heterogeneity of Rajab Interstitial Lung Disease with Brain Calcifications + +Also see Rajab interstitial disease with brain calcifications-2 (RILDBC2; previous studies), caused by mutation in the FARSA gene (previous studies)." +Orphanet_2363,"Definition: Lacrimoauriculodentodigital syndrome-1 (LADD1) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by previous studies). + + Genetic Heterogeneity of Lacrimoauriculodentodigital Syndrome + +LADD syndrome-2 (LADD2; previous studies) is caused by mutation in the FGFR3 gene (previous studies) on chromosome 4p16, and LADD syndrome-3 (LADD3; previous studies) is caused by mutation in the FGF10 gene, an FGFR ligand, on chromosome 5p12." +Orphanet_6,"Definition: 3-Methylcrotonylglycinuria is an autosomal recessive disorder of leucine catabolism. The clinical phenotype is highly variable, ranging from neonatal onset with severe neurologic involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. MCC activity in extracts of cultured fibroblasts of patients is usually less than 2% of control (summary by previous studies). + +Also see 3-methylcrotonylglycinuria II (MCC2D; previous studies), caused by mutation in the beta subunit of 3-methylcrotonyl-CoA carboxylase (MCCC2; previous studies)." +MONDO_0007118,"Definition: Isolated anhidrosis with normal sweat glands (ANHD) is characterized by absence of perspiration and subsequent heat intolerance with normal morphology and number of sweat glands. Teeth, hair, nails, and skin are normal (previous studies)." +MONDO_0007412,"Definition: Beare-Stevenson cutis gyrata syndrome (BSTVS) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death (summary by previous studies)." +Orphanet_1555,"Definition: Beare-Stevenson cutis gyrata syndrome (BSTVS) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death (summary by previous studies)." +MONDO_0007493,"Definition: Dystonia-4, also known as whispering dysphonia, is an autosomal dominant neurologic disorder characterized by onset in the second to third decade of progressive laryngeal dysphonia followed by the involvement of other muscles, such as the neck or limbs. Some patients develop an ataxic gait (summary by previous studies)." +Orphanet_98805,"Definition: Dystonia-4, also known as whispering dysphonia, is an autosomal dominant neurologic disorder characterized by onset in the second to third decade of progressive laryngeal dysphonia followed by the involvement of other muscles, such as the neck or limbs. Some patients develop an ataxic gait (summary by previous studies)." +MONDO_0008810,"Definition: Clinically and biochemically, apoC-II deficiency closely simulates lipoprotein lipase deficiency, or hyperlipoproteinemia type I (previous studies), and is therefore referred to as hyperlipoproteinemia type IB." +Orphanet_411,"Definition: Clinically and biochemically, apoC-II deficiency closely simulates lipoprotein lipase deficiency, or hyperlipoproteinemia type I (previous studies), and is therefore referred to as hyperlipoproteinemia type IB." +MONDO_0009069,"Definition: Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see previous studies). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0010543,"Definition: Barth syndrome (BTHS) is an X-linked disease conventionally characterized by dilated cardiomyopathy (CMD) with endocardial fibroelastosis (EFE), a predominantly proximal skeletal myopathy, growth retardation, neutropenia, and organic aciduria, particularly excess of 3-methylglutaconic acid. Features of the disease that are less well known include hypertrophic cardiomyopathy, isolated left ventricular noncompaction (LVNC), ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +MONDO_0013962,Definition: SPG53 is an autosomal recessive neurologic disorder characterized by onset in infancy of delayed motor development progressing to upper and lower limb spasticity with impaired walking. Affected individuals also show mild to moderate cognitive impairment (summary by previous studies). +Orphanet_319199,Definition: SPG53 is an autosomal recessive neurologic disorder characterized by onset in infancy of delayed motor development progressing to upper and lower limb spasticity with impaired walking. Affected individuals also show mild to moderate cognitive impairment (summary by previous studies). +MONDO_0014018,"Definition: Spastic paraplegia-54 is a complicated form of spastic paraplegia, a neurodegenerative disorder affecting fibers of the corticospinal tract. Affected individuals have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions. Brain magnetic resonance spectroscopy shows an abnormal lipid peak (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +Orphanet_320380,"Definition: Spastic paraplegia-54 is a complicated form of spastic paraplegia, a neurodegenerative disorder affecting fibers of the corticospinal tract. Affected individuals have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions. Brain magnetic resonance spectroscopy shows an abnormal lipid peak (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +MONDO_0014493,"Definition: Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL) is an autosomal dominant complex immune disorder with highly variable presentation and clinical manifestations. Prominent features include recurrent infections often associated with hypogammaglobulinemia, autoimmune features such as autoimmune cytopenias, and abnormal lymphocytic infiltration of nonlymphoid organs, including the lungs, brain, and gastrointestinal tract, resulting in enteropathy. Laboratory studies often show lymphopenia and abnormal T and B cell subsets. The variable features are a result of impaired function of Treg cells, which play a role in immune homeostasis (summary by previous studies; previous studies, and previous studies). + +The disorder shows overlapping features with autoimmune lymphoproliferative syndrome (ALPS); for a general description and a discussion of genetic heterogeneity of ALPS, see previous studies." +MONDO_0030294,"Definition: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare congenital defect of visceral smooth muscle, primarily affecting females who present at birth with functional obstruction of the intestine, microcolon, dilation of the bladder, and secondary hydronephrosis. Total parenteral nutrition, adequate intermittent catheterization of bladder, and surgical corrections for intestinal malrotation are frequent modes of treatment for this disease without which rapid death ensues. In some instances, multivisceral organ transplantation has been undertaken with some success. Despite these clinical interventions, MMIHS often leads to premature death due to complications of therapy (summary by previous studies). + +For a discussion of genetic heterogeneity of MMIHS, see previous studies." +Orphanet_77298,"Definition: Syndromic microphthalmia-3 (MCOPS3) is characterized by clinical anophthalmia or microphthalmia with or without defects of the optic nerve, optic chiasm, and optic tract. Extraocular abnormalities include brain anomalies, seizures, motor disability, neurocognitive delays, sensorineural hearing loss, and esophageal atresia. Hypoplasia of the anterior pituitary is another major complication, which frequently results in growth hormone deficiency; however, gonadotropin deficiency is likely to be the most consistent endocrinopathy in patients with SOX2 mutation (summary by previous studies)." +MONDO_0008799,"Definition: Syndromic microphthalmia-3 (MCOPS3) is characterized by clinical anophthalmia or microphthalmia with or without defects of the optic nerve, optic chiasm, and optic tract. Extraocular abnormalities include brain anomalies, seizures, motor disability, neurocognitive delays, sensorineural hearing loss, and esophageal atresia. Hypoplasia of the anterior pituitary is another major complication, which frequently results in growth hormone deficiency; however, gonadotropin deficiency is likely to be the most consistent endocrinopathy in patients with SOX2 mutation (summary by previous studies)." +EFO_0004720,"Definition: Kuru, a fatal neurodegenerative condition, is a human prion disease that primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning ('transumption'). The incidence has fallen dramatically since the cessation of cannibalism in the 1950s (summary by previous studies)." +EFO_0010251,"Definition: SCA48 is an autosomal dominant neurodegenerative disorder characterized by onset of gait ataxia and/or cognitive-affective symptoms in midadulthood. Patients may present with involvement of either system, but most eventually develop impairment in both. Features include gait ataxia, dysarthria, and dysphagia, as well as cognitive decline, deficits in executive function, and psychiatric or affective manifestations, such as depression, anxiety, and apathy. Additional more variable features may include movement abnormalities, such as parkinsonism, tremor, chorea, dystonia, and dysmetria; spasticity is not observed. Brain imaging shows selective atrophy of the posterior areas of the cerebellar vermis, often with bilateral T2-weighted hyperintensities in the dentate nuclei (the 'crab sign'), and diffusion tensor imaging (DTI) may show paucity of cerebellar connections to the brainstem and cerebrum. The presentation is consistent with a clinical diagnosis of cerebellar cognitive-affective syndrome (CCAS). The phenotype shows both inter- and intrafamilial variability as well as some clinical overlap with SCAR16, suggesting that mutations in the STUB1 gene result in a spectrum of neurodegenerative manifestations (summary by previous studies; previous studies; previous studies; previous studies). + +previous studies found evidence that heterozygous STUB1 variants alone do not cause disease but require a concurrent expanded repeat allele of the TBP gene (previous studies) for disease manifestation; see MOLECULAR GENETICS." +MONDO_0007315,"Definition: Cherubism is characterized by a loss of bone, restricted to the jaws, and by the replacement of this bone with fibrous tissues, leading to facial swelling. Involvement of the infraorbital rim and the orbital floor leads to the upward tilting of the eyeballs and consequent exposure of the inferior part of the sclerae, giving a 'cherubic' appearance. Submandibular lymph node enlargement is often reported. Functional impairment includes mastication and speech problems, tooth alterations, and loss of normal vision. Onset of the disease is usually between 14 months and 4 years of age. The disease progresses through puberty, then stabilizes, and in some cases regresses without treatment (summary by previous studies)." +MONDO_0007635,"Definition: Frasier syndrome is a rare disorder defined by pseudohermaphroditism and progressive glomerulopathy (previous studies; previous studies; previous studies). Patients present with normal female external genitalia, streak gonads, and XY karyotype, and frequently develop gonadoblastoma (previous studies). Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by nonspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood. Wilms tumor is not a usual feature (previous studies)." +MONDO_0007844,"Definition: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +Although HH was initially considered to be a monogenic disorder, the presence of marked locus heterogeneity, incomplete penetrance within pedigrees, and variable expressivity of pathogenic alleles, together with evidence for mutations in multiple genes in some affected individuals, resulted in a conceptual shift from monogenicity to an oligogenic framework in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction (previous studies). + + Genetic Heterogeneity of Hypogonadotropic Hypogonadism with or without Anosmia + +Other forms of autosomal hypogonadotropic hypogonadism with or without anosmia include HH3 (previous studies), caused by mutation in the PROKR2 gene (previous studies); HH4 (previous studies), caused by mutation in the PROK2 gene (previous studies); HH5 (previous studies), caused by mutation in the CHD7 gene (previous studies); HH6 (previous studies), caused by mutation in the FGF8 gene (previous studies); HH7 (previous studies), caused by mutation in the GNRHR gene (previous studies); HH8 (previous studies), caused by mutation in the KISS1R gene (previous studies); HH9 (previous studies), caused by mutation in the NELF gene (previous studies); HH10 (previous studies), caused by mutation in the TAC3 gene (previous studies); HH11 (previous studies), caused by mutation in the TACR3 gene (previous studies); HH12 (previous studies), caused by mutation in the GNRH1 gene (previous studies); HH13 (previous studies), caused by mutation in the KISS1 gene (previous studies); HH14 (previous studies), caused by mutation in the WDR11 gene (previous studies); HH15 (previous studies), caused by mutation in the HS6ST1 gene (previous studies); HH16 (previous studies), caused by mutation in the SEMA3A gene (previous studies); HH17 (previous studies), caused by mutation in the SPRY4 gene (previous studies); HH18 (previous studies), caused by mutation in the IL17RD gene (previous studies); HH19 (previous studies), caused by mutation in the DUSP6 gene (previous studies); HH20 (previous studies), caused by mutation in the FGF17 gene (previous studies); HH21 (previous studies), caused by mutation in the FLRT3 gene (previous studies); HH22 (previous studies), caused by mutation in the FEZF1 gene (previous studies); HH23 (previous studies), caused by mutation in the LHB gene (previous studies); HH24 (previous studies), caused by mutation in the FSHB gene (previous studies); HH25 (previous studies), caused by mutation in the NDNF gene (previous studies); and HH26 (previous studies), caused by mutation in the TCF12 gene. + +There is also an X-linked form of the disorder (HH1; previous studies), caused by mutation in the KAL1 gene (previous studies). + +There is evidence that mutation in 2 or more of these genes can work in combination (oligogenicity) to produce GnRH-deficient conditions (summary by previous studies). previous studies, for example, demonstrated that of patients with an identifiable coding sequence mutation in 1 of 8 genes responsible for isolated GnRH deficiency, 11% carried mutations in at least one other of these genes as well. + + Reviews + +previous studies reviewed the reproductive, neurodevelopmental, and genetic aspects of hypogonadotropic hypogonadism in human pathology. + +previous studies reviewed the genetics, diagnosis, and clinical management of patients with congenital hypogonadotropic hypogonadism." +MONDO_0008272,"Definition: Although both preaxial polydactyly and syndactyly are cardinal features of this malformation, it is classified as a form of polydactyly because syndactyly does not occur in the absence of polydactyly (previous studies), the opposite not being true. On the other hand, polysyndactyly is here classified as a type of syndactyly because polydactyly (of the third or fourth fingers and fifth toes) does not occur in the absence of syndactyly. The thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4. The foot malformation is more constant and consists of duplication of part or all of the first or second toes and syndactyly affects all of the toes, especially the second and third." +Orphanet_93338,"Definition: Although both preaxial polydactyly and syndactyly are cardinal features of this malformation, it is classified as a form of polydactyly because syndactyly does not occur in the absence of polydactyly (previous studies), the opposite not being true. On the other hand, polysyndactyly is here classified as a type of syndactyly because polydactyly (of the third or fourth fingers and fifth toes) does not occur in the absence of syndactyly. The thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4. The foot malformation is more constant and consists of duplication of part or all of the first or second toes and syndactyly affects all of the toes, especially the second and third." +MONDO_0009657,"Definition: Sanfilippo syndrome comprises several forms of lysosomal storage diseases due to impaired degradation of heparan sulfate. The deficient enzyme in Sanfilippo syndrome C, or MPS IIIC, is an acetyltransferase that catalyzes the conversion of alpha-glucosaminide residues to N-acetylglucosaminide in the presence of acetyl-CoA. + +For a general phenotypic description and a discussion of genetic heterogeneity of Sanfilippo syndrome, see MPS IIIA (previous studies)." +MONDO_0010966,"Definition: The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (previous studies; previous studies). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. + + Classification of Achondrogenesis + +Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). previous studies suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA (ACG1A; previous studies), corresponding to the cases originally published by previous studies and previous studies, and type IB, corresponding to the case originally published by previous studies. Analysis of the case reported by previous studies by previous studies suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (previous studies). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. previous studies suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder." +Orphanet_93298,"Definition: The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (previous studies; previous studies). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. + + Classification of Achondrogenesis + +Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). previous studies suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA (ACG1A; previous studies), corresponding to the cases originally published by previous studies and previous studies, and type IB, corresponding to the case originally published by previous studies. Analysis of the case reported by previous studies by previous studies suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (previous studies). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. previous studies suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder." +MONDO_0011397,"Definition: ADCADN is an autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy/cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression (summary by previous studies)." +MONDO_0013771,"Definition: Transient infantile hypertriglyceridemia is an autosomal recessive disorder characterized by onset of moderate to severe transient hypertriglyceridemia in infancy that normalizes with age. The hypertriglyceridemia is associated with hepatomegaly, moderately elevated transaminases, persistent fatty liver, and the development of hepatic fibrosis. The long-term outcome of affected individuals is unclear (summary by previous studies)." +MONDO_0014159,"Definition: Autosomal recessive spinocerebellar ataxia-14 (SCAR14) is a neurologic disorder characterized by delayed psychomotor development, severe early-onset gait ataxia, eye movement abnormalities, cerebellar atrophy on brain imaging, and impaired intellectual development (summary by previous studies)." +Orphanet_352403,"Definition: Autosomal recessive spinocerebellar ataxia-14 (SCAR14) is a neurologic disorder characterized by delayed psychomotor development, severe early-onset gait ataxia, eye movement abnormalities, cerebellar atrophy on brain imaging, and impaired intellectual development (summary by previous studies)." +MONDO_0032915,"Definition: LQT16 + +Long QT syndrome-16 (LQT16) is characterized by a markedly prolonged corrected QT (QTc) interval and 2:1 atrioventricular (AV) block, with onset in the perinatal period. Patients experience bradycardia or ventricular tachyarrhythmias that may result in syncope, cardiac arrest, and/or sudden death (previous studies; previous studies). + +Patients with LQT14 (previous studies), LQT15 (previous studies), or LQT16, resulting from mutation in calmodulin genes CALM1 (previous studies), CALM2 (previous studies), or CALM3, respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (previous studies). + + CPVT6 + +Catecholaminergic polymorphic ventricular tachycardia-6 (CPVT6) is characterized by childhood-onset syncopal episodes with exercise or stress. Electrocardiogram (ECG) shows a normal QT interval with a prominent U wave, and stress testing reveals premature ventricular contractions (PVCs) that may occur as bigeminy or couplets, and nonsustained ventricular tachycardia (previous studies)." +MONDO_0800043,"Definition: Stuve-Wiedemann syndrome is an autosomal recessive disorder characterized by bowing of the long bones and other skeletal anomalies, episodic hyperthermia, respiratory distress, and feeding difficulties usually resulting in early death (previous studies). + +See also 'classic' Schwartz-Jampel syndrome type 1 (SJS1; previous studies), a phenotypically similar but genetically distinct disorder caused by mutation in the HSPG2 gene (previous studies) on chromosome 1p36. + + Genetic Heterogeneity of Stuve-Wiedemann Syndrome + +Stuve-Wiedemann syndrome-2 (STWS2; previous studies) is caused by mutation in the IL6ST gene (previous studies) on chromosome 5q11." +MONDO_0800104,"Definition: Immunodeficiency-105 (IMD105) is an autosomal recessive disorder characterized by onset of recurrent infections in early infancy. Manifestations may include pneumonia, dermatitis, and lymphadenopathy. B-cell lymphoma was reported in 1 patient. Laboratory studies show decreased or absent numbers of nonfunctional T cells, normal or increased levels of B cells, hypogammaglobulinemia, and normal or low NK cells. The disorder is caused by a deficiency of transmembrane protein CD45 (PTPRC) on leukocytes, which plays an important role in T- and B-cell development (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see previous studies." +MONDO_0005090,"Definition: Schizophrenia is a psychosis, a disorder of thought and sense of self. Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. There is no characteristic pathology, such as neurofibrillary tangles in Alzheimer disease (previous studies). Schizophrenia is a common disorder with a lifetime prevalence of approximately 1%. It is highly heritable but the genetics are complex. This may not be a single entity. + +Schizophrenia and bipolar disorder (see previous studies) are generally considered to be separate entities, but patients who exhibit multiple symptoms of both disorders are often given the hybrid diagnosis schizoaffective disorder (previous studies). + + Genetic Heterogeneity of Schizophrenia with or without an Affective Disorder + +SCZD4 (previous studies) is associated with variation in the PRODH gene (previous studies); SCZD9 (previous studies) with variation in the DISC1 gene (previous studies); SCZD15 (previous studies) with variation in the SHANK3 gene (previous studies); SCZD16 (previous studies) with a chromosome duplication involving the VIPR2 gene (previous studies); SCZD17 (see previous studies) with variation in the NRXN1 gene (previous studies); SCZD18 (previous studies) with variation in the SLC1A1 gene (previous studies); and SCZD19 (previous studies) with variation in the RBM12 gene (previous studies). + +For associations pending confirmation, see MAPPING and MOLECULAR GENETICS." +MONDO_0010011,"Definition: previous studies described schizencephaly as an extremely rare congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. The clefts are lined with gray matter and most commonly involve the parasylvian regions (previous studies). Large portions of the cerebral hemispheres may be absent and replaced by cerebrospinal fluid. Two types of schizencephaly have been described, depending on the size of the area involved and the separation of the cleft lips (previous studies). Type I schizencephaly consists of a fused cleft. This fused pial-ependymal seam forms a furrow in the developing brain, and is lined by polymicrogyric gray matter. In type II schizencephaly, there is a large defect, a holohemispheric cleft in the cerebral cortex filled with fluid and lined by polymicrogyric gray matter. The clinical manifestations depend on the severity of the lesion. Patients with type I are often almost normal; they may have seizures and spasticity. In type II abnormalities, there is usually mental retardation, seizures, hypotonia, spasticity, inability to walk or speak, and blindness. + +Schizencephaly may be part of the larger phenotypic spectrum of holoprosencephaly (HPE; see previous studies)." +MONDO_0010635,"Definition: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia.' + +For information on the autosomal forms of hypogonadotropic hypogonadism with or without anosmia, see previous studies." +MONDO_0012449,"Definition: Spinocerebellar ataxia-23 (SCA23) is an adult-onset autosomal dominant neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, with variable additional features, including peripheral neuropathy and dysarthria (previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0013364,"Definition: Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The classic facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile (previous studies; review by previous studies). + +About 50 to 70% of patients have RSTS1 due to mutation in the CREBBP gene (previous studies). RSTS2 is much less common, and about 3% of patients have mutations in the EP300 gene. RSTS2 appears to be associated with a milder phenotype than RSTS1. Patients with RSTS2 have less severe facial dysmorphism and better cognitive function, but may have more severe microcephaly and malformation of facial bone structures compared to those with RSTS1 (previous studies). + +For a discussion of genetic heterogeneity of Rubinstein-Taybi syndrome, see RSTS1 (previous studies)." +MONDO_0013382,"Definition: Thiamine metabolism dysfunction syndrome-4 is an autosomal recessive metabolic disorder characterized by childhood onset of episodic encephalopathy, often associated with a febrile illness, and causing transient neurologic dysfunction. Most patients recover fully, but some may have mild residual weakness. Affected individuals also develop a slowly progressive axonal polyneuropathy beginning in childhood. Brain imaging during the acute episodes shows lesions consistent with bilateral striatal degeneration or necrosis (summary by previous studies). + +For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (previous studies)." +MONDO_0013394,"Definition: HDBSCC is an autosomal recessive disorder with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy (summary by previous studies)." +MONDO_0013843,"Definition: Meconium ileus refers to intestinal obstruction due to inspissated meconium in the distal ileum and cecum, which develops in utero and presents shortly after birth as a failure to pass meconium (summary by previous studies). Meconium ileus is a known clinical manifestation of cystic fibrosis (CF; previous studies), and meconium ileus in the absence of CF is a rare phenomenon (summary by previous studies)." +MONDO_0013947,"Definition: DSMA5 is an autosomal recessive neurologic disorder characterized by young adult onset of slowly progressive distal muscle weakness and atrophy resulting in gait impairment and loss of reflexes due to impaired function of motor nerves. Sensation and cognition are not impaired (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of distal SMA, see HMN1 (previous studies)." +MONDO_0013969,"Definition: COXPD11 is a severe multisystemic autosomal recessive disorder characterized by neonatal hypotonia and lactic acidosis. Affected individuals may have respiratory insufficiency, foot deformities, or seizures, and all reported patients have died in infancy. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0014719,"Definition: Developmental and epileptic encephalopathy-35 (DEE35) is an autosomal recessive neurodegenerative disorder characterized by onset of seizures in the first months of life associated with essentially no normal development. Brain imaging shows a characteristic pattern consistent with lack of myelination of early structures, including the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices. Many patients die in early childhood (summary by previous studies) + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0020854,"Definition: Liddle syndrome is an autosomal dominant form of hypertension characterized by early onset of hypertension associated with hypokalemia, suppressed plasma renin activity, and suppressed secretion of the mineralocorticoid hormone aldosterone (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Liddle syndrome, see previous studies." +MONDO_0044306,"Definition: Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination is a syndromic form of severe to profound intellectual disability with onset of delayed psychomotor development and seizures in infancy. Affected children have hypotonia, feeding difficulties resulting in failure to thrive, and inability to speak or walk, and they tend to show repetitive stereotypic behaviors. Brain imaging shows cerebral atrophy and delayed myelination (summary by previous studies)." +MONDO_0100297,"Definition: Patients with SSFSC1 have short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies. Distinctive facial features include midface retrusion, short upturned nose, long philtrum, high-arched or cleft palate, and variable degrees of micrognathia and dental crowding. Skeletal anomalies include patterning defects of the axial skeleton, characterized by 11 pairs of ribs and brachydactyly of the fifth ray. Congenital heart defects are variably observed and appear to involve primarily the cardiac outflow tract (previous studies). + + Genetic Heterogeneity of Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies + +SSFSC2 (previous studies) is caused by mutation in the SCUBE3 gene (previous studies) on chromosome 6p21." +MONDO_0800044,"Definition: Congenital disorder of deglycosylation-1 (CDDG1) is an autosomal recessive multisystem disorder characterized by global developmental delay, hypotonia, abnormal involuntary movements, and alacrima or poor tear production. Other common features include microcephaly, intractable seizures, abnormal eye movements, and evidence of liver dysfunction. Liver biopsy shows cytoplasmic accumulation of storage material in vacuoles (summary by previous studies). + + Genetic Heterogeneity of Congenital Disorder of Deglycosylation + +See also CDDG2 (previous studies), caused by mutation in the MAN2C1 gene (previous studies). + +For a discussion of the classification of congenital disorders of glycosylation, see CDG1A (previous studies)." +Orphanet_404454,"Definition: Congenital disorder of deglycosylation-1 (CDDG1) is an autosomal recessive multisystem disorder characterized by global developmental delay, hypotonia, abnormal involuntary movements, and alacrima or poor tear production. Other common features include microcephaly, intractable seizures, abnormal eye movements, and evidence of liver dysfunction. Liver biopsy shows cytoplasmic accumulation of storage material in vacuoles (summary by previous studies). + + Genetic Heterogeneity of Congenital Disorder of Deglycosylation + +See also CDDG2 (previous studies), caused by mutation in the MAN2C1 gene (previous studies). + +For a discussion of the classification of congenital disorders of glycosylation, see CDG1A (previous studies)." +Orphanet_2451,"Definition: Cutaneomucosal venous malformation (VMCM) is an uncommon, heritable form of venous malformation in which lesions tend to be multifocal and small. They are composed of grossly dilated vascular spaces lined by a single continuous layer of endothelial cells, with areas of relative lack of surrounding mural cells, suggesting a defect in their recruitment. Some VMCM patients have venous malformations located in internal organs, and some have additional anomalies, including cardiac malformations (summary by previous studies). + +Another form of autosomal dominant venous malformation, blue rubber bleb nevus (previous studies), is of uncertain relationship to VMCM. Multiple cerebrovenous anomalies without cutaneous lesions are also familial; see cerebral cavernous malformations (previous studies). Glomuvenous malformations (previous studies) are similar to but clinically distinguishable from VMCMs." +MONDO_0010842,"Definition: Cutaneomucosal venous malformation (VMCM) is an uncommon, heritable form of venous malformation in which lesions tend to be multifocal and small. They are composed of grossly dilated vascular spaces lined by a single continuous layer of endothelial cells, with areas of relative lack of surrounding mural cells, suggesting a defect in their recruitment. Some VMCM patients have venous malformations located in internal organs, and some have additional anomalies, including cardiac malformations (summary by previous studies). + +Another form of autosomal dominant venous malformation, blue rubber bleb nevus (previous studies), is of uncertain relationship to VMCM. Multiple cerebrovenous anomalies without cutaneous lesions are also familial; see cerebral cavernous malformations (previous studies). Glomuvenous malformations (previous studies) are similar to but clinically distinguishable from VMCMs." +Orphanet_93372,"Definition: Familial hypocalciuric hypercalcemia (HHC) is a heritable disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. HHC is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone (PTH; previous studies) level. Hypermagnesemia is typically present. Individuals with HHC are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults (summary by previous studies). + +Characteristic features of familial hypocalciuric hypercalcemia include mild to moderate hypercalcemia, nonsuppressed parathyroid hormone, relative hypocalciuria while hypercalcemic (calcium/creatinine clearance ratio less than 0.01, or 24-hr urine calcium less than 6.25 mmol), almost 100% penetrance of hypercalcemia from birth, absence of complications, persistence of hypercalcemia following subtotal parathyroidectomy, and normal parathyroid size, weight, and histology at surgery. However, atypical presentations with severe hypercalcemia, hypercalciuria with or without nephrolithiasis or nephrocalcinosis, kindreds with affected members displaying either hypercalciuria or hypocalciuria, postoperative normocalcemia, and pancreatitis have all been described in FHH (previous studies). + + Genetic Heterogeneity of Hypocalciuric Hypercalcemia + +Familial hypocalciuric hypercalcemia type II (HHC2; previous studies) is caused by mutation in the GNA11 gene (previous studies) on chromosome 19p13, and HHC3 (previous studies) is caused by mutation in the AP2S1 gene (previous studies) on chromosome 19q13." +MONDO_0007791,"Definition: Familial hypocalciuric hypercalcemia (HHC) is a heritable disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. HHC is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone (PTH; previous studies) level. Hypermagnesemia is typically present. Individuals with HHC are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults (summary by previous studies). + +Characteristic features of familial hypocalciuric hypercalcemia include mild to moderate hypercalcemia, nonsuppressed parathyroid hormone, relative hypocalciuria while hypercalcemic (calcium/creatinine clearance ratio less than 0.01, or 24-hr urine calcium less than 6.25 mmol), almost 100% penetrance of hypercalcemia from birth, absence of complications, persistence of hypercalcemia following subtotal parathyroidectomy, and normal parathyroid size, weight, and histology at surgery. However, atypical presentations with severe hypercalcemia, hypercalciuria with or without nephrolithiasis or nephrocalcinosis, kindreds with affected members displaying either hypercalciuria or hypocalciuria, postoperative normocalcemia, and pancreatitis have all been described in FHH (previous studies). + + Genetic Heterogeneity of Hypocalciuric Hypercalcemia + +Familial hypocalciuric hypercalcemia type II (HHC2; previous studies) is caused by mutation in the GNA11 gene (previous studies) on chromosome 19p13, and HHC3 (previous studies) is caused by mutation in the AP2S1 gene (previous studies) on chromosome 19q13." +EFO_0010665,"Definition: Short stature and microcephaly with genital anomalies (SSMGA) is characterized by severe growth failure, with extreme short stature, microcephaly, and delayed and dissociated bone age. Global psychomotor developmental delay may be present, although the brain appears structurally normal. Pubertal delay and genital anomalies have been observed (previous studies)." +MONDO_0007369,"Definition: Hereditary coproporphyria (HCP), an acute hepatic porphyria, is characterized by acute attacks of neurologic dysfunction often provoked by drugs, fasting, menstrual cycle, or infectious diseases. Skin photosensitivity may also be present. Inheritance is usually autosomal dominant, but autosomal recessive inheritance can also occur. Excretion of large amounts of coproporphyrin III, mostly in feces and urine, is observed (review by previous studies)." +MONDO_0007534,"Definition: Beckwith-Wiedemann syndrome is a pediatric overgrowth disorder involving a predisposition to tumor development. The clinical presentation is highly variable; some cases lack the hallmark features of exomphalos, macroglossia, and gigantism as originally described by previous studies and previous studies (summary by previous studies). + +previous studies provided a review of Beckwith-Wiedemann syndrome, including the wide spectrum of phenotypic manifestations, delineation of the frequencies of manifestations according to genotype, and discussion of the molecular and epigenetic defects that underlie the disorder." +MONDO_0007739,"Definition: Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder with a distinct phenotype characterized by chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. There is progressive, selective neural cell loss and atrophy in the caudate and putamen. previous studies provided a detailed review of Huntington disease, including clinical features, population genetics, molecular biology, and animal models." +MONDO_0007758,"Definition: Epidermolytic palmoplantar keratoderma-1 (EPPK1) is an autosomal dominant skin disorder characterized clinically by diffuse, yellow thickening of the skin of the palms and soles. There is no extension of the keratoderma to dorsal surfaces of hands and feet, inner wrists, and Achilles tendon area (transgrediens). Knuckle pads may be present in some individuals (summary by previous studies, previous studies). + + Genetic Heterogeneity of Epidermolytic Palmoplantar Keratoderma + +Epidermolytic palmoplantar keratoderma-2 (EPPK2; previous studies) is caused by mutation in the keratin-1 gene (KRT1; previous studies) on chromosome 12q13. + + Classification of Palmoplantar Keratoderma + +PPK has been classified into diffuse, focal, and punctate forms according to the pattern of hyperkeratosis on the palms and soles (previous studies). Diffuse PPK develops at birth or shortly thereafter and involves the entire palm and sole with a sharp cutoff at an erythematous border; there are no lesions outside the volar skin, and, in particular, no follicular or oral lesions. In contrast, focal PPK is a late-onset form in which focal hyperkeratotic lesions develop in response to mechanical trauma; an important distinguishing feature is the presence of lesions at other body sites, e.g., oral and follicular hyperkeratosis (previous studies). Palmoplantar keratodermas can be further subdivided histologically into epidermolytic and nonepidermolytic PPK (previous studies). + + Genetic Heterogeneity of Palmoplantar Keratoderma + +Nonepidermolytic palmoplantar keratoderma (NEPPK; previous studies) is caused by mutation in the KRT1 gene. A focal form of NEPPK (FNEPPK1; previous studies) is caused by mutation in the KRT16 gene (previous studies). Another focal form, FNEPPK2 (previous studies), is caused by mutation in the TRPV3 gene (previous studies); mutation in TRPV3 can also cause Olmsted syndrome (OLMS; previous studies), a severe mutilating form of PPK. The diffuse Bothnian form of NEPPK (PPKB; previous studies) is caused by mutation in the AQP5 gene (previous studies). The Nagashima type of nonepidermolytic diffuse PPK (PPKN; previous studies) is caused by mutation in the SERPINB7 gene (previous studies). + +A generalized form of epidermolytic hyperkeratosis (EHK; previous studies), also designated bullous congenital ichthyosiform erythroderma (BCIE), is caused by mutation in the keratin genes KRT1 and KRT10 (previous studies). + +For a discussion of punctate PPK, see previous studies; for a discussion of striate PPK, see previous studies." +MONDO_0009823,"Definition: Primary hyperoxaluria type I is an autosomal recessive disorder characterized by an accumulation of calcium oxalate in various bodily tissues, especially the kidney, resulting in renal failure. Affected individuals have decreased or absent AGXT activity and a failure to transaminate glyoxylate, which causes the accumulated glyoxylate to be oxidized to oxalate. This overproduction of oxalate results in the accumulation of nonsoluble calcium oxalate in various body tissues, with pathologic sequelae (previous studies; previous studies; previous studies) + + Genetic Heterogeneity of Primary Hyperoxaluria + +Type II primary hyperoxaluria (HP2; previous studies) is caused by mutation in the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR; previous studies) on chromosome 9. Type III primary hyperoxaluria (HP3; previous studies) is caused by mutation in the mitochondrial dihydrodipicolinate synthase-like gene (DHDPSL; previous studies) on chromosome 10q24." +MONDO_0009901,"Definition: Bartsocas-Papas syndrome-1 (BPS1) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (summary by previous studies). + + Genetic Heterogeneity of Bartsocas-Papas Syndrome + +Bartsocas-Papas syndrome-2 (BPS2) is caused by mutation in the CHUK gene (previous studies). + +A less severe form of popliteal pterygium syndrome (PPS; previous studies) is caused by mutation in the IRF6 gene (previous studies)." +MONDO_0010224,"Definition: Proud syndrome is an X-linked developmental disorder characterized by agenesis of the corpus callosum, severe mental retardation, seizures, and spasticity. Males are severely affected, whereas females may be unaffected or have a milder phenotype (previous studies). Proud syndrome is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; previous studies) to Proud syndrome to infantile spasms without brain malformations (DEE1; previous studies) to syndromic (previous studies) and nonsyndromic (previous studies) mental retardation (previous studies; previous studies)." +MONDO_0010455,"Definition: XMEN is an X-linked recessive immunodeficiency characterized by CD4 (previous studies) lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation (previous studies). Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders. Magnesium supplementation may be therapeutic (summary by previous studies)." +MONDO_0011968,"Definition: Autosomal recessive limb-girdle muscular dystrophy-3 (LGMDR3) affects mainly the proximal muscles and results in difficulty walking. Most individuals have onset in childhood; the disorder is progressive. Other features may include scapular winging, calf pseudohypertrophy, and contractures. Cardiomyopathy has rarely been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (previous studies)." +MONDO_0012166,"Definition: Autosomal dominant sensory ataxia-1 (SNAX1) is a peripheral neuropathy resulting from the degeneration of dorsal root ganglia that affects both central and peripheral neurites of sensory neurons. Affected individuals show adult onset of slowly progressive clumsiness, gait ataxia, walking difficulties, and distal sensory loss which may be associated with abnormal sensory nerve conduction values. Some patients have vestibular ocular dysfunction. Muscle weakness and atrophy are not observed, and brain imaging is normal (summary by previous studies)." +MONDO_0012393,"Definition: Congenital glutamine deficiency is a severe autosomal recessive disorder characterized by onset at birth of encephalopathy, lack of normal development, seizures, and hypotonia associated with variable brain abnormalities (summary by previous studies)." +MONDO_0012701,"Definition: Mutations in the BFSP2 gene have been found to cause multiple types of cataract, which have been described as juvenile-onset lamellar, cortical, nuclear embryonic; and congenital nuclear, sutural, stellate, Y-sutural, and punctate cortical." +Orphanet_98992,"Definition: Mutations in the BFSP2 gene have been found to cause multiple types of cataract, which have been described as juvenile-onset lamellar, cortical, nuclear embryonic; and congenital nuclear, sutural, stellate, Y-sutural, and punctate cortical." +MONDO_0013674,"Definition: Neurodegeneration with brain iron accumulation-4 (NBIA4) is a neurodegenerative disorder characterized by progressive spastic paraplegia, parkinsonism unresponsive to L-DOPA treatment, and psychiatric or behavioral symptoms. Other neurologic features, including optic atrophy, eye movement abnormalities, dystonia, dysphagia, dysarthria, and motor axonal neuropathy, may occur. Brain MRI shows T2-weighted hypointensities in the globus pallidus and substantia nigra. Onset is usually in the first 2 decades, but later onset has been reported (summary by previous studies). There is phenotypic variation: some patients may not have extrapyramidal signs and may have muscle weakness and atrophy as well as cognitive impairment or developmental delay (previous studies). Both autosomal recessive and autosomal dominant inheritance have been reported (see INHERITANCE and MOLECULAR GENETICS). + +For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (previous studies)." +MONDO_0014735,"Definition: Charcot-Marie-Tooth disease type 2Y is an autosomal dominant peripheral neuropathy characterized by distal muscle weakness and atrophy associated with length-dependent sensory loss. Most patients have involvement of both the lower and upper limbs. The age at onset and the severity of the disorder are highly variable (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0030024,"Definition: Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is an early-onset neurologic disorder characterized by global developmental delay, poor or absent speech and language development, and behavioral abnormalities reminiscent of autism spectrum disorder (ASD; previous studies) or Angelman syndrome (AS; previous studies). Additional features may include poor overall growth with small head circumference, axial hypotonia, spasticity, and seizures. Some patients have abnormal findings on brain imaging, including cerebral atrophy, cerebellar atrophy, and/or thin corpus callosum (summary by previous studies)." +MONDO_0030087,"Definition: Permanent neonatal diabetes mellitus-2 (PNDM2) is characterized by onset of insulin-requiring hyperglycemia within the first months of life that requires insulin therapy throughout life. Some patients additionally have marked developmental delay, muscle weakness, and epilepsy (previous studies). The triad of developmental delay, epilepsy, and neonatal diabetes is known as DEND (previous studies). + +previous studies stated that heterozygous activating mutations in KCNJ11 are the most common cause of PNDM and account for 26 to 64% of cases, and that neurologic features are found in 20% of patients with KCNJ11 mutations. + +For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (previous studies)." +MONDO_0060707,"Definition: Ververi-Brady syndrome (VEBRAS) is characterized by mild developmental delay, mildly impaired intellectual development and speech delay, and mild dysmorphic facial features. Affected individuals can usually attend mainstream schools with support, and may also show autistic features (summary by previous studies)." +Orphanet_329466,"Definition: Dystonia-25 is an autosomal dominant neurologic disorder characterized by adult onset of focal dystonia, usually involving the neck. The dystonia most often progresses to involve other regions, particularly the face and laryngeal muscles, and less commonly the trunk and limbs (summary by previous studies)." +MONDO_0014033,"Definition: Dystonia-25 is an autosomal dominant neurologic disorder characterized by adult onset of focal dystonia, usually involving the neck. The dystonia most often progresses to involve other regions, particularly the face and laryngeal muscles, and less commonly the trunk and limbs (summary by previous studies)." +EFO_1000120,"Definition: Pilomatrixoma, also known as calcifying epithelioma of Malherbe, is a superficial benign skin tumor that arises from hair follicle matrix cells. The lesions occur most commonly in the first or second decades. They occur thoughout the body but most often in the head and neck region (review by previous studies)." +MONDO_0007615,"Definition: Laurin-Sandrow syndrome (LSS) is an autosomal dominant disorder characterized by polysyndactyly of hands and feet, mirror image duplication of feet, and nasal defects (hypoplastic alae nasi, short columella), in connection with absent patella and duplicated fibula (summary by previous studies)." +MONDO_0007768,"Definition: Hyperparathyroidism-jaw tumor syndrome is a rare autosomal dominant disorder characterized by synchronous or metachronous occurrence of primary hyperparathyroidism, ossifying fibroma of the maxilla and/or mandible, renal tumor, and uterine tumors. It is associated with increased risk of parathyroid cancer (summary by previous studies). + +For a discussion of genetic heterogeneity of hyperparathyroidism, see HRPT1 (previous studies)." +Orphanet_99880,"Definition: Hyperparathyroidism-jaw tumor syndrome is a rare autosomal dominant disorder characterized by synchronous or metachronous occurrence of primary hyperparathyroidism, ossifying fibroma of the maxilla and/or mandible, renal tumor, and uterine tumors. It is associated with increased risk of parathyroid cancer (summary by previous studies). + +For a discussion of genetic heterogeneity of hyperparathyroidism, see HRPT1 (previous studies)." +MONDO_0009206,"Definition: Combined deficiency of factor V and factor VIII (F5F8D1) is characterized by bleeding symptoms similar to those in hemophilia (previous studies) or parahemophilia (previous studies), caused by single deficiency of factor V (previous studies) or factor VIII (previous studies), respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by previous studies). + + Genetic Heterogeneity of Combined Deficiency of Factor V and Factor VIII + +Another form of combined deficiency of factor V and factor VIII (F5F8D2; previous studies) is caused by mutation in the MCFD2 gene (previous studies) on chromosome 2p21." +MONDO_0010264,"Definition: Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see previous studies) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. The remaining cells are termed 'cytomegalic' because they are larger than typical fetal adrenal cells (previous studies; previous studies). + +Patients with AHC usually present in early infancy with primary adrenal failure. Hypogonadotropic hypogonadism (HHG) is a hallmark of the disorder, and is recognized during adolescence because of the absence or interruption of normal pubertal development. Abnormal spermatogenesis has also been observed in these patients. Milder forms of the disease have been described, with adrenal insufficiency sometimes occurring in childhood or even early adulthood. A few cases of partial HHG have been reported (summary by previous studies). Transient precocious sexual development in infancy or early childhood can be a prominent feature of AHC (previous studies). + +A contiguous gene syndrome involving a combination of congenital adrenal hypoplasia, glycerol kinase deficiency (previous studies), and Duchenne muscular dystrophy (DMD; previous studies) is caused by deletion of multiple genes on chromosome Xp21 (see previous studies)." +Orphanet_95702,"Definition: Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see previous studies) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. The remaining cells are termed 'cytomegalic' because they are larger than typical fetal adrenal cells (previous studies; previous studies). + +Patients with AHC usually present in early infancy with primary adrenal failure. Hypogonadotropic hypogonadism (HHG) is a hallmark of the disorder, and is recognized during adolescence because of the absence or interruption of normal pubertal development. Abnormal spermatogenesis has also been observed in these patients. Milder forms of the disease have been described, with adrenal insufficiency sometimes occurring in childhood or even early adulthood. A few cases of partial HHG have been reported (summary by previous studies). Transient precocious sexual development in infancy or early childhood can be a prominent feature of AHC (previous studies). + +A contiguous gene syndrome involving a combination of congenital adrenal hypoplasia, glycerol kinase deficiency (previous studies), and Duchenne muscular dystrophy (DMD; previous studies) is caused by deletion of multiple genes on chromosome Xp21 (see previous studies)." +MONDO_0011242,"Definition: Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (previous studies). + +Patients with antenatal (or neonatal) forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, previous studies) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of Bartter syndrome, see previous studies." +MONDO_0011728,"Definition: Blepharospasm is a form of primary focal dystonia affecting the orbicularis oculi muscles, usually beginning in middle age. Initial symptoms include eye irritation and frequent blinking, progressing to involuntary spasms of eyelid closure. In severe cases, this can lead to functional blindness (summary by previous studies)." +Orphanet_93955,"Definition: Blepharospasm is a form of primary focal dystonia affecting the orbicularis oculi muscles, usually beginning in middle age. Initial symptoms include eye irritation and frequent blinking, progressing to involuntary spasms of eyelid closure. In severe cases, this can lead to functional blindness (summary by previous studies)." +MONDO_0011868,"Definition: Lethal congenital contracture syndrome-2 (LCCS2) is an autosomal recessive disorder characterized by severe multiple congenital contractures with muscle wasting and atrophy. Micrognathia and other craniofacial anomalies, including cleft palate, as well as cardiac defects and enlarged urinary bladder at birth have also been reported. Hydrops fetalis and multiple pterygia are absent. Most patients have died in the neonatal period, although 2 survived to early adolescence (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of LCCS, see LCCS1 (previous studies)." +Orphanet_137776,"Definition: Lethal congenital contracture syndrome-2 (LCCS2) is an autosomal recessive disorder characterized by severe multiple congenital contractures with muscle wasting and atrophy. Micrognathia and other craniofacial anomalies, including cleft palate, as well as cardiac defects and enlarged urinary bladder at birth have also been reported. Hydrops fetalis and multiple pterygia are absent. Most patients have died in the neonatal period, although 2 survived to early adolescence (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of LCCS, see LCCS1 (previous studies)." +MONDO_0012103,"Definition: Spinocerebellar ataxia-25 (SCA25) is an autosomal dominant neurologic disorder characterized by the onset of lower limb ataxia resulting in gait difficulties in the first few decades of life, although later onset has been reported. Affected individuals often have upper limb involvement, dysarthria, scoliosis, abnormal eye movements, and sensory neuropathy with decreased reflexes. Some patients have sensorineural hearing loss. Brain imaging shows cerebellar atrophy. There is incomplete penetrance and variable expressivity, even within families (previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0012117,"Definition: Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type I. For a general description and a discussion of the classification of CDGs, see CDG1A (previous studies)." +MONDO_0013310,"Definition: This rare variant of congenital adrenal hyperplasia, caused by mutations in the POR gene, results in apparent combined deficiency of P450C17 (previous studies) and P450C21 (previous studies) and accumulation of steroid metabolites. The most striking phenotypic feature is that affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. After birth, however, virilization does not progress and amounts of circulating androgens are low or normal. Affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, sometimes suggesting the pattern seen in patients with Antley-Bixler syndrome (see previous studies) (summary by previous studies)." +MONDO_0013411,"Definition: Mutations in the CRYAB gene have been found to cause multiple types of cataract, which have been described as congenital posterior polar, congenital lamellar, and juvenile. Autosomal dominant and autosomal recessive forms have been described. + +The preferred title/symbol of this entry was formerly 'Cataract, Posterior Polar, 2; CTPP2.'" +MONDO_0013894,"Definition: SOFT syndrome is characterized by severely short long bones, peculiar facies associated with paucity of hair, and nail anomalies. Growth retardation is evident on prenatal ultrasound as early as the second trimester of pregnancy, and affected individuals reach a final stature consistent with a height age of 6 years to 8 years. Relative macrocephaly is present during early childhood but head circumference is markedly low by adulthood. Psychomotor development is normal. Facial dysmorphism includes a long, triangular face with prominent nose and small ears, and affected individuals have an unusual high-pitched voice. Clinodactyly, brachydactyly, and hypoplastic distal phalanges and fingernails are present in association with postpubertal sparse and short hair. Typical skeletal findings include short and thick long bones with mild irregular metaphyseal changes, short femoral necks, and hypoplastic pelvis and sacrum. All long bones of the hand are short, with major delay of carpal ossification and cone-shaped epiphyses. Vertebral body ossification is also delayed (summary by previous studies)." +MONDO_0013950,"Definition: The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see previous studies. + +Individuals with mutations in the PEX13 gene have cells of complementation group 13 (CG13, equivalent to CGH). For information on the history of PBD complementation groups, see previous studies." +MONDO_0014629,"Definition: Autoimmune interstitial lung, joint, and kidney disease is an autosomal dominant systemic autoimmune disorder characterized by interstitial lung disease, inflammatory arthritis, and immune complex-mediated renal disease. Laboratory studies show high-titer autoantibodies. Symptoms appear in the first 2 decades of life, but there is incomplete penetrance (summary by previous studies)." +EFO_0004244,"Definition: Autoimmune interstitial lung, joint, and kidney disease is an autosomal dominant systemic autoimmune disorder characterized by interstitial lung disease, inflammatory arthritis, and immune complex-mediated renal disease. Laboratory studies show high-titer autoantibodies. Symptoms appear in the first 2 decades of life, but there is incomplete penetrance (summary by previous studies)." +MONDO_0020647,"Definition: MFRG is an autosomal recessive syndrome in which microcephaly, unilateral renal agenesis, ambiguous genitalia, and facial dysmorphisms, including severe micrognathia, are observed in most patients. Variable brain, cardiac, and skeletal anomalies are present, including corpus callosum agenesis or dysgenesis, lissencephaly, atrial and ventricular septal defects, patent ductus arteriosus, hypoplastic right ventricle, and joint contractures (previous studies)." +MONDO_0030089,"Definition: Permanent neonatal diabetes mellitus-4 (PNDM4) is characterized by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life (summary by previous studies). + +For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (previous studies)." +MONDO_0030329,"Definition: Megacystis-microcolon-intestinal hypoperistalsis syndrome-5 (MMIHS5) is a form of visceral myopathy characterized by significant inter- and intrafamilial variability, with the most severely affected patients exhibiting prenatal bladder enlargement, intestinal malrotation, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition (TPN) and urinary catheterization (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of MMIHS, see MMIHS1 (previous studies)." +EFO_0020038,"Definition: Megacystis-microcolon-intestinal hypoperistalsis syndrome-5 (MMIHS5) is a form of visceral myopathy characterized by significant inter- and intrafamilial variability, with the most severely affected patients exhibiting prenatal bladder enlargement, intestinal malrotation, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition (TPN) and urinary catheterization (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of MMIHS, see MMIHS1 (previous studies)." +MONDO_0030963,"Definition: Li-Campeau syndrome (LICAS) is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, dysmorphic facial features, hypothyroidism, and variable abnormalities of the cardiac and genital systems. Additional features may include seizures, short stature, hypotonia, and brain imaging anomalies, such as cortical atrophy (summary by previous studies)." +MONDO_0044324,"Definition: Al Kaissi syndrome is an autosomal recessive developmental disorder characterized by growth retardation, spine malformation, particularly of the cervical spine, dysmorphic facial features, and delayed psychomotor development with moderate to severe intellectual disability (summary by previous studies)." +EFO_0009062,Definition: Temple-Baraitser syndrome is a rare developmental disorder characterized by severe mental retardation and anomalies of the first ray of the upper and lower limbs with absence/hypoplasia of the nails. Most patients also have seizures; various dysmorphic facial features have been reported (summary by previous studies). +EFO_0010737,"Definition: Autoinflammation with episodic fever and lymphadenopathy (AIEFL) is an autosomal dominant immunologic disorder characterized by onset of recurrent episodes of unexplained fever beginning in early infancy. The episodes occur in a cyclic pattern with a frequency of every week or every few weeks and a duration of several days. Patients have accompanying lymphadenopathy, and some may have hepatosplenomegaly. Rash and genital ulcers are not observed. Patient serum shows increased levels of inflammatory cytokines and chemokines, including IL6 (previous studies) and TNF (previous studies), consistent with abnormal activation of the innate inflammatory system. Treatment with anti-IL6R (previous studies) antibodies may result in clinical improvement (summary by previous studies)." +MONDO_0007556,"Definition: Epidermolysis bullosa simplex-2F with mottled pigmentation (EBS2F) is characterized by generalized skin blistering of intermediate severity beginning at birth, with mottled or reticulate pigmentation developing gradually. Focal keratoses of palms and soles and dystrophic, thickened nails develop over time. Although a single pathologic mutation in the KRT5 gene (P25L; previous studies) typically causes this phenotype, EBS patients with mottled pigmentation with other mutations in KRT5 or in other genes have been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +Orphanet_79397,"Definition: Epidermolysis bullosa simplex-2F with mottled pigmentation (EBS2F) is characterized by generalized skin blistering of intermediate severity beginning at birth, with mottled or reticulate pigmentation developing gradually. Focal keratoses of palms and soles and dystrophic, thickened nails develop over time. Although a single pathologic mutation in the KRT5 gene (P25L; previous studies) typically causes this phenotype, EBS patients with mottled pigmentation with other mutations in KRT5 or in other genes have been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0008428,"Definition: Septooptic dysplasia is a clinically heterogeneous disorder loosely defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum (previous studies). The diagnosis of this rare congenital anomaly is made when 2 or more features of the classic triad are present. Approximately 30% of patients have complete manifestations, 62% display hypopituitarism, and 60% have an absent septum pellucidum. The disorder is equally prevalent in males and females and is more common in infants born to younger mothers, with a reported incidence of 1 in 10,000 live births (summary by previous studies). + +Also see previous studies for a form of septooptic dysplasia associated with cardiomyopathy and exercise intolerance." +Orphanet_3157,"Definition: Septooptic dysplasia is a clinically heterogeneous disorder loosely defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum (previous studies). The diagnosis of this rare congenital anomaly is made when 2 or more features of the classic triad are present. Approximately 30% of patients have complete manifestations, 62% display hypopituitarism, and 60% have an absent septum pellucidum. The disorder is equally prevalent in males and females and is more common in infants born to younger mothers, with a reported incidence of 1 in 10,000 live births (summary by previous studies). + +Also see previous studies for a form of septooptic dysplasia associated with cardiomyopathy and exercise intolerance." +MONDO_0008654,"Definition: Spinocerebellar ataxia-27A (SCA27A) is an autosomal dominant neurologic disorder characterized by general cerebellar dysfunction manifest as gait disturbances, ataxia, tremor, dysarthria, and gaze-evoked nystagmus. The age at onset is highly variable: some patients present in infancy with nystagmus or delayed motor development, whereas others present as adults with tremor or gait difficulties. The disorder is slowly progressive, and ataxia may be very subtle or even absent. Cerebellar atrophy may or may not be observed on brain imaging. Individuals with SCA27A often show mild developmental delay with variably impaired intellectual development. Many patients report an exacerbation of symptoms with fever, emotional stress, or exercise, which can be reminiscent of episodic ataxia or be associated with outbursts, depression, or other behavioral and psychiatric disturbances. There is significant inter- and intrafamilial variability and patients show various combinations of neurologic features (summary by previous studies; previous studies; previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0009440,"Definition: Autosomal recessive keratitis-ichthyosis-deafness syndrome (KIDAR) is characterized by neonatal-onset ichthyotic erythroderma and profound sensorineural deafness, with failure to thrive and developmental delay in childhood. Severe corneal scarring with vision loss has been observed in adulthood. Low plasma copper and ceruloplasmin levels have been reported in some patients (previous studies; previous studies). + +An autosomal dominant form of KID syndrome (KIDAD; previous studies) is caused by mutation in the GJB2 gene (previous studies) on chromosome 13q12. + +Mutation in the AP1S1 gene (previous studies) causes a disorder with overlapping features (MEDNIK; previous studies)." +MONDO_0009664,"Definition: Mulibrey nanism (MUL) is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor (summary by previous studies)." +MONDO_0012084,"Definition: Aromatic L-amino acid decarboxylase deficiency (AADCD) is an autosomal recessive inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency (previous studies). The disorder is clinically characterized by vegetative symptoms, oculogyric crises, dystonia, and severe neurologic dysfunction, usually beginning in infancy or childhood (summary by previous studies)." +MONDO_0012591,"Definition: Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, previous studies developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (previous studies); perinatal lethal OI type II, also known as congenital OI (previous studies); OI type III, a progressively deforming form with normal sclerae (previous studies); and OI type IV, with normal sclerae (previous studies). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (previous studies) and COL1A2 (previous studies). + +previous studies described a novel autosomal dominant form of OI, which they designated OI type V (OI5), in 7 patients. The disorder was similar to OI type IV but had distinctive clinical, histologic, and molecular characteristics. OI type V is characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation (summary by previous studies). OI type V has a variable phenotype. For example, in patients with the more common c.-14C-T variant (previous studies), distinctive radiographic findings (calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation) are often seen, whereas these findings are not seen in patients with the less common S40L variant (previous studies)." +MONDO_0012662,"Definition: Usher syndrome is a clinically and genetically heterogeneous autosomal recessive disorder characterized by sensorineural hearing deficiencies at birth and later development of progressive retinitis pigmentosa (RP). It is the most frequent cause of combined deafness and blindness in adults and affects 3 to 6% of children born with hearing impairment. In brief, patients with Usher syndrome type II have mild hearing impairment with normal vestibular responses. Type II is the most common of the 3 Usher syndromes (previous studies). + +See previous studies for clinical characterization of Usher syndrome types I, II, and III. + +For a discussion of genetic heterogeneity of Usher syndrome type II, see USH2A (previous studies)." +MONDO_0013869,"Definition: APRT deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic (summary by previous studies). + +Two types of APRT deficiency have been described based on the level of residual enzyme activity in in vitro studies of erythrocytes. Type I deficiency is characterized by complete enzyme deficiency in intact cells and in cell lysates, whereas type II deficiency is characterized by complete enzyme deficiency in intact cells, but only a partial deficiency in cell lysates. Type II alleles show reduced affinity for phosphoribosyl pyrophosphate (PRPP) compared to wildtype. In both types, APRT activity is not functional in vivo. Type II deficiency is most common among Japanese. Heterozygotes of either type do not appear to have any clinical or biochemical abnormalities (summary by previous studies)." +MONDO_0014391,"Definition: IMD24 is an autosomal recessive immunodeficiency characterized by the impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. Patients have early onset of severe chronic viral infections, mostly caused by herpesviruses, including Epstein-Barr virus (EBV) and varicella zoster virus (VZV); they also suffer from recurrent encapsulated bacterial infections, a spectrum typical of a combined deficiency of adaptive immunity (CID) (summary by previous studies)." +MONDO_0014963,"Definition: Shashi-Pena syndrome is a neurodevelopmental syndrome characterized by delayed psychomotor development, variable intellectual disability, hypotonia, facial dysmorphism, and some unusual features, including enlarged head circumference, glabellar nevus flammeus, and deep palmar creases. Some patients may also have atrial septal defect, episodic hypoglycemia, changes in bone mineral density, and/or seizures (summary by previous studies)." +MONDO_0020718,"Definition: Infants with congenital short bowel syndrome (CSBS) are born with a shortened small intestine, with a mean length of 50 cm compared to the normal length of 190 to 280 cm, and intestinal malrotation. Severe malnutrition develops as a result of the hugely reduced absorptive surface of the small intestine, and infants require parenteral nutrition for survival; however, parenteral nutrition itself causes life-threatening complications such as sepsis and liver failure which are associated with a high rate of mortality early in life (summary by previous studies). + +A possible form of congenital short bowel syndrome (see previous studies) is caused by mutation in the FLNA gene (previous studies) on chromosome Xq28." +MONDO_0060591,"Definition: IMDDHH is a multisystem disorder characterized by immunodeficiency, mildly delayed psychomotor development, poor overall growth from infancy, and hypohomocysteinemia. Additional features, such as congenital heart defects and liver involvement, are more variable (summary by previous studies)." +Orphanet_2066,"Definition: GABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Electroencephalograms show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most patients have profound developmental impairment and some patients die in infancy (summary by previous studies)." +MONDO_0013166,"Definition: GABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Electroencephalograms show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most patients have profound developmental impairment and some patients die in infancy (summary by previous studies)." +Orphanet_228366,"Definition: The neuronal ceroid lipofuscinoses (NCL, or CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0012588,"Definition: The neuronal ceroid lipofuscinoses (NCL, or CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_3042,"Definition: Primrose syndrome (PRIMS) consists of recognizable facial features, macrocephaly, mental retardation, enlarged and calcified external ears, sparse body hair, and distal muscle wasting (summary by previous studies). + +Patients with a deletion syndrome involving 3q13.31 (previous studies) exhibit features overlapping those of Primrose syndrome." +MONDO_0009798,"Definition: Primrose syndrome (PRIMS) consists of recognizable facial features, macrocephaly, mental retardation, enlarged and calcified external ears, sparse body hair, and distal muscle wasting (summary by previous studies). + +Patients with a deletion syndrome involving 3q13.31 (previous studies) exhibit features overlapping those of Primrose syndrome." +Orphanet_397685,"Definition: Hyperprolactinemia unrelated to pregnancy occurs in approximately 0.1 to 0.3% of the general population and may result in infertility, hypogonadism, and galactorrhea. Such nonphysiologic hyperprolactinemia is caused mainly by drugs or by tumors in the anterior pituitary gland, primarily prolactinomas (see previous studies). However, 10 to 60% of patients with hyperprolactinemia who undergo MRI have normal findings (summary by previous studies). + +Patients with hyperprolactinemia may also experience agalactia (previous studies)." +MONDO_0014250,"Definition: Hyperprolactinemia unrelated to pregnancy occurs in approximately 0.1 to 0.3% of the general population and may result in infertility, hypogonadism, and galactorrhea. Such nonphysiologic hyperprolactinemia is caused mainly by drugs or by tumors in the anterior pituitary gland, primarily prolactinomas (see previous studies). However, 10 to 60% of patients with hyperprolactinemia who undergo MRI have normal findings (summary by previous studies). + +Patients with hyperprolactinemia may also experience agalactia (previous studies)." +MONDO_0007342,"Definition: Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (previous studies). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, previous studies). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (previous studies; previous studies)." +MONDO_0007726,"Definition: Beukes hip dysplasia is characterized by severe progressive degenerative osteoarthritis of the hip joint in early adulthood, with underlying dysplasia confined to that region. Affected individuals are of normal stature and have no associated health problems. Symptoms of hip joint discomfort usually develop in infancy or later childhood, but may present as late as the fourth decade. Phenotypic expression is age-related and variable in severity; penetrance is incomplete and has been estimated to be 80%. The earliest primary radiographic features of BHD include bilateral shortening and broadening of the femoral neck, delayed appearance of the secondary ossification center, coxa vara, displacement of the femoral head in the acetabulum, and overgrowth of the greater trochanters. After onset of symptoms, the characteristic signs of osteoarthritis develop, including bone sclerosis, cyst formation, and narrowing of the joint space, with rapid deterioration of the joint (summary by previous studies)." +MONDO_0008244,"Definition: Piebaldism is a rare autosomal dominant trait characterized by the congenital absence of melanocytes in affected areas of the skin and hair. A white forelock of hair, often triangular in shape, may be the only manifestation, or both the hair and the underlying forehead may be involved. The eyebrows and eyelashes may be affected. Irregularly shaped white patches may be observed on the face, trunk, and extremities, usually in a symmetrical distribution. Typically, islands of hyperpigmentation are present within and at the border of depigmented areas (summary by previous studies)." +MONDO_0008266,"Definition: Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by previous studies). + + Genetic Heterogeneity of Postaxial Polydactyly + +Other forms of postaxial polydactyly type A include PAPA2 (previous studies) on chromosome 13q21; PAPA3 (previous studies) on chromosome 19p13; PAPA4 (previous studies) on chromosome 7q22; PAPA5 (previous studies) on chromosome 13q13; PAPA6 (previous studies), caused by mutation in the ZNF141 gene (previous studies) on chromosome 4p16; PAPA7 (previous studies), caused by mutation in the IQCE gene (previous studies) on chromosome 7p22; PAPA8 (previous studies), caused by mutation in the GLI1 gene (previous studies) on chromosome 12q13; PAPA9 (previous studies), caused by mutation in the FAM98A gene (previous studies) on chromosome 8q22; and PAPA10 (previous studies), caused by mutation in the KIAA0825 gene (previous studies) on chromosome 5q15." +MONDO_0008416,"Definition: Huriez syndrome (HRZ) is characterized by the triad of congenital scleroatrophy of the distal extremities, palmoplantar keratoderma, and hypoplastic nail changes. The development of aggressive squamous cell carcinoma (SCC) in areas of affected skin is a distinctive feature of the syndrome, occurring in approximately 15% of patients. HRZ-associated SCC shows early onset, mostly in the third to fourth decades of life, and early metastasis formation (summary by previous studies). + +See also previous studies for description of a disorder resembling Huriez syndrome, involving palmoplantar hyperkeratosis and squamous cell carcinoma in association with SRY (previous studies)-negative female-to-male XX sex reversal, caused by mutation in the RSPO1 gene (previous studies)." +MONDO_0008520,Definition: Liebenberg syndrome is an upper limb malformation characterized by the combination of dysplastic elbow joints and the fusion of wrist bones with consequent radial deviation (summary by previous studies). +Orphanet_1275,Definition: Liebenberg syndrome is an upper limb malformation characterized by the combination of dysplastic elbow joints and the fusion of wrist bones with consequent radial deviation (summary by previous studies). +MONDO_0008972,"Definition: Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 is the most frequent form of RCDP (summary by previous studies). + +Individuals with RCDP1, carrying mutations in the PEX7 gene, have cells of peroxisome biogenesis disorder (PBD) complementation group 11 (CG11, equivalent to CGR). For information on the history of PBD complementation groups, see previous studies. + + Genetic Heterogeneity of Rhizomelic Chondrodysplasia Punctata + +RCDP2 (previous studies) is caused by mutation in the gene encoding acyl-CoA:dihydroxyacetonephosphate acyltransferase (GNPAT; previous studies) on chromosome 1q42. RCDP3 (previous studies) is caused by mutation in the gene encoding alkyldihydroxyacetonephosphate synthase (alkyl-DHAP synthase) (AGPS; previous studies) on chromosome 2q31. RCDP5 (previous studies) is caused by mutation in the gene encoding peroxisomal biogenesis factor-5 (PEX5; previous studies) on chromosome 12p13. + +Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 and RCDP3 are classified as single peroxisome enzyme deficiencies (previous studies)." +MONDO_0010000,"Definition: Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD) is characterized by onset of hearing impairment and reduced vision within the first 5 years of life. Renal dysfunction results in rickets-like skeletal changes, and death may occur in childhood or young adulthood due to renal failure (previous studies)." +MONDO_0011504,"Definition: Microhydranencephaly (MHAC) is a severe neurodevelopmental defect characterized by extreme microcephaly, profound motor and mental retardation, spasticity, and incomplete cerebral formation. Radiologic studies show gross dilation of the ventricles resulting from the absence of cerebral hemispheres or severe delay in their development, as well as hypoplasia of the corpus callosum, cerebellum, and brainstem (summary by previous studies)." +MONDO_0011528,"Definition: Hyper-IgM syndrome type 2 (HIGM2) is a rare immunodeficiency characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections. + +For a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (previous studies)." +MONDO_0012120,"Definition: Pyruvate dehydrogenase phosphatase deficiency (PDHPD) is an autosomal recessive disorder of pyruvate metabolism characterized by neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, and hypotonia (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase (PDH) deficiency, see previous studies." +MONDO_0012639,Definition: Spastic paraplegia-18 (SPG18) is a severe autosomal recessive neurologic disorder characterized by onset in early childhood of progressive spastic paraplegia resulting in motor disability. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures (summary by previous studies and previous studies). +Orphanet_209951,Definition: Spastic paraplegia-18 (SPG18) is a severe autosomal recessive neurologic disorder characterized by onset in early childhood of progressive spastic paraplegia resulting in motor disability. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures (summary by previous studies and previous studies). +MONDO_0014332,"Definition: Carbonic anhydrase VA deficiency is an autosomal recessive inborn error of metabolism characterized clinically by acute onset of encephalopathy in infancy or early childhood. Biochemical evaluation shows multiple metabolic abnormalities, including metabolic acidosis and respiratory alkalosis. Other abnormalities include hypoglycemia, increased serum lactate and alanine, and evidence of impaired provision of bicarbonate to essential mitochondrial enzymes. Apart from episodic acute events in early childhood, the disorder shows a relatively benign course. Treatment with carglumic acid can result in neurologic improvement (summary by previous studies)." +MONDO_0014912,"Definition: Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein (CRP), leukocytosis, and neutrophilia in the absence of any infection. Patients exhibit no overt primary immunodeficiency (previous studies and previous studies)." +MONDO_0030534,"Definition: HH26 is characterized by micropenis and cryptorchidism at birth in male patients, and absent puberty and anosmia in male or female patients. Some affected individuals also exhibit craniosynostosis (previous studies). + +Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see previous studies." +MONDO_0033670,"Definition: Autosomal recessive deafness-116 (DFNB116) is characterized by slowly progressive moderate to profound sensorineural hearing loss (SNHL), with a steeply sloping audiogram in the high frequencies in younger patients (previous studies)." +MONDO_0054845,"Definition: Developmental and epileptic encephalopathy-66 (DEE66) is a neurologic disorder characterized by the onset of various types of seizures in the first days or weeks of life. Most seizures have focal origins; secondary generalization is common. Seizure control is difficult at first, but may become easier with time. Affected individuals show global developmental delay with hypotonia, behavioral abnormalities, and dysmorphic features or ophthalmologic defects. Brain imaging often shows cerebellar dysgenesis. A subset of patients have extraneurologic manifestations, including hematologic and distal limb abnormalities (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +Orphanet_231531,"Definition: Hermansky-Pudlak syndrome-7 (HPS7) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and prolonged bleeding. Granulomatous colitis has also been reported (previous studies, previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (previous studies)." +MONDO_0013559,"Definition: Hermansky-Pudlak syndrome-7 (HPS7) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and prolonged bleeding. Granulomatous colitis has also been reported (previous studies, previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (previous studies)." +Orphanet_41751,"Definition: Bietti crystalline corneoretinal dystrophy is an autosomal recessive retinal dystrophy characterized by numerous tiny glistening yellow-white crystals at the posterior pole of the retina, associated with atrophy of the retinal pigment epithelium (RPE), pigment clumps, and choroidal sclerosis. Most cases have similar crystals at the corneoscleral limbus. The disorder is progressive; most patients develop decreased vision, nyctalopia, and paracentral scotomata between the second and fourth decades of life. Patients later develop peripheral visual field loss and marked visual impairment, usually progressing to legal blindness by the fifth or sixth decade of life. In a series of European patients diagnosed with nonsyndromic retinitis pigmentosa (RP; see previous studies), BCD accounted for approximately 3% of all nonsyndromic RP and 10% of nonsyndromic autosomal recessive RP. Histopathology shows advanced panchorioretinal atrophy, with crystals and complex lipid inclusions seen in choroidal fibroblasts, corneal keratocytes, and conjunctival and skin fibroblasts, as well as in circulating lymphocytes, suggesting that BCD may result from a systemic abnormality of lipid metabolism (summary by previous studies)." +MONDO_0008865,"Definition: Bietti crystalline corneoretinal dystrophy is an autosomal recessive retinal dystrophy characterized by numerous tiny glistening yellow-white crystals at the posterior pole of the retina, associated with atrophy of the retinal pigment epithelium (RPE), pigment clumps, and choroidal sclerosis. Most cases have similar crystals at the corneoscleral limbus. The disorder is progressive; most patients develop decreased vision, nyctalopia, and paracentral scotomata between the second and fourth decades of life. Patients later develop peripheral visual field loss and marked visual impairment, usually progressing to legal blindness by the fifth or sixth decade of life. In a series of European patients diagnosed with nonsyndromic retinitis pigmentosa (RP; see previous studies), BCD accounted for approximately 3% of all nonsyndromic RP and 10% of nonsyndromic autosomal recessive RP. Histopathology shows advanced panchorioretinal atrophy, with crystals and complex lipid inclusions seen in choroidal fibroblasts, corneal keratocytes, and conjunctival and skin fibroblasts, as well as in circulating lymphocytes, suggesting that BCD may result from a systemic abnormality of lipid metabolism (summary by previous studies)." +Orphanet_859,"Definition: Transcobalamin II deficiency is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities (summary by previous studies). + +previous studies gave a clinically oriented review of congenital defects of vitamin B12 transport, and previous studies gave a genetically oriented review." +MONDO_0010149,"Definition: Transcobalamin II deficiency is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities (summary by previous studies). + +previous studies gave a clinically oriented review of congenital defects of vitamin B12 transport, and previous studies gave a genetically oriented review." +EFO_0005560,"Definition: Hereditary multiple exostoses is an autosomal dominant disorder characterized by multiple exostoses most commonly arising from the juxtaepiphyseal region of the long bones. + +For a general phenotypic description and a discussion of genetic heterogeneity of multiple exostoses, see EXT1 (previous studies)." +MONDO_0007586,"Definition: Hereditary multiple exostoses is an autosomal dominant disorder characterized by multiple exostoses most commonly arising from the juxtaepiphyseal region of the long bones. + +For a general phenotypic description and a discussion of genetic heterogeneity of multiple exostoses, see EXT1 (previous studies)." +MONDO_0007086,"Definition: Alport syndrome classically comprises nephritis, often progressing to renal failure, and sensorineural hearing loss (previous studies). + +For a general phenotypic description of Alport syndrome, see the X-linked dominant form (ATS1; previous studies). Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (ATS2; previous studies); autosomal dominant inheritance is rare (previous studies). + +Also see benign familial hematuria (BFH; previous studies), a similar but milder disorder also caused by mutation in the COL4A3 gene." +MONDO_0008179,"Definition: Paroxysmal extreme pain disorder (PEXPD), formerly known as familial rectal pain, is characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. Onset is usually in the neonatal period or infancy (previous studies)." +MONDO_0008710,"Definition: Carpenter syndrome is a rare autosomal recessive disorder with the cardinal features of acrocephaly with variable synostosis of the sagittal, lambdoid, and coronal sutures; peculiar facies; brachydactyly of the hands with syndactyly; preaxial polydactyly and syndactyly of the feet; congenital heart defects; growth retardation; mental retardation; hypogenitalism; and obesity. In addition, cerebral malformations, oral and dental abnormalities, coxa valga, genu valgum, hydronephrosis, precocious puberty, and hearing loss may be observed (summary by previous studies). + + Genetic Heterogeneity of Carpenter Syndrome + +Carpenter syndrome-2 (CRPT2; previous studies), in which the features of Carpenter syndrome are sometimes associated with defective lateralization, is caused by mutation in the MEGF8 gene (previous studies)." +MONDO_0008876,"Definition: Bloom syndrome (BLM) is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency; photosensitive skin changes; immune deficiency; insulin resistance; increased risk for diabetes; greatly increased risk of early onset of cancer and for the development of multiple cancers; and chromosomal instability (summary by previous studies). + + Genetic Heterogeneity of Microcephaly, Growth Restriction, and Increased Sister Chromatid Exchange + +See also MGRISCE2 (previous studies), caused by mutation in the TOP3A gene (previous studies) on chromosome 17p12." +MONDO_0011086,"Definition: Severe combined immunodeficiency refers to a genetically and clinically heterogeneous group of disorders with defective cellular and humoral immune function. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms, including Candida albicans, Pneumocystis carinii, and cytomegalovirus, among many others. Laboratory analysis shows profound lymphopenia with diminished or absent immunoglobulins. The common characteristic of all types of SCID is absence of T cell-mediated cellular immunity due to a defect in T-cell development. Without treatment, patients usually die within the first year of life. The overall prevalence of all types of SCID is approximately 1 in 75,000 births (previous studies; previous studies). + + Genetic Heterogeneity of SCID + +SCID can be divided into 2 main classes: those with B lymphocytes (B+ SCID) and those without (B- SCID). Presence or absence of NK cells is variable within these groups. + +The most common form of SCID is X-linked T-, B+, NK- SCID (SCIDX1; previous studies) caused by mutation in the IL2RG gene (previous studies) on chromosome Xq13.1. + +Autosomal recessive SCID includes T-, B-, NK+ SCID, caused by mutation in the RAG1 and RAG2 genes on 11p13; T-, B+, NK- SCID (previous studies), caused by mutation in the JAK3 gene (previous studies) on 19p13; T-, B+, NK+ SCID (IMD104; previous studies), caused by mutation in the IL7R gene (previous studies) on 5p13; T-, B+, NK+ SCID (IMD105; previous studies), caused by mutation in the CD45 gene (PTPRC; previous studies) on 1q31-q32; T-, B+, NK+ SCID (IMD19; previous studies), caused by mutation in the CD3D gene (previous studies) on 11q23; T-, B-, NK- SCID (previous studies) caused by mutation in the ADA (previous studies) gene on 20q13; and T-, B-, NK+ SCID with sensitivity to ionizing radiation (previous studies), caused by mutation in the Artemis gene (DCLRE1C; previous studies) on 10p13 (previous studies); and T-, B-, NK+ SCID with microcephaly, growth retardation, and sensitivity to ionizing radiation (previous studies), caused by mutation in the NHEJ1 gene (previous studies) on 2q35. + +Approximately 20 to 30% of all SCID patients are T-, B-, NK+, and approximately half of these patients have mutations in the RAG1 or RAG2 genes (previous studies; previous studies)." +MONDO_0013839,"Definition: Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by previous studies). + +For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (previous studies)." +MONDO_0014836,"Definition: Axonal Charcot-Marie-Tooth disease type 2CC is an autosomal dominant peripheral neuropathy that predominantly affects the lower limbs, resulting in muscle weakness and atrophy and gait impairment. Other features include distal sensory impairment and less severe involvement of the upper limbs. The age at onset and severity are variable (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (previous studies)." +MONDO_0014878,"Definition: The ductus arteriosus is a muscular artery connecting the pulmonary artery and the aorta during fetal life, shunting blood away from the lungs. It normally occludes shortly after birth. Failure of ductal closure results in PDA, one of the most common congenital heart defects, affecting 1 in 2,000 to 1 in 5,000 full-term infants and constituting 5% to 7% of all congenital heart defects (summary by previous studies). PDA can be an isolated anomaly or occur in association with other congenital anomalies (summary by previous studies). + +For a discussion of genetic heterogeneity of isolated PDA, see PDA1 (previous studies)." +MONDO_0024528,"Definition: Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe (previous studies; previous studies). + +PEO caused by mutation in the POLG gene is associated with more complicated phenotypes than those forms caused by mutation in the ANT1 or C10ORF2 genes (previous studies). + + Genetic Heterogeneity of Autosomal Dominant Progressive External Ophthalmoplegia with DNA Deletions + +See also PEOA2 (previous studies), caused by mutation in the ANT1 gene (SLC25A4; previous studies) on chromosome 4q34; PEOA3 (previous studies), caused by mutation in the TWNK gene (previous studies) on chromosome 10q24; PEOA4 (previous studies), caused by mutation in the POLG2 gene (previous studies) on chromosome 17q; PEOA5 (previous studies), caused by mutation in the RRM2B gene (previous studies) on chromosome 8q23; and PEOA6 (previous studies), caused by mutation in the DNA2 gene (previous studies) on chromosome 10q." +MONDO_0700087,"Definition: Usher syndrome type I is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually evident within the first decade), and constant vestibular dysfunction. Type I is distinguished from type II (previous studies) on the basis of severity of hearing loss and the extent of vestibular involvement. Type I patients are profoundly deaf, whereas type II patients are 'hard of hearing.' Vestibular function is defective in type I patients, whereas type II patients have normal vestibular function (previous studies). Patients with type III (USH3; previous studies) have progressive hearing loss. Patients with type IV (USH4; previous studies) have late onset of both retinitis pigmentosa and progressive, moderate to severe sensorineural hearing loss without vestibular involvement (previous studies). + + Genetic Heterogeneity of Usher Syndrome Type I + +USH type I is genetically heterogeneous. USH1C (previous studies), the 'Acadian variety,' is caused by mutation in harmonin (previous studies), on 11p15. USH1D (previous studies) is caused by mutation in the cadherin-23 (CDH23; previous studies) on 10q21. USH1F (previous studies) is caused by mutation in the protocadherin-15 (PCDH15; previous studies) on 10q22. USH1G (previous studies) is caused by mutation in the SANS gene (previous studies), on 17q25. USH1E (previous studies) maps to 21q21, and USH1H (previous studies) maps to 15q22-q23. USH1J (previous studies) is caused by mutation in the CIB2 gene (previous studies) on 15q24. USH1K (previous studies) maps to chromosome 10p11.21-q21.1. + +A form of USH type I in which affected members carried heterozygous mutations in both CDH23 and PCDH15 has been reported (USH1D/F; see previous studies), thus supporting a digenic model for some individuals with this phenotype. + +previous studies presented evidence that the form of USH1 previously called USH1A, or the 'French variety,' and mapped to chromosome 14 does not in fact exist; mutations in the MYO7A gene were found in most of these families, and in others the phenotype was found to map to other loci. + +previous studies reviewed the molecular genetics of Usher syndrome and indicated that at least 12 loci had been identified as underlying the 3 different clinical subtypes." +Orphanet_1276,"Definition: The hypertension and brachydactyly syndrome is characterized by brachydactyly type E, severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation, and death from stroke before age 50 years when untreated (summary by previous studies)." +MONDO_0007211,"Definition: The hypertension and brachydactyly syndrome is characterized by brachydactyly type E, severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation, and death from stroke before age 50 years when untreated (summary by previous studies)." +Orphanet_1899,"Definition: Arthrochalasia-type EDS is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement (previous studies; previous studies). + + Genetic Heterogeneity of Arthrochalasia-type Ehlers-Danlos Syndrome + +See EDSARTH2 (previous studies), caused by mutation in the COL1A2 gene (previous studies)." +MONDO_0007525,"Definition: Arthrochalasia-type EDS is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement (previous studies; previous studies). + + Genetic Heterogeneity of Arthrochalasia-type Ehlers-Danlos Syndrome + +See EDSARTH2 (previous studies), caused by mutation in the COL1A2 gene (previous studies)." +Orphanet_247522,"Definition: X-linked retinitis pigmentosa and sinorespiratory infections with or without deafness (RPSRDF) is characterized by typical features of RP, including night blindness, constricted visual fields, progressive reduction in visual acuity, bone-spicule pigmentation, and extinguished responses on electroretinography. Affected individuals also experience severe recurrent sinorespiratory infections, and some develop progressive hearing loss. Carrier females may show an attenuated ocular and/or respiratory phenotype (previous studies; previous studies)." +Orphanet_247820,"Definition: Ectodermal dysplasia-syndactyly syndrome (EDSS) is characterized by sparse to absent scalp hair, eyebrows, and eyelashes, hypoplastic nails, tooth enamel hypoplasia, conical-shaped teeth, palmoplantar keratoderma, and partial cutaneous syndactyly (summary by previous studies). + + Genetic Heterogeneity of Ectodermal Dysplasia-Syndactyly Syndrome + +Ectodermal dysplasia-syndactyly syndrome-2 (EDSS2; previous studies) maps to chromosome 7p21-p14." +Orphanet_3051,"Definition: Nicolaides-Baraitser syndrome (NCBRS) is characterized by severe mental retardation, early-onset seizures, short stature, dysmorphic facial features, and sparse hair (summary by previous studies)." +MONDO_0011053,"Definition: Nicolaides-Baraitser syndrome (NCBRS) is characterized by severe mental retardation, early-onset seizures, short stature, dysmorphic facial features, and sparse hair (summary by previous studies)." +Orphanet_324604,"Definition: Congenital myopathy-3 with rigid spine (CMYP3) is an autosomal recessive disorder of the skeletal muscle characterized by hypotonia and proximal muscle weakness apparent from birth or early childhood. Affected individuals show delayed motor development and develop progressive severe and deforming scoliosis ('rigid spine') in the first or second decades. Respiratory involvement due to diaphragmatic weakness is common, and most patients require ventilatory support due to nocturnal hypoventilation; recurrent respiratory infections are also observed. Additional features may include facial muscle weakness, amyotrophy, joint contractures, distal hyperlaxity, pulmonary hypertension with secondary cardiac dysfunction, and insulin resistance in those with a low BMI. The muscle weakness is not progressive, and most patients remain ambulatory. Skeletal muscle biopsy typically shows multiminicores, although there are often other abnormal nonspecific myopathic findings. This phenotype has been referred to as 'rigid spine syndrome' (previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0011271,"Definition: Congenital myopathy-3 with rigid spine (CMYP3) is an autosomal recessive disorder of the skeletal muscle characterized by hypotonia and proximal muscle weakness apparent from birth or early childhood. Affected individuals show delayed motor development and develop progressive severe and deforming scoliosis ('rigid spine') in the first or second decades. Respiratory involvement due to diaphragmatic weakness is common, and most patients require ventilatory support due to nocturnal hypoventilation; recurrent respiratory infections are also observed. Additional features may include facial muscle weakness, amyotrophy, joint contractures, distal hyperlaxity, pulmonary hypertension with secondary cardiac dysfunction, and insulin resistance in those with a low BMI. The muscle weakness is not progressive, and most patients remain ambulatory. Skeletal muscle biopsy typically shows multiminicores, although there are often other abnormal nonspecific myopathic findings. This phenotype has been referred to as 'rigid spine syndrome' (previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0008218,"Definition: Hailey-Hailey disease, also known as benign chronic pemphigus, is a rare autosomal dominant cutaneous disorder that usually becomes manifest in the third or fourth decade of life with erythema, vesicles, and erosions involving the body folds, particularly the groin and axillary regions. Other sites of the body, such as the neck, perianal, and submammary regions, may likewise be affected (summary by previous studies). + +This disorder was first described by the dermatologist brothers previous studies." +Orphanet_2841,"Definition: Hailey-Hailey disease, also known as benign chronic pemphigus, is a rare autosomal dominant cutaneous disorder that usually becomes manifest in the third or fourth decade of life with erythema, vesicles, and erosions involving the body folds, particularly the groin and axillary regions. Other sites of the body, such as the neck, perianal, and submammary regions, may likewise be affected (summary by previous studies). + +This disorder was first described by the dermatologist brothers previous studies." +MONDO_0008660,"Definition: Autosomal dominant hypophosphatemic rickets (ADHR) is characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses. In contrast to X-linked dominant hypophosphatemic rickets (XLH; previous studies), ADHR shows incomplete penetrance, variable age at onset (childhood to adult), and resolution of the phosphate-wasting defect in rare cases (previous studies). + +See also hypophosphatemic bone disease (previous studies). + + Genetic Heterogeneity of Hypophosphatemic Rickets + +Other forms of hypophosphatemic rickets include autosomal recessive forms, i.e., ARHR1 (previous studies), caused by mutation in the DMP1 gene (previous studies) on chromosome 4q21, and ARHR2 (previous studies), caused by mutation in the ENPP1 gene (previous studies) on chromosome 6q23. An X-linked dominant form (XLHR; previous studies) is caused by mutation in the PHEX gene (previous studies), and an X-linked recessive form (previous studies) is caused by mutation in the CLCN5 gene (previous studies). + + Clinical Variability of Hypophosphatemic Rickets + +Hypophosphatemic rickets can be caused by disorders of vitamin D metabolism or action (see VDDR1A, previous studies). A form of hypophosphatemic rickets with hypercalciuria (HHRH; previous studies) is caused by mutation in the SLC34A3 gene (previous studies), and there is evidence that a form of hypophosphatemic rickets with hyperparathyroidism (previous studies) may be caused by a translocation that results in an increase in alpha-klotho levels (KLOTHO; previous studies)." +MONDO_0009162,"Definition: Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by previous studies). + +The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (previous studies) or in the EVC2 gene (previous studies) (previous studies, previous studies)." +Orphanet_289,"Definition: Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by previous studies). + +The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (previous studies) or in the EVC2 gene (previous studies) (previous studies, previous studies)." +MONDO_0009238,"Definition: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system (summary by previous studies)." +MONDO_0009904,"Definition: Gitelman syndrome is an autosomal recessive renal tubular salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. It is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most patients have onset of symptoms as adults, but some can present in childhood. Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis (summary by previous studies). Gitelman syndrome is sometimes referred to as a mild variant of classic Bartter syndrome (previous studies). + +For a discussion of genetic heterogeneity of Bartter syndrome, see previous studies." +MONDO_0010044,"Definition: Spastic paraplegia-15 (SPG15) is an autosomal recessive neurodegenerative disorder characterized by progressive spasticity primarily affecting the lower limbs. It is a complex form of spastic paraplegia, associated with other neurologic dysfunction, including variable mental retardation, hearing and visual defects, and thin corpus callosum (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +Orphanet_100996,"Definition: Spastic paraplegia-15 (SPG15) is an autosomal recessive neurodegenerative disorder characterized by progressive spasticity primarily affecting the lower limbs. It is a complex form of spastic paraplegia, associated with other neurologic dysfunction, including variable mental retardation, hearing and visual defects, and thin corpus callosum (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +MONDO_0010258,"Definition: MEHMO syndrome is a rare intellectual disability disorder that exhibits phenotypic heterogeneity and is variably characterized by mental retardation, epileptic seizures, hypogonadism with hypogenitalism, microcephaly, and obesity. Life expectancy ranges from less than 1 year to adulthood, and the condition is associated with significant morbidity and mortality (summary by previous studies)." +MONDO_0010830,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN8 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_228354,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN8 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0010939,"Definition: In general, gallbladder disease (GBD) is one of the major digestive diseases. GBD prevalence is particularly high in some minority populations in the United States, including Native and Mexican Americans. Gallstones composed of cholesterol (cholelithiasis) are the common manifestations of GBD in western countries, including the United States. Most people with gallstones remain asymptomatic through their lifetimes; however, it is estimated that approximately 10 to 50% of individuals eventually develop symptoms. Significant risk factors associated with GBD are age, female sex, obesity (especially central obesity), lipids, diet, parity, type 2 diabetes (previous studies), medications, and Mexican American ethnicity. GBD appears to be strongly related to the metabolic syndrome (previous studies) and/or its major components, such as hyperinsulinism, dyslipidemia, and abdominal adiposity (previous studies; previous studies). Infection, specifically by Helicobacter, has been implicated in cholelithiasis and cholecystitis (previous studies; previous studies). + +Low phospholipid-associated cholelithiasis is a specific form of gallbladder disease characterized by young-adult onset of chronic cholestasis with intrahepatic sludge and cholesterol cholelithiasis. Affected individuals have recurrence of the disorder after cholecystectomy and show a favorable response to treatment with ursodeoxycholic acid (UDCA) (summary by previous studies). + +Mutation in the ABCB4 gene can cause a spectrum of related diseases, including the more severe progressive familial intrahepatic cholestasis-3 (PFIC3; previous studies), intrahepatic cholestasis of pregnancy-3 (ICP3; previous studies), andoral contraceptive-induced cholestasis (OCIC; see previous studies). + + Genetic Heterogeneity of Gallbladder Disease + +Two major susceptibility loci for symptomatic gallbladder disease have been identified on chromosome 1p in Mexican Americans (GBD2, previous studies; GBD3, previous studies). In addition, variations in the ABCG8 gene (previous studies) on chromosome 2p21 confer susceptibility to gallbladder disease (GBD4; previous studies)." +MONDO_0011670,"Definition: Classic-like Ehlers-Danlos syndrome is a connective tissue disorder characterized by hyperextensible skin, hypermobile joints, and tissue fragility (previous studies). + +For a phenotypic description of classic-type EDS, see previous studies." +MONDO_0013452,"Definition: Multisystemic smooth muscle dysfunction syndrome (MSMDS) presents with a recognizable pattern of complications, including congenital mydriasis, patent ductus arteriosus (PDA), pulmonary artery hypertension, aortic and other arterial aneurysms, moyamoya-like cerebrovascular disease, intestinal hypoperistalsis and malrotation, and hypotonic bladder. It is caused by heterozygous mutations of the ACTA2 gene altering the arginine-179 codon (summary by previous studies)." +MONDO_0014464,"Definition: 2,4-Dienoyl-CoA reductase deficiency (DECRD) is a rare autosomal recessive inborn error of metabolism resulting in mitochondrial dysfunction due to impaired production of NADPH, which is an essential cofactor for several mitochondrial enzymes. Affected individuals have a variable phenotype: some may have severe neurologic symptoms and metabolic dysfunction beginning in early infancy, whereas others may present with more subtle features, such as childhood-onset optic atrophy or intermittent muscle weakness. The variable severity is putatively dependent on the effect of the mutation on the NADK2 enzyme. Biochemical analysis typically shows hyperlysinemia, due to defective activity of the mitochondrial NADP(H)-dependent enzyme AASS (previous studies), which is usually a benign finding. More severe cases have increased C10:2-carnitine levels, due to defective activity of the enzyme DECR (DECR1; previous studies) (summary by previous studies and previous studies)." +MONDO_0014832,"Definition: Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (NEDHSCA) is an autosomal recessive disorder characterized by severely delayed psychomotor development, hypotonia apparent since infancy, and early-onset seizures in most patients. Some patients may have additional features, such as cerebellar atrophy, ataxia, and nonspecific dysmorphic features. NEDHSCA is one of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway. Some patients with NEDHSCA may have the Emm-null blood group phenotype (see previous studies) (summary by previous studies; previous studies). + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +MONDO_0014920,"Definition: Patterned macular dystrophy-3 (MDPT3), also called Martinique crinkled retinal pigment epitheliopathy, appears in the fourth or fifth decade of life and is characterized by a 'dry desert land' pattern of the fundus, involving the posterior pole initially and progressing from the temporal fovea to the periphery of the retina. Polypoid choroidal vasculopathy, choroidal neovascularization, or atrophic fibrous macular scarring can cause reduced visual acuity after age 50. Late-stage MDPT3 consists of a retinitis pigmentosa (RP; see previous studies)-like phenotype due to death of retinal pigment epithelium (RPE) and photoreceptor cells. The dry desert land pattern observed on fundus examination corresponds to an irregular thickness of the Bruch membrane and the RPE, with a scalloped elevation ('crinkling') of the RPE observed on optical coherence tomography (OCT). Full-field electroretinography may be normal at preclinical and early stages of the dystrophy, but later cone and rod responses are severely reduced, consistent with progressive photoreceptor cell dysfunction and death at the final state (summary by previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of patterned macular dystrophy, see MDPT1 (previous studies)." +MONDO_0029130,"Definition: Postaxial polydactyly type A8 (PAPA8) is characterized by the presence of postaxial extra digits (hexadactyly) on the hands and/or the feet. The anomalous digits are well formed and have nails (previous studies). + +For a discussion of genetic heterogeneity of postaxial polydactyly, see previous studies." +MONDO_0030727,"Definition: Developmental and epileptic encephalopathy-101 (DEE101) is a severe autosomal recessive disorder characterized by early infantile epileptic encephalopathy and severe global developmental delay (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0030809,"Definition: Spermatogenic failure-72 (SPGF72) is characterized by male infertility due to multiple morphologic abnormalities of the flagella (MMAF), including coiled, short, angulated, absent, and irregular-caliber flagella, resulting in lack of sperm motility (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0033668,Definition: Autosomal dominant deafness-79 (DFNA79) is a nonsyndromic form of progressive sensorineural hearing loss with age of onset ranging from 20 years to 65 years. Affected females appear to have milder hearing loss than males (previous studies). +Orphanet_252202,"Definition: Mismatch repair cancer syndrome (MMRCS) is a rare autosomal recessive childhood cancer predisposition syndrome with 4 main tumor types: hematologic malignancies, brain/central nervous system tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma. Many patients show signs reminiscent of neurofibromatosis type I (NF1; previous studies), particularly multiple cafe-au-lait macules (summary by previous studies). + +previous studies provided a review of the mismatch cancer repair syndrome and suggested that the prevalence may be underestimated. + + Genetic Heterogeneity of Mismatch Repair Cancer Syndrome + +MMRCS2 (previous studies) is caused by mutation in the MSH2 gene (previous studies) on chromosome 2p21-p16. MMRCS3 (previous studies) is caused by mutation in the MSH6 gene (previous studies) on chromosome 2p16. MMRCS4 (previous studies) is caused by mutation in the PMS2 gene (previous studies) on chromosome 7p22. + +Patients with familial adenomatous polyposis (FAP; previous studies), an autosomal dominant disorder that results from heterozygous mutations in the APC gene, may also develop brain tumors or extracolonic malignancies, resulting in a similar clinical phenotype. + +Heterozygous mutations in the MMR genes result in hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1, previous studies)." +MONDO_0010159,"Definition: Mismatch repair cancer syndrome (MMRCS) is a rare autosomal recessive childhood cancer predisposition syndrome with 4 main tumor types: hematologic malignancies, brain/central nervous system tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma. Many patients show signs reminiscent of neurofibromatosis type I (NF1; previous studies), particularly multiple cafe-au-lait macules (summary by previous studies). + +previous studies provided a review of the mismatch cancer repair syndrome and suggested that the prevalence may be underestimated. + + Genetic Heterogeneity of Mismatch Repair Cancer Syndrome + +MMRCS2 (previous studies) is caused by mutation in the MSH2 gene (previous studies) on chromosome 2p21-p16. MMRCS3 (previous studies) is caused by mutation in the MSH6 gene (previous studies) on chromosome 2p16. MMRCS4 (previous studies) is caused by mutation in the PMS2 gene (previous studies) on chromosome 7p22. + +Patients with familial adenomatous polyposis (FAP; previous studies), an autosomal dominant disorder that results from heterozygous mutations in the APC gene, may also develop brain tumors or extracolonic malignancies, resulting in a similar clinical phenotype. + +Heterozygous mutations in the MMR genes result in hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1, previous studies)." +Orphanet_99817,"Definition: Mismatch repair cancer syndrome (MMRCS) is a rare autosomal recessive childhood cancer predisposition syndrome with 4 main tumor types: hematologic malignancies, brain/central nervous system tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma. Many patients show signs reminiscent of neurofibromatosis type I (NF1; previous studies), particularly multiple cafe-au-lait macules (summary by previous studies). + +previous studies provided a review of the mismatch cancer repair syndrome and suggested that the prevalence may be underestimated. + + Genetic Heterogeneity of Mismatch Repair Cancer Syndrome + +MMRCS2 (previous studies) is caused by mutation in the MSH2 gene (previous studies) on chromosome 2p21-p16. MMRCS3 (previous studies) is caused by mutation in the MSH6 gene (previous studies) on chromosome 2p16. MMRCS4 (previous studies) is caused by mutation in the PMS2 gene (previous studies) on chromosome 7p22. + +Patients with familial adenomatous polyposis (FAP; previous studies), an autosomal dominant disorder that results from heterozygous mutations in the APC gene, may also develop brain tumors or extracolonic malignancies, resulting in a similar clinical phenotype. + +Heterozygous mutations in the MMR genes result in hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1, previous studies)." +Orphanet_330050,"Definition: Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by previous studies; previous studies). + + Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission + +See also EMPF2 (previous studies), caused by mutation in the MFF gene (previous studies) on chromosome 2q36." +MONDO_0013726,"Definition: Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by previous studies; previous studies). + + Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission + +See also EMPF2 (previous studies), caused by mutation in the MFF gene (previous studies) on chromosome 2q36." +Orphanet_79351,"Definition: Phosphoglycerate dehydrogenase deficiency is an autosomal recessive inborn error of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures (summary by previous studies)." +MONDO_0011152,"Definition: Phosphoglycerate dehydrogenase deficiency is an autosomal recessive inborn error of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures (summary by previous studies)." +Orphanet_90,"Definition: Arginase deficiency is an autosomal recessive inborn error of metabolism caused by a defect in the final step in the urea cycle, the hydrolysis of arginine to urea and ornithine. + +Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (previous studies), carbamyl phosphate synthetase deficiency (previous studies), argininosuccinate synthetase deficiency, or citrullinemia (previous studies), argininosuccinate lyase deficiency (previous studies), and arginase deficiency." +MONDO_0008814,"Definition: Arginase deficiency is an autosomal recessive inborn error of metabolism caused by a defect in the final step in the urea cycle, the hydrolysis of arginine to urea and ornithine. + +Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (previous studies), carbamyl phosphate synthetase deficiency (previous studies), argininosuccinate synthetase deficiency, or citrullinemia (previous studies), argininosuccinate lyase deficiency (previous studies), and arginase deficiency." +EFO_0003758,"Definition: Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (previous studies; previous studies). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; previous studies) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (previous studies). Genetic studies in autism often include family members with these less stringent diagnoses (previous studies). + +For a discussion of heterogeneity of autism, see previous studies." +EFO_0005545,"Definition: Developmental and epileptic encephalopathy-50 (DEE50) is an autosomal recessive progressive neurodegenerative neurometabolic disorder characterized by delayed psychomotor development, early-onset refractory seizures, severe developmental regression, and normocytic anemia. Onset is within the first months or years of life. Evidence suggests that affected children can have a favorable response to treatment with uridine (summary by previous studies). + +For a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0008672,"Definition: Watson syndrome is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability (previous studies), and short stature (previous studies). Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibroma (previous studies)." +MONDO_0009504,"Definition: Mitochondrial DNA depletion syndrome-9 is a severe autosomal recessive disorder characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. Some patients die in early infancy (summary by previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +Orphanet_17,"Definition: Mitochondrial DNA depletion syndrome-9 is a severe autosomal recessive disorder characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. Some patients die in early infancy (summary by previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0013016,"Definition: Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (previous studies)-like immune deficiency and Glanzmann thrombasthenia (GT; previous studies)-like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with beta-integrins in hematopoietic cells. In LAD3, the adhesive functions of integrins on both leukocytes and platelets are disrupted, most likely due to defects in activation-dependent alterations of surface integrins that enable high-avidity binding to ligands on target cells, a process termed 'inside-out signaling' (previous studies; previous studies). + +For a discussion of genetic heterogeneity of leukocyte adhesion deficiency, see previous studies." +Orphanet_99844,"Definition: Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (previous studies)-like immune deficiency and Glanzmann thrombasthenia (GT; previous studies)-like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with beta-integrins in hematopoietic cells. In LAD3, the adhesive functions of integrins on both leukocytes and platelets are disrupted, most likely due to defects in activation-dependent alterations of surface integrins that enable high-avidity binding to ligands on target cells, a process termed 'inside-out signaling' (previous studies; previous studies). + +For a discussion of genetic heterogeneity of leukocyte adhesion deficiency, see previous studies." +MONDO_0014221,"Definition: Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by previous studies)." +Orphanet_868,"Definition: Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by previous studies)." +MONDO_0032751,Definition: Distal arthrogryposis type 2B3 (DA2B3) is characterized by facial dysmorphism and congenital joint contractures with predominantly distal involvement. Some patients exhibit muscle weakness (previous studies). Considerable inter- and intrafamilial variability has been reported (previous studies). +MONDO_0033547,"Definition: Li-Ghorbani-Weisz-Hubshman syndrome (LIGOWS) is a neurodevelopmental disorder characterized by global developmental delay, mild to moderately impaired intellectual development with language delay, and mild dysmorphic features. Affected individuals may have behavioral abnormalities and difficulties with numbers and understanding certain concepts, such as money. Some patients have seizures. Brain imaging often shows enlarged ventricles, thin corpus callosum, and gray matter nodular heterotopia, suggesting abnormal cortical brain development. More variable additional features may be present (summary by previous studies)." +MONDO_0859233,"Definition: Junctional epidermolysis bullosa-6 with pyloric atresia (JEB6) is an autosomal recessive blistering disease of skin and mucous membranes. Pyloric atresia is usually evident within a few days of life. Full thickness skin loss (aplasia cutis congenita) may also occur. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. JEB5B is usually lethal within the first few weeks of life despite surgical correction of pyloric atresia (summary by previous studies). + +Another form of junctional epidermolysis bullosa with pyloric atresia (JEB5B; previous studies) is caused by mutation in the integrin-beta-4 gene (ITGB4; previous studies). + +See also epidermolysis bullosa simplex with pyloric atresia (EBS5C; previous studies), which is caused by mutation in the PLEC1 gene (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +Orphanet_53,"Definition: Autosomal dominant osteopetrosis-2 is characterized by segmentary osteosclerosis, predominantly at the vertebral endplates ('rugger-jersey spine'), iliac wings ('bone within bone' sign), and skull base. Clinical manifestations include cranial nerve palsies, mandibular osteomyelitis, osteoarthritis of the hip, and nontraumatic fractures, particularly of the long bones (previous studies). OPTA2 accounts for 70% of cases of autosomal dominant osteopetrosis (previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant osteopetrosis, see OPTA1 (previous studies)." +MONDO_0008156,"Definition: Autosomal dominant osteopetrosis-2 is characterized by segmentary osteosclerosis, predominantly at the vertebral endplates ('rugger-jersey spine'), iliac wings ('bone within bone' sign), and skull base. Clinical manifestations include cranial nerve palsies, mandibular osteomyelitis, osteoarthritis of the hip, and nontraumatic fractures, particularly of the long bones (previous studies). OPTA2 accounts for 70% of cases of autosomal dominant osteopetrosis (previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant osteopetrosis, see OPTA1 (previous studies)." +EFO_0000666,"Definition: Noncirrhotic portal hypertension-1 (NCPH1) is an autosomal recessive disorder characterized by onset of portal hypertension associated with hepatosplenomegaly in the first or second decades of life, in the absence of cirrhosis, known extrahepatic diseases, or splanchnic venous thrombosis. Liver function is normal, and the disorder is relatively benign (previous studies). + + Genetic Heterogeneity of NCPH + +See also NCPH2 (previous studies), caused by mutation in the GIMAP5 gene (previous studies) on chromosome 7q36." +HP_0001915,"Definition: Aplastic anemia is a serious disorder of the bone marrow that affects between 2 and 5 persons per million per year. About 75% of these cases are classified as idiopathic (previous studies). In about 15% of cases a drug or infection can be identified that precipitates the aplasia, although why only some individuals are susceptible is unclear. In about 5 to 10% of patients, the aplastic anemia is constitutional--i.e., is familial or presents with one or more associated somatic abnormalities (summary by previous studies)." +MONDO_0012197,"Definition: Aplastic anemia is a serious disorder of the bone marrow that affects between 2 and 5 persons per million per year. About 75% of these cases are classified as idiopathic (previous studies). In about 15% of cases a drug or infection can be identified that precipitates the aplasia, although why only some individuals are susceptible is unclear. In about 5 to 10% of patients, the aplastic anemia is constitutional--i.e., is familial or presents with one or more associated somatic abnormalities (summary by previous studies)." +MONDO_0007445,"Definition: Dermatopathia pigmentosa reticularis (DPR) is a rare heritable disorder consisting of a triad of cutaneous findings including reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy. Variable features include adermatoglyphia, hypohidrosis or hyperhidrosis, and palmoplantar hyperkeratosis (previous studies)." +MONDO_0011489,"Definition: Spastic paraplegia-12 is an autosomal dominant neurodegenerative disorder characterized by lower limb spasticity and hyperreflexia, resulting in walking difficulties. Some patients may have urinary symptoms and distal sensory impairment. The age at onset is variable and can range from childhood to adulthood (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +Orphanet_100993,"Definition: Spastic paraplegia-12 is an autosomal dominant neurodegenerative disorder characterized by lower limb spasticity and hyperreflexia, resulting in walking difficulties. Some patients may have urinary symptoms and distal sensory impairment. The age at onset is variable and can range from childhood to adulthood (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +MONDO_0011570,"Definition: Charcot-Marie-Tooth disease type 2B2 (CMT2B2) is an autosomal recessive sensorineural axonal peripheral neuropathy manifest as distal muscle weakness and atrophy and distal sensory impairment. The disorder predominantly affects the lower limbs, resulting in gait impairment, although upper limb and hand involvement also occurs. The age at onset and severity is variable: most have onset in the third decade, although earlier onset has been reported. The disorder is slowly progressive, and some patients may lose independent ambulation later in life. More variable features may include ataxia, dysarthria, cerebellar atrophy, and eye movement abnormalities (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A1 (previous studies)." +MONDO_0011970,"Definition: Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC) is an autosomal recessive neurologic disorder characterized by onset of focal seizures in infancy and exercise-induced dystonia in childhood. Features usually include involuntary movements, including facial movements, and difficulties with fine motor skills of the hand. Seizures often respond to medication and remit with age; the dystonia tends to persist (summary by previous studies)." +Orphanet_163727,"Definition: Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC) is an autosomal recessive neurologic disorder characterized by onset of focal seizures in infancy and exercise-induced dystonia in childhood. Features usually include involuntary movements, including facial movements, and difficulties with fine motor skills of the hand. Seizures often respond to medication and remit with age; the dystonia tends to persist (summary by previous studies)." +MONDO_0012391,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN8 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_1947,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN8 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0012475,"Definition: Cone dystrophy with supernormal rod responses (CDSRR) is characterized by onset in the first or second decade of life of very marked photophobia, myopia, reduced color vision along the red-green axis with relatively preserved tritan discrimination, and central scotomata with peripheral widespread sensitivity loss predominating in the superior visual field. Nyctalopia is a later feature of the disorder. There is often retinal pigment epithelium disturbance at the macula with a normal retinal periphery. Autofluorescence (AF) imaging shows either a perifoveal ring or a central macular area of relative increased AF (summary by previous studies)." +MONDO_0012880,"Definition: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see previous studies." +MONDO_0013225,"Definition: Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (previous studies) with muscular dystrophy and cardiac conduction anomalies (previous studies). + +For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (previous studies)." +Orphanet_228429,"Definition: Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (previous studies) with muscular dystrophy and cardiac conduction anomalies (previous studies). + +For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (previous studies)." +MONDO_0013440,"Definition: MDDGC9 is an autosomal recessive muscular dystrophy showing onset in early childhood. It is part of a group of similar disorders resulting from defective glycosylation of DAG1, collectively known as 'dystroglycanopathies' (summary by previous studies). + +For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (previous studies)." +MONDO_0014449,"Definition: Analbuminemia (ANALBA) is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. Affected individuals have few clinical symptoms other than mild edema, hypotension, fatigue, and occasionally a peculiar lower body lipodystrophy (mainly in adult females). The most common biochemical finding is a gross hyperlipidemia, with a significant increase in the total and LDL cholesterol concentrations, but normal concentrations of HDL cholesterol and triglycerides. Analbuminemia often leads to fetal or neonatal death in sibs in families of analbuminemic individuals, which may explain the rarity of the trait (summary by previous studies)." +MONDO_0024771,"Definition: X-linked adult-onset distal myopathy-7 (MPD7) is an X-linked recessive disorder that affects only males. It is characterized by onset of distal muscle weakness predominantly affecting the lower limbs between 20 and 60 years of age. The disorder is slowly progressive, with most affected individuals developing distal upper limb involvement and some developing proximal muscle involvement, although patients remain ambulatory. Muscle biopsy shows variable myopathic changes as well as sarcoplasmic inclusions that may represent abnormally aggregated proteins (summary by previous studies)." +MONDO_0030059,"Definition: Developmental and epileptic encephalopathy-87 (DEE87) is a neurologic disorder characterized by global developmental delay, hypotonia, and onset of frequent refractory seizures or infantile spasms between 6 and 15 months of age. Affected individuals have severely impaired motor and cognitive development with little or absent speech and poor visual tracking. More variable features include facial dysmorphisms, joint laxity, and nonspecific brain imaging findings (summary by previous studies)." +MONDO_0030105,"Definition: Galactosemia IV (GALAC4) is an inborn error of galactose metabolism that presents in the neonatal period. Of the 8 affected children that have thus far been reported, none had gastrointestinal symptoms or severe liver dysfunction. Two had bilateral cataracts. All had normal growth and development (summary by previous studies). + +For a discussion of genetic heterogeneity of galactosemia, see GALAC1 (previous studies)." +MONDO_0030500,"Definition: Loeys-Dietz syndrome-6 (LDS6) is characterized by aortic/arterial aneurysm and dissection in association with connective tissue findings. Most patients have thoracic aortic aneurysm involving the ascending aorta and/or aortic root, but cerebral and iliac arteries can be affected, and abdominal aortic aneurysm has been observed. Arterial tortuosity involving cerebral vessels, the aorta, and/or iliac arteries has also been reported (previous studies; previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of LDS, see LDS1 (previous studies)." +MONDO_0032913,"Definition: Multiple types of congenital heart defects-7 (CHTD7) is an autosomal dominant disorder with incomplete penetrance characterized mainly by tetralogy of Fallot but also including right-sided aortic arch, absent pulmonary valve, and other cardiac abnormalities (previous studies, previous studies)." +MONDO_0032916,"Definition: Imagawa-Matsumoto syndrome (IMMAS) is characterized by variable pre- and postnatal overgrowth; dysmorphic features including postnatal macrocephaly, prominent forehead, round face, hypertelorism, downslanting palpebral fissures, and low and broad nasal bridge; and variable musculoskeletal abnormalities. Developmental delay and impaired intellectual development are common, whereas abnormalities of cerebral imaging are uncommon but may be significant. Some patients exhibit genitourinary abnormalities, and respiratory issues have been reported (previous studies)." +Orphanet_559,"Definition: Marinesco-Sjogren syndrome (MSS) is an autosomal recessive disorder characterized primarily by congenital cataracts, cerebellar ataxia, progressive muscle weakness due to myopathy, and delayed psychomotor development. Other features include short stature, hypergonadotropic hypogonadism, and skeletal deformities due to muscle weakness. MSS is genetically distinct from congenital cataracts, facial dysmorphism, and neuropathy (CCFDN; previous studies), which is caused by mutation in the CTDP1 gene (previous studies) on chromosome 18q23, although the 2 disorders share some overlapping features, including congenital cataracts, delayed psychomotor development, and ataxia. The major distinguishing features are the presence of peripheral neuropathy, facial dysmorphism, and microcornea in CCFDN (previous studies)." +MONDO_0009567,"Definition: Marinesco-Sjogren syndrome (MSS) is an autosomal recessive disorder characterized primarily by congenital cataracts, cerebellar ataxia, progressive muscle weakness due to myopathy, and delayed psychomotor development. Other features include short stature, hypergonadotropic hypogonadism, and skeletal deformities due to muscle weakness. MSS is genetically distinct from congenital cataracts, facial dysmorphism, and neuropathy (CCFDN; previous studies), which is caused by mutation in the CTDP1 gene (previous studies) on chromosome 18q23, although the 2 disorders share some overlapping features, including congenital cataracts, delayed psychomotor development, and ataxia. The major distinguishing features are the presence of peripheral neuropathy, facial dysmorphism, and microcornea in CCFDN (previous studies)." +Orphanet_79400,"Definition: Localized epidermolysis bullosa simplex-1C (EBS1C) is an autosomal dominant skin disorder with intraepidermal blistering after minor trauma mainly restricted to hands and feet beginning in infancy. Nails may be thick and dystrophic (summary by previous studies). Localized epidermolysis bullosa simplex has previously been known as the Weber-Cockayne type. + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility. + +previous studies reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system." +MONDO_0007551,"Definition: Localized epidermolysis bullosa simplex-1C (EBS1C) is an autosomal dominant skin disorder with intraepidermal blistering after minor trauma mainly restricted to hands and feet beginning in infancy. Nails may be thick and dystrophic (summary by previous studies). Localized epidermolysis bullosa simplex has previously been known as the Weber-Cockayne type. + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility. + +previous studies reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system." +EFO_0010257,"Definition: Patients with global developmental delay, progressive ataxia, and elevated glutamine (GDPAG) present in early childhood with delay of both gross and fine motor skills and delayed speech. Ataxia develops by mid- to late childhood, necessitating use of a walker or wheelchair. Plasma glutamine is persistently elevated by a factor of 2.5 despite normal plasma ammonia levels. Residual glutaminase (GLS) activity can be detected in fibroblasts and lymphocytes. One or both alleles of the GLS gene carry an expanded GCA trinucleotide repeat in the 5-prime untranslated region (UTR); the repeat expansion may be found in compound heterozygosity with another GLS mutation. Three patients have been reported (summary by previous studies)." +MONDO_0008002,"Definition: Mirror movements are contralateral involuntary movements that mirror voluntary ones. Whereas mirror movements are occasionally found in normal young children, persistence beyond the age of 10 years is abnormal. Congenital mirror movements tend to persist throughout adulthood and tend to occur more commonly in the upper extremities (summary by previous studies and previous studies). Some patients with DCC mutations have agenesis of the corpus callosum (previous studies). + + Genetic Heterogeneity of Mirror Movements + +See also MRMV2 (previous studies), caused by mutation in the RAD51 gene (previous studies) on chromosome 15q15; MRMV3 (previous studies), caused by mutation in the DNAL4 gene (previous studies) on chromosome 22q13; and MRMV4 (previous studies), caused by mutation in the NTN1 gene (previous studies) on chromosome 17p13." +MONDO_0009406,"Definition: Cantu syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair which extends onto the forehead and to a general increase in body hair. Some features are suggestive of a storage disorder, including macrocephaly and coarse facial features, with a broad nasal bridge, epicanthal folds, wide mouth, and full lips. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability (summary by previous studies)." +Orphanet_1517,"Definition: Cantu syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair which extends onto the forehead and to a general increase in body hair. Some features are suggestive of a storage disorder, including macrocephaly and coarse facial features, with a broad nasal bridge, epicanthal folds, wide mouth, and full lips. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability (summary by previous studies)." +MONDO_0009619,"Definition: Microcephaly-micromelia syndrome (MIMIS) is a severe autosomal recessive disorder that usually results in death in utero or in the perinatal period. Affected individuals have severe growth retardation with microcephaly and variable malformations of the limbs, particularly the upper limbs. Defects include radial ray anomalies, malformed digits, and clubfeet (summary by previous studies)." +MONDO_0009892,"Definition: Familial erythrocytosis-2 (ECYT2) is an autosomal recessive disorder characterized by increased red blood cell mass, increased serum levels of erythropoietin (EPO; previous studies), and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events (previous studies). Familial erythrocytosis-2 has features of both primary and secondary erythrocytosis. In addition to increased circulating levels of EPO, consistent with a secondary, extrinsic process, erythroid progenitors may be hypersensitive to EPO, consistent with a primary, intrinsic process (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (previous studies)." +Orphanet_238557,"Definition: Familial erythrocytosis-2 (ECYT2) is an autosomal recessive disorder characterized by increased red blood cell mass, increased serum levels of erythropoietin (EPO; previous studies), and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events (previous studies). Familial erythrocytosis-2 has features of both primary and secondary erythrocytosis. In addition to increased circulating levels of EPO, consistent with a secondary, extrinsic process, erythroid progenitors may be hypersensitive to EPO, consistent with a primary, intrinsic process (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (previous studies)." +MONDO_0011359,"Definition: previous studies described a rare variant of frontonasal dysplasia (see FND1, previous studies), designated acromelic frontonasal dysplasia (AFND), in which similar craniofacial anomalies are associated with variable central nervous system malformations and limb defects including tibial hypoplasia/aplasia, talipes equinovarus, and preaxial polydactyly of the feet." +Orphanet_1827,"Definition: previous studies described a rare variant of frontonasal dysplasia (see FND1, previous studies), designated acromelic frontonasal dysplasia (AFND), in which similar craniofacial anomalies are associated with variable central nervous system malformations and limb defects including tibial hypoplasia/aplasia, talipes equinovarus, and preaxial polydactyly of the feet." +MONDO_0011377,"Definition: Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (previous studies). + +For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (previous studies)." +MONDO_0011812,"Definition: Duane-radial ray syndrome, also known as Okihiro syndrome, is an autosomal dominant disorder characterized by upper limb anomalies, ocular anomalies, and, in some cases, renal anomalies. The combination of the 3 findings was earlier referred to as 'acro-renal-ocular syndrome.' The ocular anomalies usually include Duane anomaly (see previous studies), but this finding may be absent in some patients (previous studies). Similarly, renal anomalies are not always seen and may not have been investigated, particularly in cases reported before routine renal imaging (previous studies). Other less common features include sensorineural deafness and gastrointestinal anomalies, such as imperforate anus. + +The Holt-Oram syndrome (previous studies), caused by mutation in the TBX5 gene (previous studies) on chromosome 12q24, shows similar anomalies of the upper limb, but can be differentiated from Duane-radial ray syndrome by the absence of ocular and renal anomalies and the presence of severe congenital heart defects (previous studies)." +Orphanet_93293,"Definition: Duane-radial ray syndrome, also known as Okihiro syndrome, is an autosomal dominant disorder characterized by upper limb anomalies, ocular anomalies, and, in some cases, renal anomalies. The combination of the 3 findings was earlier referred to as 'acro-renal-ocular syndrome.' The ocular anomalies usually include Duane anomaly (see previous studies), but this finding may be absent in some patients (previous studies). Similarly, renal anomalies are not always seen and may not have been investigated, particularly in cases reported before routine renal imaging (previous studies). Other less common features include sensorineural deafness and gastrointestinal anomalies, such as imperforate anus. + +The Holt-Oram syndrome (previous studies), caused by mutation in the TBX5 gene (previous studies) on chromosome 12q24, shows similar anomalies of the upper limb, but can be differentiated from Duane-radial ray syndrome by the absence of ocular and renal anomalies and the presence of severe congenital heart defects (previous studies)." +MONDO_0012290,"Definition: Cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK) refers to a unique constellation of clinical manifestations including global developmental delay with hypotonia, roving eye movements or nystagmus, poor motor skills, and impaired intellectual development with speech delay. More variable features include microcephaly, feeding difficulties, seizures, ocular anomalies, hearing loss, and nonspecific dysmorphic facial features. Palmoplantar keratoderma and ichthyosis or neuropathy develop in some patients. Brain magnetic resonance imaging (MRI) shows varying degrees of cerebral dysgenesis, including absence of the corpus callosum and cortical dysplasia, as well as hypomyelination, white matter loss, and white matter signal anomalies suggestive of a leukodystrophy. Some patients may show developmental regression; many die in childhood (previous studies; previous studies). With more patients being reported, several authors (previous studies; previous studies; previous studies) have observed that the dermatologic features and peripheral neuropathy show reduced penetrance and are more variable manifestations of this disorder, as they are not observed in all patients with biallelic SNAP29 mutations." +MONDO_0014444,"Definition: BBS16 is an autosomal recessive ciliopathy characterized by retinal degeneration, obesity, renal disease, and cognitive impairment. Although polydactyly is considered a primary feature of BBS overall, it has not been reported in any BBS16 patient (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +MONDO_0015003,"Definition: Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG) is an autosomal recessive neurologic disorder characterized by onset of involuntary movements in the first decade of life. Optic atrophy develops around the same time or slightly later. Severity is variable, and some patients lose independent ambulation. Brain imaging shows abnormalities in the basal ganglia. Cognition appears to be unaffected (summary by previous studies)." +MONDO_0016489,"Definition: Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. Expression of the HBG1 and HBG2 genes, which encode the gamma isoforms of HbF, is normally suppressed shortly before birth and replaced by expression of the beta- (HBB; previous studies) or delta- (HBD; previous studies) chains, which form adult hemoglobin. Adults normally have less than 1% HbF, whereas heterozygotes for HPFH have 5 to 30% HbF. HPFH heterozygotes have essentially normal red cell indices and a rather homogeneous distribution of HbF among red cells, termed 'pancellular.' Homozygotes for HPFH can express HbF in up to 100% of red blood cells (previous studies). + +Delta-beta thalassemia is a hemoglobin disorder characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis from the affected chromosome. Individuals with delta-beta thalassemia have hypochromic, microcytic anemia and increased HbF, which may mitigate the anemia depending on the level of HbF. Delta-beta thalassemia and some forms of HPFH result from deletions within the beta-globin gene cluster on chromosome 11p15; this has been referred to as 'deletional' HPFH. HPFH can also result from point mutations in the promoter regions of the gamma globulin genes HBG1 and HBG2; this has been referred to as 'non-deletional' HPFH (previous studies; previous studies). + +previous studies noted that HPFH and delta-beta thalassemia are not clearly distinct disorders, but rather show partially overlapping features that may defy classification. Higher expression of HbF is often termed 'pancellular,' whereas lower expression of HbF is often termed 'heterocellular,' although these represent a spectrum. + +Approximately 10% of the population has HPFH manifest as modest elevations of HbF (1 to 4%) present in a subset of red cells (about 4.5%) termed F cells. This is also sometimes referred to as 'heterocellular' HPFH, and is considered to be a multifactorial trait influenced by multiple genetic loci (previous studies)." +MONDO_0020628,"Definition: MGRISCE2 is an autosomal recessive disorder characterized by intrauterine growth restriction, poor postnatal growth with short stature and microcephaly, and increased sister chromatid exchange on cell studies. The disorder results from defective DNA decatenation. The pathogenesis of the disorder is similar to that of Bloom syndrome (BLM; previous studies), but patients with mutations in the TOP3A gene do not have a malar rash (summary by previous studies). + +For a discussion of genetic heterogeneity of MGRISCE, see Bloom syndrome (BLM; MGRISCE1; previous studies)" +MONDO_0025353,"Definition: Developmental and epileptic encephalopathy-90 (DEE90) is an X-linked neurologic disorder characterized by onset of refractory seizures in the first days or months of life. Although most patients have focal seizures associated with oromotor automatisms and apnea, various seizure types may occur, including epileptic spasms, generalized tonic-clonic, and absence. EEG shows multifocal discharges; hypsarrhythmia, intermittent burst suppression, and slow spike-wave background resembling Lennox-Gastaut syndrome may also be observed. Affected individuals have global developmental delay with variable severity, but it is usually profound or severe. Some are unable to walk or speak, whereas others may achieve some milestones and show autistic features (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0030693,"Definition: Immunodeficiency-96 (IMD96) is an autosomal recessive disorder characterized by onset of recurrent, usually viral, respiratory infections in infancy or early childhood. Other infections, including gastrointestinal and urinary tract infections, may also occur. Laboratory studies show hypogammaglobulinemia, lymphopenia with increased gamma/delta T cells, and erythrocyte macrocytosis. The disorder results from defective cellular DNA repair (summary by previous studies)." +MONDO_0032889,"Definition: Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a neurologic disorder characterized in most cases by early-onset seizures and variably impaired intellectual development (ID). The severity of neurologic impairment is highly variable: some patients may have refractory seizures and be bedridden with no meaningful speech, whereas others may have treatment-responsive seizures and achieve normal psychomotor development (summary by previous studies)." +MONDO_0859150,"Definition: BDV syndrome (BDVS) is an autosomal recessive disorder characterized by early-onset profound obesity, hyperphagia, and moderately impaired intellectual development accompanied by infantile hypotonia and other endocrine disorders including hypogonadotropic hypogonadism, hypothyroidism, and insulin resistance (summary by previous studies)." +Orphanet_1171,"Definition: Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) is an autosomal dominant neurologic disorder characterized by early-childhood onset of recurrent episodes of acute ataxic encephalopathy associated with febrile illnesses. These acute episodes tend to decrease with time, but the neurologic sequelae are permanent and progressive, resulting in gait and limb ataxia and areflexia. Affected individuals also develop progressive visual impairment due to optic atrophy and sensorineural hearing loss beginning in childhood. More variable features include abnormal eye movements, pes cavus, and dysphagia (summary by previous studies)." +MONDO_0011038,"Definition: Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) is an autosomal dominant neurologic disorder characterized by early-childhood onset of recurrent episodes of acute ataxic encephalopathy associated with febrile illnesses. These acute episodes tend to decrease with time, but the neurologic sequelae are permanent and progressive, resulting in gait and limb ataxia and areflexia. Affected individuals also develop progressive visual impairment due to optic atrophy and sensorineural hearing loss beginning in childhood. More variable features include abnormal eye movements, pes cavus, and dysphagia (summary by previous studies)." +Orphanet_369891,"Definition: Impaired intellectual development and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries (summary by previous studies)." +MONDO_0014773,"Definition: Impaired intellectual development and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries (summary by previous studies)." +Orphanet_94122,"Definition: Cayman cerebellar ataxia (ATCAY) is an autosomal recessive neurologic disorder characterized by hypotonia from birth, variable psychomotor retardation, and cerebellar dysfunction, including nystagmus, intention tremor, dysarthria, ataxic gait, and truncal ataxia. Although the disorder was initially believed to be restricted to an isolated region of Grand Cayman Island (summary by previous studies; previous studies), one Pakistani family with the disorder and an ATCAY mutation has been reported, thus expanding the ethnic distribution (previous studies)." +MONDO_0011025,"Definition: Cayman cerebellar ataxia (ATCAY) is an autosomal recessive neurologic disorder characterized by hypotonia from birth, variable psychomotor retardation, and cerebellar dysfunction, including nystagmus, intention tremor, dysarthria, ataxic gait, and truncal ataxia. Although the disorder was initially believed to be restricted to an isolated region of Grand Cayman Island (summary by previous studies; previous studies), one Pakistani family with the disorder and an ATCAY mutation has been reported, thus expanding the ethnic distribution (previous studies)." +MONDO_0003789,"Definition: Hereditary papillary renal cell carcinoma is characterized by the development of multiple, bilateral papillary renal tumors (previous studies). The transmission pattern is consistent with autosomal dominant inheritance with incomplete penetrance. + +Papillary renal cell carcinoma is histologically and genetically distinct from 2 other forms of inherited renal carcinoma, von Hippel Lindau disease (previous studies), caused by mutation in the VHL gene (previous studies) on chromosome 3, and a form associated with the chromosome translocation t(3;8), as described by previous studies. previous studies reviewed the molecular genetics of familial and nonfamilial cases of renal cell carcinoma, including the roles of VHL, MET, and translocations involving chromosomes 1, 3, and X. + +For background information and a discussion of genetic heterogeneity of nonpapillary renal cell carcinoma, see RCC (previous studies). + +See also a hereditary syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma (HLRCC; previous studies) caused by germline mutation in the FH gene (previous studies)." +EFO_0001075,"Definition: Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (previous studies). These typical features relate to the biology of the disease, which is a principal determinant of outcome (previous studies). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (previous studies; previous studies)." +MONDO_0008170,"Definition: Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (previous studies). These typical features relate to the biology of the disease, which is a principal determinant of outcome (previous studies). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (previous studies; previous studies)." +MONDO_0007298,"Definition: Spinocerebellar ataxia-29 (SCA29) is an autosomal dominant neurologic disorder characterized by onset in infancy of delayed motor development and mild cognitive delay. Affected individuals develop a very slowly progressive or nonprogressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor (summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0007983,"Definition: Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature and bowing of the long bones; radiographic features include widening and irregularity of the growth plates, especially in the distal and proximal femora (summary by previous studies)." +Orphanet_174,"Definition: Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature and bowing of the long bones; radiographic features include widening and irregularity of the growth plates, especially in the distal and proximal femora (summary by previous studies)." +MONDO_0008962,"Definition: Griscelli syndrome type 1 (GS1) is a rare autosomal recessive disorder that results in pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. In addition to the characteristic silvery-gray appearance of hair and pigmentary defects of skin, GS1 is characterized by primary neurologic deficits that usually are apparent in early infancy and include hypotonia, developmental delay, intellectual disability, and seizures. Immune impairment is not present (summary by previous studies). + +previous studies characterized GS1 as comprising hypomelanosis and severe central nervous system dysfunction, corresponding to the 'dilute' phenotype in the mouse, and GS2 as comprising hypomelanosis and lymphohistiocytic hemophagocytosis, corresponding to the 'ashen' phenotype in mouse. + +previous studies, previous studies, previous studies, and previous studies suggested that Elejalde neuroectodermal melanolysosomal syndrome (previous studies) in some patients and GS1 represent the same entity. + + Genetic Heterogeneity of Griscelli Syndrome + +Griscelli syndrome type 2 (GS2; previous studies), characterized by hypomelanosis with immunologic impairment, is caused by mutation in the RAB27A gene (previous studies). Griscelli syndrome type 3 (GS3; previous studies), characterized by hypomelanosis with no immunologic or neurologic manifestations, is caused by mutation in the melanophilin (MLPH; previous studies) gene." +Orphanet_79476,"Definition: Griscelli syndrome type 1 (GS1) is a rare autosomal recessive disorder that results in pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. In addition to the characteristic silvery-gray appearance of hair and pigmentary defects of skin, GS1 is characterized by primary neurologic deficits that usually are apparent in early infancy and include hypotonia, developmental delay, intellectual disability, and seizures. Immune impairment is not present (summary by previous studies). + +previous studies characterized GS1 as comprising hypomelanosis and severe central nervous system dysfunction, corresponding to the 'dilute' phenotype in the mouse, and GS2 as comprising hypomelanosis and lymphohistiocytic hemophagocytosis, corresponding to the 'ashen' phenotype in mouse. + +previous studies, previous studies, previous studies, and previous studies suggested that Elejalde neuroectodermal melanolysosomal syndrome (previous studies) in some patients and GS1 represent the same entity. + + Genetic Heterogeneity of Griscelli Syndrome + +Griscelli syndrome type 2 (GS2; previous studies), characterized by hypomelanosis with immunologic impairment, is caused by mutation in the RAB27A gene (previous studies). Griscelli syndrome type 3 (GS3; previous studies), characterized by hypomelanosis with no immunologic or neurologic manifestations, is caused by mutation in the melanophilin (MLPH; previous studies) gene." +MONDO_0009579,"Definition: The primary characteristics of the Frank-ter Haar syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by previous studies). + +Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (previous studies)." +MONDO_0010026,"Definition: 'Short,' the mnemonic designation for this syndrome, is an acronym: S = stature; H = hyperextensibility of joints or hernia (inguinal) or both; O = ocular depression; R = Rieger anomaly; T = teething delay. The name was given by previous studies, who described the syndrome in 2 brothers. + +previous studies noted that the features listed in the acronym for SHORT syndrome do not capture the full range of the clinical phenotype, which can include a recognizable facial gestalt consisting of triangular facies, lack of facial fat, and hypoplastic nasal alae with overhanging columella, as well as near-universal partial lipodystrophy, insulin resistance, nephrocalcinosis, and hearing deficits. Notably, both developmental milestones and cognition are normal for individuals with SHORT syndrome." +MONDO_0011877,"Definition: The osteopetroses are a heterogeneous group of genetic disorders characterized by increased bone density due to impaired bone resorption by osteoclasts. Autosomal dominant osteopetrosis-1 is characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. It appears to be the only type of osteopetrosis not associated with an increased fracture rate (summary by previous studies). + + Genetic Heterogeneity of Autosomal Dominant Osteopetrosis + +Autosomal dominant osteopetrosis-2 (OPTA2; previous studies) is caused by mutation in the CLCN7 gene (previous studies) on chromosome 16p13. Autosomal dominant osteopetrosis-3 (OPTA3; previous studies) is caused by mutation in the PLEKHM1 gene (previous studies) on chromosome 17q21." +Orphanet_2783,"Definition: The osteopetroses are a heterogeneous group of genetic disorders characterized by increased bone density due to impaired bone resorption by osteoclasts. Autosomal dominant osteopetrosis-1 is characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. It appears to be the only type of osteopetrosis not associated with an increased fracture rate (summary by previous studies). + + Genetic Heterogeneity of Autosomal Dominant Osteopetrosis + +Autosomal dominant osteopetrosis-2 (OPTA2; previous studies) is caused by mutation in the CLCN7 gene (previous studies) on chromosome 16p13. Autosomal dominant osteopetrosis-3 (OPTA3; previous studies) is caused by mutation in the PLEKHM1 gene (previous studies) on chromosome 17q21." +MONDO_0012335,"Definition: OBAIRH is an autosomal recessive endocrine disorder characterized by early-onset obesity due to severe hyperphagia, pigmentary abnormalities, mainly pale skin and red hair, and secondary hypocortisolism. In the neonatal period, affected individuals are prone to hypoglycemia, hyperbilirubinemia, and cholestasis that may result in death if not treated. The disorder results from mutation in the POMC gene, which encodes a preproprotein that is processed into a range of bioactive peptides, including alpha-melanocyte-stimulating hormone (MSH) and ACTH (summary by previous studies and previous studies)." +MONDO_0012792,"Definition: Mitochondrial DNA depletion syndrome-8A is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration. Renal tubular involvement may also occur (previous studies). + +Mitochondrial DNA depletion syndrome-8B is characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and brain MRI changes, known as the MNGIE phenotype (previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +Orphanet_255235,"Definition: Mitochondrial DNA depletion syndrome-8A is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration. Renal tubular involvement may also occur (previous studies). + +Mitochondrial DNA depletion syndrome-8B is characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and brain MRI changes, known as the MNGIE phenotype (previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0013594,"Definition: SCA36 is a slowly progressive neurodegenerative disorder characterized by adult-onset gait ataxia, eye movement abnormalities, tongue fasciculations, and variable upper motor neuron signs. Some affected individuals may develop hearing loss (summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0014074,"Definition: CMTDIF is an autosomal dominant neurologic disorder characterized by onset around adolescence of slowly progressive distal muscle atrophy and weakness affecting the upper and lower limbs and resulting in steppage gait. There is distal sensory impairment with decreased reflexes. Nerve conduction velocities are variable, ranging from the demyelinating to the axonal range (summary by previous studies). + +For a discussion of genetic heterogeneity of CMTDI, see previous studies." +Orphanet_352670,"Definition: CMTDIF is an autosomal dominant neurologic disorder characterized by onset around adolescence of slowly progressive distal muscle atrophy and weakness affecting the upper and lower limbs and resulting in steppage gait. There is distal sensory impairment with decreased reflexes. Nerve conduction velocities are variable, ranging from the demyelinating to the axonal range (summary by previous studies). + +For a discussion of genetic heterogeneity of CMTDI, see previous studies." +MONDO_0014472,"Definition: Autoinflammation with infantile enterocolitis is an autosomal dominant disorder characterized by onset of recurrent flares of autoinflammation in early infancy. Affected individuals tend to have poor overall growth and gastrointestinal symptoms in infancy associated with laboratory evidence of activated inflammation. This initial presentation is followed by recurrent febrile episodes with splenomegaly and sometimes hematologic disturbances, arthralgias, or myalgias. The disorder results from overactivation of an arm of the immune response system (previous studies; previous studies)." +MONDO_0014487,"Definition: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by previous studies)." +MONDO_0014855,"Definition: Autosomal dominant intellectual developmental disorder-42 (MRD42) is characterized by global developmental delay and impaired intellectual development. More variable features include hypotonia, often later associated with limb hypertonia, seizures of various types, and poor overall growth. Strabismus, cortical visual impairment, and autistic features may also be present (summary by previous studies)." +MONDO_0016862,"Definition: Alagille syndrome is an autosomal dominant disorder that traditionally has been defined by a paucity of intrahepatic bile ducts, in association with 5 main clinical abnormalities: cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and a characteristic facial phenotype (previous studies). Cholestasis is a direct consequence of the paucity of bile ducts. About 39% of patients also have renal involvement, mainly renal dysplasia (previous studies). + +previous studies reviewed the clinical features, diagnosis, pathogenesis, and genetics of Alagille syndrome. + + Genetic Heterogeneity of Alagille Syndrome + +Another form of Alagille syndrome (ALGS2; previous studies) is caused by mutation in the NOTCH2 gene (previous studies)." +MONDO_0032688,"Definition: Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome is an autosomal recessive disorder with a highly variable phenotype. Although all patients have polymicrogyria and other variable structural brain anomalies on imaging, only some show developmental delay and/or seizures. Similarly, only some patients have connective tissue defects that particularly affect the vascular system and can result in early death (summary by previous studies)." +MONDO_0032887,"Definition: Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS) is an autosomal recessive disorder characterized by severe to profound global developmental delay, early-onset seizures, microcephaly, and polymicrogyria and/or cerebral atrophy on brain imaging. Most affected individuals are unable to walk or speak and have profoundly impaired intellectual development, as well as axial hypotonia and peripheral spasticity. Rare individuals may be less severely affected (summary by previous studies)." +MONDO_0044327,"Definition: PCLD4 is an autosomal dominant disease characterized by adult-onset of liver cysts arising from the bile duct epithelium. Some patients may develop a few kidney cysts, but these are often incidental and do not result in renal failure (summary by previous studies). + +For a discussion of genetic heterogeneity of polycystic liver disease, see PCLD1 (previous studies)." +MONDO_0060729,"Definition: Erythropoietic porphyria-2 is an autosomal dominant metabolic disorder of heme biosynthesis, resulting in abnormal accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Affected individuals may have photosensitivity (summary by previous studies) + +For discussion of genetic heterogeneity of EPP, see EPP1 (previous studies)." +Orphanet_100985,"Definition: The hereditary spastic paraplegias (SPG, HSP) are a group of clinically and genetically diverse inherited disorders characterized predominantly by progressive lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated') or with other neurologic abnormalities ('complicated'). + +Pure SPG4 is the most common form of autosomal dominant hereditary SPG, comprising up to 45% of cases (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +MONDO_0008438,"Definition: The hereditary spastic paraplegias (SPG, HSP) are a group of clinically and genetically diverse inherited disorders characterized predominantly by progressive lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated') or with other neurologic abnormalities ('complicated'). + +Pure SPG4 is the most common form of autosomal dominant hereditary SPG, comprising up to 45% of cases (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +Orphanet_289157,"Definition: Vitamin D3 (cholecalciferol), synthesized in the epidermis in response to UV radiation, and dietary vitamin D2 (ergocalciferol, synthesized in plants) are devoid of any biologic activity. Vitamin D hormonal activity is due primarily to the hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the actions of which are mediated by the vitamin D receptor (VDR; previous studies) (previous studies; previous studies). + +In the liver, vitamin D 25-hydroxylase (CYP2R1; previous studies) catalyzes the initial hydroxylation of vitamin D at carbon 25; in the kidney, 1-alpha-hydroxylase (CYP27B1; previous studies) catalyzes the hydroxylation and metabolic activation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3. The active metabolite 1,25(OH)2D3 binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis and cellular differentiation and proliferation (previous studies). + +Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (previous studies). + + Genetic Heterogeneity of Vitamin D-Dependent Rickets + +Vitamin D-dependent rickets type 1A (VDDR1A) is due to an enzymatic defect in synthesis of the active form of vitamin D caused by mutation in the CYP27B1 gene. VDDR1B (previous studies) is a form of rickets due to mutation in the gene encoding a vitamin D 25-hydroxylase (CYP2R1; previous studies), another enzyme necessary for the synthesis of active vitamin D. Vitamin D-dependent rickets type 2A (VDDR2A; previous studies) is caused by end-organ unresponsiveness of active vitamin D due to mutation in the gene encoding the vitamin D receptor (VDR; previous studies). VDDR2B (previous studies) is an unusual form of end-organ unresponsiveness to active vitamin D due to an abnormal protein (see HNRNPC, previous studies) that interferes with the function of the VDR. VDDR3 (previous studies) is a dominant form of VDDR caused by accelerated inactivation of vitamin D metabolites due to mutation in the CYP3A4 gene (previous studies). + + Other Forms of Hypophosphatemic Rickets + +For a discussion of other forms of hypophosphatemic rickets, see ADHR (previous studies)." +MONDO_0020723,"Definition: Vitamin D3 (cholecalciferol), synthesized in the epidermis in response to UV radiation, and dietary vitamin D2 (ergocalciferol, synthesized in plants) are devoid of any biologic activity. Vitamin D hormonal activity is due primarily to the hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the actions of which are mediated by the vitamin D receptor (VDR; previous studies) (previous studies; previous studies). + +In the liver, vitamin D 25-hydroxylase (CYP2R1; previous studies) catalyzes the initial hydroxylation of vitamin D at carbon 25; in the kidney, 1-alpha-hydroxylase (CYP27B1; previous studies) catalyzes the hydroxylation and metabolic activation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3. The active metabolite 1,25(OH)2D3 binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis and cellular differentiation and proliferation (previous studies). + +Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (previous studies). + + Genetic Heterogeneity of Vitamin D-Dependent Rickets + +Vitamin D-dependent rickets type 1A (VDDR1A) is due to an enzymatic defect in synthesis of the active form of vitamin D caused by mutation in the CYP27B1 gene. VDDR1B (previous studies) is a form of rickets due to mutation in the gene encoding a vitamin D 25-hydroxylase (CYP2R1; previous studies), another enzyme necessary for the synthesis of active vitamin D. Vitamin D-dependent rickets type 2A (VDDR2A; previous studies) is caused by end-organ unresponsiveness of active vitamin D due to mutation in the gene encoding the vitamin D receptor (VDR; previous studies). VDDR2B (previous studies) is an unusual form of end-organ unresponsiveness to active vitamin D due to an abnormal protein (see HNRNPC, previous studies) that interferes with the function of the VDR. VDDR3 (previous studies) is a dominant form of VDDR caused by accelerated inactivation of vitamin D metabolites due to mutation in the CYP3A4 gene (previous studies). + + Other Forms of Hypophosphatemic Rickets + +For a discussion of other forms of hypophosphatemic rickets, see ADHR (previous studies)." +MONDO_0008329,"Definition: Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by previous studies). + +Autosomal recessive pseudohypoaldosteronism type I (PHA1B; previous studies), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood." +Orphanet_171871,"Definition: Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by previous studies). + +Autosomal recessive pseudohypoaldosteronism type I (PHA1B; previous studies), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood." +MONDO_0008908,"Definition: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs (see, e.g., CDG1A, previous studies) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. The biochemical changes of CDGs are most readily observed in serum transferrin (TF; previous studies), and the diagnosis is usually made by isoelectric focusing of this glycoprotein (reviews by previous studies; previous studies). + + Genetic Heterogeneity of Congenital Disorder of Glycosylation Type II + +Multiple forms of CDG type II have been identified; see CDG2B (previous studies) through CDG2Z (previous studies)." +MONDO_0009856,"Definition: Patients with Peters-plus syndrome exhibit ocular features, systemic malformations, and variable degrees of developmental delay. Ocular abnormalities involve the anterior chamber, and in most patients consist of Peters anomaly, which is characterized by corneal clouding and iridolenticulocorneal adhesions. Growth retardation, short stature, and brachydactyly appear to be present in all patients, and developmental delay is frequent, whereas external ear anomalies, cleft lip and/or palate, and cardiac and genitourinary malformations are less common (previous studies)." +MONDO_0010680,"Definition: Emery-Dreifuss muscular dystrophy (EDMD1) is a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system. Flexion deformities of the elbows dating from early childhood, mild pectus excavatum, signs of cardiac involvement and absence of muscle pseudohypertrophy, involvement of the forearm muscles, and mental retardation distinguish the Emery-Dreifuss form (EDMD1) from the Becker form (previous studies). + + Genetic Heterogeneity of Emery-Dreifuss Muscular Dystrophy + +Autosomal dominant Emery-Dreifuss muscular dystrophy-2 (EDMD2; previous studies) is caused by mutation in the lamin A/C gene (LMNA; previous studies); autosomal recessive EDMD3 (previous studies) is also caused by mutation in the LMNA gene. Additional autosomal dominant forms include EDMD4 (previous studies), caused by mutation in the SYNE1 gene (previous studies); EDMD5 (previous studies), caused by mutation in the SYNE2 gene (previous studies); and EDMD7 (previous studies), caused by mutation in the TMEM43 gene (previous studies). A second X-linked form (EDMD6; see previous studies) is caused by mutation in the FHL1 gene (previous studies)." +MONDO_0012041,"Definition: Autosomal recessive colorectal adenomatous polyposis is a disorder characterized by adult-onset of multiple colorectal adenomas and adenomatous polyposis. Affected individuals have a significantly increased risk of colorectal cancer (summary by previous studies). + +previous studies reviewed the molecular pathology and biochemistry of MYH colonic polyposis. + +For a discussion of genetic heterogeneity of FAP, see previous studies." +MONDO_0013522,"Definition: Dyskeratosis congenita is an inherited bone marrow failure syndrome classically characterized by the triad of mucosal leukoplakia, nail dysplasia, and abnormal skin pigmentation. Affected individuals have an increased risk of aplastic anemia and malignancy. Less common features include epiphora, premature gray hair, microcephaly, developmental delay, pulmonary fibrosis, portal hypertension, immunodeficiency, and gastrointestinal disease. The phenotype is highly variable. All affected individuals have shortened telomeres due to a defect in telomere maintenance (summary by previous studies). + +For a discussion of genetic heterogeneity of dyskeratosis congenita, see DCKA1 (previous studies)." +MONDO_0030995,"Definition: Global developmental delay with speech and behavioral abnormalities (GDSBA) is characterized by developmental delay apparent from infancy or early childhood. Affected individuals have mildly delayed fine and motor skills with walking by 3 years of age, mildly impaired intellectual development, speech and language delay, and variable behavioral abnormalities, mostly autism and ADHD. Some patients may have additional nonspecific features, such as facial dysmorphism, myopia or strabismus, and skeletal defects, including joint hypermobility, pes planus, or slender fingers (summary by previous studies)." +Orphanet_313808,"Definition: Hereditary diffuse leukoencephalopathy with spheroids-1 (HDLS1) is an autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes (summary by previous studies). + + Genetic Heterogeneity of HDLS + +See also HDLS2 (previous studies), caused by mutation in the AARS1 gene (previous studies) on chromosome 16q22." +MONDO_0800027,"Definition: Hereditary diffuse leukoencephalopathy with spheroids-1 (HDLS1) is an autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes (summary by previous studies). + + Genetic Heterogeneity of HDLS + +See also HDLS2 (previous studies), caused by mutation in the AARS1 gene (previous studies) on chromosome 16q22." +Orphanet_98909,"Definition: Myofibrillar myopathy (MFM) is a noncommittal term that refers to a group of morphologically homogeneous, but genetically heterogeneous chronic neuromuscular disorders. The morphologic changes in skeletal muscle in MFM result from disintegration of the sarcomeric Z disc and the myofibrils, followed by abnormal ectopic accumulation of multiple proteins involved in the structure of the Z disc, including desmin, alpha-B-crystallin (CRYAB; previous studies), dystrophin (previous studies), and myotilin (TTID; previous studies). + + Genetic Heterogeneity of Myofibrillar Myopathy + +Other forms of MFM include MFM2 (previous studies), caused by mutation in the CRYAB gene (previous studies); MFM3 (previous studies), caused by mutation in the MYOT gene (previous studies); MFM4 (previous studies), caused by mutation in the ZASP gene (LDB3; previous studies); MFM5 (previous studies), caused by mutation in the FLNC gene (previous studies); MFM6 (previous studies), caused by mutation in the BAG3 gene (previous studies); MFM7 (previous studies), caused by mutation in the KY gene (previous studies); MFM8 (previous studies), caused by mutation in the PYROXD1 gene (previous studies); MFM9 (previous studies), caused by mutation in the TTN gene (previous studies); MFM10 (previous studies), caused by mutation in the SVIL UNC45B gene (previous studies); MFM11 (previous studies), caused by mutation in the UNC45B gene (previous studies); and MFM12 (previous studies), caused by mutation in the MYL2 gene (previous studies). + +'Desmin-related myopathy' is another term referring to MFM in which there are intrasarcoplasmic aggregates of desmin, usually in addition to other sarcomeric proteins. Rigid spine syndrome (previous studies), caused by mutation in the SEPN1 gene (previous studies), is another desmin-related myopathy. previous studies provided a review of desmin-related myopathy." +MONDO_0007656,"Definition: Gerstmann-Straussler disease (GSD) is a rare inherited prion disease characterized by adult onset of memory loss, dementia, ataxia, and pathologic deposition of amyloid-like plaques in the brain (previous studies). GSD typically presents with progressive limb and truncal ataxia, dysarthria, and cognitive decline in the thirties and forties, and the average disease duration is 7 years. GSD can be distinguished from CJD by earlier age at onset, longer disease duration, and prominent cerebellar ataxia (previous studies). + +On the basis of clinical and pathologic criteria, previous studies suggested that Gerstmann-Straussler syndrome could be classified into 3 forms: an 'ataxic' form, a 'dementing' form, and a dementing form that is accompanied by pathologic quantities of neurofibrillary tangles (NFTs). However, these distinctions may only underscore the phenotypic variability in presentation and progression of the disease (previous studies). + +PRNP-related amyloid angiopathy is usually not a feature of CJD, GSD, or FFI. However, PRNP-immunoreactive amyloid deposits within the walls of cerebral vessels have been observed in patients with truncating mutations in the PRNP gene. Data suggest that C-terminal-truncated PRNP proteins lacking the glycosylphosphatidylinositol (GPI) anchor required to attach the protein to the plasma membrane may readily form amyloid fibrils that result in cerebrovascular amyloid deposition (summary by previous studies)." +MONDO_0008310,"Definition: Hutchinson-Gilford progeria syndrome is a rare disorder characterized by short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early death. Cognitive development is normal. Onset is usually within the first year of life (review by previous studies). The designation Hutchinson-Gilford progeria syndrome appears to have been first used by previous studies. + +A subset of patients with heterozygous mutations in the LMNA gene and a phenotype similar to HGPS have shown onset of the disorder in late childhood or in the early teenage years, and have longer survival than observed in classic HGPS (previous studies; previous studies). + +Other disorders with a less severe, but overlapping phenotype include mandibuloacral dysplasia (MADA; previous studies), an autosomal disorder caused by homozygous or compound heterozygous mutations in the LMNA gene, dilated cardiomyopathy with hypergonadotropic hypogonadism (previous studies), caused by heterozygous mutation in the LMNA gene, and Werner syndrome (previous studies), an autosomal recessive progeroid syndrome caused by homozygous or compound heterozygous mutations in the RECQL2 gene (previous studies)." +MONDO_0009364,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is a genetically heterogeneous autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. More variable features include macrocephaly or microcephaly, hypoplasia of midline brain structures, ventricular dilatation, microphthalmia, cleft lip/palate, and congenital contractures (previous studies). Those with a more severe phenotype characterized as Walker-Warburg syndrome often die within the first year of life, whereas those characterized as having muscle-eye-brain disease may rarely acquire the ability to walk and to speak a few words. These are part of a group of disorders resulting from defective glycosylation of DAG1 (previous studies), collectively known as 'dystroglycanopathies' (previous studies). + + Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies (Type A) + +Muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is genetically heterogeneous and can be caused by mutation in other genes involved in DAG1 glycosylation: see MDDGA2 (previous studies), caused by mutation in the POMT2 gene (previous studies); MDDGA3 (previous studies), caused by mutation in the POMGNT1 gene (previous studies); MDDGA4 (previous studies), caused by mutation in the FKTN gene (previous studies); MDDGA5 (previous studies), caused by mutation in the FKRP gene (previous studies); MDDGA6 (previous studies), caused by mutation in the LARGE gene (previous studies); MDDGA7 (previous studies), caused by mutation in the ISPD gene (CRPPA; previous studies); MDDGA8 (previous studies) caused by mutation in the GTDC2 gene (POMGNT2; previous studies); MDDGA9 (previous studies), caused by mutation in the DAG1 gene (previous studies); MDDGA10 (previous studies), caused by mutation in the TMEM5 gene (RXYLT1; previous studies); MDDGA11 (previous studies), caused by mutation in the B3GALNT2 gene (previous studies); MDDGA12 (previous studies), caused by mutation in the SGK196 gene (POMK; previous studies); MDDGA13 (previous studies), caused by mutation in the B3GNT1 gene (B4GAT1; previous studies); and MDDGA14 (previous studies), caused by mutation in the GMPPB gene (previous studies)." +MONDO_0009482,"Definition: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +For a discussion of genetic heterogeneity of autosomal hypogonadotropic hypogonadism with or without anosmia, see previous studies." +MONDO_0009646,"Definition: Monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1) is an autosomal dominant hematologic disorder with highly variable manifestations. Most patients present in early childhood with pancytopenia and dyspoietic or dysplastic changes in the bone marrow. These abnormalities are almost always associated with monosomy 7 in the bone marrow. In severely affected individuals, the phenotype progresses to frank myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Less severely affected individuals may have transient thrombocytopenia or anemia, or have normal peripheral blood counts with transient bone marrow abnormalities or transient monosomy 7. Germline mutations in the SAMD9L gene, located on chromosome 7q, have a gain-of-function suppressive effect on the cell cycle, resulting in decreased cellular proliferation. It is hypothesized that this germline defect leads to selective pressure favoring somatic loss of the chromosome 7 harboring the mutant allele (adaptation by aneuploidy) (summary by previous studies). + +Monosomy 7 or partial deletion of the long arm of chromosome 7 (7q-) is a frequent cytogenetic finding in the bone marrow of patients with myelodysplasia and acute myelogenous leukemia. Furthermore, monosomy 7 or 7q- is the most frequent abnormality of karyotype in cases of AML that occur after cytotoxic cancer therapy or occupational exposure to mutagens. The age distribution of de novo cases shows peaks in the first and fifth decades. Monosomy 7 is found in about 5% of de novo and 40% of secondary cases of AML. These findings suggest that loss of certain genes at this region is an important event in the development of myelodysplasia (summary by previous studies). + + Genetic Heterogeneity of Monosomy 7 Myelodysplastic and Leukemia Syndrome + +See also M7MLS2 (previous studies), caused by germline mutation in the SAMD9 gene (previous studies) on chromosome 7q21." +MONDO_0010184,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC, cblD (previous studies), cblF (previous studies), and cblJ (previous studies). + +Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (previous studies) is caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (previous studies) is caused by mutation in the MMAA gene (previous studies) on 4q31; and MMA cblB (previous studies) is caused by mutation in the MMAB gene (previous studies) on 12q24. + +Methylmalonic aciduria and homocystinuria of cblC type is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases (previous studies). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood (previous studies)." +Orphanet_79282,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC, cblD (previous studies), cblF (previous studies), and cblJ (previous studies). + +Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (previous studies) is caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (previous studies) is caused by mutation in the MMAA gene (previous studies) on 4q31; and MMA cblB (previous studies) is caused by mutation in the MMAB gene (previous studies) on 12q24. + +Methylmalonic aciduria and homocystinuria of cblC type is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases (previous studies). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood (previous studies)." +MONDO_0010395,"Definition: Phosphoribosylpyrophosphate synthetase I superactivity is an X-linked inborn error of metabolism in which increased enzyme activity is associated with hyperuricemia and gout. Some affected individuals have neurodevelopmental abnormalities, particularly sensorineural deafness (previous studies; previous studies). + +Although different kinetic defects affecting the PRPS1 enzyme have been identified in this disorder, the common pathway involves increased synthesis of phosphoribosylpyrophosphate (PRPP), which leads to increased uric acid and purine production (previous studies)." +MONDO_0010711,"Definition: The classic features of TARP syndrome are talipes equinovarus, atrial septal defect, Robin sequence (micrognathia, cleft palate, and glossoptosis), and persistent left superior vena cava. Not all patients have all classic features. Some patients have the additional features of central nervous system dysfunction, renal abnormalities, variable cardiac anomalies including hypertrophic obstructive cardiomyopathy, and variable distal limb defects including syndactyly. Most patients die in late prenatal or early postnatal stages (summary by previous studies)." +MONDO_0010829,"Definition: Autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is a nonhypertensive cerebral small vessel arteriopathy characterized by alopecia, spondylosis, and progressive motor dysfunction and dementia. Onset is usually in the second or third decade (summary by previous studies)." +Orphanet_199354,"Definition: Autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is a nonhypertensive cerebral small vessel arteriopathy characterized by alopecia, spondylosis, and progressive motor dysfunction and dementia. Onset is usually in the second or third decade (summary by previous studies)." +MONDO_0010914,"Definition: Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. The infantile form usually presents between 6 and 24 months of age with recurrent attacks of hypoketotic hypoglycemia causing loss of consciousness and seizures, liver failure, and transient hepatomegaly. Some children also have heart involvement with cardiomyopathy and arrhythmia. Episodes are triggered by infections, fever, or fasting. Laboratory studies usually indicate hyperammonemia, metabolic acidosis, and hypoketotic hypoglycemia with elevated levels of creatine kinase (summary by previous studies). + +See also the lethal neonatal (previous studies) and adult-onset (previous studies) forms of the disorder, which are also caused by mutation in the CPT2 gene." +MONDO_0011229,"Definition: Ethylmalonic encephalopathy (EE) is an autosomal recessive severe metabolic disorder of infancy affecting the brain, gastrointestinal tract, and peripheral vessels. The disorder is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Brain MRI shows necrotic lesions in deep gray matter structures. Death usually occurs in the first decade of life (summary by previous studies)." +MONDO_0013184,"Definition: Congenital tufting enteropathy (CTE) is a rare inherited intractable diarrhea of infancy characterized by villous atrophy and absence of inflammation, with intestinal epithelial cell dysplasia manifesting as focal epithelial tufts in the duodenum and jejunum. CTE presents in the first few months of life with chronic watery diarrhea and failure to thrive, and most affected individuals require parenteral nutrition for normal growth and development (summary by previous studies). + +Semiquantitative assessment of the epithelial surface in CTE patients revealed that 80 to 90% contained tufts, compared to only 16% in patients with celiac disease and less than 10% in normal jejunum (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +Orphanet_92050,"Definition: Congenital tufting enteropathy (CTE) is a rare inherited intractable diarrhea of infancy characterized by villous atrophy and absence of inflammation, with intestinal epithelial cell dysplasia manifesting as focal epithelial tufts in the duodenum and jejunum. CTE presents in the first few months of life with chronic watery diarrhea and failure to thrive, and most affected individuals require parenteral nutrition for normal growth and development (summary by previous studies). + +Semiquantitative assessment of the epithelial surface in CTE patients revealed that 80 to 90% contained tufts, compared to only 16% in patients with celiac disease and less than 10% in normal jejunum (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +MONDO_0013747,"Definition: The term 'atrioventricular septal defect' (AVSD) covers a spectrum of congenital heart malformations characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. In ostium primum atrial septal defect (ASD) there are separate atrioventricular valvar orifices despite a common junction, whereas in complete AVSD the valve itself is also shared (summary by previous studies). + +AVSD, also designated endocardial cushion defect or atrioventricular canal defect (AVCD), is known to occur in either a nonsyndromic (isolated) form or, more commonly, as part of a malformation syndrome. The 2 syndromes most frequently associated with AVSD are Down syndrome (previous studies), in which AVSD is the most frequent congenital heart defect, and Ivemark syndrome (previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of atrioventricular septal defects, see AVSD1 (previous studies)." +MONDO_0013825,"Definition: Diarrhea-6 is a relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +Orphanet_314373,"Definition: Diarrhea-6 is a relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +MONDO_0013992,"Definition: Leptin receptor deficiency is characterized by severe early-onset obesity, major hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (summary by previous studies)." +MONDO_0013999,"Definition: Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH) is an autosomal dominant disorder in which affected individuals present in childhood with reduced vision associated with papilledema and low-grade ocular inflammation. Progressive deterioration of visual acuity results in counting fingers to no light perception by the third decade of life. Patients also show anhidrosis, as well as splenomegaly and mild pancytopenia, and most experience headaches that may be migraine-like in nature (previous studies)." +MONDO_0014869,"Definition: Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) is an autosomal recessive multisystem disorder characterized by the onset of hydrops in utero. The severity of the hydrops and the disorder in general is highly variable. At birth, affected infants usually show poor growth, lactic acidosis, pulmonary hypertension with hypoxic respiratory insufficiency, and sideroblastic anemia. More variable features may include hepatosplenomegaly or cholestasis, hypoglycemia, pancreatic insufficiency, and micropenis or hypospadias. Death in infancy may occur. Those who survive tend to have resolution of lactic acidosis and anemia, but may show developmental delay and sensorineural deafness (summary by previous studies)." +MONDO_0033656,"Definition: Mitochondrial complex IV deficiency nuclear type 21 (MC4DN21) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals present with congenital lactic acidosis and later show global developmental delay with delayed speech and learning disabilities. Additional features include motor dysfunction manifest as spasticity, dystonia, and pyramidal tract signs. Ataxia, peripheral neuropathy, and seizures may also occur. Brain imaging shows T2-weighted hyperintensities in subcortical regions, consistent with a clinical diagnosis of Leigh syndrome (see previous studies). Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV (previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0042490,"Definition: Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections (previous studies). About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations, resulting in a form of severe congenital neutropenia, which is designated here as SCN1. + + Genetic Heterogeneity of Severe Congenital Neutropenia + +Severe congenital neutropenia is a genetically heterogeneous disorder showing autosomal dominant, autosomal recessive, and X-linked inheritance. Other autosomal dominant forms are SCN2 (previous studies), caused by mutation in the protooncogene GFI1 (previous studies) on 1p22; SCN8 (previous studies), caused by mutation in the SRP54 gene (previous studies) on 14q13; and SCN9 (previous studies), caused by mutation in the CLPB gene (previous studies) on 11q13. + +Autosomal recessive forms include SCN3 (previous studies), caused by mutation in the HAX1 gene (previous studies) on 1q21; SCN4 (previous studies), caused by mutation in the G6PC3 gene (previous studies) on 17q21; SCN5 (previous studies), caused by mutation in the VPS45 gene (previous studies) on 1q21; SCN6 (previous studies), caused by mutation in the JAGN1 gene (previous studies) on 3p25; and SCN7 (previous studies), caused by mutation in the CSF3R gene (previous studies) on 1p34. + +X-linked SCN (SCNX; previous studies) is caused by mutation in the WAS gene (previous studies) on Xp11. + +See also adult chronic idiopathic nonimmune neutropenia (previous studies) and chronic benign familial neutropenia (previous studies). + + Susceptibility to Myelodysplastic Syndrome/Acute Myeloid Leukemia + +SCN patients with acquired mutations in the granulocyte colony-stimulating factor receptor (CSF3R; previous studies) in hematopoietic cells define a group with high risk for progression to myelodysplastic syndrome and/or acute myeloid leukemia. Approximately 80% of SCN patients who develop AML are heterozygous for somatic CSF3R mutations (summary by previous studies)." +Orphanet_1229,"Definition: Pseudo-TORCH syndrome-1 (PTORCH1) is an autosomal recessive neurologic disorder with characteristic clinical and neuroradiologic features that mimic intrauterine TORCH infection in the absence of evidence of infection. Affected individuals have congenital microcephaly, intracranial calcifications, simplified gyration and polymicrogyria, and severe developmental delay (previous studies; previous studies). + +previous studies called attention to the phenotypic overlap of pseudo-TORCH syndrome and Aicardi-Goutieres syndrome (AGS; previous studies), and even suggested that some cases may represent the same disorder. Congenital microcephaly, thrombocytopenia, hepatic dysfunction, and hepatosplenomegaly are usually associated with pseudo-TORCH syndrome and not with AGS, but some patients with AGS have shown these features. + + Genetic Heterogeneity of Pseudo-TORCH Syndrome + +See also PTORCH2 (previous studies), caused by mutation in the USP18 gene (previous studies) on chromosome 22q11, and PTORCH3 (previous studies), caused by mutation in the STAT2 gene (previous studies) on chromosome 12q13." +MONDO_0007728,"Definition: Acne inversa, also known as hidradenitis suppurativa, is a chronic relapsing inflammatory skin disease characterized by recurrent draining sinuses and abscesses, predominantly in skin folds that carry terminal hairs and apocrine glands. Healing occurs with substantial scarring (summary by previous studies). Squamous cell carcinoma is a rare but potentially lethal complication that may develop in affected skin (previous studies). + +previous studies provided a detailed history and review of the disorder. + + Genetic Heterogeneity of Familial Acne Inversa + +Familial acne inversa-2 with or without Dowling-Degos disease (ACNINV2; previous studies) is caused by mutation in the PSENEN gene (previous studies) on chromosome 19q13, and familial acne inversa-3 (ACNINV3; previous studies) is caused by mutation in the PSEN1 gene (previous studies) on chromosome 14q24." +MONDO_0007834,"Definition: Insulinomatosis and diabetes mellitus syndrome is an autosomal dominant disorder in which affected individuals within a family present with either hyperinsulinemic hypoglycemia secondary to pancreatic neuroendocrine tumors, or a noninsulin-dependent form of diabetes mellitus. A few affected individuals show only impaired glucose tolerance. Some patients also exhibit congenital cataract and/or congenital glaucoma (previous studies)." +MONDO_0009252,"Definition: Essential fructosuria is a benign, asymptomatic defect of intermediary metabolism characterized by the intermittent appearance of fructose in the urine (summary by previous studies)." +MONDO_0009737,"Definition: Galactosialidosis (GSL) is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase (previous studies) and neuraminidase (previous studies), secondary to a defect in protective protein/cathepsin A (PPCA). All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and rare occurrence of neurologic signs. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival. The majority of reported patients belong to the juvenile/adult group and are mainly of Japanese origin (summary by previous studies)." +MONDO_0009958,"Definition: Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells. However, not all patients show all these features. All patients have accumulation of an unusual branched-chain fatty acid, phytanic acid, in blood and tissues. Other variable features include cardiac dysfunction, nerve deafness, ichthyosis, and multiple epiphyseal dysplasia (review by previous studies). + +Increased levels of phytanic acid can also be found in peroxisomal biogenesis disorders; see Zellweger syndrome (see previous studies) (previous studies). + +Infantile Refsum disease (see PBD1B, previous studies) is a distinct disorder with a different phenotype and genetic basis. + +A phenotype clinically indistinguishable from that of classic Refsum disease (PBD9B; previous studies), but with a different biochemical profile, can be caused by mutation in the gene encoding peroxin-7 (PEX7; previous studies) on chromosome 6q." +MONDO_0010221,"Definition: CHIME syndrome, also known as Zunich neuroectodermal syndrome, is an extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME). Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties (summary by previous studies). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +MONDO_0012929,"Definition: Congenital myopathy-12 (CMYP12) is an autosomal recessive disorder characterized by severe neonatal hypotonia resulting in feeding difficulties and respiratory failure within the first months of life. There is evidence of the disorder in utero, with decreased fetal movements and polyhydramnios. Additional features may include high-arched palate and contractures. Skeletal muscle biopsy shows myopathic changes with disrupted sarcomeres and minicore-like structures (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +Orphanet_210163,"Definition: Congenital myopathy-12 (CMYP12) is an autosomal recessive disorder characterized by severe neonatal hypotonia resulting in feeding difficulties and respiratory failure within the first months of life. There is evidence of the disorder in utero, with decreased fetal movements and polyhydramnios. Additional features may include high-arched palate and contractures. Skeletal muscle biopsy shows myopathic changes with disrupted sarcomeres and minicore-like structures (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0013282,"Definition: Alpha-1-antitrypsin deficiency is an autosomal recessive disorder. The most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age (previous studies)." +Orphanet_60,"Definition: Alpha-1-antitrypsin deficiency is an autosomal recessive disorder. The most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age (previous studies)." +MONDO_0013746,"Definition: Ventricular septal defect (VSD) is the most common form of congenital cardiovascular anomaly, occurring in nearly 50% of all infants with a congenital heart defect and accounting for 14 to 16% of cardiac defects that require invasive treatment within the first year of life. Congenital VSDs may occur alone or in combination with other cardiac malformations. Large VSDs that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death (summary by previous studies). + +Other congenital cardiac defects caused by mutation in the GATA4 gene include atrial septal defect (ASD2; previous studies), tetralogy of Fallot (see TOF, previous studies), and endocardial cushion defects (AVSD4; previous studies). + + Genetic Heterogeneity of Ventricular Septal Defect + +VSD2 (previous studies) is caused by mutation in the CITED2 gene (previous studies) on chromosome 6q24; VSD3 (previous studies) is caused by mutation in the NKX2-5 gene (previous studies) on chromosome 5q34. + +Somatic mutations in the HAND1 gene (previous studies) have been identified in tissue samples from patients with VSD." +MONDO_0013927,"Definition: The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 3 (CG3) have mutations in the PEX12 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0014339,"Definition: Autosomal recessive spinocerebellar ataxia-16 (SCAR16) is a progressive neurologic disorder characterized by truncal and limb ataxia, resulting in gait instability, associated with cerebellar atrophy on brain imaging. Most patients have onset in the teenage years, although earlier and later onset have been reported. Additional features may include dysarthria, nystagmus, hyperreflexia of the lower limbs, and mild peripheral sensory neuropathy. Some patients have gonadal dysfunction or hypogonadism and/or cognitive deficits. The phenotype represents a spectrum or continuum of neurodegenerative features that may overlap with those of SCA48 (summary by previous studies and previous studies)." +MONDO_0014993,"Definition: Myofibrillar myopathy-8 (MFM8) is an autosomal recessive myopathy characterized by slowly progressive proximal muscle weakness and atrophy affecting the upper and lower limbs, resulting in increased falls, gait problems, difficulty running or climbing stairs, and upper limb weakness or scapular winging. Some patients develop distal muscle weakness and atrophy. The phenotype may also be consistent with a clinical diagnosis of limb-girdle muscular dystrophy (LGMD). Age at symptom onset ranges from infancy to adulthood. Ambulation is generally preserved and cardiac involvement is rare, but respiratory compromise with decreased forced vital capacity often occurs. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization; some patients have been reported to have dystrophic changes on muscle biopsy (previous studies; previous studies). There is significant phenotypic variation, even in patients with the same mutation, which must be taken into account when counseling affecting individuals (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (previous studies)." +MONDO_0030606,"Definition: Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include abnormal head shape, variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by previous studies). + + Genetic Heterogeneity of Bryant-Li-Bhoj Neurodevelopmental Syndrome + +See also BRYLIB2 (previous studies), caused by heterozygous mutation in the H3F3B gene (previous studies)." +MONDO_0100218,"Definition: Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disorder characterized by severe joint contractures apparent at birth. Affected individuals usually have hypertonia and abnormal movements suggestive of dystonia, as well as feeding and/or breathing difficulties. More variable features may include poor overall growth, strabismus, dysmorphic facies, and global developmental delay with impaired speech (summary by previous studies)." +MONDO_0859187,"Definition: Neurodevelopmental disorder with hypotonia and brain abnormalities (NEDHYBA) is characterized by impaired development of motor skills, cognitive function, and speech acquisition beginning in infancy or early childhood. Some affected individuals may have feeding difficulties, seizures, behavioral abnormalities, and nonspecific dysmorphic facial features. Brain imaging shows variable abnormalities, including corpus callosum defects, cerebellar defects, and decreased white matter volume. There is significant phenotypic variability (summary by previous studies)." +MONDO_0859207,"Definition: Neurodevelopmental disorder with hypotonia and gross motor and speech delay (NEDHMS) is an autosomal recessive disorder characterized by severe global developmental delay apparent from infancy. Affected individuals have axial hypotonia and limited ability to walk, including some who are nonambulatory with lower limb spasticity, impaired intellectual development, and poor or absent speech and language. Additional more variable features may include seizures, behavioral problems, distal skeletal anomalies, and dysmorphic facial features (previous studies)." +Orphanet_101150,"Definition: Segawa syndrome is an autosomal recessive neurologic disorder characterized by onset in infancy of dopa-responsive dystonia. There are 2 main phenotypes: one is a severe complex encephalopathy apparent in the perinatal period, with diurnal fluctuations and autonomic disturbances, and the other shows a less severe course with onset in the first year of life of a progressive hypokinetic-rigid syndrome and generalized dystonia. The less severe type shows a better response to levodopa compared to the more severe type (summary by previous studies). + +See also infantile parkinsonism-dystonia syndrome (previous studies), caused by mutation in the SLC6A3 gene (previous studies)." +MONDO_0011551,"Definition: Segawa syndrome is an autosomal recessive neurologic disorder characterized by onset in infancy of dopa-responsive dystonia. There are 2 main phenotypes: one is a severe complex encephalopathy apparent in the perinatal period, with diurnal fluctuations and autonomic disturbances, and the other shows a less severe course with onset in the first year of life of a progressive hypokinetic-rigid syndrome and generalized dystonia. The less severe type shows a better response to levodopa compared to the more severe type (summary by previous studies). + +See also infantile parkinsonism-dystonia syndrome (previous studies), caused by mutation in the SLC6A3 gene (previous studies)." +Orphanet_1394,"Definition: Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1) is characterized by cranial involvement with macrocrania at birth, brachycephaly, anomalies of middle fossa structures including hypoplasia of corpus callosum, enlargement of septum pellucidum, and dilated lateral ventricles, as well as cortical atrophy and hypodensity of the gray matter. Facial dysmorphisms include flat face, hypertelorism, epicanthal folds, synophrys, broad nasal bridge, cleft lip and cleft palate, and low-set posteriorly rotated ears. Patients also exhibit short neck and multiple costal and vertebral anomalies. The face is rather characteristic, and various authors have consistently reported affable/friendly personality, despite intellectual delay (summary by previous studies). + + Genetic Heterogeneity of Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation Syndrome + +CFSMR2 (previous studies) is caused by mutation in the RAB5IF gene (previous studies) on chromosome 20q11." +MONDO_0011028,"Definition: Autosomal recessive limb-girdle muscular dystrophy-6 (LGMDR6) is a very rare and severe neuromuscular disorder with onset in most patients in the first decade of life. Generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs is progressive, and patients require walking aids or become wheelchair-bound. Some patients have cardiomyopathy or heart rhythm abnormalities, or require ventilatory support (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (previous studies)." +MONDO_0013214,"Definition: Primary bile acid malabsorption (PBAM) is an intestinal disorder associated with chronic watery diarrhea, excess fecal bile acids, and steatorrhea. Bile acid malabsorption has been classified into 3 main types depending on the etiology. Types 1 and 3 are secondary disorders: type 1 is due to ileal dysfunction resulting from Crohn disease or ileal resection, and type 3 is secondary to other conditions, including cholecystectomy, post-vagotomy, celiac disease, and pancreatic insufficiency. Type 2 bile acid malabsorption is a primary congenital disorder, including the rare type due to mutations in the SLC10A2 gene (review by previous studies). + + Genetic Heterogeneity of Primary Bile Acid Malabsorption + +Also see PBAM2 (previous studies), caused by mutation in the SLC51B gene (previous studies)." +MONDO_0013810,"Definition: CDG2L is an autosomal recessive multisystem disorder apparent from birth or early infancy. It is characterized by poor growth, gastrointestinal and liver abnormalities, delayed psychomotor development, hypotonia, recurrent infections, hematologic abnormalities, increased bleeding tendency, and hyperhidrosis or hyperkeratosis. More variable features include nonspecific dysmorphic facial features and cardiac septal defects. The disorder often results in death in infancy or the first years of life (summary by previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies) and CDG2A (previous studies)." +MONDO_0014175,"Definition: Mitochondrial DNA depletion syndrome-12B is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance, and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged-red fibers, mtDNA depletion, and accumulation of abnormal mitochondria (summary by previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +Orphanet_1369,"Definition: Mitochondrial DNA depletion syndrome-12B is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance, and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged-red fibers, mtDNA depletion, and accumulation of abnormal mitochondria (summary by previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0014408,"Definition: This disorder comprises macrocephaly, megalencephaly, ventriculomegaly, polymicrogyria, and polydactyly. Most affected individuals have severely delayed psychomotor development (summary by previous studies). + +For a discussion of genetic heterogeneity of MPPH, see MPPH1 (previous studies)." +MONDO_0030993,"Definition: Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (previous studies). + +For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (previous studies)." +MONDO_0032651,"Definition: Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) is characterized by severe progressive cerebropulmonary symptoms, resulting in death in infancy from respiratory failure. Features include malabsorption, progressive growth failure, recurrent infections, chronic hemolytic anemia, and transient liver dysfunction. Neuropathology shows increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and granuloma-like lesions are seen in the lungs, and there is hepatomegaly with steatosis and collagen accumulation (previous studies)." +MONDO_0032884,"Definition: EDFAOB is characterized by linear hypopigmentation and craniofacial asymmetry in association with ocular, dental, and acral anomalies. Brain imaging has revealed some abnormalities, including diffuse cystic leukoencephalopathy and mildly enlarged lateral ventricles, but patients show no intellectual or neurologic impairment (previous studies)." +MONDO_0054782,"Definition: Hypomyelinating leukodystrophy-15 is an autosomal recessive neurodegenerative disorder characterized by onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum. The severity of the disorder is variable (summary by previous studies) + +For a discussion of genetic heterogeneity of HLD, see previous studies." +Orphanet_228343,"Definition: Neuronal ceroid lipofuscinosis-4 (CLN4) is an autosomal dominant neurodegenerative disorder characterized by onset of symptoms in adulthood. It belongs to a group of progressive neurodegenerative diseases characterized by accumulation of intracellular autofluorescent lipopigment storage material in the brain and other tissues. Several different forms have been described according to age of onset (see, e.g., CLN3, previous studies). Individuals with the adult form, sometimes referred to as Kufs disease, develop psychiatric manifestations, seizures, cerebellar ataxia, and cognitive decline. Retinal degeneration is usually not present (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0008083,"Definition: Neuronal ceroid lipofuscinosis-4 (CLN4) is an autosomal dominant neurodegenerative disorder characterized by onset of symptoms in adulthood. It belongs to a group of progressive neurodegenerative diseases characterized by accumulation of intracellular autofluorescent lipopigment storage material in the brain and other tissues. Several different forms have been described according to age of onset (see, e.g., CLN3, previous studies). Individuals with the adult form, sometimes referred to as Kufs disease, develop psychiatric manifestations, seizures, cerebellar ataxia, and cognitive decline. Retinal degeneration is usually not present (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_94065,"Definition: Witteveen-Kolk syndrome (WITKOS) is an autosomal dominant disorder with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging (summary by previous studies)." +MONDO_0013256,"Definition: Witteveen-Kolk syndrome (WITKOS) is an autosomal dominant disorder with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging (summary by previous studies)." +MONDO_0007343,"Definition: Digital clubbing is characterized by enlargement of the nail plate and terminal segments of the fingers and toes, resulting from proliferation of the connective tissues between the nail matrix and the distal phalanx (previous studies)." +MONDO_0007571,"Definition: 'Primary erythermalgia' is an autosomal dominant disorder characterized by childhood or adolescent onset of episodic symmetrical red congestion, vasodilatation, and burning pain of the feet and lower legs provoked by exercise, long standing, and exposure to warmth. Relief is obtained with cold (previous studies). The severity of the disorder may progress with age, and symptoms may extend over a larger body area, such as over the ankles and lower legs, and become constant (previous studies). + +previous studies provided a review of primary erythermalgia. + +Although 'primary' or 'familial erythromelalgia' are sometimes used as alternative terms for primary erythermalgia (previous studies), secondary erythromelalgia is a distinct acquired disorder associated with thrombocythemia or myeloproliferative disorders. It has relatively late onset and symptoms are caused by platelet aggregation in end-arteriolar circulation, leading to ischemia and symptoms (previous studies). Treatment with aspirin, which irreversibly inhibits platelet cyclooxygenase activity, affords relief from acquired erythromelalgia (previous studies; previous studies). Similarly, acquired erythromelalgia vanishes with lowering the platelet count to normal with chemotherapy (previous studies). + +previous studies emphasized the distinction between hereditary erythermalgia and acquired erythromelalgia. In primary erythermalgia, the burning pain, redness, and warmth of feet and lower legs, with relative sparing of the toes, are easily provoked by warmth and exercise. In contrast, in acquired erythromelalgia the burning pain and red congestion preferentially involves one or more toes or fingers or sole of the forefoot (previous studies). previous studies noted that 3 of the 5 patients reported by previous studies were not consistent with the diagnosis of primary erythromelalgia because the symptoms were relieved promptly by aspirin, consistent with acquired erythromelalgia. + + Small Fiber Neuropathy + +Small nerve fiber neuropathy (SFNP) is a relatively common disorder of thinly myelinated and unmyelinated nerve fibers characterized clinically by adult onset of neuropathic pain, often of a burning quality, and autonomic symptoms. Affected individuals have reduced intraepidermal nerve fiber density affecting the small diameter nerve fibers; large diameter fibers are spared (summary by previous studies)." +MONDO_0008260,"Definition: Kindler syndrome is an autosomal recessive dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling (summary by previous studies)." +MONDO_0009735,"Definition: Netherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by previous studies)." +MONDO_0010013,"Definition: Schneckenbecken dysplasia (SHNKND) is a perinatally lethal skeletal dysplasia. The German term 'Schneckenbecken' refers to the distinctive, snail-like appearance of the ilia that results from a medial bone projection from the inner iliac margin. Other hallmarks of the disorder include thoracic hypoplasia, severe flattening of the vertebral bodies, and short, thick long bones (summary by previous studies)." +MONDO_0010334,"Definition: Deafness, dystonia, and cerebral hypomyelination is an X-linked recessive mental retardation syndrome characterized by almost no psychomotor development, dysmorphic facial features, sensorineural deafness, dystonia, pyramidal signs, and hypomyelination on brain imaging (summary by previous studies)." +MONDO_0010359,"Definition: Dent disease-2 (DENT2) is an X-linked disorder of renal tubular epithelial function in which all of the clinical findings may be traced to impaired reabsorption of filtered solutes. Characteristic abnormalities include low molecular weight proteinuria and other features of Fanconi syndrome (see previous studies), such as glycosuria, aminoaciduria, and phosphaturia, but typically do not include proximal renal tubular acidosis. Progressive renal failure is common, as are nephrocalcinosis and kidney stones (summary by previous studies). + +For a discussion of genetic heterogeneity of Dent disease, see previous studies." +MONDO_0010621,"Definition: CHILD syndrome is an acronym for an X-linked dominant disorder characterized by congenital hemidysplasia with ichthyosiform erythroderma and limb defects. The mutations are lethal in hemizygous males (previous studies). + +CK syndrome (previous studies), an X-linked recessive mental retardation syndrome, is an allelic disorder with a less severe phenotype." +MONDO_0011327,"Definition: Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant, slowly progressive neurodegenerative disorder characterized by a wide range of clinical manifestations, including pyramidal and extrapyramidal symptoms, cerebellar ataxia, cognitive decline and dementia, peripheral neuropathy, and autonomic dysfunction. The age at onset varies, but most individuals present as adults between about 30 and 70 years of age. Pathologic investigation shows eosinophilic intranuclear inclusions in almost all cell types, including neurons, skin cells, fibroblasts, and skeletal muscle. Brain imaging shows a characteristic leukoencephalopathy with high intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI), as well as white matter abnormalities in subcortical and brainstem regions. Skin biopsy combined with brain imaging is useful for diagnosis (summary by previous studies). + +The phenotype in some cases is suggestive of Parkinson disease (see previous studies) and/or Alzheimer disease (see previous studies), consistent with an evolving phenotypic spectrum of adult-onset NIID (summary by previous studies)." +MONDO_0013560,"Definition: Hermansky-Pudlak syndrome-8 (HPS8) is a rare autosomal recessive disorder characterized by generalized hypopigmentation, reduced visual acuity, and prolonged bleeding of varying severity. The eye phenotype includes nystagmus, iris transilluminancy, foveal hypoplasia, and evidence of optic pathway misrouting (previous studies, previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (previous studies)." +Orphanet_231537,"Definition: Hermansky-Pudlak syndrome-8 (HPS8) is a rare autosomal recessive disorder characterized by generalized hypopigmentation, reduced visual acuity, and prolonged bleeding of varying severity. The eye phenotype includes nystagmus, iris transilluminancy, foveal hypoplasia, and evidence of optic pathway misrouting (previous studies, previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (previous studies)." +MONDO_0014331,"Definition: Moyamoya disease-6 is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory neovascularization and the moyamoya, or 'puff of smoke,' appearance of these vessels on angiogram. Affected individuals may present with ischemic strokes, intracerebral hemorrhage, or transient ischemic attacks. Patients with MYMY6 usually present early in life with achalasia. Hypertension and Raynaud phenomenon may be associated features (summary by previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (previous studies)." +MONDO_0014419,"Definition: Poretti-Boltshauser syndrome is an autosomal recessive disorder characterized by cerebellar dysplasia, cerebellar vermis hypoplasia, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities. Affected individuals have delayed motor development and often have speech delay. Cognitive function can range from normal to intellectually disabled (summary by previous studies)." +Orphanet_370022,"Definition: Poretti-Boltshauser syndrome is an autosomal recessive disorder characterized by cerebellar dysplasia, cerebellar vermis hypoplasia, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities. Affected individuals have delayed motor development and often have speech delay. Cognitive function can range from normal to intellectually disabled (summary by previous studies)." +MONDO_0014846,"Definition: Autosomal recessive spinocerebellar ataxia-23 is a neurologic disorder characterized by epilepsy, intellectual disability, and gait ataxia (summary by previous studies)." +Orphanet_404493,"Definition: Autosomal recessive spinocerebellar ataxia-23 is a neurologic disorder characterized by epilepsy, intellectual disability, and gait ataxia (summary by previous studies)." +MONDO_0015353,"Definition: Distal hereditary motor neuronopathy type VA (dHMN5A or HMN5A) is an autosomal dominant neuromuscular disorder characterized by onset of distal muscle weakness and atrophy predominantly affecting the upper limbs in the first few decades of life. The disorder is slowly progressive, and most patients eventually have lower limb involvement with foot deformities. Although sensory impairment is uncommon, some patients show this feature, illustrating the phenotypic overlap with CMT2D. Rare patients may have pyramidal signs or hyperreflexia (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMN1 (previous studies)." +Orphanet_139536,"Definition: Distal hereditary motor neuronopathy type VA (dHMN5A or HMN5A) is an autosomal dominant neuromuscular disorder characterized by onset of distal muscle weakness and atrophy predominantly affecting the upper limbs in the first few decades of life. The disorder is slowly progressive, and most patients eventually have lower limb involvement with foot deformities. Although sensory impairment is uncommon, some patients show this feature, illustrating the phenotypic overlap with CMT2D. Rare patients may have pyramidal signs or hyperreflexia (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMN1 (previous studies)." +MONDO_0030981,"Definition: Immunodeficiency-79 (IMD79) is an autosomal recessive disorder characterized by childhood onset of recurrent and recalcitrant skin warts due to uncontrolled viral infection with human papillomavirus (HPV). Some patients may also have recurrent respiratory infections beginning in childhood, but the phenotype overall is mild compared to other primary immunodeficiencies. Patients may not come to attention until adulthood. Laboratory studies show absence of the CD4 antigen on T cells, monocytes, and dendritic cells, with variable secondary abnormalities in B cells and NK cells due to lack of CD4+ T cells (summary by previous studies)." +MONDO_0033532,"Definition: Suleiman-El-Hattab syndrome (SULEHS) is an autosomal recessive multisystem developmental disorder characterized by hypotonia and feeding difficulties soon after birth, global developmental delay with impaired intellectual development and poor expressive speech, and a general happy demeanor. There is a distinctive facial appearance with microcephaly, thick arched eyebrows with synophrys, hypertelorism, epicanthal folds, low-set ears, broad nasal bridge, and thin upper lip. Additional more variable features include recurrent respiratory infections, cardiovascular malformations, cryptorchidism, seizures, and distal anomalies of the hands and feet (summary by previous studies)." +MONDO_0100344,"Definition: Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (previous studies). + +Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, previous studies) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of Bartter syndrome, see previous studies." +Orphanet_277,"Definition: Severe combined immunodeficiency (SCID) resulting from inherited ADA deficiency causes a variable phenotypic spectrum, the most severe being SCID presenting in infancy and usually resulting in early death. Ten to 15% of patients have a 'delayed' clinical onset by age 6 to 24 months, and a smaller percentage of patients have 'later' onset, diagnosed from ages 4 years to adulthood, showing less severe infections and gradual immunologic deterioration. Finally, 'partial' ADA deficiency occurs in a subset of immunocompetent individuals who show decreased enzyme activity in erythrocytes, but retain substantial enzyme activity ranging from 5 to 80% of normal in leukocytes and other nucleated cells (summary by previous studies). ADA deficiency accounts for approximately 15% of all SCID cases and one-third of cases of autosomal recessive SCID (previous studies)." +MONDO_0007064,"Definition: Severe combined immunodeficiency (SCID) resulting from inherited ADA deficiency causes a variable phenotypic spectrum, the most severe being SCID presenting in infancy and usually resulting in early death. Ten to 15% of patients have a 'delayed' clinical onset by age 6 to 24 months, and a smaller percentage of patients have 'later' onset, diagnosed from ages 4 years to adulthood, showing less severe infections and gradual immunologic deterioration. Finally, 'partial' ADA deficiency occurs in a subset of immunocompetent individuals who show decreased enzyme activity in erythrocytes, but retain substantial enzyme activity ranging from 5 to 80% of normal in leukocytes and other nucleated cells (summary by previous studies). ADA deficiency accounts for approximately 15% of all SCID cases and one-third of cases of autosomal recessive SCID (previous studies)." +Orphanet_69735,"Definition: Hypotrichosis-lymphedema-telangiectasia syndrome is an autosomal recessive disorder characterized by these 3 features, which begin at birth or in early childhood and are progressive (summary by previous studies)." +EFO_0010263,Definition: Recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP) is an autosomal recessive disorder characterized by onset of severe gastrointestinal mucosal ulceration in early childhood. Affected individuals may have secondary iron deficiency anemia or malnourishment. Studies of platelet aggregation show a functional defect associated with decreased thromboxane-A2 production and decreased eicosanoid biosynthesis. The gastrointestinal disease is believed to result from decreased or absent production of prostaglandins that protect the gut mucosa (summary by previous studies and previous studies). +MONDO_0018794,Definition: Recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP) is an autosomal recessive disorder characterized by onset of severe gastrointestinal mucosal ulceration in early childhood. Affected individuals may have secondary iron deficiency anemia or malnourishment. Studies of platelet aggregation show a functional defect associated with decreased thromboxane-A2 production and decreased eicosanoid biosynthesis. The gastrointestinal disease is believed to result from decreased or absent production of prostaglandins that protect the gut mucosa (summary by previous studies and previous studies). +MONDO_0007152,"Definition: Arrhythmogenic right ventricular dysplasia (ARVD) is a clinical and pathologic entity for which the diagnosis rests on electrocardiographic and angiographic criteria; pathologic findings, replacement of ventricular myocardium with fatty and fibrous elements, preferentially involve the right ventricular free wall. It is inherited in an autosomal dominant manner with reduced penetrance and is one of the major genetic causes of juvenile sudden death. When the dysplasia is extensive, it may represent the Uhl anomaly ('parchment right ventricle'). The presenting finding is usually recurrent, sustained ventricular tachycardia with left bundle branch block configuration. previous studies provided a detailed review of ARVD, including diagnosis, pathogenesis, treatment options, and genetics. + + Genetic Heterogeneity of Familial Arrhythmogenic Right Ventricular Dysplasia + +Other forms of ARVD include ARVD3 (previous studies), mapped to chromosome 14q12-q22; ARVD4 (previous studies), mapped to chromosome 2q32.1-q32.3; ARVD5 (previous studies), caused by mutation in the TMEM43 gene (previous studies) on chromosome 3p23; ARVD6 (previous studies), mapped to chromosome 10p14-p12; ARVD8 (previous studies), caused by mutation in the DSP gene (previous studies) on chromosome 6p24; ARVD9 (previous studies), caused by mutation in the PKP2 gene (previous studies) on chromosome 12p11; ARVD10 (previous studies), caused by mutation in the DSG2 (previous studies) on chromosome 18q12; ARVD11 (previous studies), caused by mutation in the DSC2 gene (previous studies) on chromosome 18q12.1; ARVD12 (previous studies), caused by mutation in the JUP gene (previous studies) on chromosome 17q21; ARVD13 (previous studies), caused by mutation in the CTNNA3 gene (previous studies) on chromosome 10q21; ARVD14 (previous studies), caused by mutation in the CDH2 gene (previous studies) on chromosome 18q12; and ARVD15 (see previous studies), caused by mutation in the FLNC gene (previous studies) on chromosome 7q32. + +The designation ARVD2 had been used for patients reported to have a form of arrhythmogenic cardiomyopathy resulting from mutation in the RYR2 gene (previous studies); it was later recognized that the patients had catecholamine-induced ventricular tachycardia (CPVT1; previous studies) rather than arrhythmogenic cardiomyopathy (previous studies). + +ARVD7 is a former designation for a form of myopathy and ARVD mapped to chromosome 10q22, which was later found to be a form of myofibrillar myopathy (MFM1; previous studies) caused by mutation in the DES gene (previous studies) on chromosome 2q35. + +previous studies screened 65 ARVD probands for mutations in 5 desmosomal genes as well as the TGFB3 gene (previous studies), and identified 19 different mutations in the desmosomal genes in 12 of the families, including 7 with more than 1 mutation. In 6 families, digenic mutation carriers were identified, with at least 1 of the mutations being absent in the control population. The authors stated that their findings partially supported a gene dosage effect, although phenotypic variation was large. + +previous studies reviewed desmosome biology in cardiocutaneous syndromes and inherited skin disease, including discussion of the involvement of the DSP, PKP2, DSG2, DSC2, and JUP genes." +MONDO_0007640,Definition: Sorsby fundus dystrophy is an autosomal dominant retinal dystrophy characterized by the loss of central vision as a result of macular disease by the fourth to fifth decade and peripheral visual loss in late life (summary by previous studies). +Orphanet_59181,Definition: Sorsby fundus dystrophy is an autosomal dominant retinal dystrophy characterized by the loss of central vision as a result of macular disease by the fourth to fifth decade and peripheral visual loss in late life (summary by previous studies). +MONDO_0008250,"Definition: Type II IGHD is an autosomal dominant disorder characterized by low but detectable levels of growth hormone (GH), variable height deficit and age at presentation, and good response to rhGH. Patients may show anterior pituitary hypoplasia on MRI (summary by previous studies; previous studies)." +MONDO_0008702,"Definition: Achondrogenesis type II (ACG2) is characterized by severe micromelic dwarfism with small chest and prominent abdomen, incomplete ossification of the vertebral bodies, and disorganization of the costochondral junction. ACG2 is an autosomal dominant trait occurring mostly as new mutations. However, somatic and germline mosaicism have been reported (summary by previous studies)." +Orphanet_93296,"Definition: Achondrogenesis type II (ACG2) is characterized by severe micromelic dwarfism with small chest and prominent abdomen, incomplete ossification of the vertebral bodies, and disorganization of the costochondral junction. ACG2 is an autosomal dominant trait occurring mostly as new mutations. However, somatic and germline mosaicism have been reported (summary by previous studies)." +MONDO_0008762,"Definition: Alport syndrome is a hereditary disorder of the basement membrane, resulting in a glomerulonephropathy causing renal failure. Progressive deafness and ocular anomalies may also occur (previous studies; previous studies). + +For a general phenotypic description of Alport syndrome, see the X-linked dominant form (ATS1; previous studies). Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive; autosomal dominant inheritance (ATS3; previous studies) is rare (previous studies). + +See also benign familial hematuria (BFH; previous studies), a similar but milder disorder." +MONDO_0009659,"Definition: Mucopolysaccharidosis type IVA is an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal and there is no direct central nervous system (CNS) involvement, although the skeletal changes may result in neurologic complications. There is variable severity, but patients with the severe phenotype usually do not survive past the second or third decade of life (previous studies). + +previous studies noted that between 1929 and 1959, a miscellany of skeletal disorders was included in the Morquio category, including various types of spondyloepiphyseal dysplasia (see, e.g., previous studies) and multiple epiphyseal dysplasia (see, e.g., previous studies). + +previous studies proposed the division of MPS IVA into 3 subgroups: severe classic, intermediate, and mild, reflecting clinical variability observed in 12 enzymatically proven cases. Those who were only mildly affected showed a relatively high residual enzyme activity." +MONDO_0010427,"Definition: Raymond-type X-linked syndromic intellectual developmental disorder (MRXSR) is characterized by mildly to severely impaired intellectual development with speech and language difficulties associated with variable additional features, including marfanoid habitus, epilepsy, facial dysmorphism, hypotonia, and behavioral problems (summary by previous studies and previous studies)." +MONDO_0010745,"Definition: XLTT is an X-linked recessive hematologic disorder characterized by variable thrombocytopenia, hemolytic anemia, splenomegaly, and abnormalities in hemoglobin chain synthesis (summary by previous studies and previous studies)." +Orphanet_231393,"Definition: XLTT is an X-linked recessive hematologic disorder characterized by variable thrombocytopenia, hemolytic anemia, splenomegaly, and abnormalities in hemoglobin chain synthesis (summary by previous studies and previous studies)." +MONDO_0011510,"Definition: Bohring-Opitz syndrome is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound mental retardation, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints (summary by previous studies). + +See also the C syndrome (previous studies), a disorder with a similar phenotype caused by heterozygous mutation in the CD96 gene (previous studies) on chromosome 3q13." +MONDO_0012280,"Definition: Goldberg-Shprintzen syndrome (GOSHS) is an autosomal recessive multiple congenital anomaly syndrome characterized by impaired intellectual development, microcephaly, and dysmorphic facial features. Most patients also have Hirschsprung disease and/or gyral abnormalities of the brain, consistent with defects in migration of neural crest cells and neurons. Other features, such as megalocornea or urogenital anomalies, may also be present. Goldberg-Shprintzen syndrome has some resemblance to Mowat-Wilson syndrome (MOWS; previous studies) but is genetically distinct (summary by previous studies)." +MONDO_0012526,"Definition: Hereditary angioedema-3 (HAE3) is a rare disorder characterized clinically by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The disorder occurs almost exclusively in women and is often precipitated or worsened by high estrogen levels (e.g., during pregnancy or treatment with oral contraceptives). Both concentration and function of C1 inhibitor (C1NH; previous studies) are normal (summary by previous studies). + +For a discussion of genetic heterogeneity of HAE, see previous studies." +MONDO_0020738,"Definition: Congenital symmetric circumferential skin creases is characterized by the folding of excess skin, which leads to ringed creases, primarily of the limbs. Affected individuals also exhibit intellectual disability, cleft palate, and dysmorphic features (summary by previous studies). + + Genetic Heterogeneity of Congenital Symmetric Circumferential Skin Creases + +CSCSC2 (previous studies) is caused by mutation in the MAPRE2 gene (previous studies) on chromosome 18q12." +MONDO_0030020,"Definition: Combined oxidative phosphorylation deficiency-44 (COXPD44) is an autosomal recessive mitochondrial disorder with multisystemic manifestations. Most affected individuals present in infancy or early childhood with global developmental delay, hypotonia, and abnormal movements. Most patients develop seizures, often associated with status epilepticus, and some patients may have optic atrophy. One patient with hypertrophic cardiomyopathy has been reported. Serum lactate may be increased, although that finding is inconsistent. Detailed biochemical analysis shows variable combined deficiencies of mitochondrial oxidative complexes that appear to be tissue-specific (summary by previous studies). + +For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0032935,"Definition: Rhizomelic limb shortening with dysmorphic features (RLSDF) is characterized by rhizomelic shortening of the extremities, predominantly of the upper limbs, and variable dysmorphic features, including macrocephaly, prominent forehead, hypertelorism, depressed or broad nasal bridge, and micrognathia. Hearing loss has also been observed (previous studies; previous studies)." +Orphanet_47,"Definition: Immunodeficiency-61 (IMD61) is an X-linked recessive primary immunodeficiency characterized by onset of recurrent infections in early childhood due to impaired antibody production. Affected individuals have normal numbers of circulating B and T cells, but B cells have an intrinsic defect in antibody production (summary by previous studies). + +For a general phenotypic description of X-linked agammaglobulinemia, see previous studies." +MONDO_0007492,"Definition: 'Dystonia' describes a neurologic condition characterized by involuntary, sustained muscle contractions affecting one or more sites of the body; 'torsion' refers to the twisting nature of body movements observed in dystonia. Dystonia has been classified as primary (dystonia as the sole or major symptom) or secondary (a symptom of another disorder), and by age of onset, muscle groups affected, and mode of inheritance (previous studies; previous studies)." +MONDO_0008387,Definition: Ring dermoid of cornea (RDC) is an autosomal dominant condition characterized by bilateral annular limbal dermoids with corneal and conjunctival extension (summary by previous studies). +MONDO_0008740,"Definition: Agnathia-otocephaly is a rare condition characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. The disorder is almost always lethal (review by previous studies)." +Orphanet_990,"Definition: Agnathia-otocephaly is a rare condition characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. The disorder is almost always lethal (review by previous studies)." +MONDO_0010709,"Definition: Waisman syndrome is an X-linked neurologic disorder characterized by delayed psychomotor development, impaired intellectual development, and early-onset Parkinson disease (summary by previous studies)." +Orphanet_2379,"Definition: Waisman syndrome is an X-linked neurologic disorder characterized by delayed psychomotor development, impaired intellectual development, and early-onset Parkinson disease (summary by previous studies)." +MONDO_0011833,"Definition: Spinocerebellar ataxia-21 (SCA21) is an autosomal dominant neurologic disorder characterized by onset in the first decades of life of slowly progressive cerebellar ataxia, which is associated with cognitive impairment in most patients (summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0012256,"Definition: Spastic paraplegia-29 (SPG28) is an autosomal recessive neurodegenerative disorder characterized by early-onset, slowly progressive lower-limb spasticity resulting in walking difficulties. Some patients also have distal sensory impairment (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +Orphanet_101008,"Definition: Spastic paraplegia-29 (SPG28) is an autosomal recessive neurodegenerative disorder characterized by early-onset, slowly progressive lower-limb spasticity resulting in walking difficulties. Some patients also have distal sensory impairment (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +MONDO_0029144,Definition: Extraoral halitosis due to methanethiol oxidase deficiency (EHMTO) is a malodor syndrome resulting from an inborn error of metabolism. Breath odor is cabbage-like and results from high levels of methanethiol and dimethylsulfide in breath. Elevated urinary excretion of dimethylsulfone (DMSO2) is diagnostic (previous studies). +MONDO_0032900,"Definition: Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements (NEDHAHM) is characterized by axial hypotonia apparent from birth, global developmental delay with impaired intellectual development and poor or absent language acquisition, and behavioral abnormalities, including autistic features, poor social interaction, and hang-wringing. Most patients have childhood-onset seizures that are usually responsive to medication, and a subset of patients develop cortical visual impairment and involuntary hyperkinetic movements, including chorea and dystonia. Some of the features are reminiscent of Rett syndrome (RTT; previous studies) (summary by previous studies)." +MONDO_0032905,"Definition: Spastic paraplegia-81 (SPG81) is an autosomal recessive neurologic disorder with onset in infancy. Affected individuals have delayed motor development, progressive spasticity, and other neurologic impairment, including impaired intellectual development and speech delay. Some patients may have additional features, including bifid uvula, microcephaly, seizures, and variable ocular anomalies. One severely affected patient was reported to have cortical visual loss, sensorineural deafness, and achievement of almost no developmental milestones. Brain imaging shows white matter abnormalities, hypomyelination with progressive white matter loss, and sometimes cerebral atrophy. These significant additional abnormalities enable classification of this disorder as a complicated form of SPG (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +Orphanet_1358,"Definition: Carey-Fineman-Ziter syndrome-1 (CFZS1) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS1 may be secondary effects of muscle weakness during development or brainstem anomalies (summary by previous studies). + +previous studies determined that CFZS1 represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion. + + Genetic Heterogeneity of Carey-Fineman-Ziter Syndrome + +Carey-Fineman-Ziter syndrome-2 (CFZS2) is caused by mutation in the MYMX gene (previous studies) on chromosome 6p21." +Orphanet_324977,"Definition: This autosomal recessive systemic autoinflammatory disorder is characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by previous studies; previous studies; previous studies). + +This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both previous studies and previous studies contributed to the original phenotypic descriptions. + + Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome + +See also PRAAS2 (previous studies), caused by mutation in the POMP gene (previous studies) on chromosome 13q12; PRAAS3 (previous studies), caused by mutation in the PSMB4 gene (previous studies) on chromosome 1q21; PRAAS4 (previous studies), caused by mutation in the PSMG2 gene (previous studies) on chromosome 18p11; and PRAAS5 (previous studies), caused by mutation in the PSMB10 gene (previous studies) on chromosome 16q22." +Orphanet_93114,"Definition: Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS, including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy (summary by previous studies). + +Isolated focal segmental glomerulosclerosis-5 (FSGS5; previous studies) is also caused by heterozygous mutation in the INF2 gene. + +For a discussion of genetic heterogeneity of CMTDI, see previous studies." +MONDO_0013758,"Definition: Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS, including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy (summary by previous studies). + +Isolated focal segmental glomerulosclerosis-5 (FSGS5; previous studies) is also caused by heterozygous mutation in the INF2 gene. + +For a discussion of genetic heterogeneity of CMTDI, see previous studies." +EFO_0001063,"Definition: DFNX7 is a congenital form of bilateral mixed or conductive hearing loss, which may be progressive. It is not associated with vestibular symptoms (previous studies)." +EFO_0009063,"Definition: Autosomal dominant Wolfram-like syndrome is characterized by the clinical triad of congenital progressive hearing impairment, diabetes mellitus, and optic atrophy. The hearing impairment, which is usually diagnosed in the first decade of life, is relatively constant and alters mainly low- and middle-frequency ranges (summary by previous studies). + +Wolfram syndrome (WFS1; previous studies) is an autosomal recessive allelic disorder characterized by optic atrophy, diabetes mellitus, hearing loss, and diabetes insipidus, and is caused by homozygous or compound heterozygous mutation in the WFS1 gene. + +An autosomal dominant syndrome involving optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (previous studies), is caused by heterozygous mutation in the OPA1 gene (previous studies)." +EFO_0022191,"Definition: Late-onset spinocerebellar ataxia-27B (SCA27B) is an autosomal dominant neurodegenerative disorder characterized by the onset of gait and appendicular ataxia in adulthood, usually around age 55 (range 30 to late eighties). About half of patients present with episodic features. The disorder is slowly progressive, and some patients may lose independent ambulation. Additional features include downbeat and horizontal nystagmus, diplopia, vertigo, and dysarthria. Brain imaging tends to show cerebellar atrophy (previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0008692,"Definition: Abetalipoproteinemia and familial hypobetalipoproteinemia (FBHL; previous studies) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy, and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein B-containing particles. Obligate heterozygous parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, whereas obligate heterozygous parents of FBHL patients typically have half normal levels of apoB-containing lipoproteins consistent with autosomal codominant inheritance (summary by previous studies)." +MONDO_0008727,"Definition: Classic 3-beta-hydroxysteroid dehydrogenase deficiency is an autosomal recessive form of CAH characterized by a severe impairment of steroid biosynthesis in both the adrenals and the gonads, resulting in decreased excretion of cortisol and aldosterone and of progesterone, androgens, and estrogens by these tissues. Affected newborns exhibit signs and symptoms of glucocorticoid and mineralocorticoid deficiencies, which may be fatal if not diagnosed and treated early, especially in the severe salt-wasting form. Moreover, male newborns exhibit pseudohermaphroditism with incomplete masculinization of the external genitalia due to an impairment of androgen biosynthesis in the testis. In contrast, affected females exhibit normal sexual differentiation or partial virilization (summary by previous studies)." +MONDO_0008974,"Definition: Greenberg dysplasia (GRBGD), also known as hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, is a rare autosomal recessive osteochondrodysplasia characterized by gross fetal hydrops, severe shortening of all long bones with a moth-eaten radiographic appearance, platyspondyly, disorganization of chondroosseous calcification, and ectopic ossification centers. It is lethal in utero. Patient fibroblasts show increased levels of cholesta-8,14-dien-3-beta-ol, suggesting a defect of sterol metabolism (summary by previous studies). + +previous studies reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in postsqualene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; previous studies), desmosterolosis (previous studies), X-linked dominant chondrodysplasia punctata (CDPX2; previous studies), CHILD syndrome (previous studies), lathosterolosis (previous studies), and HEM skeletal dysplasia." +MONDO_0009947,"Definition: Glutathione synthetase deficiency, or 5-oxoprolinuria, is an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The metabolic defect results in decreased levels of cellular glutathione, which overstimulates the synthesis of gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline (previous studies)." +MONDO_0010256,"Definition: X-linked intellectual developmental disorder-21 (XLID21) is characterized by a spectrum of cognitive neurologic impairments or disabilities ranging from moderately impaired intellectual development to high-functioning autism. Males are typically severely affected, but some carrier females may manifest milder deficits (summary by previous studies)." +MONDO_0010626,"Definition: HIGM is a rare immunodeficiency characterized by normal or elevated serum IgM levels associated with markedly decreased IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections and an increased susceptibility to opportunistic infections. Patients with X-linked HIGM also tend to have neutropenia, as well as a high rate of gastrointestinal and central nervous system infections, often resulting in severe liver disease and/or neurodegeneration (summary by previous studies). + + Genetic Heterogeneity of Immunodeficiency with Hyper-IgM + +Other forms of HIGM include HIGM2 (previous studies), which results from mutation in the AICDA gene (previous studies), HIGM3 (previous studies), which results from mutation in the CD40 gene (previous studies), and HIGM5 (previous studies), which results from mutation in the UNG gene (previous studies). See also HIGM4 (previous studies)." +Orphanet_101088,"Definition: HIGM is a rare immunodeficiency characterized by normal or elevated serum IgM levels associated with markedly decreased IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections and an increased susceptibility to opportunistic infections. Patients with X-linked HIGM also tend to have neutropenia, as well as a high rate of gastrointestinal and central nervous system infections, often resulting in severe liver disease and/or neurodegeneration (summary by previous studies). + + Genetic Heterogeneity of Immunodeficiency with Hyper-IgM + +Other forms of HIGM include HIGM2 (previous studies), which results from mutation in the AICDA gene (previous studies), HIGM3 (previous studies), which results from mutation in the CD40 gene (previous studies), and HIGM5 (previous studies), which results from mutation in the UNG gene (previous studies). See also HIGM4 (previous studies)." +MONDO_0013621,"Definition: Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus (summary by previous studies). + +Mutation in the LAMB2 gene can also cause Pierson syndrome (previous studies), which is characterized by nephrotic syndrome, distinct ocular anomalies, namely microcoria, and neurodevelopmental delay. + +For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (previous studies)." +MONDO_0014899,"Definition: Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4) is an autosomal recessive disorder characterized by adult onset of eye muscle weakness and proximal limb muscle weakness associated with deletions of mtDNA on skeletal muscle biopsy, which results from defective mtDNA replication in post-mitotic muscle tissue. Additional features are more variable (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (previous studies)." +MONDO_0014900,"Definition: Autosomal recessive myopathy with rigid spine and distal joint contractures (MRRSDC) is characterized by onset of slowly progressive muscle weakness in the first or second decades of life. There is initial involvement of the proximal lower limbs, followed by distal upper and lower limb muscle weakness and atrophy. Other features include joint contractures, rigid spine, and restricted pulmonary function; some patients may have mild cardiac involvement (summary by previous studies)." +MONDO_0033671,"Definition: Spermatogenic failure-45 (SPGF45) is characterized by male infertility due to severe teratozoospermia. Sperm in affected men exhibit multiple morphologic abnormalities of the flagella (MMAF), including flagella that are short, absent, coiled, angulated, and/or of irregular caliber; some sperm also show abnormalities of the head. Ultrastructural analysis shows severe disruption of the axonemal complex and mitochondrial sheath (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0100255,"Definition: Hypermethioninemia due to adenosine kinase deficiency is an autosomal recessive inborn error of metabolism characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically normal (summary by previous studies)." +Orphanet_26106,"Definition: Diffuse gastric cancer and lobular breast cancer syndrome (DGLBC) is an autosomal dominant cancer predisposition syndrome. Heterozygous CDH1 mutation carriers have a 70 to 80% lifetime risk of developing diffuse gastric cancer. In addition to gastric cancer, up to 60% of female mutation carriers develop lobular carcinoma of the breast, and some carriers may develop colorectal cancer. Identification of mutation carriers is important, because the characteristic microscopic foci of signet ring cell adenocarcinoma in HDGC usually involves the submucosa and is often not readily detectable by routine upper endoscopy screening (summary by previous studies). + +DGLBC is considered to be a distinct disease entity from the more common sporadic occurrence of gastric cancer (previous studies), which can be associated with environmental factors such as Helicobacter pylori infection, high-fat diet, or smoking and is often associated with somatic mutations in disease tissue." +EFO_0000349,"Definition: The Heidelberg histologic classification of renal cell tumors subdivides renal cell tumors into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most common documented genetic abnormalities (previous studies). Malignant tumors are subclassified into common or conventional renal cell carcinoma (clear cell); papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and unclassified renal cell carcinoma. The common or conventional type accounts for about 75% of renal cell neoplasms and is characterized genetically by a highly specific deletion of chromosome 3p. Papillary renal cell carcinoma (see previous studies) accounts for about 10% of renal cell tumors. Chromophobe renal cell carcinoma accounts for approximately 5% of renal cell neoplasms. Genetically, chromophobe RCC is characterized by a combination of loss of heterozygosity of chromosomes 1, 2, 6, 10, 13, 17, and 21 and hypodiploid DNA content. Collecting duct carcinoma accounts for about 1% of renal cell carcinoma. + +Renal cell carcinoma occurs nearly twice as often in men as in women; incidence in the United States is equivalent among whites and blacks. Cigarette smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one-third of cases. Obesity is also a risk factor, particularly in women. Other risk factors include hypertension, unopposed estrogen therapy, and occupational exposure to petroleum products, heavy metals, or asbestos (summary by previous studies). + + Genetic Heterogeneity of Renal Cell Carcinoma + +Germline mutation resulting in nonpapillary renal cell carcinoma of the clear cell and chromophobe type occurs in the HNF1A gene (previous studies) and the HNF1B gene (previous studies). + +Somatic mutations in renal cell carcinomas occur in the VHL gene (previous studies), the TRC8 gene (previous studies), the OGG1 gene (previous studies), the ARMET gene (previous studies), the FLCN gene (previous studies), and the BAP1 gene (previous studies). + +See also RCCX1 (previous studies) for a discussion of renal cell carcinoma associated with translocations of chromosome Xp11.2 involving the TFE3 gene (previous studies). + +For a discussion of papillary renal cell carcinoma, see RCCP1 (previous studies). + + Occurrence of Renal Cell Carcinoma in Other Disorders + +Von Hippel-Lindau syndrome (previous studies) is a familial multicancer syndrome in which there is a susceptibility to a variety of neoplasms, including renal cell carcinoma of clear cell histology and renal cysts. A syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma has been reported (previous studies). Medullary carcinoma of the kidney is believed to arise from the collecting ducts of the renal medulla and is associated with sickle cell trait (previous studies) (previous studies). Renal cell carcinoma occurs in patients with the Birt-Hogg-Dube syndrome (previous studies). + +previous studies identified a missense mutation in the MITF (previous studies) gene that increases the risk of renal cell carcinoma with or without malignant melanoma (CMM8; previous studies)." +EFO_0000681,"Definition: The Heidelberg histologic classification of renal cell tumors subdivides renal cell tumors into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most common documented genetic abnormalities (previous studies). Malignant tumors are subclassified into common or conventional renal cell carcinoma (clear cell); papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and unclassified renal cell carcinoma. The common or conventional type accounts for about 75% of renal cell neoplasms and is characterized genetically by a highly specific deletion of chromosome 3p. Papillary renal cell carcinoma (see previous studies) accounts for about 10% of renal cell tumors. Chromophobe renal cell carcinoma accounts for approximately 5% of renal cell neoplasms. Genetically, chromophobe RCC is characterized by a combination of loss of heterozygosity of chromosomes 1, 2, 6, 10, 13, 17, and 21 and hypodiploid DNA content. Collecting duct carcinoma accounts for about 1% of renal cell carcinoma. + +Renal cell carcinoma occurs nearly twice as often in men as in women; incidence in the United States is equivalent among whites and blacks. Cigarette smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one-third of cases. Obesity is also a risk factor, particularly in women. Other risk factors include hypertension, unopposed estrogen therapy, and occupational exposure to petroleum products, heavy metals, or asbestos (summary by previous studies). + + Genetic Heterogeneity of Renal Cell Carcinoma + +Germline mutation resulting in nonpapillary renal cell carcinoma of the clear cell and chromophobe type occurs in the HNF1A gene (previous studies) and the HNF1B gene (previous studies). + +Somatic mutations in renal cell carcinomas occur in the VHL gene (previous studies), the TRC8 gene (previous studies), the OGG1 gene (previous studies), the ARMET gene (previous studies), the FLCN gene (previous studies), and the BAP1 gene (previous studies). + +See also RCCX1 (previous studies) for a discussion of renal cell carcinoma associated with translocations of chromosome Xp11.2 involving the TFE3 gene (previous studies). + +For a discussion of papillary renal cell carcinoma, see RCCP1 (previous studies). + + Occurrence of Renal Cell Carcinoma in Other Disorders + +Von Hippel-Lindau syndrome (previous studies) is a familial multicancer syndrome in which there is a susceptibility to a variety of neoplasms, including renal cell carcinoma of clear cell histology and renal cysts. A syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma has been reported (previous studies). Medullary carcinoma of the kidney is believed to arise from the collecting ducts of the renal medulla and is associated with sickle cell trait (previous studies) (previous studies). Renal cell carcinoma occurs in patients with the Birt-Hogg-Dube syndrome (previous studies). + +previous studies identified a missense mutation in the MITF (previous studies) gene that increases the risk of renal cell carcinoma with or without malignant melanoma (CMM8; previous studies)." +EFO_0002890,"Definition: The Heidelberg histologic classification of renal cell tumors subdivides renal cell tumors into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most common documented genetic abnormalities (previous studies). Malignant tumors are subclassified into common or conventional renal cell carcinoma (clear cell); papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and unclassified renal cell carcinoma. The common or conventional type accounts for about 75% of renal cell neoplasms and is characterized genetically by a highly specific deletion of chromosome 3p. Papillary renal cell carcinoma (see previous studies) accounts for about 10% of renal cell tumors. Chromophobe renal cell carcinoma accounts for approximately 5% of renal cell neoplasms. Genetically, chromophobe RCC is characterized by a combination of loss of heterozygosity of chromosomes 1, 2, 6, 10, 13, 17, and 21 and hypodiploid DNA content. Collecting duct carcinoma accounts for about 1% of renal cell carcinoma. + +Renal cell carcinoma occurs nearly twice as often in men as in women; incidence in the United States is equivalent among whites and blacks. Cigarette smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one-third of cases. Obesity is also a risk factor, particularly in women. Other risk factors include hypertension, unopposed estrogen therapy, and occupational exposure to petroleum products, heavy metals, or asbestos (summary by previous studies). + + Genetic Heterogeneity of Renal Cell Carcinoma + +Germline mutation resulting in nonpapillary renal cell carcinoma of the clear cell and chromophobe type occurs in the HNF1A gene (previous studies) and the HNF1B gene (previous studies). + +Somatic mutations in renal cell carcinomas occur in the VHL gene (previous studies), the TRC8 gene (previous studies), the OGG1 gene (previous studies), the ARMET gene (previous studies), the FLCN gene (previous studies), and the BAP1 gene (previous studies). + +See also RCCX1 (previous studies) for a discussion of renal cell carcinoma associated with translocations of chromosome Xp11.2 involving the TFE3 gene (previous studies). + +For a discussion of papillary renal cell carcinoma, see RCCP1 (previous studies). + + Occurrence of Renal Cell Carcinoma in Other Disorders + +Von Hippel-Lindau syndrome (previous studies) is a familial multicancer syndrome in which there is a susceptibility to a variety of neoplasms, including renal cell carcinoma of clear cell histology and renal cysts. A syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma has been reported (previous studies). Medullary carcinoma of the kidney is believed to arise from the collecting ducts of the renal medulla and is associated with sickle cell trait (previous studies) (previous studies). Renal cell carcinoma occurs in patients with the Birt-Hogg-Dube syndrome (previous studies). + +previous studies identified a missense mutation in the MITF (previous studies) gene that increases the risk of renal cell carcinoma with or without malignant melanoma (CMM8; previous studies)." +MONDO_0007763,"Definition: The Heidelberg histologic classification of renal cell tumors subdivides renal cell tumors into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most common documented genetic abnormalities (previous studies). Malignant tumors are subclassified into common or conventional renal cell carcinoma (clear cell); papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and unclassified renal cell carcinoma. The common or conventional type accounts for about 75% of renal cell neoplasms and is characterized genetically by a highly specific deletion of chromosome 3p. Papillary renal cell carcinoma (see previous studies) accounts for about 10% of renal cell tumors. Chromophobe renal cell carcinoma accounts for approximately 5% of renal cell neoplasms. Genetically, chromophobe RCC is characterized by a combination of loss of heterozygosity of chromosomes 1, 2, 6, 10, 13, 17, and 21 and hypodiploid DNA content. Collecting duct carcinoma accounts for about 1% of renal cell carcinoma. + +Renal cell carcinoma occurs nearly twice as often in men as in women; incidence in the United States is equivalent among whites and blacks. Cigarette smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one-third of cases. Obesity is also a risk factor, particularly in women. Other risk factors include hypertension, unopposed estrogen therapy, and occupational exposure to petroleum products, heavy metals, or asbestos (summary by previous studies). + + Genetic Heterogeneity of Renal Cell Carcinoma + +Germline mutation resulting in nonpapillary renal cell carcinoma of the clear cell and chromophobe type occurs in the HNF1A gene (previous studies) and the HNF1B gene (previous studies). + +Somatic mutations in renal cell carcinomas occur in the VHL gene (previous studies), the TRC8 gene (previous studies), the OGG1 gene (previous studies), the ARMET gene (previous studies), the FLCN gene (previous studies), and the BAP1 gene (previous studies). + +See also RCCX1 (previous studies) for a discussion of renal cell carcinoma associated with translocations of chromosome Xp11.2 involving the TFE3 gene (previous studies). + +For a discussion of papillary renal cell carcinoma, see RCCP1 (previous studies). + + Occurrence of Renal Cell Carcinoma in Other Disorders + +Von Hippel-Lindau syndrome (previous studies) is a familial multicancer syndrome in which there is a susceptibility to a variety of neoplasms, including renal cell carcinoma of clear cell histology and renal cysts. A syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma has been reported (previous studies). Medullary carcinoma of the kidney is believed to arise from the collecting ducts of the renal medulla and is associated with sickle cell trait (previous studies) (previous studies). Renal cell carcinoma occurs in patients with the Birt-Hogg-Dube syndrome (previous studies). + +previous studies identified a missense mutation in the MITF (previous studies) gene that increases the risk of renal cell carcinoma with or without malignant melanoma (CMM8; previous studies)." +EFO_0001645,"Definition: Hyperlipoproteinemia type III, also called dysbetalipoproteinemia, is characterized by hyperlipidemia due to accumulation of remnants of the triglyceride (TG)-rich lipoproteins (TGRL), very low density lipoproteins (VLDL), and chylomicrons (CM), in response to dysfunctional genetic variants of apolipoprotein E or absence of apoE (summary by previous studies)." +MONDO_0018473,"Definition: Hyperlipoproteinemia type III, also called dysbetalipoproteinemia, is characterized by hyperlipidemia due to accumulation of remnants of the triglyceride (TG)-rich lipoproteins (TGRL), very low density lipoproteins (VLDL), and chylomicrons (CM), in response to dysfunctional genetic variants of apolipoprotein E or absence of apoE (summary by previous studies)." +MONDO_0007374,"Definition: Schnyder corneal dystrophy (SCCD), also known as Schnyder crystalline corneal dystrophy, is an autosomal dominant eye disease characterized by abnormal deposition of cholesterol and phospholipids in the cornea. The consequent corneal opacification is progressive and bilateral, resulting in glare and loss of vision that is postulated to be caused by light scattering. Patients demonstrate a characteristic pattern of corneal opacification dependent on age, and only half have crystalline corneal cholesterol deposits. Patients with noncrystalline disease have a more subtle presentation with only corneal haze, which may be difficult to diagnose (summary by previous studies)." +MONDO_0007781,"Definition: The Pickering school held that blood pressure has a continuous distribution, that multiple genes and multiple environmental factors determine the level of one's blood pressure just as the determination of stature and intelligence is multifactorial, and that 'essential hypertension' is merely the upper end of the distribution (previous studies). In this view the person with essential hypertension is one who happens to inherit an aggregate of genes determining hypertension (and also is exposed to exogenous factors that favor hypertension). The Platt school took the view that essential hypertension is a simple mendelian dominant trait (previous studies). previous studies defended the monogenic idea. See previous studies and previous studies for reviews. previous studies reviewed the Platt-Pickering controversy as an 'episode in recent medical history.' The Pickering point of view appears to be more consistent with the observations." +EFO_0000537,"Definition: The Pickering school held that blood pressure has a continuous distribution, that multiple genes and multiple environmental factors determine the level of one's blood pressure just as the determination of stature and intelligence is multifactorial, and that 'essential hypertension' is merely the upper end of the distribution (previous studies). In this view the person with essential hypertension is one who happens to inherit an aggregate of genes determining hypertension (and also is exposed to exogenous factors that favor hypertension). The Platt school took the view that essential hypertension is a simple mendelian dominant trait (previous studies). previous studies defended the monogenic idea. See previous studies and previous studies for reviews. previous studies reviewed the Platt-Pickering controversy as an 'episode in recent medical history.' The Pickering point of view appears to be more consistent with the observations." +MONDO_0009251,"Definition: Fructose-1,6-bisphosphatase deficiency is an autosomal recessive disorder characterized by impaired gluconeogenesis. Patients present with hypoglycemia and metabolic acidosis on fasting and may have episodes of hyperventilation, apnea, hypoglycemia, and ketosis. Although the disorder may be lethal in the newborn period, proper treatment yields an excellent prognosis (previous studies; previous studies)." +MONDO_0009469,"Definition: Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without extrahepatic bile duct obstruction. There is initial elevation of serum bile acids, followed by cholestatic jaundice which generally spontaneously resolves after periods of weeks to months (previous studies; previous studies; previous studies). + +previous studies stated that referring to this disorder as 'benign' is a misnomer, because the disease has an impact on the quality of life in some patients. They preferred the term 'recurrent familial intrahepatic cholestasis.' + + Genetic Heterogeneity of Benign Recurrent Intrahepatic Cholestasis + +See also BRIC2 (previous studies), caused by mutation in the ABCB11 gene (previous studies) on chromosome 2q24." +MONDO_0013389,"Definition: Developmental and epileptic encephalopathy-12 (DEE12) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first year of life. Affected infants may have normal or mildly delayed development before the onset of seizures, but thereafter show severe developmental regression and stagnation. Seizure types vary: focal seizures, infantile spasms, and generalized tonic-clonic seizures may occur, even within the same patient. EEG may show hypsarrhythmia, consistent with West syndrome, or a pattern consistent with 'malignant migrating partial seizures in infancy' (MMPSI). Patients have little or no developmental progress: there is absent speech, hypotonia, poor motor skills, peripheral spasticity, and impaired visual fixation (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see previous studies." +MONDO_0013875,"Definition: MEGDEL is an autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia, and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellar atrophy as well as lesions in the basal ganglia reminiscent of Leigh syndrome (previous studies). Laboratory studies show increased serum lactate and alanine, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, abnormal phosphatidylglycerol and cardiolipin profiles in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells (summary by previous studies). About 50% of patients develop severe, but transient, liver dysfunction and/or signs of liver failure, in the neonatal period or during the first year of life, prompting some authors to suggest the name 'MEGDHEL' syndrome, with the 'H' referring to 'hepatopathy' (summary by previous studies). Some patients may have a milder presentation with juvenile-onset spasticity and mild cognitive impairment, indicating a broader phenotypic spectrum (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +Orphanet_352328,"Definition: MEGDEL is an autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia, and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellar atrophy as well as lesions in the basal ganglia reminiscent of Leigh syndrome (previous studies). Laboratory studies show increased serum lactate and alanine, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, abnormal phosphatidylglycerol and cardiolipin profiles in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells (summary by previous studies). About 50% of patients develop severe, but transient, liver dysfunction and/or signs of liver failure, in the neonatal period or during the first year of life, prompting some authors to suggest the name 'MEGDHEL' syndrome, with the 'H' referring to 'hepatopathy' (summary by previous studies). Some patients may have a milder presentation with juvenile-onset spasticity and mild cognitive impairment, indicating a broader phenotypic spectrum (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +MONDO_0014349,"Definition: Pontocerebellar hypoplasia type 10 is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination. Some patients have dysmorphic features and an axonal sensorimotor neuropathy (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (previous studies)." +MONDO_0014407,"Definition: MPPH2 is an overgrowth syndrome comprising megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome (MCAP; previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of MPPH, see previous studies." +MONDO_0014572,Definition: Lichtenstein-Knorr syndrome is an autosomal recessive neurologic disorder characterized by postnatal onset of severe progressive sensorineural hearing loss and progressive cerebellar ataxia. Features usually develop in childhood or young adulthood (summary by previous studies). Some patients with SLC9A1 mutations may not have deafness (previous studies) +MONDO_0014632,"Definition: Hypomyelinating leukodystrophy-10 is an autosomal recessive neurologic disorder characterized by postnatal progressive microcephaly, severely delayed psychomotor development, and hypomyelination on brain imaging (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see previous studies." +MONDO_0020741,"Definition: Pyridoxine-dependent epilepsy, characterized by a combination of various seizure types, usually occurs in the first hours of life and is unresponsive to standard anticonvulsants, responding only to immediate administration of pyridoxine hydrochloride. The dependence is permanent, and the interruption of daily pyridoxine supplementation leads to the recurrence of seizures. Some patients show developmental delay. The prevalence is estimated at 1 in 400,000 to 700,000 (previous studies)." +MONDO_0032656,"Definition: The MCIDDS syndrome is characterized by microcephaly and growth retardation, congenital cataracts, impaired intellectual development with attention deficit-hyperactivity disorder, and dystonia, with striatal thinning seen on MRI (previous studies)." +Orphanet_53583,"Definition: Dystonia-9 is an autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia (summary by previous studies)." +MONDO_0010983,"Definition: Dystonia-9 is an autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia (summary by previous studies)." +EFO_0009159,"Definition: COXPD33 is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. The phenotype is highly variable, ranging from death in infancy to adult-onset progressive external ophthalmoplegia (PEO) and myopathy. A common finding is cardiomyopathy and increased serum lactate (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +Orphanet_35696,"Definition: COXPD33 is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. The phenotype is highly variable, ranging from death in infancy to adult-onset progressive external ophthalmoplegia (PEO) and myopathy. A common finding is cardiomyopathy and increased serum lactate (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0007470,"Definition: Calvarial doughnut lesions with bone fragility (CDL) is characterized by low bone mineral density, multiple spinal and peripheral fractures beginning in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Some more severely affected individuals exhibit neonatal onset of fractures, severe short stature, marked cranial sclerosis, and spondylometaphyseal dysplasia (CDLSMD) (previous studies)." +Orphanet_85192,"Definition: Calvarial doughnut lesions with bone fragility (CDL) is characterized by low bone mineral density, multiple spinal and peripheral fractures beginning in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Some more severely affected individuals exhibit neonatal onset of fractures, severe short stature, marked cranial sclerosis, and spondylometaphyseal dysplasia (CDLSMD) (previous studies)." +MONDO_0007561,"Definition: Multiple epiphyseal dysplasia is a skeletal disorder characterized by short stature and early-onset osteoarthrosis (previous studies). + + Genetic Heterogeneity of Multiple Epiphyseal Dysplasia + +Multiple epiphyseal dysplasia is a genetically heterogeneous disorder. See also EDM2 (previous studies), caused by mutation in the COL9A2 gene (previous studies); EDM3 (previous studies), caused by mutation in the COL9A3 gene (previous studies); EDM4 (previous studies), caused by mutation in the DTDST gene (previous studies); EDM5 (previous studies), caused by mutation in the MATN3 gene (previous studies); EDM6 (previous studies), caused by mutation in the COL9A1 gene (previous studies); and EDM7 (previous studies), caused by mutation in the CANT1 gene (previous studies)." +MONDO_0007672,"Definition: Glomuvenous malformations, also known as 'venous malformations with glomus cells' or glomangiomas, are similar to mucocutaneous venous malformations (VMCM; previous studies), but clinically are distinguishable: they have a cobble-stone appearance, have a consistency harder than that of venous malformations, and are painful on palpation. Histologically, GVMs are distinguishable by the presence of pathognomonic rounded cells (glomus cells) around the distended vein-like channels. The term glomus (Latin for ball) stems from the morphologically similar contractile cells of the Sucquet-Hoyer arteriovenous anastomoses in glomus bodies that are involved in cutaneous thermoregulation. Glomus cells in GVMs appear to be incompletely or improperly differentiated vascular smooth muscle cells, since they stain positively with smooth muscle cell alpha-actin (previous studies) and vimentin (previous studies) (summary by previous studies). The genetic distinctness of glomuvenous malformations from mucocutaneous venous malformations is indicated by the fact that mutations have been found in the TIE2/TEK gene (previous studies) in mucocutaneous venous malformations and not in glomuvenous malformations." +MONDO_0007962,"Definition: Macrodactyly is a congenital anomaly characterized by fibrofatty tissue enlargement and bony overgrowth in affected digits with resultant loss of function. Macrodactyly affects a 'nerve territory,' and the individual peripheral nerve is both enlarged and elongated (summary by previous studies)." +Orphanet_294953,"Definition: Macrodactyly is a congenital anomaly characterized by fibrofatty tissue enlargement and bony overgrowth in affected digits with resultant loss of function. Macrodactyly affects a 'nerve territory,' and the individual peripheral nerve is both enlarged and elongated (summary by previous studies)." +MONDO_0009185,"Definition: Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Impaired intellectual development is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (summary by previous studies and previous studies). + +See also Kohlschutter-Tonz syndrome-like (KTZSL; previous studies), caused by heterozygous mutation in the SATB1 gene (previous studies) on chromosome 3p23." +Orphanet_1946,"Definition: Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Impaired intellectual development is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (summary by previous studies and previous studies). + +See also Kohlschutter-Tonz syndrome-like (KTZSL; previous studies), caused by heterozygous mutation in the SATB1 gene (previous studies) on chromosome 3p23." +MONDO_0009211,"Definition: Factor VII deficiency is an autosomal recessive bleeding disorder showing variable severity (summary by previous studies). + +previous studies provided a comprehensive review of factor VII deficiency with a description of F7 polymorphisms, gene structure, and a summary of 120 mutations." +MONDO_0011399,"Definition: Alpha-thalassemia is one of the most common hemoglobin genetic abnormalities and is caused by the reduced or absent production of the alpha-globin chains. Four clinical conditions of increased severity are recognized: the silent carrier state (clinically and hematologically normal); thalassemia trait (microcytosis, hypochromia, and mild anemia); hemoglobin H (HbH) disease (previous studies; moderate to severe microcytic, hypochromic, hemolytic anemia, mild jaundice, moderate hepatosplenomegaly); and Hb Bart hydrops fetalis syndrome (severe anemia, generalized edema, ascites, marked hepatosplenomegaly, skeletal and cardiac malformations, usually death in utero) (summary by previous studies)." +Orphanet_846,"Definition: Alpha-thalassemia is one of the most common hemoglobin genetic abnormalities and is caused by the reduced or absent production of the alpha-globin chains. Four clinical conditions of increased severity are recognized: the silent carrier state (clinically and hematologically normal); thalassemia trait (microcytosis, hypochromia, and mild anemia); hemoglobin H (HbH) disease (previous studies; moderate to severe microcytic, hypochromic, hemolytic anemia, mild jaundice, moderate hepatosplenomegaly); and Hb Bart hydrops fetalis syndrome (severe anemia, generalized edema, ascites, marked hepatosplenomegaly, skeletal and cardiac malformations, usually death in utero) (summary by previous studies)." +MONDO_0027407,"Definition: Submicroscopic subtelomeric deletions of chromosome 9q are associated with a recognizable mental retardation syndrome (previous studies; previous studies; previous studies; previous studies). Common features in patients with 9q subtelomeric deletion syndrome are severe mental retardation, hypotonia, brachy(micro)cephaly, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, carp mouth with macroglossia, and heart defects. + + Genetic Heterogeneity of Kleefstra Syndrome + +KLEFS2 (previous studies) is caused by mutation in the KMT2C gene (previous studies) on chromosome 7q36." +MONDO_0029145,Definition: Orofacial cleft-8 (OFC8) is characterized by unilateral or bilateral cleft lip (previous studies; previous studies). +MONDO_0030844,"Definition: Spermatogenic failure-47 (SPGF47) is characterized by male infertility due to asthenoteratospermia. Affected individuals have reduced sperm concentrations and spermatozoa are immotile, with short or absent flagella as well as centriolar abnormalities (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see previous studies." +MONDO_8000011,"Definition: Autosomal recessive familial visceral neuropathy-1 (VSCN1) is characterized by a broad spectrum of developmental anomalies associating neural crest and extraneural crest features, including intestinal dysmotility due to aganglionosis (Hirschsprung disease), hypoganglionosis, and/or chronic intestinal pseudoobstruction. Some patients develop progressive peripheral neuropathy, and arthrogryposis has been observed. Hypoplasia or aplasia of the olfactory bulb and of the external auditory canals, as well as microtia or anotia, have been reported. Patients also exhibit facial dysmorphisms, including microretrognathia in most; other variable features include structural cardiac anomalies and arthrogryposis with multiple pterygia (previous studies). + + Genetic Heterogeneity of Familial Visceral Neuropathy + +Autosomal recessive familial visceral neuropathy-2 (VSCN2; previous studies) is caused by mutation in the ERBB2 gene (previous studies) on chromosome 17q12. Also see VSCN3 (previous studies) for an autosomal dominant form of the disorder." +Orphanet_169446,Definition: Immunodeficiency-35 (IMD35) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to localized or disseminated mycobacterial infection after BCG vaccination. Some patients may have increased susceptibility to infection with other intracellular organisms and/or viral infections. Fungal infections are not observed. Laboratory studies show normal levels of immune cells but defective signaling in specific immunologic pathways (summary by previous studies). +Orphanet_331226,Definition: Immunodeficiency-35 (IMD35) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to localized or disseminated mycobacterial infection after BCG vaccination. Some patients may have increased susceptibility to infection with other intracellular organisms and/or viral infections. Fungal infections are not observed. Laboratory studies show normal levels of immune cells but defective signaling in specific immunologic pathways (summary by previous studies). +Orphanet_228329,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment pattern seen most often in CLN1 is referred to as granular osmiophilic deposits (GROD). The patterns most often observed in CLN2 and CLN3 are 'curvilinear' and 'fingerprint' profiles, respectively. CLN4, CLN5, CLN6, CLN7, and CLN8 show mixed combinations of granular, curvilinear, fingerprint, and rectilinear profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +previous studies referred to these conditions as the 'neuronal ceroid lipofuscinoses.' previous studies provided a comprehensive review of the NCLs and noted that they are possibly the most common group of neurodegenerative diseases in children. + +previous studies provided a detailed clinical and genetic review of the neuronal ceroid lipofuscinoses. + + Genetic Heterogeneity of Neuronal Ceroid Lipofuscinosis + +See also CLN2 (previous studies), caused by mutation in the TPP1 gene (previous studies) on chromosome 11p15; CLN3 (previous studies), caused by mutation in the CLN3 gene (previous studies) on 16p12; CLN4 (previous studies), caused by mutation in the DNAJC5 gene (previous studies) on 20q13; CLN5 (previous studies), caused by mutation in the CLN5 gene (previous studies) on 13q22; CLN6A (previous studies) and CLN6B (previous studies), both caused by mutation in the CLN6 gene (previous studies) on 15q21; CLN7 (previous studies), caused by mutation in the MFSD8 gene (previous studies) on 4q28; CLN8 (previous studies) and the Northern epilepsy variant of CLN8 (previous studies), both caused by mutation in the CLN8 gene (previous studies) on 8p23; CLN10 (previous studies), caused by mutation in the CTSD gene (previous studies) on 11p15; CLN11 (previous studies), caused by mutation in the GRN gene (previous studies) on 17q21; CLN13 (previous studies), caused by mutation in the CTSF gene (previous studies) on 11q13; and CLN14 (previous studies), caused by mutation in the KCTD7 gene (previous studies) on 7q11. + +CLN9 (previous studies) has not been molecularly characterized. + +A disorder that was formerly designated neuronal ceroid lipofuscinosis-12 (CLN12) is now considered to be a variable form of Kufor-Rakeb syndrome (KRS; previous studies)." +Orphanet_3077,"Definition: The MECP2 gene is mutated in Rett syndrome (RTT; previous studies), a severe neurodevelopmental disorder that almost always occurs in females. Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes, including X-linked syndromic intellectual developmental disorder-13, described here, and Lubs-type X-linked syndromic intellectual developmental disorder (MRXSL; previous studies). Males with RTT-associated MECP2 mutations have neonatal severe encephalopathy that is usually lethal (previous studies) (previous studies; previous studies)." +MONDO_0010235,"Definition: The MECP2 gene is mutated in Rett syndrome (RTT; previous studies), a severe neurodevelopmental disorder that almost always occurs in females. Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes, including X-linked syndromic intellectual developmental disorder-13, described here, and Lubs-type X-linked syndromic intellectual developmental disorder (MRXSL; previous studies). Males with RTT-associated MECP2 mutations have neonatal severe encephalopathy that is usually lethal (previous studies) (previous studies; previous studies)." +Orphanet_79403,"Definition: Junctional epidermolysis bullosa 5B with pyloric atresia (JEB5B) is an autosomal recessive blistering disease of skin and mucous membranes. Severity of skin involvement ranges from extensive full thickness skin loss (aplasia cutis congenita) to mild epidermolysis bullosa that improves with age. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Pyloric atresia is usually evident within a few days to weeks of life. Atresia may occur at other gastrointestinal sites including the esophagus and duodenum. JEB5B is usually lethal within the first few weeks of life despite surgical correction of pyloric atresia. Milder, non-lethal forms with less skin blistering have been reported (summary by previous studies). + +Another form of junctional epidermolysis bullosa with pyloric atresia (JEB6; previous studies) is caused by mutations in the integrin-alpha-6 gene (ITGA6; previous studies). + +See also epidermolysis bullosa simplex with pyloric atresia (EBS5C; previous studies), which is caused by mutations in the PLEC1 gene (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa. + +In a study involving 265 cases of junctional or hemidesmosomal EB, previous studies reviewed the clinical and molecular heterogeneity of these subtypes of EB, discussed exceptions to the general rules on genotype-phenotype correlations, and noted unusual phenotypes and genetics observed in patients and families with EB." +MONDO_0009183,"Definition: Junctional epidermolysis bullosa 5B with pyloric atresia (JEB5B) is an autosomal recessive blistering disease of skin and mucous membranes. Severity of skin involvement ranges from extensive full thickness skin loss (aplasia cutis congenita) to mild epidermolysis bullosa that improves with age. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Pyloric atresia is usually evident within a few days to weeks of life. Atresia may occur at other gastrointestinal sites including the esophagus and duodenum. JEB5B is usually lethal within the first few weeks of life despite surgical correction of pyloric atresia. Milder, non-lethal forms with less skin blistering have been reported (summary by previous studies). + +Another form of junctional epidermolysis bullosa with pyloric atresia (JEB6; previous studies) is caused by mutations in the integrin-alpha-6 gene (ITGA6; previous studies). + +See also epidermolysis bullosa simplex with pyloric atresia (EBS5C; previous studies), which is caused by mutations in the PLEC1 gene (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa. + +In a study involving 265 cases of junctional or hemidesmosomal EB, previous studies reviewed the clinical and molecular heterogeneity of these subtypes of EB, discussed exceptions to the general rules on genotype-phenotype correlations, and noted unusual phenotypes and genetics observed in patients and families with EB." +Orphanet_89936,"Definition: X-linked dominant hypophosphatemic rickets, although variable in its expressivity, is characterized by rickets with bone deformities, short stature, dental anomalies, and at the biologic level, hypophosphatemia with low renal phosphate reabsorption, normal serum calcium level with hypocalciuria, normal or low serum level of vitamin D (1,25(OH)2D3, or calcitriol), normal serum level of PTH, and increased activity of serum alkaline phosphatases (summary by previous studies)." +MONDO_0010619,"Definition: X-linked dominant hypophosphatemic rickets, although variable in its expressivity, is characterized by rickets with bone deformities, short stature, dental anomalies, and at the biologic level, hypophosphatemia with low renal phosphate reabsorption, normal serum calcium level with hypocalciuria, normal or low serum level of vitamin D (1,25(OH)2D3, or calcitriol), normal serum level of PTH, and increased activity of serum alkaline phosphatases (summary by previous studies)." +EFO_0003860,"Definition: Pancreatic cancer shows among the highest mortality rates of any cancer, with a 5-year relative survival rate of less than 5%. By the time of initial diagnosis, metastatic disease is commonly present. Established risk factors include a family history of pancreatic cancer, a medical history of diabetes type 2, and cigarette smoking (summary by previous studies). + + Genetic Heterogeneity of Pancreatic Cancer + +Somatic mutations in pancreatic cancer occur in the KRAS (previous studies), CDKN2A (previous studies), MADH4 (previous studies), TP53 (previous studies), ARMET (previous studies), STK11 (previous studies), ACVR1B (previous studies), and RBBP8 (previous studies) genes. + +Susceptibility loci for pancreatic cancer include PNCA1 (previous studies), related to mutation in the PALLD gene on chromosome 4q32 (previous studies); PNCA2 (previous studies), related to mutation in the BRCA2 gene on chromosome 13q12 (previous studies); PNCA3 (previous studies), related to mutation in the PALB2 gene on chromosome 16p12 (previous studies); PNCA4 (previous studies), related to mutation in the BRCA1 gene on chromosome 17q21 (previous studies); and PNCA5 (previous studies), related to mutation in the RABL3 gene on chromosome 3q13 (previous studies). + + Occurrence of Pancreatic Cancer in Other Disorders + +Several familial cancer syndromes increase the risk of pancreatic cancer. The best characterized include hereditary nonpolyposis colon cancer syndrome (HNPCC; see previous studies); hereditary breast-ovarian cancer syndrome due to mutations in BRCA2; Peutz-Jeghers syndrome (previous studies); the melanoma-pancreatic cancer syndrome (previous studies), caused by mutations in CDKN2A (previous studies); von Hippel-Lindau syndrome (previous studies), ataxia-telangiectasia (previous studies) (previous studies), and juvenile polyposis syndrome (previous studies). + +Patients with hereditary pancreatitis (previous studies) resulting from gain-of-function mutations in the protease serine-1 gene (PRSS1; previous studies) have a lifetime pancreatic cancer risk ratio of 57 and a cumulative incidence, to age 70 years, of 40% (previous studies)." +MONDO_0015278,"Definition: Pancreatic cancer shows among the highest mortality rates of any cancer, with a 5-year relative survival rate of less than 5%. By the time of initial diagnosis, metastatic disease is commonly present. Established risk factors include a family history of pancreatic cancer, a medical history of diabetes type 2, and cigarette smoking (summary by previous studies). + + Genetic Heterogeneity of Pancreatic Cancer + +Somatic mutations in pancreatic cancer occur in the KRAS (previous studies), CDKN2A (previous studies), MADH4 (previous studies), TP53 (previous studies), ARMET (previous studies), STK11 (previous studies), ACVR1B (previous studies), and RBBP8 (previous studies) genes. + +Susceptibility loci for pancreatic cancer include PNCA1 (previous studies), related to mutation in the PALLD gene on chromosome 4q32 (previous studies); PNCA2 (previous studies), related to mutation in the BRCA2 gene on chromosome 13q12 (previous studies); PNCA3 (previous studies), related to mutation in the PALB2 gene on chromosome 16p12 (previous studies); PNCA4 (previous studies), related to mutation in the BRCA1 gene on chromosome 17q21 (previous studies); and PNCA5 (previous studies), related to mutation in the RABL3 gene on chromosome 3q13 (previous studies). + + Occurrence of Pancreatic Cancer in Other Disorders + +Several familial cancer syndromes increase the risk of pancreatic cancer. The best characterized include hereditary nonpolyposis colon cancer syndrome (HNPCC; see previous studies); hereditary breast-ovarian cancer syndrome due to mutations in BRCA2; Peutz-Jeghers syndrome (previous studies); the melanoma-pancreatic cancer syndrome (previous studies), caused by mutations in CDKN2A (previous studies); von Hippel-Lindau syndrome (previous studies), ataxia-telangiectasia (previous studies) (previous studies), and juvenile polyposis syndrome (previous studies). + +Patients with hereditary pancreatitis (previous studies) resulting from gain-of-function mutations in the protease serine-1 gene (PRSS1; previous studies) have a lifetime pancreatic cancer risk ratio of 57 and a cumulative incidence, to age 70 years, of 40% (previous studies)." +EFO_0002618,"Definition: Pancreatic cancer shows among the highest mortality rates of any cancer, with a 5-year relative survival rate of less than 5%. By the time of initial diagnosis, metastatic disease is commonly present. Established risk factors include a family history of pancreatic cancer, a medical history of diabetes type 2, and cigarette smoking (summary by previous studies). + + Genetic Heterogeneity of Pancreatic Cancer + +Somatic mutations in pancreatic cancer occur in the KRAS (previous studies), CDKN2A (previous studies), MADH4 (previous studies), TP53 (previous studies), ARMET (previous studies), STK11 (previous studies), ACVR1B (previous studies), and RBBP8 (previous studies) genes. + +Susceptibility loci for pancreatic cancer include PNCA1 (previous studies), related to mutation in the PALLD gene on chromosome 4q32 (previous studies); PNCA2 (previous studies), related to mutation in the BRCA2 gene on chromosome 13q12 (previous studies); PNCA3 (previous studies), related to mutation in the PALB2 gene on chromosome 16p12 (previous studies); PNCA4 (previous studies), related to mutation in the BRCA1 gene on chromosome 17q21 (previous studies); and PNCA5 (previous studies), related to mutation in the RABL3 gene on chromosome 3q13 (previous studies). + + Occurrence of Pancreatic Cancer in Other Disorders + +Several familial cancer syndromes increase the risk of pancreatic cancer. The best characterized include hereditary nonpolyposis colon cancer syndrome (HNPCC; see previous studies); hereditary breast-ovarian cancer syndrome due to mutations in BRCA2; Peutz-Jeghers syndrome (previous studies); the melanoma-pancreatic cancer syndrome (previous studies), caused by mutations in CDKN2A (previous studies); von Hippel-Lindau syndrome (previous studies), ataxia-telangiectasia (previous studies) (previous studies), and juvenile polyposis syndrome (previous studies). + +Patients with hereditary pancreatitis (previous studies) resulting from gain-of-function mutations in the protease serine-1 gene (PRSS1; previous studies) have a lifetime pancreatic cancer risk ratio of 57 and a cumulative incidence, to age 70 years, of 40% (previous studies)." +MONDO_0007395,"Definition: Craniofacial-deafness-hand syndrome (CDHS) is an autosomal dominant disorder characterized by dysmorphic facial features, hand abnormalities, absent or hypoplastic nasal and wrist bones, and severe sensorineural hearing impairment (summary by previous studies)." +MONDO_0007565,"Definition: The disorders classically referred to as familial cylindromatosis, Brooke-Spiegler syndrome, and multiple familial trichoepithelioma were originally described as distinct clinical entities. Patients with BRSS develop multiple skin appendage tumors including cylindromas, trichoepitheliomas, and spiradenomas. Patients with familial cylindromatosis have only cylindromas, and those with MFT1 have only trichoepitheliomas. However, because these disorders show overlapping phenotypic features, and because different manifestations of each have been described within a single family, many consider these disorders to represent a phenotypic spectrum of a single disease entity (previous studies; previous studies; previous studies; previous studies; previous studies; previous studies; previous studies). + +previous studies, who preferred the designation 'dermal eccrine cylindromatosis' for familial cylindromatosis, provided a review. 'Eccrine' referred to histologic evidence that the tumors may originate from the eccrine sweat glands. + +previous studies provided a detailed review of the spectrum of disorders associated with CYLD mutations." +MONDO_0008123,"Definition: Omodysplasia-2 (OMOD2) is a rare autosomal dominant skeletal dysplasia characterized by shortened humeri, dislocated radial heads, shortened first metacarpals, craniofacial dysmorphism, and variable genitourinary anomalies (previous studies). + +For a discussion of genetic heterogeneity of OMOD, see previous studies." +MONDO_0008693,"Definition: Ablepharon-macrostomia syndrome (AMS) is a congenital ectodermal dysplasia characterized by absent eyelids, macrostomia, microtia, redundant skin, sparse hair, dysmorphic nose and ears, variable abnormalities of the nipples, genitalia, fingers, and hands, largely normal intellectual and motor development, and poor growth (summary by previous studies)." +MONDO_0009181,"Definition: Epidermolysis bullosa simplex with muscular dystrophy (EBS5B) is an autosomal recessive disorder characterized by early childhood onset of progressive muscular dystrophy and blistering skin changes (previous studies). + +previous studies reported a revised classification of the subtypes of inherited epidermolysis bullosa. + +In reports of 2 consensus meetings on EB, previous studies referred to EB with muscular dystrophy due to PLEC1 mutations as a form of basal simplex EB. previous studies also eliminated the term 'hemidesmosomal,' which had previously been proposed for this entity (previous studies) because ultrastructural analysis can demonstrate tissue abnormalities of the hemidesmosomes. + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +Orphanet_257,"Definition: Epidermolysis bullosa simplex with muscular dystrophy (EBS5B) is an autosomal recessive disorder characterized by early childhood onset of progressive muscular dystrophy and blistering skin changes (previous studies). + +previous studies reported a revised classification of the subtypes of inherited epidermolysis bullosa. + +In reports of 2 consensus meetings on EB, previous studies referred to EB with muscular dystrophy due to PLEC1 mutations as a form of basal simplex EB. previous studies also eliminated the term 'hemidesmosomal,' which had previously been proposed for this entity (previous studies) because ultrastructural analysis can demonstrate tissue abnormalities of the hemidesmosomes. + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0009633,"Definition: Microspherophakia (MSP) is a rare disease characterized by smaller and more spherical lenses than normal bilaterally, an increased anteroposterior thickness of the lens, and highly myopic eyes. Lens dislocation or subluxation may occur, leading to defective accommodation (summary by previous studies). + +Microspherophakia may occur in association with ectopia lentis and glaucoma, Marfan syndrome (MFS; previous studies), and Weill-Marchesani syndrome (WMS; previous studies)." +MONDO_0011141,"Definition: Folate-responsive megaloblastic anemia (MEGAF) is an autosomal recessive metabolic disorder characterized by megaloblastic anemia resulting from decreased folate transport into erythrocytes. Although serum levels of folate are normal, there is folate deficiency in tissues, including erythrocytes and possibly nerve cells. Serum homocysteine levels are increased and vitamin B12 levels may be decreased. Treatment with oral folate corrects the anemia and normalizes homocysteine (summary by previous studies)" +MONDO_0011706,"Definition: Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; see previous studies) (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see previous studies. + +Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia-78 (SPG78; previous studies), an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by previous studies)." +MONDO_0012143,"Definition: Stomatin-deficient cryohydrocytosis with neurologic defects is an autosomal dominant disorder characterized by delayed psychomotor development, seizures, cataracts, and pseudohyperkalemia resulting from defects in the red blood cell membrane. The disorder combines the neurologic features of Glut1 deficiency syndrome-1 (GLUT1DS1; previous studies), resulting from impaired glucose transport at the blood-brain barrier, and hemolytic anemia/pseudohyperkalemia with stomatocytosis, resulting from a cation leak in erythrocytes (summary by previous studies). + +For a discussion of clinical and genetic heterogeneity of red cell stomatocyte disorders, see previous studies." +MONDO_0013937,"Definition: The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood. Some patients with PEX10 mutations have a milder disorder characterized by childhood-onset cerebellar ataxia and neuropathy without mental retardation (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see previous studies. + +Individuals with mutations in the PEX10 gene have cells of complementation group 7 (CG7, equivalent to CGB). For information on the history of PBD complementation groups, see previous studies." +MONDO_0019570,"Definition: Cockayne syndrome B (CSB) is a multisystem disorder characterized by severe physical and mental retardation, microcephaly, progressive neurologic and retinal degeneration, skeletal abnormalities, gait defects, and sun sensitivity with no increased frequency of cancer (summary by previous studies). + +Cockayne syndrome A (CSA; previous studies) is caused by mutation in the ERCC8 gene (previous studies) on chromosome 5q11. Among patients with Cockayne syndrome, approximately 80% have mutations in the ERCC6 gene (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Cockayne syndrome, see previous studies." +MONDO_0020754,"Definition: Familial visceral myopathy (VSCM) is a rare inherited form of myopathic pseudoobstruction, characterized by impaired function of enteric smooth muscle cells resulting in abnormal intestinal mobility, severe abdominal pain, malnutrition, and even death (previous studies). Visceral myopathy represents a phenotypic spectrum of disease characterized by inter- and intrafamilial variability, in which the most severely affected patients exhibit prenatal bladder enlargement, intestinal malrotation, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition (TPN) and urinary catheterization (summary by previous studies). + +Another form of visceral myopathy with functional gastrointestinal obstruction is associated with external ophthalmoplegia (previous studies). + +Functional gastrointestinal obstruction also occurs in association with other abnormalities, such as 'prune belly' syndrome (previous studies) and Barrett esophagus (Mungan syndrome; previous studies). Chronic intestinal pseudoobstruction can also be neuropathic in origin (see previous studies). + + Genetic Heterogeneity of Visceral Myopathy + +VSCM2 (previous studies) is caused by mutation in the MYH11 gene (previous studies) on chromosome 16p13." +MONDO_0030527,"Definition: Localized epidermolysis bullosa simplex-2C (EBS2C) is an autosomal dominant skin disorder with intraepidermal blistering after minor trauma mainly restricted to hands and feet beginning in infancy. Nails may be thick and dystrophic (summary by previous studies). Localized epidermolysis bullosa simplex has previously been known as the Weber-Cockayne type. + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility." +MONDO_0031011,"Definition: Neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS) is an autosomal recessive disorder characterized by global developmental delay apparent in early childhood. Patients have mildly impaired intellectual development, often with speech delay or behavioral abnormalities. Some may have seizures. Most have nonspecific dysmorphic facial features. Additional findings may include brain imaging abnormalities, mild skeletal defects, and renal abnormalities, although the renal anomalies may be unrelated (summary by previous studies)." +MONDO_0054701,"Definition: Kleefstra syndrome-2 (KLEFS2) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variable intellectual disability, and mild dysmorphic features (summary by previous studies). + +For a discussion of genetic heterogeneity of Kleefstra syndrome, see KLEFS1 (previous studies)." +Orphanet_163746,"Definition: PCWH syndrome is a complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy (see previous studies), central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (see previous studies) (previous studies). previous studies proposed the acronym PCWH for this disorder." +MONDO_0012198,"Definition: PCWH syndrome is a complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy (see previous studies), central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (see previous studies) (previous studies). previous studies proposed the acronym PCWH for this disorder." +Orphanet_324723,"Definition: Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (previous studies)." +Orphanet_324708,"Definition: Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (previous studies)." +MONDO_0011583,"Definition: Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (previous studies)." +Orphanet_324718,"Definition: Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (previous studies)." +Orphanet_100006,"Definition: Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (previous studies)." +Orphanet_324703,"Definition: Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (previous studies)." +Orphanet_324713,"Definition: Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (previous studies)." +EFO_0005207,"Definition: The multiple types of congenital heart defects observed in CHTD4 include atrial, ventricular, and atrioventricular septal defects, double-outlet right ventricle, tetralogy of Fallot, hypoplastic left heart syndrome, aortic stenosis, and coarctation of the aorta. Intrafamilial variability and incomplete penetrance has been reported (previous studies; previous studies). Some patients exhibit syndromic features such as developmental delay, congenital diaphragmatic hernia, and severe gastroesophageal reflux (previous studies; previous studies). + +For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see CHTD1 (previous studies)." +MONDO_0009282,"Definition: Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (GA1; previous studies) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (previous studies; previous studies). + +The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by previous studies). + +Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (previous studies)." +MONDO_0011822,"Definition: Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (previous studies). + +Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, previous studies) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by previous studies and previous studies). + + Genetic Heterogeneity of Bartter Syndrome + +Antenatal Bartter syndrome type 1 (previous studies) is caused by loss-of-function mutations in the butmetanide-sensitive Na-K-2Cl cotransporter NKCC2 (SLC12A1; previous studies). Antenatal Bartter syndrome type 2 (previous studies) is caused by loss-of-function mutations in the ATP-sensitive potassium channel ROMK (KCNJ1; previous studies). One form of neonatal Bartter syndrome with sensorineural deafness, Bartter syndrome type 4A (previous studies), is caused by mutation in the BSND gene (previous studies). Another form of neonatal Bartter syndrome with sensorineural deafness, Bartter syndrome type 4B (previous studies), is caused by simultaneous mutation in both the CLCNKA (602024) and CLCNKB (602023) genes. + +Also see autosomal dominant hypocalcemia-1 with Bartter syndrome (previous studies), which is sometimes referred to as Bartter syndrome type 5 (previous studies), caused by mutation in the CASR gene (previous studies). + +See Gitelman syndrome (GTLMN; previous studies), which is often referred to as a mild variant of Bartter syndrome, caused by mutation in the thiazide-sensitive sodium-chloride cotransporter SLC12A3 (previous studies)." +MONDO_0012277,"Definition: Myofibrillar myopathy-4 (MFM4) is an autosomal dominant disorder characterized by adult-onset distal muscle weakness primarily affecting the lower limbs at onset. Affected individuals usually present with gait difficulties in their forties, followed by slow progression with eventual involvement of the hands and proximal muscles of the lower limbs. Rare patients may develop cardiomyopathy. Skeletal muscle biopsy shows myopathic changes with myofibrillar changes (previous studies; previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (previous studies)." +Orphanet_98912,"Definition: Myofibrillar myopathy-4 (MFM4) is an autosomal dominant disorder characterized by adult-onset distal muscle weakness primarily affecting the lower limbs at onset. Affected individuals usually present with gait difficulties in their forties, followed by slow progression with eventual involvement of the hands and proximal muscles of the lower limbs. Rare patients may develop cardiomyopathy. Skeletal muscle biopsy shows myopathic changes with myofibrillar changes (previous studies; previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (previous studies)." +MONDO_0013555,"Definition: Hermansky-Pudlak syndrome-3 (HPS3) is characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies. Clinically, affected individuals have a bleeding diathesis, horizontal nystagmus, decreased vision and very mild pigment dilution of hair, skin, and irides (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (previous studies)." +MONDO_0013776,"Definition: Spastic ataxia-5 (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (summary by previous studies). + +For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (previous studies)." +Orphanet_313772,"Definition: Spastic ataxia-5 (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (summary by previous studies). + +For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (previous studies)." +MONDO_0013952,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group K (CGK) have mutations in the PEX14 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0100522,"Definition: Hypotrichosis-4 (HYPT4), also known as Marie Unna hereditary hypotrichosis-1 (MUHH1), is an autosomal dominant form of hair loss characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth. Coarse, wiry hair begins to grow during childhood. Around puberty, progressive hair loss occurs in the affected patients. Although the disorder has the potential to affect all hair shafts, progressive and patterned alopecia of the scalp is the main manifestation of the disorder (summary by previous studies). + +For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see previous studies. + + Genetic Heterogeneity of Marie Unna Hereditary Hypotrichosis + +See also MUHH2 (HYPT5; previous studies), caused by heterozygous mutation in the EPS8L3 gene (previous studies) on chromosome 1p13." +Orphanet_3320,"Definition: The thrombocytopenia-absent radius syndrome (TAR) is characterized by reduction in the number of platelets and absence of the radius; preservation of the thumb distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia (see previous studies). Individuals with TAR have low numbers of megakaryocytes, platelet precursor cells that reside in bone marrow, and frequently present with bleeding episodes in the first year of life that diminish in frequency and severity with age. The severity of skeletal anomalies varies from absence of radii to virtual absence of upper limbs, with or without lower limb defects such as malformations of the hip and knee (summary by previous studies)." +MONDO_0010121,"Definition: The thrombocytopenia-absent radius syndrome (TAR) is characterized by reduction in the number of platelets and absence of the radius; preservation of the thumb distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia (see previous studies). Individuals with TAR have low numbers of megakaryocytes, platelet precursor cells that reside in bone marrow, and frequently present with bleeding episodes in the first year of life that diminish in frequency and severity with age. The severity of skeletal anomalies varies from absence of radii to virtual absence of upper limbs, with or without lower limb defects such as malformations of the hip and knee (summary by previous studies)." +Orphanet_95710,"Definition: Premature ovarian failure-15 (POF15) is characterized by onset of oligomenorrhea in the third decade of life, with small ovaries, reduced number of follicles, and elevated gonadotropic hormones (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (previous studies)." +MONDO_0007239,"Definition: Epidermolytic hyperkeratosis-1 (EHK1) is a rare autosomal dominant disorder of cornification. The disorder usually presents at birth with erythema and blistering and is characterized in adulthood by warty flexural hyperkeratosis with fewer erosions and blisters. Ultrastructural analysis reveals clumping of the intermediate filaments within keratinocytes of the spinous and granular layers (summary by previous studies). + +A form of epidermolytic hyperkeratosis that is limited to the palms and soles, designated palmoplantar keratoderma (EPPK; previous studies), can also be caused by mutation in KRT1, as well KRT9 (previous studies). + + Genetic Heterogeneity of Epidermolytic Hyperkeratosis + +EHK2 (previous studies) is caused by mutation in the KRT10 gene (previous studies)." +MONDO_0007319,"Definition: Chondrocalcinosis, or cartilage calcification, is a common condition that usually results from deposition of crystals of calcium pyrophosphate dihydrate (CPPD) in articular hyaline and fibro-cartilage. CPPD crystal deposition may be asymptomatic or associated with characteristic acute attacks ('pseudogout') or chronic arthritis. It can be detected radiographically. Chondrocalcinosis occurs in 3 forms: a primary hereditary form (e.g., CCAL2); a form associated with metabolic disorders (e.g., hyperparathyroidism, hemochromatosis, and hypomagnesemia); and a sporadic form, which may in some cases represent the hereditary form (summary by previous studies and previous studies). + + Genetic Heterogeneity of Chondrocalcinosis + +Another form of chondrocalcinosis (CCAL1; previous studies) has been mapped to chromosome 8q." +MONDO_0007634,"Definition: FRA12A is a folate-sensitive chromosomal fragile site prone to breakage. No consistent phenotype has been observed with FRA12A, and it can be inherited without phenotypic effect (previous studies). However, impaired intellectual development with or without other anomalies has been described in patients with over 40% of cells expressing FRA12A (previous studies)." +MONDO_0009291,"Definition: Glycogen storage disease III is an autosomal recessive metabolic disorder caused by deficiency of the glycogen debrancher enzyme and associated with an accumulation of abnormal glycogen with short outer chains. Most patients are enzyme-deficient in both liver and muscle (IIIa), but about 15% are enzyme-deficient in liver only (IIIb) (previous studies). These subtypes have been explained by differences in tissue expression of the deficient enzyme (previous studies). In rare cases, selective loss of only 1 of the 2 debranching activities, glucosidase or transferase, results in type IIIc or IIId, respectively. (previous studies; previous studies). + +Clinically, patients with GSD III present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness in those with IIIa is minimal in childhood but can become more severe in adults; some patients develop cardiomyopathy (previous studies). + +previous studies provided a review of GSD III." +MONDO_0009925,"Definition: Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye, including peau d'orange, angioid streaks, and choroidal neovascularizations (CNVs); of the skin, including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces; and of the cardiovascular system, with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings (summary by previous studies). + +Generalized arterial calcification of infancy-2 (GACI2; previous studies) is an allelic disorder, also caused by homozygous or compound heterozygous mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (previous studies)." +Orphanet_758,"Definition: Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye, including peau d'orange, angioid streaks, and choroidal neovascularizations (CNVs); of the skin, including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces; and of the cardiovascular system, with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings (summary by previous studies). + +Generalized arterial calcification of infancy-2 (GACI2; previous studies) is an allelic disorder, also caused by homozygous or compound heterozygous mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (previous studies)." +MONDO_0011330,"Definition: The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders characterized by ataxia, dysarthria, dysmetria, and intention tremor. All ADCAs involve some degree of cerebellar dysfunction and a varying degree of signs from other components of the nervous system. A commonly accepted clinical classification (previous studies) divides ADCAs into 3 different groups based on the presence or absence of associated symptoms such as brainstem signs or retinopathy. The presence of pyramidal and extrapyramidal symptoms and ophthalmoplegia makes the diagnosis of ADCA I, the presence of retinopathy points to ADCA II, and the absence of associated signs to ADCA III. Genetic linkage and molecular analyses revealed that ADCAs are genetically heterogeneous even within the various subtypes. + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0011585,"Definition: Distal spinal muscular atrophy-2 is an autosomal recessive neuromuscular disorder characterized by onset of distal muscle weakness and wasting affecting the lower and upper limbs in the first decade; there is no sensory involvement (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DSMA, see HMN1 (previous studies)." +MONDO_0011787,"Definition: MDGDC5 is an autosomal recessive muscular dystrophy characterized by variable age at onset, normal cognition, and no structural brain changes (previous studies). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (previous studies)." +MONDO_0014342,"Definition: Female infertility often results from problems connected to producing eggs. Oocyte maturation is a complex process that includes meiotic division and recombination, nuclear maturation, and epigenetic modification. Each stage of this process is regulated by a large network of genes. Pathogenic variants in these genes can result in the recurrent failures of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programs due to a poor response to ovarian stimulation, oocyte maturation arrest, poor quality of gametes, fertilization failure, or early embryonic development arrest (previous studies). + +The zona pellucida (ZP) is a glycoprotein matrix that surrounds oocytes and has an average thickness of 17 micrometers. It is vital for the production of oocytes in early development, for fertilization, and for protection of early embryos before implantation. Absence of the zona pellucida in OOMD1 results in sterility (summary by previous studies). + + Reviews + +previous studies reviewed the genetics of oocyte maturation defects and early embryo development arrest. + + Genetic Heterogeneity of Oocyte/Zygote/Embryo Maturation Arrest + +Also see OZEMA2 (previous studies), caused by mutation in the TUBB8 gene (previous studies) on chromosome 10p15; OZEMA3 (previous studies), caused by mutation in the ZP3 gene (previous studies) on chromosome 7q11; OZEMA4 (previous studies), caused by mutation in the PATL2 gene (previous studies) on chromosome 15q21; OZEMA5 (previous studies), caused by mutation in the WEE2 gene (previous studies) on chromosome 7q34; OZEMA6 (previous studies), caused by mutation in the ZP2 gene (previous studies) on chromosome 16p12; OZEMA7 (previous studies), caused by mutation in the PANX1 gene (previous studies) on chromosome 11q21; OZEMA8 (previous studies), caused by mutation in the BTG4 gene (previous studies) on chromosome 11q23; OZEMA9 (previous studies), caused by mutation in the TRIP13 gene (previous studies) on chromosome 5p15; OZEMA10 (previous studies), caused by mutation in the REC114 gene (previous studies) on chromosome 15q24; OZEMA11 (previous studies), caused by mutation in the ASTL gene (previous studies) on chromosome 2q11; OZEMA12 (previous studies), caused by mutation in the FBXO43 gene (previous studies) on chromosome 8q22; OZEMA13 (previous studies), caused by mutation in the ZFP36L2 gene (previous studies) on chromosome 2p21; OZEMA14 (previous studies), caused by mutation in the CDC20 gene (previous studies) on chromosome 1p34; OZEMA15 (previous studies), caused by mutation in the TLE6 gene (previous studies) on chromosome 19p13; OZEMA16 (previous studies), caused by mutation in the PADI6 gene (previous studies) on chromosome 1p36; OZEMA17 (previous studies), caused by mutation in the KPNA7 gene (previous studies) on chromosome 7q22; OZEMA18 (previous studies), caused by mutation in the NLRP2 gene (previous studies) on chromosome 19q13; OZEMA19 (previous studies), caused by mutation in the NLRP5 gene (previous studies) on chromosome 19q13; and OZEMA20 (previous studies), caused by mutation in the MOS gene (previous studies) on chromosome 8q12." +MONDO_0014956,"Definition: Chitayat syndrome (CHYTS) is a rare condition characterized by respiratory distress presenting at birth, bilateral accessory phalanx resulting in shortened index fingers with ulnar deviation, hallux valgus, and characteristic facial features including prominent eyes, hypertelorism, depressed nasal bridge, full lips, and upturned nose (summary by previous studies)." +MONDO_0024519,"Definition: Renal hypodysplasia/aplasia belongs to a group of perinatally lethal renal diseases, including bilateral renal aplasia, unilateral renal agenesis with contralateral dysplasia (URA/RD), and severe obstructive uropathy. Renal aplasia falls at the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT; previous studies), and usually results in death in utero or in the perinatal period. Families have been documented in which bilateral renal agenesis or aplasia coexists with unilateral renal aplasia, renal dysplasia, or renal aplasia with renal dysplasia, suggesting that these conditions may belong to a pathogenic continuum or phenotypic spectrum (summary by previous studies; previous studies). + + Genetic Heterogeneity of Renal Hypodysplasia/Aplasia + +See also RHDA2 (previous studies), caused by mutation in the FGF20 gene (previous studies) on chromosome 8p22; RHDA3 (previous studies), caused by mutation in the GREB1L gene (previous studies) on chromosome 18q11; and RHDA4 (previous studies), caused by mutation in the GFRA1 gene (previous studies) on chromosome 10q25." +MONDO_0030854,"Definition: Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1) is an autosomal dominant generalized connective tissue disorder characterized by features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae) and Ehlers-Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility) (summary by previous studies; previous studies). + + Genetic Heterogeneity of Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome + +Also see OIEDS2 (previous studies), caused by mutation in the COL1A2 gene (previous studies) on chromosome 7q21." +MONDO_0033563,"Definition: Retinitis pigmentosa-90 (RP90) is characterized by early-onset night blindness, within the first decade of life. Patients exhibit other typical features of RP, including retinal vessel attenuation, optic disc pallor, and retinal pigment epithelium (RPE) atrophy and pigmentation abnormalities. Macular pseudocoloboma and cystoid macular edema have also been observed (previous studies). + +For a discussion of genetic heterogeneity of RP, see previous studies." +Orphanet_98920,"Definition: Congenital myopathy-10A (CMYP10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (previous studies). + +Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYP10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYP10B) (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0013731,"Definition: Congenital myopathy-10A (CMYP10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (previous studies). + +Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYP10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYP10B) (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0007548,"Definition: Transient bullous dermolysis of the newborn is a rare form of dystrophic epidermolysis bullosa (DEB) that presents with neonatal skin blistering but usually improves markedly during early life and even remits completely. Skin biopsies reveal abnormal intraepidermal accumulation of type VII collagen, which results in poorly constructed anchoring fibrils and a sublamina densa plane of blister formation (summary by previous studies)." +MONDO_0009293,"Definition: McArdle disease is an autosomal recessive metabolic disorder characterized by onset of exercise intolerance and muscle cramps in childhood or adolescence. Transient myoglobinuria may occur after exercise, due to rhabdomyolysis. Severe myoglobinuria may lead to acute renal failure. Patients may report muscle weakness, myalgia, and lack of endurance since childhood or adolescence. Later in adult life, there is persistent and progressive muscle weakness and atrophy with fatty replacement. McArdle disease is a relatively benign disorder, except for possible renal failure as a complication of myoglobinuria (summary by previous studies)." +MONDO_0009550,"Definition: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (summary by previous studies). Amelogenesis imperfecta may also be present in some patients (previous studies). + +A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; previous studies) is caused by mutations in another tight-junction gene, CLDN19 (previous studies), and is distinguished by the association of severe ocular involvement. + +For a discussion of phenotypic and genetic heterogeneity of familial hypomagnesemia, see HOMG1 (previous studies)." +MONDO_0009897,"Definition: Adult polyglucosan body neuropathy (APBN) is a late-onset, slowly progressive disorder affecting the central and peripheral nervous systems. Patients typically present after age 40 years with a variable combination of cognitive impairment, pyramidal tetraparesis, peripheral neuropathy, and neurogenic bladder. Other manifestations include cerebellar dysfunction and extrapyramidal signs. The pathologic hallmark of the disorder is the widespread accumulation of round, intracellular polyglucosan bodies throughout the nervous system, which are confined to neuronal and astrocytic processes (summary by previous studies)." +MONDO_0010169,"Definition: Usher syndrome is a clinically and genetically heterogeneous autosomal recessive disorder characterized by sensorineural hearing deficiencies at birth and later development of progressive retinitis pigmentosa (RP). It is the most frequent cause of combined deafness and blindness in adults and affects 3 to 6% of children born with hearing impairment. In brief, patients with Usher syndrome type II have mild hearing impairment with normal vestibular responses. Type II is the most common of the 3 Usher syndromes (previous studies). See previous studies for clinical characterization of Usher syndrome types I, II, and III. + + Genetic Heterogeneity of Usher Syndrome Type II + +Usher syndrome type II is genetically heterogeneous. USH2C (previous studies) is caused by mutation in the ADGRV1 gene (previous studies) or by biallelic digenic mutation in the ADGRV1 and PDZD7 (previous studies) genes. USH2D (previous studies) is caused by mutation in the WHRN gene (previous studies). + +The locus designation USH2B has been withdrawn; see HISTORY." +MONDO_0010674,"Definition: Mucopolysaccharidosis II (MPS2) is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme iduronate sulfatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues, and organs. Patients with MPS II excrete excessive amounts of chondroitin sulfate B (dermatan sulfate) and heparitin sulfate (heparan sulfate) in the urine (previous studies; previous studies)." +MONDO_0010953,"Definition: Fanconi anemia (FA) is characterized by bone marrow failure, developmental abnormalities, cancer predisposition, and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0012177,Definition: Posterior column ataxia with retinitis pigmentosa is an autosomal recessive neurologic disorder characterized by childhood-onset retinitis pigmentosa and later onset of gait ataxia due to sensory loss (summary by previous studies). +Orphanet_88628,Definition: Posterior column ataxia with retinitis pigmentosa is an autosomal recessive neurologic disorder characterized by childhood-onset retinitis pigmentosa and later onset of gait ataxia due to sensory loss (summary by previous studies). +MONDO_0013158,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0013228,Definition: Spondylo-megaepiphyseal-metaphyseal dysplasia is a rare autosomal recessive skeletal dysplasia characterized by disproportionate short stature with a short and stiff neck and trunk; relatively long limbs that may show flexion contractures of the distal joints; delayed and impaired ossification of the vertebral bodies and the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones; and numerous pseudoepiphyses of the short tubular bones in hands and feet (summary by previous studies). +MONDO_0013993,"Definition: Pontocerebellar hypoplasia type 7 is a severe neurologic condition characterized by delayed psychomotor development, hypotonia, breathing abnormalities, and gonadal abnormalities (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (previous studies)." +MONDO_0030069,"Definition: Autosomal recessive hyper-IgE recurrent infection syndrome-5 (HEIS5) is an immunologic disorder characterized by onset of recurrent sinopulmonary and deep skin infections in early childhood. The infections are mostly caused by bacteria, including H. influenza and Staphylococcus aureus. Additional features include atopic dermatitis, impaired inflammatory responses during infection, increased serum IgE, and increased IL6 (previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see HIES1 (previous studies)." +MONDO_0030893,"Definition: Infantile-onset progressive leukoencephalopathy with or without deafness (LEPID) is an autosomal recessive complex neurodegenerative disorder with onset of symptoms in infancy or early childhood. Most patients present with sensorineural deafness or hypoacousia and global developmental delay. Affected individuals show episodic regression with progressive motor deterioration resulting in spastic tetraplegia and loss of ambulation, as well as impaired intellectual development with poor or absent speech. Additional more variable features may include poor overall growth with microcephaly, seizures, visual loss, microcytic anemia, and hepatic enlargement or abnormal liver enzymes. Brain imaging shows deep white matter abnormalities consistent with a progressive leukoencephalopathy. The brain and spinal cord are usually both involved; calcifications of these regions are often observed. Laboratory studies show increased serum lactate and deficiencies of mitochondrial respiratory chain complexes, consistent with global mitochondrial dysfunction. Early death often occurs (summary by previous studies)." +MONDO_0030926,"Definition: Spermatogenic failure-51 (SPGF51) is characterized by male infertility due to severe asthenoteratozoospermia. Patients exhibit multiple morphologic abnormalities of the flagella (MMAF), including absent, short, bent, coiled, and irregular-caliber tails, resulting in severely reduced to absent motility. Abnormalities of the sperm head, base, and acrosome have also been observed (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0030939,"Definition: Premature ovarian failure-18 (POF18) is characterized by irregular menstrual cycles and cessation of menstruation in the third decade of life. The uterus is small; ovaries may be small or rudimentary, and do not show follicular activity (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (previous studies)." +MONDO_0032637,"Definition: Primary ciliary dyskinesia-39 (CILD39) is an autosomal recessive disorder characterized by chronic sinopulmonary infections beginning soon after birth and laterality defects in about 50% of patients. Although patient nasal ciliary samples have normal structure, detailed studies may show ciliary kinetic defects in some patients (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see previous studies." +MONDO_0032899,"Definition: Autosomal dominant severe congenital neutropenia-8 (SCN8) is a pleiotropic disorder with the consistent feature of decreased neutrophils associated with recurrent bacterial infections apparent from early infancy. Other hematologic parameters are usually normal, although some patients may have mild anemia. Bone marrow examination shows hypocellularity with arrested maturation of the granulocyte lineage at the level of promyelocytes or myeloblasts. Treatment with granulocyte colony-stimulating factor (GCSF; previous studies) is usually ineffective or only partially effective, whereas hematopoietic bone marrow transplantation is effective. A subset of patients have additional features, including exocrine pancreatic insufficiency, which resembles Shwachman-Diamond syndrome (see SDS1, previous studies), and/or neurologic deficits, including developmental delay, impaired intellectual development, speech delay, and/or autistic features (summary by previous studies and previous studies). + +For discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (previous studies)." +MONDO_0033371,"Definition: Developmental and epileptic encephalopathy-62 (DEE62) is a severe neurologic disorder characterized by the onset of various types of refractory seizures in the first weeks or months of life. Affected individuals have severe to profound developmental delay with hypotonia and impaired motor and cognitive development. Additional features may include spasticity, microcephaly, and brain imaging abnormalities (summary by previous studies). + +For a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0033643,"Definition: Inflammatory bowel disease-30 (IBD30) is characterized by abdominal pain and watery or bloody diarrhea, with changes in the intestinal tract consistent with Crohn disease (previous studies). + +For a general description and a discussion of genetic heterogeneity of inflammatory bowel disease, including Crohn disease (CD) and ulcerative colitis (UC), see IBD1 (previous studies)." +Orphanet_1490,"Definition: Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive sensorineural deafness, and is transmitted as an autosomal recessive trait (summary by previous studies)." +MONDO_0009015,"Definition: Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive sensorineural deafness, and is transmitted as an autosomal recessive trait (summary by previous studies)." +Orphanet_66634,"Definition: 3-Methylglutaconic aciduria type V (MGCA5) is an autosomal recessive disorder characterized by the onset of dilated or noncompaction cardiomyopathy in infancy or early childhood. Many patients die of cardiac failure. Other features include microcytic anemia, growth retardation, mild ataxia, mild muscle weakness, genital anomalies in males, and increased urinary excretion of 3-methylglutaconic acid. Some patients may have optic atrophy or delayed psychomotor development (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +MONDO_0012435,"Definition: 3-Methylglutaconic aciduria type V (MGCA5) is an autosomal recessive disorder characterized by the onset of dilated or noncompaction cardiomyopathy in infancy or early childhood. Many patients die of cardiac failure. Other features include microcytic anemia, growth retardation, mild ataxia, mild muscle weakness, genital anomalies in males, and increased urinary excretion of 3-methylglutaconic acid. Some patients may have optic atrophy or delayed psychomotor development (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +EFO_1002008,"Definition: The rhabdoid tumor predisposition syndrome is an autosomal dominant cancer syndrome predisposing to renal or extrarenal malignant rhabdoid tumors and to a variety of tumors of the central nervous system, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumors (previous studies). + +Rhabdoid tumors are a highly malignant group of neoplasms that usually occur in children less than 2 years of age. Malignant rhabdoid tumors (MRTs) of the kidney were first described as a sarcomatous variant of Wilms tumors (previous studies). Later, extrarenal rhabdoid tumor was reported in numerous locations, including the central nervous system (CNS) (previous studies). Classification has been difficult because of considerable variation in the histologic and immunologic characteristics within and between rhabdoid tumors of the liver, soft tissues, and CNS. In the CNS, rhabdoid tumors may be pure rhabdoid tumors or a variant that has been designated atypical teratoid tumor (AT/RT). + + Genetic Heterogeneity of Rhabdoid Tumor Predisposition Syndrome + +See also RTPS2 (previous studies), caused by germline mutation in the SMARCA4 gene (previous studies) on chromosome 19p13." +MONDO_0007068,"Definition: Adenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (summary by previous studies)." +MONDO_0007483,"Definition: Dyschromatosis symmetrica hereditaria (DSH), also called symmetric dyschromatosis of the extremities and symmetric or reticulate acropigmentation of Dohi (previous studies), is characterized by hyperpigmented and hypopigmented macules on the face and dorsal aspects of the extremities that appear in infancy or early childhood. DSH generally shows an autosomal dominant pattern of inheritance with high penetrance. The condition has been reported predominantly in Japanese and Chinese individuals. + + Review of Reticulate Pigment Disorders + +previous studies reviewed the spectrum of reticulate pigment disorders of the skin, tabulating all reported cases of patients with Dowling-Degos disease (see DDD1; previous studies), reticulate acropigmentation of Kitamura (RAK; previous studies), reticulate acropigmentation of Dohi (RAD), Galli-Galli disease (GGD), and Haber syndrome (HS). Of 82 cases, 26 (31.7%) were clinically diagnosed as DDD, 13 (15.9%) as RAD, 11 (13.4%) as GGD, 8 (9.8%) as RAK, and 8 (9.8%) as HS; in addition, 16 (19.5%) of the cases showed overlap between DDD and RAK. previous studies also published photographs of an affected individual exhibiting an overlap of clinical features of DDD, GGD, RAD, and RAK. The authors noted that in reticulate disorders of the skin, the main disease entity is DDD, with a subset of cases exhibiting acantholysis (GGD), facial erythema (HS), or an acral distribution (RAD; RAK). previous studies concluded that all reticulate pigment diseases of the skin are varying manifestations of a single entity. + + Genetic Heterogeneity of Reticulate Pigment Disorders + +For a discussion of genetic heterogeneity of reticulate pigment disorders, see previous studies." +MONDO_0008777,"Definition: Gelatinous drop-like corneal dystrophy is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness. Clinical manifestations, which appear in the first decade of life, include blurred vision, photophobia, and foreign-body sensation. By the third decade, raised, yellowish-gray, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients (summary by previous studies)." +MONDO_0008965,"Definition: CHARGE syndrome is characterized by a pattern of congenital anomalies including choanal atresia and malformations of the heart, inner ear, and retina (summary by previous studies)." +MONDO_0009353,"Definition: Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. In the classic form, both thermostable and thermolabile enzyme variants have been identified (previous studies)." +MONDO_0009379,"Definition: The Rotor type of hyperbilirubinemia is an autosomal recessive form of primary conjugated hyperbilirubinemia. It is similar to Dubin-Johnson syndrome (DJS; previous studies) in that affected individuals develop mild jaundice not associated with hemolysis shortly after birth or in childhood. However, Rotor syndrome can be distinguished from DJS by a lack of hepatocyte pigment deposits, delayed plasma clearance of the unconjugated anionic dye bromsulfthalein, poor hepatic visualization on certain radiographic imaging studies, and prominent urinary excretion of coproporphyrin I (summary by previous studies)." +MONDO_0013700,"Definition: Congenital pancreatic lipase deficiency is a rare, monoenzymatic form of exocrine pancreatic failure. All reported patients have presented with similar symptoms and clinical findings, including oily/greasy stools from infancy or early childhood and the absence of discernible pancreatic disease. Failure to thrive has not been observed. Analyses of duodenal contents consistently show a marked decrease of pancreatic lipolytic activity (summary by previous studies)." +MONDO_0014249,Definition: Fibroadenoma represents a benign breast disease characterized by lobuloalveolar growth with abnormally high proliferation of the epithelium. Patients with more than 3 fibroadenomas in 1 breast are considered to have multiple fibroadenomas (summary by previous studies). +MONDO_0032774,"Definition: Cerebellar, ocular, craniofacial, and genital syndrome (COFG) is characterized by moderate to severe developmental delay and impaired intellectual development, severe cerebellar hypoplasia, a noticeably short forehead, medially sparse/flared and laterally extended eyebrows, corneal dystrophy, underdeveloped labioscrotal folds, and tufts of hair extruding from the lactiferous ducts with breast and nipple underdevelopment. Additional features such as pontine involvement, retinal degeneration, anteverted nares, and low-set ears have been variably observed (previous studies)." +MONDO_0859189,"Definition: Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) is an autosomal recessive systemic disorder characterized by progressive muscle weakness, sensorineural hearing loss, and endocrine abnormalities, mainly primary amenorrhea due to ovarian insufficiency. Features of the disorder appear soon after birth, although endocrine anomalies are not noted until puberty. The severity of the phenotype is variable: some patients may lose ambulation and have significant respiratory insufficiency, whereas others retain the ability to walk (previous studies)." +Orphanet_157962,"Definition: Oculoauricular syndrome (OCACS) is characterized by complex ocular anomalies, including congenital cataract, anterior segment dysgenesis, iris coloboma, and early-onset retinal dystrophy, and dysplastic ears with abnormal external ear cartilage (summary by previous studies)." +MONDO_0012802,"Definition: Oculoauricular syndrome (OCACS) is characterized by complex ocular anomalies, including congenital cataract, anterior segment dysgenesis, iris coloboma, and early-onset retinal dystrophy, and dysplastic ears with abnormal external ear cartilage (summary by previous studies)." +Orphanet_314647,"Definition: Cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA) is an autosomal dominant neurologic disorder with significant phenotypic heterogeneity, even within families. The disorder is most often diagnosed through genetic analysis with retrospective clinical phenotyping. Symptom onset is usually in early childhood, although later onset, even in adulthood, has been reported. Most affected individuals show global developmental delay from early childhood, particularly of motor and language skills. Many have mild intellectual disability; behavioral and psychiatric abnormalities such as autism and obsessive-compulsive disorder are also often observed. The movement disorder is prominent and may include cerebellar signs such as ataxia, tremor, dysmetria, poor coordination, and dysarthria. Other abnormal movements including spasticity, myoclonus, and dystonia have been reported, thus widening the phenotypic spectrum. Brain imaging is usually normal, but may show cerebellar atrophy or nonspecific white matter lesions. Variable dysmorphic facial features may also be present (summary by previous studies; previous studies; previous studies)." +MONDO_0013886,"Definition: Cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA) is an autosomal dominant neurologic disorder with significant phenotypic heterogeneity, even within families. The disorder is most often diagnosed through genetic analysis with retrospective clinical phenotyping. Symptom onset is usually in early childhood, although later onset, even in adulthood, has been reported. Most affected individuals show global developmental delay from early childhood, particularly of motor and language skills. Many have mild intellectual disability; behavioral and psychiatric abnormalities such as autism and obsessive-compulsive disorder are also often observed. The movement disorder is prominent and may include cerebellar signs such as ataxia, tremor, dysmetria, poor coordination, and dysarthria. Other abnormal movements including spasticity, myoclonus, and dystonia have been reported, thus widening the phenotypic spectrum. Brain imaging is usually normal, but may show cerebellar atrophy or nonspecific white matter lesions. Variable dysmorphic facial features may also be present (summary by previous studies; previous studies; previous studies)." +Orphanet_51636,"Definition: WHIM syndrome-1 (WHIMS1) is an autosomal dominant immunologic disorder characterized by neutropenia, hypogammaglobulinemia, and warts due to human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions (summary by previous studies). + +previous studies provided a detailed review of the clinical features, proposed pathogenesis, and possible therapeutic treatments of WHIM syndrome. There is significant phenotypic variation among patients, such that some individuals may have an 'incomplete' form of the disorder in which one or more of the classic tetrad features are not present. In general, the WHIMS phenotype comprises a spectrum of manifestations with variable expressivity. The pathogenesis of WHIMS1 is postulated to result from impaired CXCL12 (previous studies)-induced internalization of CXCR4, resulting in prolonged receptor presence at the cell surface that likely contributes to amplification of signaling with a gain-of-function effect. + + Genetic Heterogeneity of WHIM Syndrome + +See also WHIMS2 (previous studies), caused by mutation in the CXCR2 gene (previous studies) on chromosome 2q35." +Orphanet_891,"Definition: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by the incomplete development of the retinal vasculature. Its clinical appearance varies considerably, even within families, with severely affected patients often registered as blind during infancy, whereas mildly affected patients with few or no visual problems may have such a small area of avascularity in their peripheral retina that it is visible only by fluorescein angiography. It is believed that this peripheral avascularity is the primary anomaly in FEVR and results from defective retinal angiogenesis. The sight-threatening features of the FEVR phenotype are considered secondary to retinal avascularity and develop because of the resulting retinal ischemia; they include the development of hyperpermeable blood vessels, neovascularization, vitreoretinal traction, retinal folds, and retinal detachments (summary by previous studies). + +For a discussion of genetic heterogeneity of FEVR, see EVR1 (previous studies)." +EFO_0003900,"Definition: Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disorder resulting from loss of function of different parts of the primary ciliary apparatus, most often dynein arms. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus (previous studies), and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (previous studies; previous studies). + + Genetic Heterogeneity of Primary Ciliary Dyskinesia + +Other forms of primary ciliary dyskinesia include CILD2 (previous studies), caused by mutation in the DNAAF3 gene (previous studies) on 19q13; CILD3 (previous studies), caused by mutation in the DNAH5 gene (previous studies) on 5p15; CILD4 (previous studies), mapped to 15q13; CILD5 (previous studies), caused by mutation in the HYDIN gene (previous studies) on 16q22; CILD6 (previous studies), caused by mutation in the TXNDC3 gene (previous studies) on 7p14; CILD7 (previous studies), caused by mutation in the DNAH11 gene (previous studies) on 7p15; CILD8 (previous studies), mapped to 15q24-q25; CILD9 (previous studies), caused by mutation in the DNAI2 gene (previous studies) on 17q25; CILD10 (previous studies), caused by mutation in the DNAAF2 gene (previous studies) on 14q21; CILD11 (previous studies), caused by mutation in the RSPH4A gene (previous studies) on 6q22; CILD12 (previous studies), caused by mutation in the RSPH9 gene (previous studies) on 6p21; CILD13 (previous studies), caused by mutation in the DNAAF1 gene (previous studies) on 16q24; CILD14 (previous studies), caused by mutation in the CCDC39 gene (previous studies) gene on 3q26; CILD15 (previous studies), caused by mutation in the CCDC40 gene (previous studies) on 17q25; CILD16 (previous studies), caused by mutation in the DNAL1 gene (previous studies) on 14q24; CILD17 (previous studies), caused by mutation in the CCDC103 gene (previous studies) on 17q21; CILD18 (previous studies), caused by mutation in the DNAAF5 gene (previous studies) on 7p22; CILD19 (previous studies), caused by mutation in the LRRC6 gene (previous studies) on 8q24; CILD20 (previous studies), caused by mutation in the CCDC114 gene (previous studies) on 19q13; CILD21 (previous studies), caused by mutation in the DRC1 gene (previous studies) on 2p23; CILD22 (previous studies), caused by mutation in the ZMYND10 gene (previous studies) on 3p21; CILD23 (previous studies), caused by mutation in the ARMC4 gene (previous studies) on 10p; CILD24 (previous studies), caused by mutation in the RSPH1 gene (previous studies) on 21q22; CILD25 (previous studies), caused by mutation in the DYX1C1 gene (previous studies) on 15q21; CILD26 (previous studies), caused by mutation in the C21ORF59 gene (previous studies) on 21q22; CILD27 (previous studies), caused by mutation in the CCDC65 gene (previous studies) on 12q13; CILD28 (previous studies), caused by mutation in the SPAG1 gene (previous studies) on 8q22; CILD29 (previous studies), caused by mutation in the CCNO gene (previous studies) on 5q11; CILD30 (previous studies), caused by mutation in the CCDC151 gene (previous studies) on 19p13; CILD32 (previous studies), caused by mutation in the RSPH3 gene (previous studies) on 6q25; CILD33 (previous studies), caused by mutation in the GAS8 gene (previous studies) on 16q24; CILD34 (previous studies), caused by mutation in the DNAJB13 gene (previous studies) on 11q13; CILD35 (previous studies), caused by mutation in the TTC25 gene (previous studies) on 17q21; CILD36 (previous studies), caused by mutation in the PIH1D3 gene (previous studies) on Xq22; CILD37 (previous studies), caused by mutation in the DNAH1 gene (previous studies) on 3p21; CILD38 (previous studies), caused by mutation in the CFAP300 gene (previous studies) on 11q22; CILD39 (previous studies), caused by mutation in the LRRC56 gene (previous studies) on 11p15; CILD40 (previous studies), caused by mutation in the DNAH9 gene (previous studies) on 17p12; CILD41 (previous studies), caused by mutation in the GAS2L2 gene (previous studies) on 17q12; CILD42 (previous studies), caused by mutation in the MCIDAS gene (previous studies) on 5q11; CILD43 (previous studies), caused by mutation in the FOXJ1 gene (previous studies) on 17q25; CILD44 (previous studies), caused by mutation in the NEK10 gene (previous studies) on 3p24; CILD45 (previous studies), caused by mutation in the TTC12 gene (previous studies) on 11q23; CILD46 (previous studies), caused by mutation in the STK36 gene (previous studies) on 2q35; CILD47 (previous studies), caused by mutation in the TP73 gene (previous studies) on 1p36; CILD48 (previous studies), caused by mutation in the NME5 gene (previous studies) on chromosome 5q31; CILD49 (previous studies), caused by mutation in the CFAP74 gene (previous studies) on chromosome 1p36; CILD50 (previous studies), caused by mutation in the DNAH7 gene (previous studies) on chromosome 2q32; and CILD51 (previous studies), caused by mutation in the BRWD1 gene (previous studies) on chromosome 21q22. + +Ciliary abnormalities have also been reported in association with both X-linked and autosomal forms of retinitis pigmentosa. Mutations in the RPGR gene (previous studies), which underlie X-linked retinitis pigmentosa (RP3; previous studies), are in some instances (e.g., previous studies) associated with recurrent respiratory infections indistinguishable from immotile cilia syndrome; see previous studies. + +previous studies gave an extensive review of cilia and their disorders. There are also several possibly distinct CILDs described based on the electron microscopic appearance of abnormal cilia, including CILD with transposition of the microtubules (previous studies), CILD with excessively long cilia (previous studies), and CILD with defective radial spokes (previous studies)." +EFO_0009055,"Definition: RIDDLE is an acronym for the major features of this syndrome: radiosensitivity, immunodeficiency, dysmorphic facies, and learning difficulties (previous studies)." +MONDO_0007232,"Definition: Type 3 brachyolmia (BCYM3) is an autosomal dominant skeletal dysplasia affecting the spine characterized by severe kyphoscoliosis and flattened, irregular cervical vertebrae (summary by previous studies). + +For a discussion of heterogeneity of brachyolmia, see previous studies." +MONDO_0008768,"Definition: Neuronal ceroid lipofuscinosis-6B (CLN6B) is an autosomal recessive form of 'Kufs disease,' which refers in general to adult-onset neuronal ceroid lipofuscinosis without retinal involvement. CLN6B is a neurodegenerative disorder with a mean onset of symptoms at around age 28 years, although onset in the teens and later adulthood may also occur. Patients typically present with progressive myoclonus epilepsy, ataxia, loss of motor function, dysarthria, progressive dementia, and progressive cerebral and cerebellar atrophy on brain imaging. Ultrastructural examination typically shows fingerprint profiles and granular osmiophilic deposits in some tissues, including brain samples (summary by previous studies and previous studies). However, pathologic findings in peripheral tissues in adults is not as accurate for diagnosis as it is in children with the disease (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_228340,"Definition: Neuronal ceroid lipofuscinosis-6B (CLN6B) is an autosomal recessive form of 'Kufs disease,' which refers in general to adult-onset neuronal ceroid lipofuscinosis without retinal involvement. CLN6B is a neurodegenerative disorder with a mean onset of symptoms at around age 28 years, although onset in the teens and later adulthood may also occur. Patients typically present with progressive myoclonus epilepsy, ataxia, loss of motor function, dysarthria, progressive dementia, and progressive cerebral and cerebellar atrophy on brain imaging. Ultrastructural examination typically shows fingerprint profiles and granular osmiophilic deposits in some tissues, including brain samples (summary by previous studies and previous studies). However, pathologic findings in peripheral tissues in adults is not as accurate for diagnosis as it is in children with the disease (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0009025,"Definition: Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone (review by previous studies)." +MONDO_0009575,"Definition: Thiamine-responsive megaloblastic anemia syndrome (TRMA) comprises megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Onset is typically between infancy and adolescence, but all of the cardinal findings are often not present initially. The anemia, and sometimes the diabetes, improves with high doses of thiamine. Other more variable features include optic atrophy, congenital heart defects, short stature, and stroke (summary by previous studies). + + Genetic Heterogeneity of Disorders Due to Thiamine Metabolism Dysfunction + +See also episodic encephalopathies due to defects in thiamine metabolism: biotin-responsive basal ganglia disease (THMD2; previous studies), caused by mutation in the SLC19A3 gene (previous studies) on chromosome 2q36; Amish-type microcephaly (THMD3; previous studies) and bilateral striatal necrosis and progressive polyneuropathy (THMD4; previous studies), both caused by mutation in the SLC25A19 gene (previous studies) on chromosome 17q25; and THMD5 (previous studies), caused by mutation in the TPK1 gene (previous studies) on chromosome 7q35." +MONDO_0009698,"Definition: Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. Although it is considered a progressive myoclonic epilepsy, it differs from other forms in that it appears to be progressive only in adolescence, with dramatic worsening of myoclonus and ataxia in the first 6 years after onset. The disease stabilizes in early adulthood, and myoclonus and ataxia may even improve, and there is minimal to no cognitive decline (summary by previous studies). + + Genetic Heterogeneity of Progressive Myoclonic Epilepsy + +Progressive myoclonic epilepsy refers to a clinically and genetically heterogeneous group of neurodegenerative disorders, usually with debilitating symptoms, although severity varies. See also EPM1B (previous studies), caused by mutation in the PRICKLE1 gene (previous studies); Lafora disease (EPM2A/B; previous studies), caused by mutation in either the EPM2A (previous studies) or the NHLRC1 (previous studies) gene; EPM3 (previous studies), caused by mutation in the KCTD7 gene (611725); EPM4 (previous studies), caused by mutation in the SCARB2 gene (previous studies); EPM6 (previous studies), caused by mutation in the GOSR2 gene (previous studies); EPM7 (previous studies), caused by mutation in the KCNC1 gene (previous studies); EPM8 (previous studies), caused by mutation in the CERS1 gene (previous studies); EPM9 (previous studies), caused by mutation in the LMNB2 gene (previous studies); EPM10 (previous studies), caused by mutation in the PRDM8 gene (previous studies); EPM11 (previous studies), caused by mutation in the SEMA6B gene (previous studies); and EPM12 (previous studies), caused by mutation in the SLC7A6OS gene (previous studies). + +A form of progressive myoclonic epilepsy, formerly designated EPM5, is included in previous studies with the primary designation of spinocerebellar ataxia with epilepsy (SCAE). + +Other disorders characterized by progressive myoclonic epilepsy include the neuronal ceroid lipofuscinoses (see, e.g., CLN1 (previous studies); sialidosis (previous studies); MERFF (previous studies); and DRPLA (previous studies), among others (reviews by previous studies and previous studies).)" +MONDO_0010977,"Definition: Brody disease (BROD) is an autosomal recessive skeletal muscle disorder characterized by exercise-induced muscle stiffness and cramps primarily affecting the arms, legs, and eyelids, although more generalized muscle involvement may also occur. Symptom onset is most often in the first decade, but many patients present and are diagnosed later in life. Skeletal muscle biopsy typically shows variation in fiber size, increased internal nuclei, and atrophy of type II muscle fibers. Rare patients have been reported to develop malignant hyperthermia after administration of anesthesia, suggesting that patients with the disorder should be tested. The disorder results from defective relaxation of fast-twitch (type II) skeletal muscle fibers due to defects in calcium homeostasis and reuptake in the muscle fiber (summary by previous studies and previous studies)." +MONDO_0013051,"Definition: The phenotype of autosomal recessive cutis laxa type II (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (summary by previous studies). No specific clinical features distinguish ARCL2A (previous studies), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (previous studies; previous studies). + +For a phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (previous studies)." +MONDO_0014914,"Definition: Intellectual developmental disorder with persistence of fetal hemoglobin is characterized by delayed psychomotor development, intellectual disability, variable dysmorphic features, including microcephaly, downslanting palpebral fissures, strabismus, and external ear abnormalities, and asymptomatic persistence of fetal hemoglobin (HbF) (summary by previous studies). + +Many of these features overlap with chromosome 2p16.1-p15 deletion syndrome (previous studies)." +MONDO_0019666,"Definition: This form of brachyolmia, here designated brachyolmia type 4, is characterized by short-trunk stature with normal intelligence and facies. The radiographic features include rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, mildly shortened metacarpals, and mild epiphyseal and metaphyseal changes of the tubular bones (summary by previous studies)." +Orphanet_93282,"Definition: This form of brachyolmia, here designated brachyolmia type 4, is characterized by short-trunk stature with normal intelligence and facies. The radiographic features include rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, mildly shortened metacarpals, and mild epiphyseal and metaphyseal changes of the tubular bones (summary by previous studies)." +MONDO_0021547,"Definition: Hypomineralized amelogenesis imperfecta type IIIB is characterized by enamel that is reduced in mineral density and is thin, chipped, and absent in places (previous studies)." +MONDO_0030028,"Definition: Childhood-onset neurodegeneration with ataxia, tremor, optic atrophy, and cognitive decline (CONATOC) is an autosomal recessive progressive disorder with onset of symptoms in the first decade. Brain imaging may show variable features, including leukoencephalopathy and cerebellar atrophy (summary by previous studies)." +MONDO_0032707,"Definition: Turnpenny-Fry syndrome (TPFS) is characterized by developmental delay, impaired intellectual development, impaired growth, and recognizable facial features that include frontal bossing, sparse hair, malar hypoplasia, small palpebral fissures and oral stoma, and dysplastic 'satyr' ears. Other common findings include feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations (previous studies)." +MONDO_0032906,"Definition: Autosomal recessive spastic paraplegia-82 (SPG82) is a progressive neurologic disorder characterized by global developmental delay apparent from infancy, significant motor impairment, and progressive spasticity mainly affecting the lower limbs. Some patients never achieve walking, whereas others lose the ability to walk or walk with an unsteady gait. Additional features include variably impaired intellectual development with language difficulties, ocular anomalies, such as nystagmus and visual impairment, and seizures. Brain imaging shows progressive cerebral and cerebellar atrophy, as well as white matter hyperintensities. Based on the additional abnormalities, the disorder can be classified as a type of complicated SPG (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0032907,"Definition: Lymphatic malformation-8 (LMPHM8) is an autosomal recessive disorder in which affected fetuses die in utero due to nonimmune hydrops fetalis (NIHF). The fetus and placenta are edematous with interstitial accumulation of fluid and abnormally shaped vessels. The disorder results from impaired lymphangiogenesis. Carrier females have reduced fertility and recurrent miscarriages likely due to NIHF (summary by previous studies). + +For a discussion of genetic heterogeneity of lymphatic malformation, see LMPHM1 (previous studies)." +Orphanet_401849,"Definition: Hereditary spastic paraplegia-72 is a pure form of spastic paraplegia with onset of difficulty walking and stiff legs associated with hyperreflexia and extensor plantar responses in early childhood. The disorder is slowly progressive, and some patients develop the need for assistance in walking. Some patients may have pes cavus or sphincter disturbances. Cognition, speech, and ocular function are normal (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies), and for autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0014282,"Definition: Hereditary spastic paraplegia-72 is a pure form of spastic paraplegia with onset of difficulty walking and stiff legs associated with hyperreflexia and extensor plantar responses in early childhood. The disorder is slowly progressive, and some patients develop the need for assistance in walking. Some patients may have pes cavus or sphincter disturbances. Cognition, speech, and ocular function are normal (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies), and for autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +EFO_0000501,"Definition: Nonmedullary thyroid cancer (NMTC) comprises cancer of follicular cell origin and accounts for more than 95% of all cases of thyroid cancer. Familial NMTC accounts for 3 to 9% of all cases of thyroid cancer and has an autosomal dominant mode of inheritance. Most cases of familial NMTC are papillary thyroid cancer (PTC), which is the most common type of thyroid cancer (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of NMTC, see NMTC1 (previous studies)." +MONDO_0014682,"Definition: Nonmedullary thyroid cancer (NMTC) comprises cancer of follicular cell origin and accounts for more than 95% of all cases of thyroid cancer. Familial NMTC accounts for 3 to 9% of all cases of thyroid cancer and has an autosomal dominant mode of inheritance. Most cases of familial NMTC are papillary thyroid cancer (PTC), which is the most common type of thyroid cancer (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of NMTC, see NMTC1 (previous studies)." +EFO_0009149,"Definition: MDCCAID is an autosomal recessive form of muscular dystrophy with onset of progressive muscle weakness in early childhood. Almost all patients also have early-onset cataracts, most have intellectual disability of varying severity, and some have seizures (summary by previous studies and previous studies)." +MONDO_0007145,"Definition: Aplasia cutis congenita (ACC) is defined as congenital localized absence of skin. The skin appears as a thin, transparent membrane through which the underlying structures are visible. The location is usually on the scalp (previous studies). Approximately 20 to 30% of cases have underlying osseous involvement (previous studies). Autosomal dominant inheritance is most common, but recessive inheritance has also been reported. + +Cutaneous aplasia of the scalp vertex also occurs in Johanson-Blizzard syndrome (previous studies) and Adams-Oliver syndrome (AOS; previous studies). A defect in the scalp is sometimes found in cases of trisomy 13 and in about 15% of cases of deletion of the short arm of chromosome 4, the Wolf-Hirschhorn syndrome (WHS; previous studies) (previous studies; previous studies). + +previous studies provided a list of disorders associated with aplasia cutis congenita, classified according to etiology. They also tabulated points of particular significance in history taking and examination of patients with ACC." +MONDO_0009448,"Definition: The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (previous studies). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG; previous studies) (summary by previous studies). + +Iminoglycinuria also occurs as part of the generalized amino aciduria of the Fanconi renotubular syndrome (previous studies)." +MONDO_0009578,"Definition: Neurocutaneous melanosis, or neuromelanosis, is characterized by the presence of melanin-producing cells within the brain parenchyma or leptomeninges, which may lead to clinically apparent neurologic signs and symptoms, such as seizures. Other neurologic abnormalities, including hydrocephalus, arachnoid cysts, tumors, and syringomyelia, may also occur. The disorder is a rare but severe manifestation of congenital melanocytic nevus syndrome (CMNS; previous studies). Some patients with neurocutaneous melanosis or CMNS may develop malignant melanoma. The incidence of neurologic involvement, development of malignant melanoma, and death is significantly associated with the projected adult size of the largest congenital melanocytic nevus, particularly those greater than 40 cm (summary by previous studies; previous studies)." +MONDO_0009966,"Definition: This autosomal recessive disorder is designated Meckel syndrome type 7 based on the classic phenotypic triad of (1) cystic renal disease; (2) a central nervous system abnormality, and (3) hepatic abnormalities, as defined by previous studies, previous studies, and previous studies. According to these criteria, polydactyly is a variable feature. + +previous studies and previous studies concluded that Dandy-Walker malformation can be the phenotypic manifestation of a central nervous system malformation in MKS. + +For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (previous studies)." +MONDO_0010066,"Definition: Isolated congenital asplenia is a rare cause of primary immunodeficiency. Most affected individuals die of severe bacterial infections in early childhood. Isolated asplenia is distinct from asplenia associated with other complex visceral defects, notably heterotaxy syndromes such as Ivemark syndrome (previous studies) (summary by previous studies)." +MONDO_0010354,"Definition: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked condition characterized by severely impaired intellectual development, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. There is large phenotypic interfamilial and intrafamilial variability. In severe cases, patients never gain the ability to walk or talk (summary by previous studies)." +MONDO_0013034,"Definition: PPKS2 is characterized by linear hyperkeratosis of the palms, which is particularly evident in affected individuals who perform manual labor. Hyperkeratosis of the soles primarily involves pressure points, and diffuse background palmoplantar thickening may also be present. (previous studies; previous studies). + +For a discussion of genetic heterogeneity of the striate form of palmoplantar keratoderma, see PPKS1 (previous studies)." +MONDO_0014268,Definition: Immunodeficiency-16 is an autosomal recessive primary immunodeficiency associated with classic Kaposi sarcoma of childhood and poor T-cell recall immune responses due to complete functional OX40 deficiency (previous studies). +MONDO_0016368,"Definition: Rothmund-Thomson syndrome type 1 (RTS1) is an autosomal recessive disorder characterized by poikiloderma, sparse hair, and bilateral juvenile cataracts. Patients may also have growth retardation and genital, skeletal, and dental abnormalities. The disorder is not associated with an increased risk of cancer (summary by previous studies). + +For a discussion of genetic heterogeneity of Rothmund-Thomson syndrome, see RTS2 (previous studies)." +MONDO_0030261,"Definition: Pontocerebellar hypoplasia type 1F (PCH1F) is an autosomal recessive neurologic disorder characterized by hypotonia, global developmental delay, poor overall growth, and dysmorphic facial features. Brain imaging shows pontocerebellar hypoplasia, thin corpus callosum, cerebral atrophy, and delayed myelination (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (previous studies)." +MONDO_0033620,"Definition: Myofibrillar myopathy-10 (MFM10) is an autosomal recessive structural muscle disorder characterized by onset of muscle pain, cramping, and exercise fatigue in the first or second decades of life. Some patients have mild contractures of the large joints apparent in early childhood. Affected individuals have a characteristic appearance of a thick neck and prominent shoulder girdle with anteverted shoulders and a tendency toward kyphosis. There is no apparent muscle weakness, but some affected individuals show progressive muscle rigidity leading to limited mobility. There is variable cardiac involvement, ranging from chest pain with left ventricular hypertrophy to subclinical signs such as abnormal EKG or elevated cardiac enzymes. Skeletal muscle biopsy shows structural abnormalities with myofibrillar disorganization and accumulation of autophagocytic vacuoles (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (previous studies)." +MONDO_0033636,"Definition: Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show hypotonia, failure to thrive, and neurologic distress. Additional features include hepatomegaly, hepatic steatosis, increased serum lactate, and metabolic acidosis. Some patients may develop hypertrophic cardiomyopathy. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. Death usually occurs in infancy (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0033653,"Definition: Mitochondrial complex IV deficiency nuclear type 18 (MC4DN18) is an autosomal recessive metabolic disorder that primarily affects skeletal muscle tissue. Affected individuals present in infancy with hypotonia, limb muscle weakness, and high-arched palate. The severity of the disorder is variable: some patients may only have gait difficulties, whereas others may also have significant respiratory insufficiency and cardiomyopathy. Death in infancy has been reported. Patient skeletal muscle shows decreased levels and activity of mitochondrial respiratory complex IV (previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0060711,"Definition: JABELS is an autosomal recessive neurodevelopmental disorder characterized by developmental delay and intellectual disability with additional variable features. Patients have onset of symptoms in infancy, but the severity is highly variable. Some patients have social interaction and learn to walk but have an ataxic gait and abnormal movements, such as tremor or dystonia, whereas others do not achieve any motor control and are unable to speak. Additional features may include retinal anomalies, visual impairment, microcephaly, abnormal foot or hand posturing, and kyphoscoliosis; some patients have dysmorphic facial features or seizures. Brain imaging typically shows cerebellar atrophy and hypoplasia of the corpus callosum (summary by previous studies and previous studies)." +MONDO_0060724,"Definition: Glycosylphosphatidylinositol biosynthesis defect-17 (GPIBD17) is an autosomal recessive disorder characterized by variable neurologic deficits that become apparent in infancy or early childhood. Patients may present with early-onset febrile or afebrile seizures that tend to be mild or controllable. Other features may include learning disabilities, autism, behavioral abnormalities, hypotonia, and motor deficits. The phenotype is relatively mild compared to that of other GPIBDs (summary by previous studies). + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +EFO_0009025,"Definition: BBS5 is a ciliopathy associated with severe and early-onset retinal dystrophy, postaxial polydactyly, obesity, renal dysfunction, hypogonadism, and learning difficulties (summary by previous studies). Patients described by previous studies and previous studies with mutations in the BBS5 gene did not have polydactyly. The contribution of BBS5 mutations to all cases of BBS has been estimated at 2% (previous studies) and 0.40% (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +MONDO_0007164,"Definition: Hereditary spastic ataxia comprises a heterogeneous group of progressive neurodegenerative disorders characterized by lower-limb spasticity and generalized ataxia with dysarthria, impaired ocular movements, and gait disturbance. Spastic ataxia-1 (SPAX1) is an autosomal dominant form of the disorder with onset between the ages of 10 and 20 years. Other clinical features are supranuclear gaze palsy, hyperreflexia, hypertonicity, dystonia, pes cavus, mild ptosis, and decreased vibration sense in the lower limbs. Symptom severity is variable, but neither life span nor cognition is affected (summary by previous studies and previous studies). + + Genetic Heterogeneity of Spastic Ataxia + +See also SPAX2 (previous studies), caused by mutation in the KIF1C gene (previous studies) on chromosome 17p13; SPAX3 (previous studies), caused by rearrangements of the MARS2 gene (previous studies) on chromosome 2q33; SPAX4 (previous studies), caused by mutation in the MTPAP gene (previous studies) on chromosome 10p11; SPAX5 (previous studies), caused by mutation in the AFG3L2 gene (previous studies) on chromosome 18p11; SPAX6 (previous studies), caused by mutation in the SACS gene (previous studies) on chromosome 13q12; SPAX7 (previous studies); SPAX8 (previous studies), caused by mutation in the NKX6-2 gene (previous studies) on chromosome 8q21; and SPAX9 (previous studies), caused by mutation in the CHP1 gene (previous studies) on chromosome 15q15." +MONDO_0007750,"Definition: Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (previous studies). + +The FHCL1 phenotype can be modified by mutation in other genes. For example, in individuals with the LDLR mutation IVS14+1G-A (previous studies), the phenotype can be altered by a SNP in the APOA2 gene (previous studies), a SNP in the EPHX2 gene (previous studies), or a SNP in the GHR gene (previous studies). + + Genetic Heterogeneity of Familial Hypercholesterolemia + +Other forms of monogenic familial hypercholesterolemia include FHCL2 (previous studies), caused by mutation in the APOB gene (previous studies); FHCL3 (previous studies), caused by mutation in the PCSK9 gene (previous studies); and FHCL4 (previous studies), caused by mutation in the LDLRAP1 gene (previous studies)." +MONDO_0009240,"Definition: Glutamate formiminotransferase deficiency is an autosomal recessive disorder and the second most common inborn error of folate metabolism. Features of a severe phenotype include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematologic abnormalities (summary by previous studies)." +MONDO_0009267,"Definition: Gaucher disease type III (GD3) is the subacute form of neuronopathic Gaucher disease. It has later onset and slower progression compared to the acute form of neuronopathic Gaucher disease, type II. + +previous studies suggested that there are 2 phenotypic subgroups of Gaucher disease type III: type IIIA, which is characterized by myoclonus and dementia, and type IIIB, characterized by early onset of isolated horizontal supranuclear gaze palsy and aggressive systemic disease. See also Gaucher disease type IIIC (previous studies), which is associated with cardiovascular calcifications." +Orphanet_77261,"Definition: Gaucher disease type III (GD3) is the subacute form of neuronopathic Gaucher disease. It has later onset and slower progression compared to the acute form of neuronopathic Gaucher disease, type II. + +previous studies suggested that there are 2 phenotypic subgroups of Gaucher disease type III: type IIIA, which is characterized by myoclonus and dementia, and type IIIB, characterized by early onset of isolated horizontal supranuclear gaze palsy and aggressive systemic disease. See also Gaucher disease type IIIC (previous studies), which is associated with cardiovascular calcifications." +MONDO_0010651,Definition: Menkes disease (MNK) is an X-linked recessive disorder characterized by generalized copper deficiency. The clinical features result from the dysfunction of several copper-dependent enzymes. +MONDO_0011184,"Definition: Speech-language disorder-1 is an autosomal dominant disorder characterized by severe orofacial dyspraxia resulting in largely incomprehensible speech. Affected individuals were originally thought to have specific defects in the use of grammatical suffixation rules (previous studies; previous studies). The phenotype, however, is broader in nature, with virtually every aspect of grammar and language affected (previous studies). previous studies concluded that the disorder is characterized by abnormal development of several brain areas critical for both orofacial movements and sequential articulation, resulting in marked disruption of speech and expressive language. + + Relation to Specific Language Impairment + +Children who fail to develop expressive and/or receptive language normally, in the absence of explanatory factors such as neurologic disorders, hearing impairment, or lack of adequate opportunity, are clinically described as having specific language impairment (SLI; see previous studies) (previous studies). + +See also familial developmental dysphasia (previous studies)." +MONDO_0011624,"Definition: Transaldolase deficiency (TALDOD) is a rare inborn error of pentose metabolism. Typical features include intrauterine growth restriction, triangular face, loose wrinkly skin at birth, and development of progressive liver failure (summary by previous studies)." +MONDO_0014144,"Definition: Autosomal recessive limb-girdle muscular dystrophy-18 (LGMD18) is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by previous studies). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (previous studies; previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (previous studies)." +Orphanet_369840,"Definition: Autosomal recessive limb-girdle muscular dystrophy-18 (LGMD18) is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by previous studies). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (previous studies; previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (previous studies)." +MONDO_0032896,"Definition: Spermatogenic failure-42 (SPGF42) is characterized by infertility and spermatozoa with almost no progressive motility due to multiple morphologic abnormalities of the flagella (MMAF), including short, absent, coiled, irregular-caliber, and/or bent flagella. Some spermatozoa also show abnormalities of the head, acrosome, midpiece, or endpiece (previous studies; previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +Orphanet_139380,"Definition: Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by previous studies). + +There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (previous studies; previous studies)." +Orphanet_139373,"Definition: Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by previous studies). + +There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (previous studies; previous studies)." +Orphanet_164736,"Definition: Advanced sleep phase syndrome is characterized by very early sleep onset and offset (summary by previous studies). + + Genetic Heterogeneity of Advanced Sleep Phase Syndrome + +See also FASPS2 (previous studies), caused by mutation in the CSNK1D gene (previous studies) on chromosome 17q25, and FASPS3 (previous studies), caused by mutation in the PER3 gene (previous studies) on chromosome 1p36." +Orphanet_33001,"Definition: Lymphedema-distichiasis is an autosomal dominant disorder that classically presents as lymphedema of the limbs and double rows of eyelashes (distichiasis). Irritation of the cornea, with corneal ulceration in some cases, brings the patients to the attention of ophthalmologists. Other complications may include cardiac defects, varicose veins, ptosis, cleft palate, spinal extradural cysts, and photophobia (previous studies; previous studies)." +MONDO_0007922,"Definition: Lymphedema-distichiasis is an autosomal dominant disorder that classically presents as lymphedema of the limbs and double rows of eyelashes (distichiasis). Irritation of the cornea, with corneal ulceration in some cases, brings the patients to the attention of ophthalmologists. Other complications may include cardiac defects, varicose veins, ptosis, cleft palate, spinal extradural cysts, and photophobia (previous studies; previous studies)." +EFO_0005303,"Definition: Sudden infant death syndrome (SIDS) is a diagnosis of exclusion which should be made only after a thorough autopsy without identification of a specific cause of death (previous studies). + +previous studies provided a detailed review of genetic factors that have been implicated in SIDS. The authors concluded that SIDS represents more than 1 entity and has a heterogeneous etiology most likely involving several different genetically controlled metabolic pathways." +MONDO_0007422,"Definition: Classic Vohwinkel syndrome is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation, distinctive starfish-like acral keratoses, and moderate degrees of sensorineural deafness (summary by previous studies) + +A variant form of Vohwinkel syndrome, mutilating keratoderma with ichthyosis (previous studies), is caused by mutation in the gene for loricrin (LOR; previous studies) on chromosome 1q21. A form of mutilating palmoplantar keratoderma with periorificial keratotic plaques (Olmsted syndrome; previous studies) is caused by mutation in the TRPV3 gene (previous studies) on chromosome 17p13.2." +MONDO_0013762,"Definition: Hyperglycinemia, lactic acidosis, and seizures is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; previous studies), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (summary by previous studies)." +MONDO_0030625,"Definition: Autosomal recessive dyskinesia with orofacial involvement (DSKOR) is characterized by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. The severity is variable; some patients have orofacial dyskinesia resulting in speech difficulties, or develop neuropsychiatric features, including anxiety and social withdrawal. Cardiomyopathy has rarely been described and may be a manifestation of the disorder (summary by previous studies)." +MONDO_0032918,"Definition: Developmental and epileptic encephalopathy-84 (DEE84) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first months or years of life. Affected individuals have severely impaired global development with impaired intellectual development, absent speech, and inability to walk. Other features include axial hypotonia, peripheral spasticity, feeding difficulties that sometimes necessitate tube feeding, and mild dysmorphic facial features. Brain imaging may show nonspecific findings such as cerebral/cerebellar atrophy and/or hypomyelination. The severity of the disorder is variable (summary by previous studies). + +For a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0100294,"Definition: Mitochondrial complex II deficiency is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, and muscle with onset in infancy, whereas others have only isolated cardiac or muscle involvement. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by previous studies). + +Complex II, also known as succinate dehydrogenase, is part of the mitochondrial respiratory chain. + + Genetic Heterogeneity of Mitochondrial Complex II Deficiency + +See MC2DN2 (previous studies), caused by mutation in the SDHAF1 gene (previous studies) on chromosome 19q13; MC2DN3 (previous studies), caused by mutation in the SDHD gene (previous studies) on chromosome 11q23; and MC2DN4 (previous studies), caused by mutation in the SDHB gene (previous studies) on chromosome 1p36. + +previous studies reviewed the genetic basis of isolated mitochondrial complex II deficiency." +Orphanet_169355,"Definition: Immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63) is an autosomal recessive disorder characterized by immune dysregulation. Affected individuals present in infancy with features of both abnormal activation of certain immune signaling pathways, resulting in lymphoid proliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, especially CMV. Laboratory studies show increased NK cells that show impaired differentiation, as well as abnormal T cell populations or responses. Some patients may die in childhood; hematopoietic bone marrow transplantation is curative (summary by previous studies)." +Orphanet_2182,"Definition: The X-linked recessive form of congenital hydrocephalus (HYCX) is the most common of the inherited forms of hydrocephalus. The phenotype consists of enlarged cerebral ventricles and mental retardation, and often includes spastic paraparesis and adducted thumbs. The most severe cases die pre- or perinatally with gross hydrocephalus and enlarged head circumference. Stenosis of the aqueduct of Sylvius is frequently associated with the disorder (previous studies). + +See HYC1 (previous studies) for a discussion of nonsyndromic autosomal recessive forms of hydrocephalus." +MONDO_0010611,"Definition: The X-linked recessive form of congenital hydrocephalus (HYCX) is the most common of the inherited forms of hydrocephalus. The phenotype consists of enlarged cerebral ventricles and mental retardation, and often includes spastic paraparesis and adducted thumbs. The most severe cases die pre- or perinatally with gross hydrocephalus and enlarged head circumference. Stenosis of the aqueduct of Sylvius is frequently associated with the disorder (previous studies). + +See HYC1 (previous studies) for a discussion of nonsyndromic autosomal recessive forms of hydrocephalus." +Orphanet_280671,Definition: Megaconial-type congenital muscular dystrophy is an autosomal recessive disorder characterized by early-onset muscle wasting and mental retardation. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (summary by previous studies). +MONDO_0011246,Definition: Megaconial-type congenital muscular dystrophy is an autosomal recessive disorder characterized by early-onset muscle wasting and mental retardation. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (summary by previous studies). +EFO_1001229,"Definition: Mastocytosis, or mast cell disease, is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells in various tissues, especially in the skin and hematopoietic organs. Mastocytosis usually appears in infancy or early adulthood. In most pediatric cases, the disease is limited to the skin, but it can be associated with systemic symptoms due to the release of mediators from mast cells, even when there is no systemic infiltration. It usually has a good prognosis, with substantial improvement or spontaneous resolution before puberty. In rare cases, the disease may remain active through adolescence as a systemic adult mastocytosis. Cutaneous mastocytosis is characterized by macules, papules, nodules, or diffuse infiltration of the skin, often associated with localized hyperpigmentation. Gentle rubbing of the lesions induces histamine release from mechanically activated mast cells, causing local wheals, erythema, and often pruritus, a phenomenon termed the 'Darier sign.' In contrast to childhood-onset mastocytosis, adult-onset mastocytosis often persists for the lifetime of the patient and is also more likely to be a severe and systemic disease involving numerous organs. In some cases, it is associated with a clonal hematologic non-mast-cell lineage disease, such as a myelodysplastic or myeloproliferative disorder. Adult-onset mastocytosis can also lead to the rare mast cell leukemia, which carries a high risk of mortality (summary by previous studies and previous studies)." +EFO_0009001,"Definition: Mastocytosis, or mast cell disease, is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells in various tissues, especially in the skin and hematopoietic organs. Mastocytosis usually appears in infancy or early adulthood. In most pediatric cases, the disease is limited to the skin, but it can be associated with systemic symptoms due to the release of mediators from mast cells, even when there is no systemic infiltration. It usually has a good prognosis, with substantial improvement or spontaneous resolution before puberty. In rare cases, the disease may remain active through adolescence as a systemic adult mastocytosis. Cutaneous mastocytosis is characterized by macules, papules, nodules, or diffuse infiltration of the skin, often associated with localized hyperpigmentation. Gentle rubbing of the lesions induces histamine release from mechanically activated mast cells, causing local wheals, erythema, and often pruritus, a phenomenon termed the 'Darier sign.' In contrast to childhood-onset mastocytosis, adult-onset mastocytosis often persists for the lifetime of the patient and is also more likely to be a severe and systemic disease involving numerous organs. In some cases, it is associated with a clonal hematologic non-mast-cell lineage disease, such as a myelodysplastic or myeloproliferative disorder. Adult-onset mastocytosis can also lead to the rare mast cell leukemia, which carries a high risk of mortality (summary by previous studies and previous studies)." +MONDO_0009478,"Definition: Autosomal dominant hyper-IgE recurrent infection syndrome-1 (HIES1; previous studies) is a primary immunodeficiency disorder characterized by recurrent Staphylococcus aureus skin abscesses, increased serum IgE, and abnormalities of the connective tissue, skeleton, and dentition (previous studies; previous studies). + +Autosomal recessive HIES2 shares hyper-IgE, eosinophilia, and recurrent Staphylococcal infections, but is distinguished from autosomal dominant HIES1 by the lack of connective tissue and skeletal involvement (previous studies). + +See also TYK2 deficiency (previous studies), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; previous studies) (previous studies). + +For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see previous studies." +MONDO_0009697,"Definition: The Lafora type of progressive myoclonic epilepsy is an autosomal recessive disorder characterized by insidious onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, difficulties in school work, myoclonic jerks, generalized seizures, and often visual hallucination. The myoclonus, seizures, and hallucinations gradually worsen and become intractable. This is accompanied by progressive cognitive decline, resulting in dementia. About 10 years after onset, affected individuals are in near-continuous myoclonus with absence seizures, frequent generalized seizures, and profound dementia or a vegetative state. Histologic studies of multiple tissues, including brain, muscle, liver, and heart show intracellular Lafora bodies, which are dense accumulations of malformed and insoluble glycogen molecules, termed polyglucosans (review by previous studies). + +For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800)." +MONDO_0011964,"Definition: Like all CDGs, which are caused by a shortage of precursor monosaccharide phosphate or deficiencies in the glycosyltransferases required for lipid-linked oligosaccharide precursor (LLO) synthesis, CDG Ij is caused by a defect in the formation of DPAGT1, the first dolichyl-linked intermediate of the protein N-glycosylation pathway. + +For a general discussion of CDGs, see CDG1A (previous studies)." +MONDO_0013159,"Definition: Congenital muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies) are characterized by early onset of muscle weakness, usually before ambulation is achieved; mental retardation and mild brain anomalies are variable (previous studies; previous studies). Congenital muscular dystrophy-dystroglycanopathies with or without impaired intellectual development (type B) represent the intermediate range of the spectrum of dystroglycanopathies. They are less severe than muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A; see MDDGA1, previous studies), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and more severe than limb-girdle muscular dystrophy-dystroglycanopathy (type C; see MDDGC1, previous studies). + + Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with or without Impaired Intellectual Development (Type B) + +Congenital muscular dystrophy with impaired intellectual development due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGB2 (previous studies), caused by mutation in the POMT2 gene (previous studies); MDDGB3 (previous studies), caused by mutation in the POMGNT1 gene (previous studies); MDDGB4 (previous studies), caused by mutation in the FKTN gene (previous studies); MDDGB5 (previous studies), caused by mutation in the FKRP gene (previous studies); MDDGB6 (previous studies), caused by mutation in the LARGE gene (previous studies); MDDGB14 (previous studies), caused by mutation in the GMPPB gene (previous studies); and MDDGB15 (previous studies), caused by mutation in the DPM3 gene (previous studies)." +MONDO_0014300,"Definition: Myopathy with extrapyramidal signs is an autosomal recessive disorder characterized by early childhood onset of proximal muscle weakness and learning disabilities. While the muscle weakness is static, most patients develop progressive extrapyramidal signs that may become disabling (summary by previous studies). Brain MRI in 1 patient showed congenital malformations, including polymicrogyria and cerebellar dysplasia (previous studies)." +MONDO_0014919,"Definition: Sessile serrated polyposis cancer syndrome (SSPCS) is a rare disorder characterized by the presence of multiple serrated polyps in the colon and an increased personal and familial risk of colorectal cancer. SSPCS is defined by the World Health Organization (WHO) as the presence of at least 5 sessile serrated polyps (also known as 'sessile serrated adenomas,' or SSAs) proximal to the sigmoid colon, with 2 or more that are greater than 10 mm in diameter; or any number of serrated polyps in a person with a first-degree relative with SSPCS; or more than 20 serrated polyps of any size, distributed throughout the colon. SSAs are found in 2% of average-risk individuals undergoing their first screening colonoscopy, and are estimated to be responsible for 20 to 35% of all colon cancers. SSAs exhibit somatic mutations in the BRAF gene (previous studies), or less commonly in the KRAS gene (previous studies), early in their development. Individuals with SSPCS have a lifetime risk of colon cancer as high as 54% and may have a strong personal or family history of extracolonic cancers; first-degree relatives have a 32% risk of developing multiple serrated polyps and a 5-fold increased risk of colon cancer. An increased risk of pancreatic cancer has also been observed (summary by previous studies)." +MONDO_0030680,"Definition: Dilated cardiomyopathy-2F (CMD2F) is an autosomal recessive early-onset cardiomyopathy associated with refractory ventricular arrhythmias and severe heart failure requiring placement of a left ventricular assist device (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of dilated cardiomyopathy, see previous studies." +MONDO_0034145,"Definition: Oculoskeletodental syndrome (OCSKD) is characterized by congenital cataract, short stature and various skeletal anomalies, dysmorphic facial features and dental anomalies, developmental delay, and stroke. Other recurrent features include hearing loss, secondary glaucoma, and nephrocalcinosis (previous studies)." +MONDO_0044634,"Definition: SHRF is an autosomal recessive disorder characterized by short stature, brachydactyly, dysmorphic facial features, hearing loss, and visual impairment. Onset of the hearing and visual abnormalities, including retinitis pigmentosa, varies from birth to the second decade. Patients have mild intellectual disability and mild cerebellar atrophy with myelination defects on brain imaging (summary by previous studies)." +Orphanet_35173,"Definition: Chondrodysplasia punctata (CDP) is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant CDP, also known as Conradi-Hunermann syndrome, is the most well-characterized form. CDPX2 arises almost exclusively in females and is usually lethal in males. In addition to radiographic stippling, the disorder is characterized by rhizomelic shortness, transient congenital ichthyosis following the lines of Blaschko, patchy alopecia, cataracts, and midface hypoplasia. Affected males are extremely rare and the clinical features in males almost always result from postzygotic mosaicism for an EBP mutation (summary by previous studies and previous studies). + + Genetic Heterogeneity of Chondrodysplasia Punctata + +See also CDPX1 (previous studies), caused by mutation in the ARSE gene (previous studies). + +See previous studies, previous studies, and previous studies for possible autosomal dominant forms of CDP. In addition, CDP can be caused by maternal vitamin K deficiency or warfarin teratogenicity (see previous studies)." +Orphanet_391677,"Definition: Among the Yakuts, an Asian population isolate that is located in the northeastern part of Siberia, previous studies ascertained a short stature syndrome involving autosomal recessive postnatal growth failure, small hands and feet, loss of visual acuity with abnormalities of color vision, abnormal nuclear shape in neutrophil granulocytes (Pelger-Huet anomaly; see previous studies), and normal intelligence." +MONDO_0013889,"Definition: Among the Yakuts, an Asian population isolate that is located in the northeastern part of Siberia, previous studies ascertained a short stature syndrome involving autosomal recessive postnatal growth failure, small hands and feet, loss of visual acuity with abnormalities of color vision, abnormal nuclear shape in neutrophil granulocytes (Pelger-Huet anomaly; see previous studies), and normal intelligence." +MONDO_0007043,"Definition: Pfeiffer syndrome is an autosomal dominant craniosynostosis syndrome with characteristic anomalies of the hands and feet. Three clinical subtypes, which have important diagnostic and prognostic implications, have been identified. Type 1, the classic syndrome, is compatible with life and consists of craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly, and variable syndactyly. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet, together with ankylosis of the elbows. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe, and the anterior cranial base is markedly short. Various visceral malformations have been found in association with type 3. Early demise is characteristic of types 2 and 3 (previous studies). previous studies further tabulated the findings in the 3 types of Pfeiffer syndrome." +MONDO_0007900,"Definition: A white appearance of the nails can result from whitening of the nail plate (true leukonychia), the nail bed (pseudoleukonychia), or neither (apparent leukonychia), and can be due to a variety of factors including infectious, metabolic, or systemic diseases, trauma, or drugs. One of the rare causes of whitening of the nail plate is hereditary leukonychia (summary by previous studies). Leukonychia may involve all of the nail (leukonychia totalis) or only part of the nail (leukonychia partialis), or can appear as one or more transverse bands (leukonychia striata) or white spots (leukonychia punctata). + +For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (previous studies)." +MONDO_0008553,"Definition: Platelet-type bleeding disorder-17 is an autosomal dominant disorder characterized by increased bleeding tendency due to abnormal platelet function. It is a type of 'gray platelet syndrome' because the platelets appear abnormal on light microscopy. Electron microscopy shows decreased or absent alpha-granules within platelets, and bone marrow biopsy shows increased numbers of abnormal megakaryocytes, suggesting a defect in megakaryopoiesis and platelet production. The bleeding severity is variable (summary by previous studies)." +MONDO_0008567,"Definition: Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases. The remaining cancers originate from parafollicular cells (medullary thyroid cancer, MTC; previous studies). NMTC is classified into 4 groups: papillary, follicular (previous studies), Hurthle cell (previous studies), and anaplastic. Approximately 5% of NMTC is hereditary, occurring as a component of a familial cancer syndrome (e.g., familial adenomatous polyposis, previous studies; Carney complex, previous studies) or as a primary feature (familial NMTC or FNMTC). Papillary thyroid cancer (PTC) is the most common histologic subtype of FNMTC, accounting for approximately 85% of cases (summary by previous studies). + +PTC is characterized by distinctive nuclear alterations including pseudoinclusions, grooves, and chromatin clearing. PTCs smaller than 1 cm are referred to as papillary microcarcinomas. These tumors have been identified in up to 35% of individuals at autopsy, suggesting that they may be extremely common although rarely clinically relevant. PTC can also be multifocal but is typically slow-growing with a tendency to spread to lymph nodes and usually has an excellent prognosis (summary by previous studies). + + Genetic Heterogeneity of Susceptibility to Nonmedullary Thyroid Cancer + +Other susceptibilities to nonmedullary thyroid cancer include NMTC2 (previous studies), caused by mutation in the SRGAP1 gene (previous studies); NMTC3 (previous studies), mapped to chromosome 2q21; NMTC4 (previous studies), caused by mutation in the FOXE1 gene (previous studies); and NMTC5 (previous studies), caused by mutation in the HABP2 gene (previous studies). + +A susceptibility locus for familial nonmedullary thyroid carcinoma with or without cell oxyphilia (TCO; previous studies) has been mapped to chromosome 19p." +EFO_0000641,"Definition: Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases. The remaining cancers originate from parafollicular cells (medullary thyroid cancer, MTC; previous studies). NMTC is classified into 4 groups: papillary, follicular (previous studies), Hurthle cell (previous studies), and anaplastic. Approximately 5% of NMTC is hereditary, occurring as a component of a familial cancer syndrome (e.g., familial adenomatous polyposis, previous studies; Carney complex, previous studies) or as a primary feature (familial NMTC or FNMTC). Papillary thyroid cancer (PTC) is the most common histologic subtype of FNMTC, accounting for approximately 85% of cases (summary by previous studies). + +PTC is characterized by distinctive nuclear alterations including pseudoinclusions, grooves, and chromatin clearing. PTCs smaller than 1 cm are referred to as papillary microcarcinomas. These tumors have been identified in up to 35% of individuals at autopsy, suggesting that they may be extremely common although rarely clinically relevant. PTC can also be multifocal but is typically slow-growing with a tendency to spread to lymph nodes and usually has an excellent prognosis (summary by previous studies). + + Genetic Heterogeneity of Susceptibility to Nonmedullary Thyroid Cancer + +Other susceptibilities to nonmedullary thyroid cancer include NMTC2 (previous studies), caused by mutation in the SRGAP1 gene (previous studies); NMTC3 (previous studies), mapped to chromosome 2q21; NMTC4 (previous studies), caused by mutation in the FOXE1 gene (previous studies); and NMTC5 (previous studies), caused by mutation in the HABP2 gene (previous studies). + +A susceptibility locus for familial nonmedullary thyroid carcinoma with or without cell oxyphilia (TCO; previous studies) has been mapped to chromosome 19p." +MONDO_0011211,"Definition: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on electroretinogram. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora (summary by previous studies)." +MONDO_0012089,"Definition: Ichthyosis prematurity syndrome (IPS) is a rare subtype of autosomal recessive congenital ichthyosis, a clinically and genetically heterogeneous group of inherited keratinization disorders. IPS presents with complications at midtrimester of pregnancy leading to prematurity, a thick caseous and desquamating skin, respiratory complications, and persistent eosinophilia. Skin features evolve into a flat follicular hyperkeratosis with atopy (previous studies)." +MONDO_0013439,"Definition: Congenital bile acid synthesis defect-3 (CBAS3) is an autosomal recessive disorder characterized by prolonged jaundice after birth, hepatomegaly, conjugated hyperbilirubinemia, elevations in characteristic abnormal bile acids, and progressive intrahepatic cholestasis with liver fibrosis (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of congenital bile acid synthesis defects, see previous studies." +Orphanet_79302,"Definition: Congenital bile acid synthesis defect-3 (CBAS3) is an autosomal recessive disorder characterized by prolonged jaundice after birth, hepatomegaly, conjugated hyperbilirubinemia, elevations in characteristic abnormal bile acids, and progressive intrahepatic cholestasis with liver fibrosis (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of congenital bile acid synthesis defects, see previous studies." +MONDO_0014782,"Definition: Autosomal recessive limb-girdle muscular dystrophy-25 (LGMDR25) is characterized by slowly progressive onset of proximal lower limb weakness in adulthood. Affected individuals also develop cardiac arrhythmias resulting in syncopal episodes as young adults or later in life (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy (LGMD), see LGMDR1 (previous studies)." +MONDO_0015025,"Definition: Developmental and epileptic encephalopathy-51 (DEE51) is an autosomal recessive severe neurodevelopmental disorder characterized by onset of intractable seizures and hypotonia in the first days or weeks of life. Affected individuals have severely delayed psychomotor development and may show abnormal movements. Brain imaging shows nonspecific abnormalities, such as cerebral atrophy, cerebellar atrophy, and delayed myelination. Laboratory studies showed increased lactate, suggesting mitochondrial dysfunction (summary by previous studies). + +For a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0030044,"Definition: Pseudo-TORCH syndrome-3 (PTORCH3) is an autosomal recessive disorder of immune dysregulation and neuroinflammation apparent from early infancy. Affected individuals have developmental delay with acute episodes of fever and multisystemic organ involvement, including coagulopathy, elevated liver enzymes, and proteinuria, often associated with thrombotic microangiopathy. Brain imaging shows progressive intracranial calcifications, white matter abnormalities, and sometimes cerebral or cerebellar atrophy. Laboratory studies show abnormal elevation of interferon (IFN)-stimulated gene (ISG) transcripts consistent with a type I interferonopathy. The phenotype resembles the sequelae of intrauterine infection, but there is usually no evidence of an infectious agent. The disorder results from defects in negative regulation of the interferon immunologic pathway. Death in early childhood is common (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (previous studies)." +MONDO_0859184,"Definition: Ventriculomegaly and arthrogryposis (VENARG) is a severe autosomal recessive congenital disorder characterized by the onset of features in utero that are not compatible with life. Affected pregnancies are terminated spontaneously or by plan due to the severity of the defects. Prenatal ultrasound and autopsy show limb contractures consistent with arthrogryposis and enlarged brain ventricles that may be associated with hydrocephalus, abnormalities of the corpus callosum, and cerebellar hypoplasia. Some affected fetuses may also have congenital heart disease and hydrops fetalis (summary by previous studies and previous studies)." +Orphanet_3377,"Definition: The trismus-pseudocamptodactyly syndrome is a distal arthrogryposis characterized by an inability to open the mouth fully (trismus) and pseudocamptodactyly in which wrist dorsiflexion, but not volar flexion, produces involuntary flexion contracture of distal and proximal interphalangeal joints. In these patients, trismus complicates dental care, feeding during infancy, and intubation for anesthesia, and the pseudocamptodactyly impairs manual dexterity, with consequent occupational and social disability (summary by previous studies)." +MONDO_0008016,"Definition: The trismus-pseudocamptodactyly syndrome is a distal arthrogryposis characterized by an inability to open the mouth fully (trismus) and pseudocamptodactyly in which wrist dorsiflexion, but not volar flexion, produces involuntary flexion contracture of distal and proximal interphalangeal joints. In these patients, trismus complicates dental care, feeding during infancy, and intubation for anesthesia, and the pseudocamptodactyly impairs manual dexterity, with consequent occupational and social disability (summary by previous studies)." +EFO_0003099,"Definition: Adrenocorticotropic hormone (ACTH) hypersecretion by corticotroph adenomas of the pituitary result in excess cortisol secretion, or Cushing disease. The clinical features of Cushing disease include central obesity, moon facies, 'buffalo hump,' diabetes, hypertension, fatigue, easy bruising, depression, and reproductive disorders. Cushing disease is associated with increased morbidity and mortality, mainly due to cardiovascular or cerebrovascular disease and infections (summary by previous studies). + +Mutations in the USP8 gene, leading to an upregulated epidermal growth factor receptor (EGFR; previous studies) pathway, have been identified in about 36 to 62% of corticotroph adenomas (summary by previous studies)." +MONDO_0008070,"Definition: Congenital myopathy-2A (CMYP2A) is an autosomal dominant disorder of the skeletal muscle characterized by infantile- or childhood-onset myopathy with delayed motor milestones and nonprogressive muscle weakness. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype (CMYP2C; previous studies). Some patients with de novo mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation. Less frequently, autosomal dominant transmission of the disorder within a family may occur when the ACTA1 mutation produces a phenotype compatible with adult life. Of note, intrafamilial variability has also been reported: a severely affected proband may be identified and then mildly affected or even asymptomatic relatives are found to carry the same mutation. The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (previous studies; previous studies; previous studies; previous studies; previous studies; previous studies; previous studies). + +The most common histologic finding on muscle biopsy in patients with ACTA1 mutations is the presence of 'nemaline rods,' which represent abnormal thread- or rod-like structures ('nema' is Greek for 'thread'). However, skeletal muscle biopsy from patients with mutations in the ACTA1 gene can show a range of pathologic phenotypes. These include classic rods, intranuclear rods, clumped filaments, cores, or fiber-type disproportion, all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. Most patients have clinically severe disease, regardless of the histopathologic phenotype (previous studies; previous studies). ACTA1 mutations are the second most common cause of congenital myopathies classified histologically as 'nemaline myopathy' after mutations in the NEB gene (previous studies). ACTA1 mutations are overrepresented in the severe phenotype with early death (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies). + +For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (previous studies)." +MONDO_0009155,"Definition: EEM syndrome denotes a disorder characterized by ectodermal dysplasia, ectrodactyly, and macular dystrophy. The ectodermal dysplasia consists of hypotrichosis affecting scalp hair, eyebrows, and eyelashes, with partial anodontia. Different degrees of absence deformities as well as syndactyly have been described, the hands often being more severely affected than the feet. The retinal lesion appears as a central geographic atrophy of the retinal pigment epithelium and choriocapillary layer of the macular area with coarse hyperpigmentations and sparing of the larger choroidal vessels (summary by previous studies)." +MONDO_0009999,"Definition: Autosomal recessive Robinow syndrome-1 (RRS1) is a severe skeletal dysplasia characterized by dysmorphic facial features, including frontal bossing, hypertelorism, and broad nose, short-limbed dwarfism, vertebral segmentation, and genital hypoplasia (summary by previous studies). + + Genetic Heterogeneity of Robinow Syndrome + +Autosomal recessive Robinow syndrome-2 (RRS2; previous studies) is caused by mutation in the NXN gene (previous studies) on chromosome 17p13. + +See also autosomal dominant Robinow syndrome-1 (DRS1; previous studies), caused by mutation in the WNT5A gene (previous studies) on chromosome 3p14; DRS2 (previous studies), caused by mutation in the DVL1 gene (previous studies) on chromosome 1p36; and DRS3 (previous studies), caused by mutation in the DVL3 gene (previous studies) on chromosome 3q27." +MONDO_0012187,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0013767,"Definition: RAS-associated leukoproliferative disorder is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by previous studies and previous studies). + +The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; previous studies) and was originally designated ALPS IV." +Orphanet_268114,"Definition: RAS-associated leukoproliferative disorder is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by previous studies and previous studies). + +The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; previous studies) and was originally designated ALPS IV." +MONDO_0014375,"Definition: Diarrhea-7 (DIAR7) is a protein-losing enteropathy characterized by early-onset nonbloody watery diarrhea and unresponsiveness to soy-based or elemental formulas. Patients experience failure to thrive, hypogammaglobulinemia with recurrent infections, and require albumin infusions and parenteral nutrition. Hypertriglyceridemia and digital clubbing have been observed (previous studies). The malabsorption can result in severe deficiency of vitamin D and other nutrients (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +Orphanet_329242,"Definition: Diarrhea-7 (DIAR7) is a protein-losing enteropathy characterized by early-onset nonbloody watery diarrhea and unresponsiveness to soy-based or elemental formulas. Patients experience failure to thrive, hypogammaglobulinemia with recurrent infections, and require albumin infusions and parenteral nutrition. Hypertriglyceridemia and digital clubbing have been observed (previous studies). The malabsorption can result in severe deficiency of vitamin D and other nutrients (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +HP_0002014,"Definition: Diarrhea-7 (DIAR7) is a protein-losing enteropathy characterized by early-onset nonbloody watery diarrhea and unresponsiveness to soy-based or elemental formulas. Patients experience failure to thrive, hypogammaglobulinemia with recurrent infections, and require albumin infusions and parenteral nutrition. Hypertriglyceridemia and digital clubbing have been observed (previous studies). The malabsorption can result in severe deficiency of vitamin D and other nutrients (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +MONDO_0014563,"Definition: Mitochondrial short-chain enoyl-CoA hydratase-1 deficiency is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by previous studies)." +MONDO_0014662,"Definition: Hereditary sensory and autonomic neuropathy type VIII is an autosomal recessive neurologic disorder characterized by congenital insensitivity to pain resulting in ulceration to the fingers, tongue, lips, and other distal appendages. Affected individuals may also have decreased sweating and tear production (summary by previous studies). + +For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1A (previous studies)." +MONDO_0030454,"Definition: Joubert syndrome-39 (JBTS39) is an autosomal recessive neurodevelopmental disorder with variable manifestations. Most affected individuals have developmental delay with poor speech and retinal dystrophy with abnormal eye movements. Brain imaging shows the pathognomonic 'molar tooth sign,' which reflects abnormal cerebellar formation (previous studies). + +For a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (previous studies)." +MONDO_0030985,"Definition: Premature ovarian failure-19 (POF19) is characterized by irregular menses that cease in the third decade of life, associated with infertility (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (previous studies)." +MONDO_0859239,"Definition: Chilton-Okur-Chung neurodevelopmental syndrome (CHOCNS) is characterized mainly by global developmental delay with variably impaired intellectual development and occasional speech delay. Most patients have behavioral abnormalities, including autism spectrum disorder, ADHD, and aggression. About half of patients have dysmorphic facial features, and about half have nonspecific brain abnormalities, including thin corpus callosum. Rare involvement of other organ systems may be present. At least 1 child with normal development at age 2.5 years has been reported (previous studies)." +Orphanet_93951,"Definition: The Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. EEG tends to show continuous spike-wave activity or centrotemporal spikes. Some patients may have remission of seizures by adolescence. Carrier females may be mildly affected (summary by previous studies)." +Orphanet_983,"Definition: SRXY11 is characterized by a genital phenotype that may range from predominantly female to predominantly male, including marked sex ambiguity depending on the duration of normal testicular function prior to the loss of testicular tissue. Approximately half of patients present with micropenis and bilateral cryptorchidism, and half present with female-appearing or ambiguous external genitalia (previous studies; previous studies). + +The testicular regression syndrome (TRS) was delineated by previous studies, who called it the XY gonadal dysgenesis syndrome. It is characterized primarily by the absence of gonads in an XY person. In most cases, uterus and fallopian tubes are absent but small tubular structures interpreted as mullerian or wolffian rudiments (or both) are present. The range of virilizing effects due to early testicular tissue extends from none in phenotypic females with only slightly hypoplastic normal external genitalia, well-formed but hypoplastic uterus, and well-formed tubes (previous studies) to the anorchic phenotypic male (previous studies). Most affected individuals lack a vagina but a urogenital sinus or pseudovaginal urethral outpouching is found. Partial labioscrotal fusion and clitoris enlargement are common, breast development is absent, and postpubertal eunuchoid habitus is the rule. Sometimes nongenital anomalies are present (summary by previous studies)." +EFO_0000266,"Definition: Bicuspid, or bicommissural, aortic valve (BAV) describes an aortic valve with 2 rather than 3 leaflets (previous studies). In 1 to 2% of the population a bicuspid aortic valve is present. Bicuspid aortic valve is frequently an antecedent to aortic valve stenosis or insufficiency. In extreme cases the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome (previous studies) (previous studies). The valve calcification often observed in bicuspid aortic valve is a result of inappropriate activation of osteoblast-specific gene expression. Mutations in the signaling and transcription regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in nonsyndromic autosomal dominant human pedigrees. + + Genetic Heterogeneity of Aortic Valve Disease + +Also see AOVD2 (previous studies), caused by mutation in the SMAD6 gene (previous studies) on chromosome 15q22, and AOVD3 (previous studies), caused by mutation in the ROBO4 gene (previous studies) on chromosome 11q24. There is evidence for additional genetic heterogeneity (see MAPPING)." +EFO_0009027,"Definition: BBS9 is an autosomal recessive disorder characterized by obesity, polydactyly, renal anomalies, retinopathy, and mental retardation (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +EFO_0009064,"Definition: X-linked erythropoietic protoporphyria (XLEPP) is a metabolic disorder of heme biosynthesis characterized by onset in early childhood of severe photosensitivity associated with decreased iron stores and increased erythrocyte zinc- and metal-free protoporphyrin. Some patients may develop liver disease or gallstones (summary by previous studies). + +For a discussion of genetic heterogeneity of erythropoietic protoporphyria, see EPP1 (previous studies)." +MONDO_0009079,"Definition: DOOR syndrome is an autosomal recessive disorder characterized by Deafness, Onychodystrophy, Osteodystrophy, and mental Retardation. previous studies suggested this designation for the disorder, which can also include triphalangeal thumbs, seizures, and abnormal dermatoglyphics. + +See also DDOD syndrome (previous studies), which shows autosomal dominant inheritance of congenital deafness and onychodystrophy without mental retardation. See also OORS syndrome (previous studies), caused by mutation in the PIGF gene (previous studies), which shows overlapping features with the notable lack of deafness." +MONDO_0010580,"Definition: IPEX is an X-linked recessive immunologic disorder characterized by onset in infancy of severe diarrhea due to enteropathy, type 1 diabetes mellitus, and dermatitis. Other features may include hypothyroidism, autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatitis, and nephritis. The disorder may be fatal before age 2 years if not aggressively treated. Long-term therapeutic options include immunosuppression and hematopoietic stem cell transplantation (review by previous studies)." +MONDO_0011301,"Definition: Pseudohypoparathyroidism refers to a heterogeneous group of disorders characterized by resistance to parathyroid hormone (PTH; previous studies). Pseudohypoparathyroidism type Ib is characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH. Biochemical studies show a decreased response of urinary cAMP to exogenous PTH, but normal Gs activity in erythrocytes because the defect is restricted to renal tubule cells. In contrast to the findings in PHP Ia, patients with PHP Ib usually lack the physical characteristics of Albright hereditary osteodystrophy (AHO) and typically show no other endocrine abnormalities, although resistance to thyroid-stimulating hormone (TSH; previous studies) has been reported in PHP Ib (previous studies, previous studies). However, patients with PHP Ib may rarely show some features of AHO (previous studies). + +For a general phenotypic description, classification, and a discussion of molecular genetics of pseudohypoparathyroidism, see PHP1A (previous studies)." +MONDO_0011414,"Definition: Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by previous studies). + +Anterior segment dysgenesis is sometimes divided into subtypes including aniridia (see previous studies), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (previous studies). + +Patients with ASGD5 have been reported with the Peters anomaly, Axenfeld anomaly, and Rieger anomaly subtypes. + +Peters anomaly consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea (previous studies). It occurs as an isolated ocular abnormality or in association with other ocular defects. + +In Axenfeld anomaly, strands of iris tissue attach to the Schwalbe line; in Rieger anomaly, in addition to the attachment of iris tissue to the Schwalbe line, there is clinically evident iris stromal atrophy with hole or pseudo-hole formation and corectopia (summary by previous studies)." +MONDO_0011783,"Definition: Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by previous studies. The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. + +CDG1G is a multisystem disorder characterized by impaired psychomotor development, dysmorphic features, failure to thrive, male genital hypoplasia, coagulation abnormalities, and immune deficiency. More variable features include skeletal dysplasia, cardiac anomalies, ocular abnormalities, and sensorineural hearing loss. Some patients die in the early neonatal or infantile period, whereas others are mildly affected and live to adulthood (summary by previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies)." +MONDO_0012383,"Definition: Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by previous studies)." +Orphanet_75391,"Definition: Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by previous studies)." +MONDO_0014645,"Definition: B-cell expansion with NFKB and T-cell anergy is an autosomal dominant disorder characterized by onset in infancy of splenomegaly and polyclonal expansion of B cells, resulting in peripheral lymphocytosis. Affected individuals also show mild immune dysfunction, including some defective antibody responses and T-cell anergy. There may be a predisposition to the development of B-cell malignancy (summary by previous studies)." +MONDO_0019947,"Definition: Hereditary rippling muscle disease is an autosomal dominant disorder characterized by mechanically triggered contractions of skeletal muscle. In rippling muscle disease, mechanical stimulation leads to electrically silent muscle contractions that spread to neighboring fibers that cause visible ripples to move over the muscle. RMD is usually inherited as an autosomal dominant trait, but autosomal recessive inheritance has also been reported (previous studies). + + Genetic Heterogeneity of Rippling Muscle Disease + +Another locus for RMD, designated RMD1 (previous studies), maps to chromosome 1q41." +MONDO_0024464,"Definition: Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH; previous studies) and one or more of the other 5 anterior pituitary hormones. Mutations of the POU1F1 gene in the human and Pit1 in the mouse are responsible for pleiotropic deficiencies of GH, prolactin (PRL; previous studies), and thyroid-stimulating hormone (TSH; see previous studies), while the production of adrenocorticotrophic hormone (ACTH; see previous studies), luteinizing hormone (LH; previous studies), and follicle-stimulating hormone (FSH; previous studies) are preserved (previous studies). Some patients exhibit only GH deficiency, although approximately 50% of isolated GH deficiency progresses to CPHD (previous studies). In infancy severe growth deficiency from birth as well as distinctive facial features with prominent forehead, marked midfacial hypoplasia with depressed nasal bridge, deep-set eyes, and a short nose with anteverted nostrils and hypoplastic pituitary gland by MRI examination can be seen (previous studies). Some cases present with severe mental retardation along with short stature (previous studies). + + Reviews + +previous studies reviewed the development and differentiation of the 5 pituitary cell types: galactotropes, gonadotropes, corticotropes, thyrotropes, and somatotropes. As indicated by the mutations in PIT1 described later, combined pituitary hormone deficiency can have either autosomal dominant or autosomal recessive inheritance, depending on the part of the PIT1 molecule affected by the mutation. Some mutations have a dominant-negative effect. + + Genetic Heterogeneity of Combined Pituitary Hormone Deficiency + +CPHD2 (previous studies), associated with hypogonadism, is caused by mutation in the PROP1 gene (previous studies). CPHD3 (previous studies), which is associated with rigid cervical spine and variable sensorineural deafness, is caused by mutation in the LHX3 gene (previous studies). CPHD4 (previous studies) is caused by mutation in the LHX4 gene (previous studies). CPHD5 (see septooptic dysplasia, previous studies) is caused by mutation in the HESX1 gene (previous studies). CPHD6 (previous studies) is caused by mutation in the OTX2 gene (previous studies). CPHD7 (previous studies) is caused by mutation in the RNPC3 gene (previous studies)." +Orphanet_597,"Definition: Congenital myopathy-1A (CMYP1A) with susceptibility to malignant hyperthermia is an autosomal dominant disorder of skeletal muscle characterized by muscle weakness primarily affecting the proximal muscles of the lower limbs beginning in infancy or early childhood, although later onset of symptoms has been reported. There is significant phenotypic variability, even within families, and the wide clinical diversity most likely depends on the severity of the RYR1 mutation. The disorder is static or slowly progressive; affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Some patients present with orthopedic deformities. Serum creatine kinase is usually not elevated. Respiratory involvement is rare and there is no central nervous system or cardiac involvement. Patients with dominant mutations in the RYR1 gene are at risk for malignant hyperthermia and both disorders may segregate in the same family. Historically, patients with congenital myopathy due to RYR1 mutations were diagnosed based on the finding of pathologic central cores (central core disease; CCD) on muscle biopsy, which represent areas that lack oxidative enzymes and mitochondrial activity in type 1 muscle fibers. However, additional pathologic findings may also be observed, including cores and rods, central nuclei, fiber type disproportion, multiminicores, and uniform type 1 fibers. These histopathologic features are not always specific to RYR1 myopathy and often change over time (previous studies; previous studies; previous studies; previous studies). Some patients with RYR1 mutations have pathologic findings on muscle biopsy, but are clinically asymptomatic (previous studies; previous studies). + +Rare patients with a more severe phenotype have been found to carry a heterozygous mutation in the RYR1 gene inherited from an unaffected parent. However, in these cases, there is a possibility of recessive inheritance (CMYP1B; previous studies) with either a missed second RYR1 mutation in trans or a genomic rearrangement on the other allele that is undetectable on routine genomic sequencing, since the RYR1 gene is very large and genetic analysis may be difficult (previous studies). + + Genetic Heterogeneity of Congenital Myopathy + +See also CMYP1B (previous studies), caused by mutation in the RYR1 gene (previous studies) on chromosome 19q13; CMYP2A (previous studies), CMYP2B (previous studies), and CMYP2C (previous studies), caused by mutation in the ACTA1 gene (previous studies) on chromosome 1q42; CMYP3 (previous studies), caused by mutation in the SELENON gene (previous studies) on chromosome 1p36; CMYP4A (previous studies) and CMYP4B (previous studies), caused by mutation in the TPM3 gene (previous studies) on chromosome 1q21; CMYP5 (previous studies), caused by mutation in the TTN gene (previous studies) on chromosome 2q31; CMYP6 (previous studies), caused by mutation in the MYH2 gene (previous studies) on chromosome 17p13; CMYP7A (previous studies) and CMYP7B (previous studies), caused by mutation in the MYH7 gene (previous studies) on chromosome 14q11; CMYP8 (previous studies), caused by mutation in the ACTN2 gene (previous studies) on chromosome 1q43; CMYP9A (previous studies) and CMYP9B (previous studies), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYP10A (previous studies) and CMYP10B (previous studies), caused by mutation in the MEGF10 gene (previous studies) on chromosome 5q23; CMYP11 (previous studies), caused by mutation in the HACD1 gene (previous studies) on chromosome 10p12; CMYP12 (previous studies), caused by mutation in the CNTN1 gene (previous studies) on chromosome 12q12; CMYP13 (previous studies), caused by mutation in the STAC3 gene (previous studies) on chromosome 12q13; CMYP14 (previous studies), caused by mutation in the MYL1 gene (previous studies) on chromosome 2q34; CMYP15 (previous studies), caused by mutation in the TNNC2 gene (previous studies) on chromosome 20q13; CMYP16 (previous studies), caused by mutation in the MYBPC1 gene (previous studies) on chromosome 12q23; CMYP17 (previous studies), caused by mutation in the MYOD1 gene (previous studies) on chromosome 11p15; CMYP18 (previous studies), caused by mutation in the CACNA1S gene (previous studies) on chromosome 1q32; CMYP19 (previous studies), caused by mutation in the PAX7 gene (previous studies) on chromosome 1p36; CMYP20 (previous studies), caused by mutation in the RYR3 gene (previous studies) on chromosome 15q13; CMYP21 (previous studies), caused by mutation in the DNAJB4 gene (previous studies) on chromosome 1p31; CMYP22A (previous studies) and CMYP22B (previous studies), both caused by mutation in the SCN4A gene (previous studies) on chromosome 17q23; CMYP23 (previous studies), caused by mutation in the TPM2 gene (previous studies) on chromosome 9p13; and CMYP24 (previous studies), caused by mutation in the MYPN gene (previous studies) on chromosome 10q21." +EFO_0000407,"Definition: CMD2C is characterized by dilated cardiomyopathy of variable severity, with age of onset ranging from 2 to 20 years. Affected individuals exhibit reduction in coenzyme A (CoA) levels. Some severely affected children die in the first few years of life (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy (CMD), see previous studies." +EFO_0009046,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +EFO_0009070,"Definition: Intellectual developmental disorder with dysmorphic facies and ptosis is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures (summary by previous studies). + +See also chromosome 3p deletion syndrome (previous studies)." +MONDO_0007552,"Definition: Pretibial dystrophic epidermolysis bullosa is characterized by recurrent blistering and scarring, mainly in the pretibial area. The lesions often show lichenoid features (previous studies)." +MONDO_0007862,"Definition: Waardenburg syndrome type 3 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; presence of 'dystopia canthorum,' the lateral displacement of the ocular inner canthi; and upper limb abnormalities (reviews by previous studies and previous studies). WS type 3 is also referred to as 'Klein-Waardenburg syndrome' (previous studies). + + Clinical Variability of Waardenburg Syndrome Types 1-4 + +Waardenburg syndrome has been classified into 4 main phenotypes. Type I Waardenburg syndrome (WS1; previous studies) is characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia iridis and brilliant blue eyes; congenital sensorineural hearing loss; and 'dystopia canthorum.' WS type II (WS2) is distinguished from type I by the absence of dystopia canthorum. WS type III has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type IV (WS4; previous studies), also known as Waardenburg-Shah syndrome, has the additional feature of Hirschsprung disease (reviews by previous studies and previous studies)." +MONDO_0007895,"Definition: The Torrance type of platyspondylic lethal skeletal dysplasia (PLSDT) is an autosomal dominant disorder characterized by varying platyspondyly, short ribs with anterior cupping, hypoplasia of the lower ilia with broad ischial and pubic bones, and shortening of the tubular bones with splayed and cupped metaphyses. Histology of the growth plate typically shows focal hypercellularity with slightly enlarged chondrocytes in the resting cartilage and relatively well-preserved columnar formation and ossification at the chondroosseous junction. Though generally lethal in the perinatal period, longer survival has been reported (summary by previous studies)." +MONDO_0008847,"Definition: Atricia with papular lesions (APL) is characterized by hair loss soon after birth and the development, years later, of a diffuse papular rash over the entire skin surface. The papular rash distinguishes it from alopecia universalis (previous studies) (summary by previous studies)." +MONDO_0009825,"Definition: 5-Oxoprolinuria can be caused by genetic defects in either of 2 enzymes involved in the gamma-glutamyl cycle of glutathione metabolism: glutathione synthetase (GSS; previous studies) or 5-oxoprolinase (OPLAH; previous studies). GSS deficiency (previous studies) is best characterized as an inborn error of glutathione metabolism, but there is debate as to whether OPLAH deficiency represents a disorder or simply a biochemical condition with no adverse clinical effects because patients lack a consistent clinical picture apart from 5-oxoprolinuria (summary by previous studies)." +MONDO_0010478,"Definition: Congenital disorder of glycosylation type IIm, or developmental and epileptic encephalopathy-22 (DEE22), is an X-linked dominant severe neurologic disorder characterized by infantile-onset seizures, hypsarrhythmia on EEG, hypotonia, and developmental delay associated with severe intellectual disability and lack of speech. These features are consistent with developmental and epileptic encephalopathy (DEE). Brain malformations usually include cerebral and cerebellar atrophy. Additionally, some patients may have dysmorphic features or coarse facies (previous studies; previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies) and CDG2A (previous studies). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0010693,"Definition: Classic congenital or infantile nystagmus presents as conjugate, horizontal oscillations of the eyes, in primary or eccentric gaze, often with a preferred head turn or tilt. Other associated features may include mildly decreased visual acuity, strabismus, astigmatism, and occasionally head nodding. Eye movement recordings reveal that infantile nystagmus is predominantly a horizontal jerk waveform, with a diagnostic accelerating velocity slow phase. However, pendular and triangular waveforms may also be present. The nystagmus may rarely be vertical. As these patients often have normal visual acuity, it is presumed that the nystagmus represents a primary defect in the parts of the brain responsible for ocular motor control; thus the disorder has sometimes been termed 'congenital motor nystagmus' (previous studies; previous studies). + +Congenital nystagmus may also be a feature of other ocular diseases, such as albinism (see, e.g., OCA1A, previous studies), achromatopsia (see, e.g., ACHM3, previous studies), and Leber congenital amaurosis (see, e.g., LCA1, previous studies). Congenital nystagmus is associated with at least 3 X-linked disorders: Nettleship-Falls ocular albinism (OA1; previous studies), which maps to Xp22.3; complete congenital stationary night blindness (CSNB1; previous studies), which maps to Xp11.4; and blue-cone monochromatism (CBBM; previous studies), which maps to Xq28. + + Genetic Heterogeneity of Congenital Nystagmus + +Two other X-linked forms of congenital nystagmus have been reported: NYS5 (previous studies), which maps to Xp11.4-p11.3, and NYS6 (previous studies), which is caused by mutation in the GPR143 gene (previous studies) on Xp22.3. Autosomal dominant forms have been mapped to chromosomes 6p12 (NYS2; previous studies), 7p11 (NYS3; previous studies), and 1q31-q32 (NYS7; previous studies). An autosomal recessive form (NYS8; previous studies) is caused by mutation in the ROBO1 gene (previous studies) on chromosome 3p12. + +A disorder formerly designated NYS4 has been reclassified; see previous studies." +MONDO_0011381,"Definition: Dominantly inherited inclusion body beta-thalassemia is characterized by the presence of inclusion bodies in red blood cell precursors, moderately severe anemia, jaundice, and splenomegaly (summary by previous studies)." +MONDO_0014128,"Definition: Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by previous studies). Craniosynostosis-3 includes coronal, sagittal, and multisuture forms (previous studies). + +For discussion of genetic heterogeneity of craniosynostosis, see CRS1 (previous studies)." +MONDO_0014548,"Definition: LQT14 is a cardiac arrhythmia disorder characterized by ventricular arrhythmias, often life-threatening, occurring very early in life, frequent episodes of T-wave alternans, markedly prolonged QTc intervals, and intermittent 2:1 atrioventricular block (previous studies). + +Patients with LQT14, LQT15 (previous studies), or LQT16 (previous studies), resulting from mutation in calmodulin genes CALM1, CALM2 (previous studies), or CALM3 (previous studies), respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (previous studies)." +MONDO_0014807,"Definition: Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by previous studies). + +For a discussion of genetic heterogeneity of spinal muscular atrophy with congenital bone fractures, see SMABF1 (previous studies)." +MONDO_0030042,"Definition: Chronic benign proteinuria (PROCHOB) is an autosomal recessive condition characterized by onset of isolated proteinuria in the first decade of life. The proteinuria is nonprogressive; affected individuals do not develop renal disease or impaired kidney function, and they do not have additional associated abnormalities, such as hypertension. The correct diagnosis is important to avoid inefficient or invasive intervention, such as medication or renal biopsy (summary by previous studies)." +MONDO_0030723,"Definition: Autosomal dominant deafness-83 (DFNA83) is characterized by the onset of progressive sensorineural hearing loss at an average age of 24 years. A notable finding is a normal distortion product otoacoustic emissions (DPOAE) test, implicating dysfunction of spiral ganglia neurons rather than outer hair cells as a disease mechanism (previous studies)." +MONDO_0033544,"Definition: Tolchin-Le Caignec syndrome (TOLCAS) is a developmental disorder characterized by mildly to moderately impaired intellectual development and behavioral problems, such as autism, ADHD, labile mood, and aggressive episodes. Many patients have bony abnormalities, including osteochondroma, craniosynostosis, dysmorphic facies, arachnodactyly, and large head circumference. Rarely, additional congenital anomalies may also be observed. These additional features and the bony defects are highly variable (summary by previous studies)." +MONDO_0044723,"Definition: MGCA8 is an autosomal recessive metabolic disorder resulting in death in infancy. Features include hypotonia, abnormal movements, respiratory insufficiency with apneic episodes, and lack of developmental progress, often with seizures. Brain imaging is variable, but may show progressive cerebral atrophy. Laboratory studies show increased serum lactate and 3-methylglutaconic aciduria, suggesting a mitochondrial defect (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +MONDO_0054842,"Definition: Polycystic kidney disease-6 is an autosomal dominant renal disease characterized by the development of multiple small renal cysts and progression to renal insufficiency or end-stage renal disease (ESRD) most often after the sixth decade. The cysts are generally small (less than 1 to 3 cm) and the kidneys are not massively enlarged. Some patients may have evidence of chronic interstitial fibrosis and about half develop liver cysts (summary by previous studies). The renal interstitial fibrosis suggests overlap with autosomal dominant tubulointerstitial kidney disease (ADTKD; see previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of polycystic kidney disease, see PKD1 (previous studies)." +Orphanet_1243,"Definition: Best vitelliform macular dystrophy is an early-onset autosomal dominant disorder characterized by large deposits of lipofuscin-like material in the subretinal space, which creates characteristic macular lesions resembling the yolk of an egg ('vitelliform'). Although the diagnosis of Best disease is often made during the childhood years, it is more frequently made much later and into the sixth decade of life. In addition, the typical egg yolk-like lesion is present only during a limited period in the natural evolution of the disease; later, the affected area becomes deeply and irregularly pigmented and a process called 'scrambling the egg' occurs, at which point the lesion may appear as a 'bull's eye.' The disorder is progressive and loss of vision may occur. A defining characteristic of Best disease is a light peak/dark trough ratio of the electrooculogram (EOG) of less than 1.5, without aberrations in the clinical electroretinogram (ERG). Even otherwise asymptomatic carriers of BEST1 mutations, as assessed by pedigree, will exhibit an altered EOG. Histopathologically, the disease has been shown to manifest as a generalized retinal pigment epithelium (RPE) abnormality associated with excessive lipofuscin accumulation, regions of geographic RPE atrophy, and deposition of abnormal fibrillar material beneath the RPE, similar to drusen. Occasional breaks in the Bruch membrane with accompanying neovascularization have also been reported, although Best disease is not noted for extensive choroidal neovascularization. Many of these features are also found in age-related macular degeneration (see previous studies) (summary by previous studies; previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of vitelliform macular dystrophy, see VMD1 (previous studies)." +MONDO_0007931,"Definition: Best vitelliform macular dystrophy is an early-onset autosomal dominant disorder characterized by large deposits of lipofuscin-like material in the subretinal space, which creates characteristic macular lesions resembling the yolk of an egg ('vitelliform'). Although the diagnosis of Best disease is often made during the childhood years, it is more frequently made much later and into the sixth decade of life. In addition, the typical egg yolk-like lesion is present only during a limited period in the natural evolution of the disease; later, the affected area becomes deeply and irregularly pigmented and a process called 'scrambling the egg' occurs, at which point the lesion may appear as a 'bull's eye.' The disorder is progressive and loss of vision may occur. A defining characteristic of Best disease is a light peak/dark trough ratio of the electrooculogram (EOG) of less than 1.5, without aberrations in the clinical electroretinogram (ERG). Even otherwise asymptomatic carriers of BEST1 mutations, as assessed by pedigree, will exhibit an altered EOG. Histopathologically, the disease has been shown to manifest as a generalized retinal pigment epithelium (RPE) abnormality associated with excessive lipofuscin accumulation, regions of geographic RPE atrophy, and deposition of abnormal fibrillar material beneath the RPE, similar to drusen. Occasional breaks in the Bruch membrane with accompanying neovascularization have also been reported, although Best disease is not noted for extensive choroidal neovascularization. Many of these features are also found in age-related macular degeneration (see previous studies) (summary by previous studies; previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of vitelliform macular dystrophy, see VMD1 (previous studies)." +Orphanet_168588,"Definition: Cortisone reductase deficiency (CRD) results from a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase (HSD11B1; previous studies). The oxoreductase activity of 11-beta-HSD requires the NADPH-regenerating enzyme hexose-6-phosphate dehydrogenase (H6PD; previous studies) within the endoplasmic reticulum. Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting in midlife with hirsutism, oligomenorrhea, and infertility. Biochemically, CRD is diagnosed through the assessment of urinary cortisol and cortisone metabolites and consists of measuring the tetrahydrocortisol (THF) plus 5-alpha-THF/tetrahydrocortisone (THE) ratio, which in CRD patients is typically less than 0.1 (reference range, 0.7 to 1.2) (summary by previous studies). + + Genetic Heterogeneity of Cortisone Reductase Deficiency + +CORTRD2 (previous studies) is caused by mutation in the HSD11B1 gene (previous studies) on chromosome 1q32." +Orphanet_169095,"Definition: T-cell immunodeficiency, congenital alopecia, and nail dystrophy (TIDAND) is an autosomal recessive primary immunodeficiency characterized by congenital thymic aplasia and severe T-cell immunodeficiency apparent at birth or soon thereafter. Affected individuals tend to have recurrent infections, oral candidiasis, and failure to thrive. Immunologic investigations show decreased numbers of T cells with poor proliferative response to phytohemagglutinin (PHA) and variable hypogammaglobulinemia. The phenotype is consistent with a T-/B+/NK+ form of severe combined immunodeficiency (SCID; see, e.g., previous studies). Patients with FOXN1 mutations do not respond well to hematopoietic stem cell transplantation, as it is not curative; thymic transplantation offers a potential cure (previous studies)." +MONDO_0011132,"Definition: T-cell immunodeficiency, congenital alopecia, and nail dystrophy (TIDAND) is an autosomal recessive primary immunodeficiency characterized by congenital thymic aplasia and severe T-cell immunodeficiency apparent at birth or soon thereafter. Affected individuals tend to have recurrent infections, oral candidiasis, and failure to thrive. Immunologic investigations show decreased numbers of T cells with poor proliferative response to phytohemagglutinin (PHA) and variable hypogammaglobulinemia. The phenotype is consistent with a T-/B+/NK+ form of severe combined immunodeficiency (SCID; see, e.g., previous studies). Patients with FOXN1 mutations do not respond well to hematopoietic stem cell transplantation, as it is not curative; thymic transplantation offers a potential cure (previous studies)." +Orphanet_77259,"Definition: Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficient activity of beta-glucocerebrosidase. As a result of this deficiency, there is intracellular accumulation of glucosylceramide (GlcCer, glucosylcerebroside) primarily within cells of mononuclear phagocyte origin, which are the characteristic 'Gaucher cells' identified in most tissues (previous studies). + +Gaucher disease is classically categorized phenotypically into 3 main subtypes: nonneuronopathic type I, acute neuronopathic type II (GD2; previous studies), and subacute neuronopathic type III (GD3; previous studies). Type I is the most common form of Gaucher disease and lacks primary central nervous system involvement. Types II and III have central nervous system involvement and neurologic manifestations (previous studies; previous studies). + +All 3 forms of Gaucher disease are caused by mutation in the GBA gene. There are 2 additional phenotypes that may be distinguished: perinatal lethal Gaucher disease (previous studies), which is a severe form of type II, and Gaucher disease type IIIC (previous studies), which also has cardiovascular calcifications. + +See also previous studies for a form of atypical Gaucher disease caused by mutation in the gene encoding saposin C (PSAP; previous studies), which is an activator of beta-glucosidase." +MONDO_0009265,"Definition: Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficient activity of beta-glucocerebrosidase. As a result of this deficiency, there is intracellular accumulation of glucosylceramide (GlcCer, glucosylcerebroside) primarily within cells of mononuclear phagocyte origin, which are the characteristic 'Gaucher cells' identified in most tissues (previous studies). + +Gaucher disease is classically categorized phenotypically into 3 main subtypes: nonneuronopathic type I, acute neuronopathic type II (GD2; previous studies), and subacute neuronopathic type III (GD3; previous studies). Type I is the most common form of Gaucher disease and lacks primary central nervous system involvement. Types II and III have central nervous system involvement and neurologic manifestations (previous studies; previous studies). + +All 3 forms of Gaucher disease are caused by mutation in the GBA gene. There are 2 additional phenotypes that may be distinguished: perinatal lethal Gaucher disease (previous studies), which is a severe form of type II, and Gaucher disease type IIIC (previous studies), which also has cardiovascular calcifications. + +See also previous studies for a form of atypical Gaucher disease caused by mutation in the gene encoding saposin C (PSAP; previous studies), which is an activator of beta-glucosidase." +Orphanet_77260,"Definition: Type II Gaucher disease (GD2) is an acute neuronopathic form of the disorder with onset in infancy and death often by 2 years of age. Patients are usually normal at birth, but develop hepatosplenomegaly, developmental regression, and growth arrest within a few months of age. Neurologic deterioration proceeds rapidly, with cranial nerve and extrapyramidal tract involvement (previous studies)." +MONDO_0009266,"Definition: Type II Gaucher disease (GD2) is an acute neuronopathic form of the disorder with onset in infancy and death often by 2 years of age. Patients are usually normal at birth, but develop hepatosplenomegaly, developmental regression, and growth arrest within a few months of age. Neurologic deterioration proceeds rapidly, with cranial nerve and extrapyramidal tract involvement (previous studies)." +MONDO_0007681,"Definition: Multinodular goiter (MNG) is a common disorder characterized by nodular enlargement of the thyroid gland. In MNG1, some individuals may also develop Sertoli-Leydig cell tumors, usually of the ovary (summary by previous studies). + + Genetic Heterogeneity of Multinodular Goiter + +Other MNG loci map to chromosome Xp22 (MNG2; previous studies) and chromosome 3q26 (MNG3; previous studies)." +Orphanet_276399,"Definition: Multinodular goiter (MNG) is a common disorder characterized by nodular enlargement of the thyroid gland. In MNG1, some individuals may also develop Sertoli-Leydig cell tumors, usually of the ovary (summary by previous studies). + + Genetic Heterogeneity of Multinodular Goiter + +Other MNG loci map to chromosome Xp22 (MNG2; previous studies) and chromosome 3q26 (MNG3; previous studies)." +MONDO_0008679,"Definition: Wilms tumor is the most common renal tumor of childhood, occurring with an incidence of 1 in 10,000 and with a median age of diagnosis between 3 and 4 years of age. Wilms tumors are thought to develop from abnormally persistent embryonal cells within nephrogenic rests. Histologically, Wilms tumor mirrors the development of the normal kidney and classically consists of 3 cell types: blastema, epithelia, and stroma (summary by previous studies). + + Genetic Heterogeneity of Wilms Tumor + +Susceptibility to Wilms tumor is genetically heterogeneous. WT2 (previous studies) is caused by mutation in the H19/IGF2-imprinting control region (ICR1; previous studies) on chromosome 11p15. WT3 (previous studies) represents a locus mapped to chromosome 16q. WT4 (previous studies) represents a locus mapped to chromosome 17q12-q21. WT5 (previous studies) is caused by mutation in the POU6F2 gene (previous studies) on chromosome 7p14. WT6 (previous studies) is caused by mutation in the REST gene (previous studies) on chromosome 4q12. + +Mutations in the BRCA2 gene (previous studies) have also been reported in Wilms tumor. Rare somatic and constitutional disruption of the HACE1 gene (previous studies) has also been reported in Wilms tumor. + +Somatic mutations in the glypican-3 gene (GPC3; previous studies) have been described in Wilms tumor. Somatic mutations in the WTX gene (previous studies) on the single X allele in tumors from males and on the active X allele in tumors from females have also been described." +MONDO_0008757,"Definition: Alopecia universalis congenita (ALUNC) is a severe autosomal recessive form of alopecia characterized by a complete absence of hair development affecting all scalp and body hair (previous studies). + +This rare disorder is clearly distinct from alopecia areata (AA1; previous studies), which has an autoimmune basis with probable genetic predisposition." +MONDO_0008872,"Definition: Microcephalic osteodysplastic primordial dwarfism type II is characterized by intrauterine growth retardation, severe proportionate short stature, and microcephaly. It is distinct from Seckel syndrome (see previous studies) by more severe growth retardation, radiologic abnormalities, and absent or mild mental retardation (summary by previous studies)." +MONDO_0009131,"Definition: Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by previous studies). + +For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (previous studies)." +Orphanet_1764,"Definition: Hereditary sensory and autonomic neuropathy type III (HSAN3) is an autosomal recessive neurodegenerative disorder with onset soon after birth. Affected individuals show progressive symptoms resulting from depletion of sensory proprioceptive and autonomic neurons. Features include gastrointestinal dysfunction, gastroesophageal reflux, vomiting crises, recurrent pneumonia, seizures, gait abnormalities with loss of ambulation, kyphoscoliosis, postural hypotension, hypertension crises, absence of fungiform papillae on the tongue, decreased deep tendon reflexes, defective lacrimation, and impaired pain and temperature perception. The disorder is inevitably fatal, with only 50% of patients reaching 40 years of age. HSAN3 has a high carrier frequency in the Ashkenazi Jewish population (summary by previous studies). + +For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (previous studies)." +MONDO_0009492,"Definition: Ketone bodies are major vectors of energy transfer from the liver to extrahepatic tissues and are the main source of lipid-derived energy for the brain. previous studies reviewed medical aspects of ketone body metabolism, including the differential diagnosis of abnormalities. As the first step of ketone body utilization, succinyl-CoA:3-oxoacid CoA transferase (SCOT, or OXCT1; previous studies) catalyzes the reversible transfer of CoA from succinyl-CoA to acetoacetate." +MONDO_0009548,"Definition: HOMG5 is an autosomal recessive disorder characterized by severe renal magnesium wasting, progressive renal failure, nephrocalcinosis, and severe visual impairment (previous studies). Amelogenesis imperfecta may also be present in some patients (previous studies). + +For a discussion of genetic heterogeneity of renal hypomagnesemia, see previous studies." +MONDO_0009644,"Definition: Molybdenum cofactor deficiency is a rare autosomal recessive metabolic disorder characterized by neonatal onset of intractable seizures, opisthotonus, and facial dysmorphism associated with hypouricemia and elevated urinary sulfite levels. Affected individuals show severe neurologic damage and often die in early childhood (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of MOCOD, see MOCODA (previous studies), which is clinically indistinguishable from MOCODB." +MONDO_0010584,"Definition: Dyskeratosis congenita (DKC) is classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. It is characterized by short telomeres. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features, including pulmonary fibrosis, liver cirrhosis, hepatopulmonary syndrome, premature hair loss and/or graying, osteoporosis, atresia of the lacrimal ducts, gastrointestinal disease (esophageal strictures or enteropathy), and learning difficulties. Males may have testicular atrophy. Predisposition to malignancy, including hematologic malignancy and squamous cell carcinoma, is an important feature. The disorder is caused by defects in the maintenance of telomeres (summary by previous studies; previous studies; previous studies). + +Hoyeraal-Hreidarsson syndrome (HHS) refers to a clinically severe variant of DKC that is characterized by multisystem involvement and early onset in utero. Patients with HHS can show intrauterine growth retardation, microcephaly, delayed development, bone marrow failure, immunodeficiency, cerebellar hypoplasia, immune defects (B-cell lymphopenia and hypogammaglobulinemia), and gastrointestinal manifestations, including enterocolitis and enteropathy. Death often occurs in childhood (summary by previous studies). + +For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (previous studies)." +MONDO_0011484,"Definition: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disorder of the heart characterized by a reproducible form of polymorphic ventricular tachycardia induced by physical activity, stress, or catecholamine infusion, which can deteriorate into ventricular fibrillation. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. Typically, clinical cardiologic examinations, such as baseline ECG and echocardiogram, reveal mostly normal findings, and postmortem examinations, when carried out, have not disclosed any significant morphologic alterations in the fine structure of the heart, with the exception of mild fatty myocardial infiltration in a few patients. The hallmark of CPVT comprises ventricular arrhythmias of varying morphology not present under resting conditions but appearing only with physical exercise, excitement, or catecholamine administration. These arrhythmias are first seen as ventricular premature complexes, later in bigeminy, followed by bidirectional or polymorphic ventricular tachycardia, which eventually leads to ventricular fibrillation. CPVT can be inherited as an autosomal dominant or recessive trait. Clinical penetrance in this disease ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Beta-blockers without sympathomimetic activity are clinically effective in the reduction of syncope, but implantation of an automatic internal defibrillator is occasionally needed in these patients (summary by previous studies). + + Genetic Heterogeneity of Catecholaminergic Polymorphic Ventricular Tachycardia + +Also see CPVT2 (previous studies), caused by mutation in the CASQ2 gene (previous studies) on chromosome 1p13; CPVT3 (previous studies), caused by mutation in the TECRL gene (previous studies) on chromosome 4q13; CPVT4 (previous studies), caused by mutation in the CALM1 gene (previous studies) on chromosome 14q32; CPVT5 (previous studies) is caused by mutation in the TRDN gene (previous studies) on chromosome 6q22; and CPVT6 (see previous studies) is caused by mutation in the CALM3 gene (previous studies) on chromosome 19q13." +MONDO_0011527,"Definition: Congenital hypomyelinating neuropathy (CHN) is characterized clinically by onset of hypotonia at birth, areflexia, distal muscle weakness, and very slow nerve conduction velocities (often less than 10 m/s). previous studies noted that pathologic findings on sural nerve biopsies show hypomyelination of most or all fibers. Based on these findings, CHN is considered to be a result of congenital impairment in myelin formation. + +There has been some controversy and difficulty in differentiating congenital hypomyelination from Dejerine-Sottas syndrome (DSS; previous studies) because there is considerable overlap in clinical presentation. Based on pathologic findings of sural nerve biopsies (the absence of active myelin breakdown and the paucity of the onion bulbs in CHN and the presence of demyelination/remyelination and an abundance of well-organized onion bulbs in DSS; see previous studies), CHN is considered to result from a congenital impairment in myelin formation, whereas DSS is thought to be due to aberrant demyelination and subsequent remyelination of the peripheral nerve. + +There is also variation in the prognosis of patients diagnosed with CHN. In patients with CHN, previous studies showed correlation of morbidity and mortality with the presence/absence of onion bulbs: patients with few onion bulbs died in early infancy, usually because of difficulty in swallowing and respiration after birth. Patients with atypical onion bulbs survived but were affected with severe motor and sensory impairment. These differences in outcome may represent genetic heterogeneity such that mutations in essential early myelin gene(s) cause a severe phenotype, whereas mutations in other, possibly later acting gene(s), such as MPZ, lead to a less severe outcome. + + Genetic Heterogeneity of Congenital Hypomyelinating Neuropathy + +See also CHN2 (previous studies), caused by mutation in the MPZ gene (previous studies) on chromosome 1q23; and CHN3 (previous studies), caused by mutation in the CNTNAP1 gene (previous studies) on chromosome 17q21." +MONDO_0012594,"Definition: Hereditary deficiency of complement factor I is associated with a propensity to pyogenic infection and usually follows an autosomal recessive pattern of inheritance (previous studies). A subset of patients with CFID develop a renal disease termed 'C3 glomerulopathy' (C3G2), which is characterized by glomerular deposition of C3 observed on renal biopsy. Affected individuals have hematuria and proteinuria with variable progression of renal dysfunction (summary by previous studies). + +For a discussion of genetic heterogeneity of C3G, see C3G1 (previous studies), also known as complement factor H deficiency." +MONDO_0013977,"Definition: Combined oxidative phosphorylation deficiency-13 (COXPD13) is an autosomal recessive multisystem disorder resulting from mitochondrial dysfunction. Affected individuals develop severe neurologic impairment in the first months of life, including hypotonia, abnormal dystonic movements, hearing loss, poor feeding, global developmental delay, and abnormal eye movements. Brain imaging shows signal abnormalities in putamen, basal ganglia, caudate nuclei, or corpus callosum, as well as delayed myelination. Analysis of patient tissues shows multiple defects in enzymatic activities of the mitochondrial respiratory chain, although some tissues may show normal values since tissue expression of the mitochondrial defect and metabolic needs of specific tissues are variable (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0014343,"Definition: Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification (summary by previous studies). + +For a discussion of genetic heterogeneity of Desbuquois dysplasia, see DBQD1 (previous studies)." +MONDO_0014768,"Definition: Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 is a disorder of the small arterial vessels of the brain characterized by stroke, transient ischemic attacks (TIA), cognitive impairment, dementia, balance impairment, gait disturbance, headaches, and/or seizures associated with early confluent or confluent diffuse white matter hyperintensities and sometimes associated with multiple lacunar infarcts and microbleeds. Dilated perivascular spaces with a typical status cribrosum characterized by innumerable dilated Virchow-Robin spaces and resulting in a cribriform change in basal ganglia occur in most patients. CADASIL2 differs from CADASIL1 (previous studies) by a later age of onset (previous studies). + +For a discussion of genetic heterogeneity of CADASIL, see previous studies." +MONDO_0030025,"Definition: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures (NEDHYMS) is an autosomal recessive disorder characterized by global developmental delay with axial hypotonia, inability to sit or walk, and severely impaired intellectual development with absent language. Most patients develop early-onset intractable seizures that prevent normal development. Additional features include feeding difficulties with poor overall growth and microcephaly. Some patients may have spastic quadriplegia, poor eye contact due to cortical blindness, variable dysmorphic features, and nonspecific abnormalities on brain imaging (summary by previous studies)." +MONDO_0030800,"Definition: Progressive familial intrahepatic cholestasis-9 (PFIC9) is an autosomal recessive disorder characterized by onset of cholestasis associated with increased serum gamma-glutamyltransferase (GGT) in infancy or early childhood. Affected individuals have hepatosplenomegaly and may have portal hypertension or upper gastrointestinal bleeding. Liver biopsy shows fibrosis, cirrhosis, bile duct proliferation, and abnormal bile duct morphology. The disorder is thought to result from ciliary defects in cholangiocytes, consistent with a ciliopathy that appears to be restricted to the liver. Treatment with ursodeoxycholic acid (UDCA) or liver transplant is effective (previous studies). + +For a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (previous studies)." +MONDO_0030818,"Definition: Spermatogenic failure-73 (SPGF73) is characterized by male infertility, resulting from nonobstructive azoospermia due to meiotic arrest (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0060640,"Definition: NEDMEBA is an autosomal recessive neurodegenerative disorder characterized by global developmental delay, severe intellectual disability with poor or absent speech and autistic stereotypic behaviors, microcephaly, early-onset generalized seizures, and hypotonia (summary by previous studies)." +Orphanet_227535,"Definition: Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement." +MONDO_0016419,"Definition: Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement." +EFO_0000305,"Definition: Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement." +EFO_0003869,"Definition: Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement." +EFO_0003783,Definition: Fazio-Londe disease is a progressive bulbar palsy with onset in childhood that presents with hypotonia and respiratory insufficiency (summary by previous studies). +MONDO_0007688,"Definition: Myhre syndrome (MYHRS) is a rare disorder characterized by mental retardation, dysmorphic facial features, including microcephaly, midface hypoplasia, prognathism, and blepharophimosis, typical skeletal anomalies, including short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria, and cardiovascular defects with a striking fibroproliferative response to surgical intervention. All reported cases have been sporadic (summary by previous studies and previous studies)." +MONDO_0008903,"Definition: Lung cancer is the leading cause of cancer deaths in the U.S. and worldwide. The 2 major forms of lung cancer are nonsmall cell lung cancer and small cell lung cancer (see previous studies), which account for 85% and 15% of all lung cancers, respectively. Nonsmall cell lung cancer can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. Cigarette smoking causes all types of lung cancer, but it is most strongly linked with small cell lung cancer and squamous cell carcinoma. Adenocarcinoma is the most common type in patients who have never smoked. Nonsmall cell lung cancer is often diagnosed at an advanced stage and has a poor prognosis (summary by previous studies)." +EFO_0000571,"Definition: Lung cancer is the leading cause of cancer deaths in the U.S. and worldwide. The 2 major forms of lung cancer are nonsmall cell lung cancer and small cell lung cancer (see previous studies), which account for 85% and 15% of all lung cancers, respectively. Nonsmall cell lung cancer can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. Cigarette smoking causes all types of lung cancer, but it is most strongly linked with small cell lung cancer and squamous cell carcinoma. Adenocarcinoma is the most common type in patients who have never smoked. Nonsmall cell lung cancer is often diagnosed at an advanced stage and has a poor prognosis (summary by previous studies)." +EFO_0003060,"Definition: Lung cancer is the leading cause of cancer deaths in the U.S. and worldwide. The 2 major forms of lung cancer are nonsmall cell lung cancer and small cell lung cancer (see previous studies), which account for 85% and 15% of all lung cancers, respectively. Nonsmall cell lung cancer can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. Cigarette smoking causes all types of lung cancer, but it is most strongly linked with small cell lung cancer and squamous cell carcinoma. Adenocarcinoma is the most common type in patients who have never smoked. Nonsmall cell lung cancer is often diagnosed at an advanced stage and has a poor prognosis (summary by previous studies)." +MONDO_0009653,"Definition: Mucolipidosis IV is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities. The lysosomal hydrolases in ML IV are normal, in contrast to most other storage diseases. The disorder results from a defect in transport along the lysosomal pathway, affecting membrane sorting and/or late steps of endocytosis, which causes intracellular accumulation of lysosomal substrates. Over 80% of the patients in whom the diagnosis of ML IV has been made are Ashkenazi Jews, including severely affected and mildly affected patients (previous studies)." +MONDO_0010211,"Definition: Xeroderma pigmentosum is a genetically heterogeneous condition characterized by increased sensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer resulting from a defect in DNA repair. XPC is the most common form of XP in the white population, accounting for over a third of all cases in this group (review by previous studies). + +For a general discussion of xeroderma pigmentosum, see XPA (previous studies)." +Orphanet_276255,"Definition: Xeroderma pigmentosum is a genetically heterogeneous condition characterized by increased sensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer resulting from a defect in DNA repair. XPC is the most common form of XP in the white population, accounting for over a third of all cases in this group (review by previous studies). + +For a general discussion of xeroderma pigmentosum, see XPA (previous studies)." +MONDO_0012784,"Definition: Primary coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. Oral coenzyme Q10 supplementation does not result in significant improvement of neurologic symptoms (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (previous studies)." +MONDO_0008592,"Definition: Trichodentoosseous syndrome is an autosomal dominant disorder with complete penetrance characterized by abnormalities involving hair, teeth, and bone (summary by previous studies)." +MONDO_0008895,"Definition: Adult-onset calcification of the lower extremity arteries, including the iliac, femoral, and tibial arteries, and hand and foot capsule joints is an autosomal recessive condition that represents only the second mendelian disorder of isolated calcification (see generalized arterial calcification of infancy (GACI), previous studies). Age of onset has been reported as early as the second decade of life, usually involving intense joint pain or calcification in the hands (previous studies)." +MONDO_0010475,"Definition: Central hypothyroidism and testicular enlargement (CHTE) is characterized by central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasional transient partial GH deficiency. Some carrier females also exhibit central hypothyroidism and mild prolactin deficiency. Inter- and intrafamilial variability has been observed (summary by previous studies)." +MONDO_0010916,"Definition: Polycystic kidney disease-3, a form of autosomal dominant PKD (ADPKD), is characterized by renal cysts, often associated with liver cysts, that may lead to organ dysfunction. Affected individuals usually present in mid to late adulthood with progressive cysts in the kidney and/or liver. The renal disease is relatively mild, and only some patients develop hypertension; renal insufficiency usually does not occur. The liver disease shows a wide spectrum of severity: some patients have no cysts, whereas others have severe liver involvement (summary by previous studies). + +For a discussion of genetic heterogeneity of PKD, see PKD1 (previous studies)." +EFO_1001496,"Definition: Polycystic kidney disease-3, a form of autosomal dominant PKD (ADPKD), is characterized by renal cysts, often associated with liver cysts, that may lead to organ dysfunction. Affected individuals usually present in mid to late adulthood with progressive cysts in the kidney and/or liver. The renal disease is relatively mild, and only some patients develop hypertension; renal insufficiency usually does not occur. The liver disease shows a wide spectrum of severity: some patients have no cysts, whereas others have severe liver involvement (summary by previous studies). + +For a discussion of genetic heterogeneity of PKD, see PKD1 (previous studies)." +MONDO_0011339,"Definition: Spastic paraplegia-8 is an autosomal dominant neurologic disorder characterized by adult onset of progressive lower limb spasticity and hyperreflexia resulting in difficulty walking. Some patients may become wheelchair-bound after several decades. Other features may include upper limb spasticity, impaired vibration sense in the distal lower limbs, and urinary urgency or incontinence (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +Orphanet_100989,"Definition: Spastic paraplegia-8 is an autosomal dominant neurologic disorder characterized by adult onset of progressive lower limb spasticity and hyperreflexia resulting in difficulty walking. Some patients may become wheelchair-bound after several decades. Other features may include upper limb spasticity, impaired vibration sense in the distal lower limbs, and urinary urgency or incontinence (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +MONDO_0012503,"Definition: THPM1 is an autosomal recessive trait associated with severe hematopoietic toxicity when patients are treated with standard doses of the antineoplastic agents 6-mercaptopurine (6MP) or 6-thioguanine (6TG), or the immunosuppressant azathioprine (AZA) (previous studies). + +The thiopurines are prodrugs that require extensive metabolism in order to exert their cytotoxic action. Azathioprine is nonenzymatically reduced to 6MP. 6MP and 6TG are activated by HPRT (previous studies) and subsequent steps to form cytotoxic thioguanine nucleotides (TGNs) which are incorporated into DNA and/or RNA, causing DNA-protein cross-links, single-strand breaks, interstrand cross-links, and sister chromatid exchange. TPMT functions mainly to inactivate these drugs; thus, a deficiency of TPMT results in increased conversion to toxic TGNs, which can result in myelosuppression (previous studies). However, 6MP is unique in that it can also be converted via TPMT into a methyl-thioinosine 5-prime monophosphate (MeTIMP), a metabolite that inhibits de novo purine synthesis and likely contributes to the cytotoxic effect of 6MP (previous studies; previous studies; previous studies). + + Genetic Heterogeneity of Poor Thiopurine Metabolism + +See also THPM2 (previous studies), caused by variation in the NUDT15 gene (previous studies) on chromosome 13q14." +MONDO_0024457,Definition: Neurodegeneration with brain iron accumulation-2A is an autosomal recessive neurodegenerative disease characterized by onset in the first 2 years of life; it is also referred to as infantile neuroaxonal dystrophy (INAD). Pathologic findings include axonal swelling and spheroid bodies in the central nervous system (review by previous studies). +MONDO_0030972,"Definition: Spermatogenic failure-74 (SPGF74) is characterized by nonobstructive azoospermia and male infertility due to complete meiotic arrest at the spermatocyte zygotene or pachytene stage. Some men exhibit reduced testicular volume and/or reduced testosterone level (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0032664,"Definition: Primary ciliary dyskinesia-40 (CILD40) is an autosomal recessive disorder with a relatively mild respiratory phenotype compared to other CILDs. Patients present in childhood with mild upper respiratory symptoms and infections, but typically do not develop serious lung disease. Nitric oxide levels are low-normal or normal. All reported patients have had situs inversus, including several with severe congenital cardiac malformations, but left-right body asymmetry is still theoretically random and would occur in 50% of patients (summary by previous studies). + +For a discussion of genetic heterogeneity of primary ciliary dyskinesia and Kartagener syndrome, see CILD1 (previous studies)." +MONDO_0060642,"Definition: NEDMAGA is a neurodevelopmental disorder characterized by infantile-onset global developmental delay with severe to profound intellectual disability, mildly delayed walking with broad-based and unsteady gait, and absence of meaningful language. Patients have features of autism, with repetitive behaviors and poor communication, but usually are socially reactive and have a happy demeanor. More variable neurologic features include mild seizures, spasticity, and peripheral neuropathy (summary by previous studies)." +MONDO_0700089,"Definition: Paroxysmal nonkinesigenic dyskinesia-1 (PNKD1) is an autosomal dominant movement disorder characterized by attacks of dystonia, chorea, and athetosis. Attacks may be precipitated by stress, fatigue, caffeine, alcohol, ovulation, or menstruation, and may last minutes to hours (summary by previous studies, previous studies). + + Genetic Heterogeneity of Paroxysmal Nonkinesigenic Dyskinesia + +See also PNKD2 (previous studies), mapped to chromosome 2q31, and PNKD3 (previous studies), caused by mutation in the KCNMA1 gene (previous studies) on chromosome 10q22." +MONDO_0800046,"Definition: Abnormal thyroid hormone metabolism-1 (THMA1) is characterized by multiorgan defects, including abnormal thyroid hormone metabolism, myopathy, hearing loss, and male infertility (summary by previous studies). + + Genetic Heterogeneity of Abnormal Thyroid Hormone Metabolism + +THMA2 (previous studies) is caused by mutation in the DIO1 gene (previous studies) on chromosome 1p32. THMA3 (previous studies) is caused by mutation in the TRU-TCA1-1 gene (previous studies) on chromosome 19q13." +MONDO_0850514,"Definition: Inclusion body myopathy and brain white matter abnormalities (IBMWMA) is an autosomal dominant adult-onset disorder characterized predominantly by proximal limb girdle muscle weakness affecting the lower and upper limbs and resulting in gait difficulties and scapular winging. Additional features may include dysarthria, dysphagia, low back pain, and hyporeflexia. EMG is consistent with a myopathic process, although neuropathic findings have also been shown. Muscle biopsy shows fiber type variation, internal nuclei, rimmed vacuoles, and cytoplasmic protein aggregates or inclusions. Serum creatine kinase is usually elevated. Cognitive impairment or frontotemporal dementia occurs in some patients. The disorder is slowly progressive; some patients become wheelchair-bound after many years. Rare patients with this mutation develop ALS; some have both myopathy and ALS. Brain imaging shows white matter abnormalities using diffusion tensor imaging. The disorder is classified as multisystem proteinopathy-6 (MSP6) due to the characteristic disease mechanism of protein misfolding and abnormal tissue deposition (summary by previous studies)." +Orphanet_2442,"Definition: X-linked lymphoproliferative syndrome, or Duncan disease, is a primary immunodeficiency characterized by severe immune dysregulation often after viral infection, typically with Epstein-Barr virus (EBV). It is a complex phenotype manifest as severe or fatal mononucleosis, acquired hypogammaglobulinema, hemophagocytic lymphohistiocytosis (HLH), and/or malignant lymphoma. Other features may include aplastic anemia, red cell aplasia, and lymphomatoid granulomatosis (previous studies; previous studies; previous studies; previous studies; previous studies). + + Genetic Heterogeneity of X-linked/Autosomal Lymphoproliferative Syndrome + +See XLP2 (previous studies), caused by mutation in the XIAP gene (previous studies), also on Xq25; LPFS1 (previous studies), caused by mutation in the ITK gene (previous studies) on chromosome 5q33; LPFS2 (previous studies), caused by mutation in the CD27 gene (previous studies) on chromosome 12p13; and LPFS3 (previous studies), caused by mutation in the CD70 gene (TNFSF7; previous studies) on chromosome 19p13." +MONDO_0007510,"Definition: The main features of Clouston syndrome are dystrophy of the nails that tend to be hypoplastic and deformed with increased susceptibility to paronychial infections, defects of the hair that range from brittleness and slow growth rate to total alopecia, and moderate to severe palmoplantar hyperkeratosis with reduced keratinocyte desquamation (summary by previous studies)." +MONDO_0009255,"Definition: Galactosemia II (GALAC2), or galactokinase deficiency, is an autosomal recessive disorder that causes cataract formation in children not maintained on a lactose-free diet. Cataract formation is the result of osmotic phenomena caused by the accumulation of galactitol in the lens (previous studies). + +For a discussion of genetic heterogeneity of galactosemia, see GALAC1 (previous studies)." +MONDO_0009388,"Definition: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant (summary by previous studies; previous studies). + +The AASS gene encodes a bifunctional enzyme: lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type I, both enzymatic functions of AASS are defective; in hyperlysinemia type II, also known as saccharopinuria (previous studies), some of the first enzymatic function is retained (previous studies; previous studies)." +MONDO_0009411,"Definition: Autoimmune polyglandular syndrome type I is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (previous studies). However, variable APS1 phenotypes have been observed, even among sibs. In addition, some patients may exhibit apparent isolated hypoparathyroidism, an early manifestation of APS1 with peak incidence at around age 5 years; over longterm follow-up, the development of additional features of APS1 may be observed (previous studies)." +Orphanet_3453,"Definition: Autoimmune polyglandular syndrome type I is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (previous studies). However, variable APS1 phenotypes have been observed, even among sibs. In addition, some patients may exhibit apparent isolated hypoparathyroidism, an early manifestation of APS1 with peak incidence at around age 5 years; over longterm follow-up, the development of additional features of APS1 may be observed (previous studies)." +MONDO_0009436,"Definition: Pallister-Hall-like syndrome (PHLS) is a pleiotropic autosomal recessive disorder characterized by phenotypic variability. Patients exhibit postaxial polydactyly as well as hypothalamic hamartoma, cardiac and skeletal anomalies, and craniofacial dysmorphisms. Hirschsprung disease has also been observed (previous studies; previous studies). + +Pallister-Hall syndrome (previous studies) is an autosomal dominant disorder with features overlapping those of PHLS, caused by mutation in the GLI3 gene (previous studies)." +MONDO_0009491,"Definition: Haim-Munk syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, severe periodonitis, arachnodactyly, acroosteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers (summary by previous studies)." +MONDO_0009495,"Definition: Keutel syndrome (KTLS) is an autosomal recessive disorder characterized by multiple peripheral pulmonary stenoses, brachytelephalangy, inner ear deafness, and abnormal cartilage ossification or calcification (summary by previous studies)." +MONDO_0010483,"Definition: X-linked intellectual developmental disorder-98 (XLID98) is a neurodevelopmental disorder characterized by delayed psychomotor development, poor speech, behavioral abnormalities, poor overall growth, dysmorphic facial features, and often early-onset seizures. Some carrier females are unaffected, whereas other females with mutations are affected; males tend to be more severely affected than females. It is believed that the phenotypic variability and disease manifestations in female carriers results from skewed X-inactivation or cellular mosaicism (summary by previous studies)." +MONDO_0011948,"Definition: Pontocerebellar hypoplasia (PCH) refers to a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. Clinical features vary, but usually include severe developmental delay, dysmorphic features, seizures, and early death (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (previous studies)." +MONDO_0012052,"Definition: Congenital disorders of glycosylation (CDGs) comprise a group of multisystem diseases with mostly severe psychomotor and mental retardation. Type I CDG comprises those disorders in which there are defects that affect biosynthesis of dolichol-linked oligosaccharides in the cytosol or the endoplasmic reticulum (ER), as well as defects involving the transfer of oligosaccharides onto nascent glycoproteins. Type II CDG comprises all defects of further trimming and elongation of N-linked oligosaccharides in the ER and Golgi (previous studies). + +CDG1K is a type I CDG characterized by predominant neurologic involvement. Survival ranges from the second day of life to adulthood. The liver is affected in a minority of patients and shows hepatomegaly, edema, ascites, cholestatic jaundice, portal hypertension, and Budd-Chiari syndrome (summary by previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies)." +MONDO_0012624,"Definition: MC1DN20 is an autosomal recessive multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see previous studies." +MONDO_0013417,"Definition: The main clinical manifestation of primary C3 deficiency is childhood-onset of recurrent bacterial infections, mainly caused by gram-negative bacteria, such as Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenzae, and Escherichia coli; infections with gram-positive bacteria also occur. Infections in the upper and lower respiratory tract, including pneumonia, episodes of sinusitis, tonsillitis, and otitis, are the most frequent consequence of the C3 deficiency. Approximately 26% of patients with C3 deficiency develop immune complex-mediated autoimmune diseases resembling systemic lupus erythematosus (see previous studies), and about 26% of patients develop mesangiocapillary or membranoproliferative glomerulonephritis, resulting in renal failure (summary by previous studies)." +MONDO_0014284,"Definition: Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by previous studies and previous studies). + +There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, previous studies). + +For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (previous studies)." +MONDO_0014959,"Definition: MTDPS12A is characterized by severe hypotonia due to mitochondrial dysfunction apparent at birth. Affected infants have respiratory insufficiency requiring mechanical ventilation and have poor or no motor development. Many die in infancy, and those that survive have profound hypotonia with significant muscle weakness and inability to walk independently. Some patients develop hypertrophic cardiomyopathy. Muscle samples show mtDNA depletion and severe combined mitochondrial respiratory chain deficiencies (summary by previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0030064,"Definition: Episodic ataxia type 9 (EA9) is a neurologic disorder characterized by onset of ataxic episodes in the first years of life. Features may include difficulty walking, dizziness, slurred speech, headache, vomiting, and pain. The ataxic episodes vary in frequency and duration; most tend to occur every few weeks or months and last minutes to hours. Prior to the EA, most patients have neonatal- or infantile-onset tonic or generalized tonic-clonic (GTC) seizures that may be severe and refractory to medication, but remit later in infancy or early childhood, either spontaneously or concurrently with medication. Some patients have mildly delayed development with speech delay and/or autistic features or mildly impaired intellectual development. However, others show normal psychomotor development. Treatment of the ataxic episodes with acetazolamide is effective in about 50% of patients (summary by previous studies). + +For a phenotypic description and discussion of genetic heterogeneity of episodic ataxia, see EA1 (previous studies)." +MONDO_0030785,"Definition: Autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75) is characterized by global developmental delay apparent from infancy or early childhood and moderate to profoundly impaired intellectual development. Most affected individuals have behavioral abnormalities, including aggression and ADHD; a few have psychiatric manifestations, including psychosis. More variable additional features include well-controlled seizures and dysmorphic facial features. Brain imaging often shows frontal predominant pachygyria or other gyri/sulci abnormalities, consistent with a variant of lissencephaly and a malformation of cortical development (MCD) (summary by previous studies)." +MONDO_0030852,"Definition: Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB) is a syndromic disorder with multisystemic involvement. Affected individuals have severe global developmental delay with severely impaired intellectual development, poor or absent language, behavioral abnormalities, seizures, and sleep disturbances. Craniofacial dysmorphisms, while variable, include round face, prognathism, depressed nasal bridge, and cleft or high-arched palate. Brain imaging shows dysgenesis of the corpus callosum and progressive cerebellar atrophy. Additional features may include genitourinary tract anomalies, hearing loss, and mild distal skeletal defects (summary by previous studies)." +MONDO_0054700,"Definition: Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is an autosomal dominant disorder with onset in early infancy. Affected individuals develop severe inflammatory neutrophilic dermatitis, autoimmunity, and variable immunodeficiency (summary by previous studies). + +For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (previous studies)." +MONDO_0054764,"Definition: Neurodegeneration with brain iron accumulation-8 (NBIA8) is characterized by iron accumulation in the basal ganglia and manifests as a progressive extrapyramidal syndrome with dystonia, rigidity, and choreoathetosis (previous studies)." +MONDO_0060622,"Definition: NEDMIAL is a neurodevelopmental disorder characterized by delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, delayed or absent speech development, and impaired intellectual development, sometimes with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by previous studies and previous studies)." +Orphanet_369894,"Definition: Developmental and epileptic encephalopathy-18 (DEE18) is a severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, and early onset of refractory seizures. Brain imaging shows a thick corpus callosum and persistent cavum septum pellucidum on brain imaging (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0014201,"Definition: Developmental and epileptic encephalopathy-18 (DEE18) is a severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, and early onset of refractory seizures. Brain imaging shows a thick corpus callosum and persistent cavum septum pellucidum on brain imaging (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +EFO_0000706,"Definition: Spondyloarthropathy (SpA), one of the commonest chronic rheumatic diseases, includes a spectrum of related disorders comprising the prototype ankylosing spondylitis (AS), a subset of psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy (previous studies). These phenotypes are difficult to differentiate because they may occur simultaneously or sequentially in the same patient. Studies have suggested that a predominant shared component, including HLA-B27, predisposes to all phenotypic subsets, and that these subsets should be considered as various phenotypic expressions of the same disease (previous studies, previous studies). + +previous studies provided a detailed review of ankylosing spondylitis, including clinical features, pathogenesis, and management. + + Genetic Heterogeneity of Susceptibility to Spondyloarthropathy + +Additional susceptibility loci for spondyloarthropathy have been identified on chromosome 9q31-q34 (SPDA2; previous studies) and chromosome 2q36 (SPDA3; previous studies)." +MONDO_0007771,"Definition: Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is characterized by diffuse hyperpigmentation of variable intensity sometimes associated with cafe-au-lait macules and larger hypopigmented ash-leaf macules. These features, which involve the face, neck, trunk, and limbs, are seen at birth or develop early in infancy (summary by previous studies and previous studies). + +Also see familial progressive hyperpigmentation (FPH1; previous studies)." +MONDO_0008222,"Definition: Andersen-Tawil syndrome is an autosomal dominant multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. Hypoplastic kidney and valvular heart disease have also been reported. The disorder shows marked intrafamilial variability and incomplete penetrance (summary by previous studies)." +Orphanet_37553,"Definition: Andersen-Tawil syndrome is an autosomal dominant multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. Hypoplastic kidney and valvular heart disease have also been reported. The disorder shows marked intrafamilial variability and incomplete penetrance (summary by previous studies)." +MONDO_0008641,"Definition: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) is an adult-onset autosomal dominant disorder involving the microvessels of the brain and resulting in central nervous system degeneration with progressive loss of vision, stroke, motor impairment, and cognitive decline. Death occurs in most patients 5 to 10 years after onset. A subset of affected individuals have systemic vascular involvement evidenced by Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction (summary by previous studies)." +Orphanet_3421,"Definition: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) is an adult-onset autosomal dominant disorder involving the microvessels of the brain and resulting in central nervous system degeneration with progressive loss of vision, stroke, motor impairment, and cognitive decline. Death occurs in most patients 5 to 10 years after onset. A subset of affected individuals have systemic vascular involvement evidenced by Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction (summary by previous studies)." +Orphanet_63261,"Definition: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) is an adult-onset autosomal dominant disorder involving the microvessels of the brain and resulting in central nervous system degeneration with progressive loss of vision, stroke, motor impairment, and cognitive decline. Death occurs in most patients 5 to 10 years after onset. A subset of affected individuals have systemic vascular involvement evidenced by Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction (summary by previous studies)." +Orphanet_247691,"Definition: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) is an adult-onset autosomal dominant disorder involving the microvessels of the brain and resulting in central nervous system degeneration with progressive loss of vision, stroke, motor impairment, and cognitive decline. Death occurs in most patients 5 to 10 years after onset. A subset of affected individuals have systemic vascular involvement evidenced by Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction (summary by previous studies)." +Orphanet_71291,"Definition: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS) is an adult-onset autosomal dominant disorder involving the microvessels of the brain and resulting in central nervous system degeneration with progressive loss of vision, stroke, motor impairment, and cognitive decline. Death occurs in most patients 5 to 10 years after onset. A subset of affected individuals have systemic vascular involvement evidenced by Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction (summary by previous studies)." +MONDO_0009738,"Definition: Sialidosis is an autosomal recessive disorder characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. Common to the sialidoses is the accumulation and/or excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins (summary by previous studies). The sialidoses are distinct from the sialurias in which there is storage and excretion of 'free' sialic acid, rather than 'bound' sialic acid; neuraminidase activity in sialuria is normal or elevated. Salla disease (previous studies) is a form of 'free' sialic acid disease. + + Classification + +previous studies provided a logical nosology of neuraminidase deficiency into sialidosis type I and type II. Type I is the milder form, also known as the 'normosomatic' type or the cherry red spot-myoclonus syndrome. Sialidosis type II is the more severe form with an earlier onset, and is also known as the 'dysmorphic' type. Type II has been subdivided into juvenile and infantile forms. Other terms for sialidosis type II are mucolipidosis I and lipomucopolysaccharidosis." +Orphanet_812,"Definition: Sialidosis is an autosomal recessive disorder characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. Common to the sialidoses is the accumulation and/or excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins (summary by previous studies). The sialidoses are distinct from the sialurias in which there is storage and excretion of 'free' sialic acid, rather than 'bound' sialic acid; neuraminidase activity in sialuria is normal or elevated. Salla disease (previous studies) is a form of 'free' sialic acid disease. + + Classification + +previous studies provided a logical nosology of neuraminidase deficiency into sialidosis type I and type II. Type I is the milder form, also known as the 'normosomatic' type or the cherry red spot-myoclonus syndrome. Sialidosis type II is the more severe form with an earlier onset, and is also known as the 'dysmorphic' type. Type II has been subdivided into juvenile and infantile forms. Other terms for sialidosis type II are mucolipidosis I and lipomucopolysaccharidosis." +MONDO_0011512,"Definition: Brooke-Spiegler syndrome is an autosomal dominant disorder classically characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, and gradually increase in size and number throughout life (previous studies). + +Because BRSS, familial cylindromatosis, and MFT1 are allelic, and because different manifestations of each have been described within a single family, many consider these disorders to represent a phenotypic spectrum of a single disease entity (previous studies; previous studies; previous studies; previous studies; previous studies). + +previous studies provided a review of Brooke-Spiegler syndrome and pathogenic mutations in the CYLD gene." +MONDO_0013930,"Definition: The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 4 (CG4, equivalent to CG6 and CGC) have mutations in the PEX6 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0014335,"Definition: Progressive microcephaly with seizures and cerebral and cerebellar atrophy is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder with onset in the first days or months of life. Patients are born with microcephaly and soon develop intractable seizures, resulting in profoundly delayed development and hypotonia (summary by previous studies)." +Orphanet_404437,"Definition: Progressive microcephaly with seizures and cerebral and cerebellar atrophy is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder with onset in the first days or months of life. Patients are born with microcephaly and soon develop intractable seizures, resulting in profoundly delayed development and hypotonia (summary by previous studies)." +MONDO_0014382,"Definition: Tatton-Brown-Rahman syndrome (TBRS) is characterized by tall stature, a distinctive facial appearance, and impaired intellectual development (previous studies). Some patients may have increased susceptibility to the development of acute myeloid leukemia (AML; previous studies), particularly if they have DNMT3A mutations affecting the R882 residue (previous studies)." +MONDO_0030813,"Definition: Immunodeficiency-101 (varicella zoster virus-specific) (IMD101) is an autosomal dominant immunologic condition characterized by reactivation of varicella zoster virus (VZV) infection in adulthood after primary childhood infection with VZV. The viral reactivation manifests as central nervous system vasculitis with stroke-like episodes and lacunar infarcts on brain imaging. Features include headache, hemiparesis, impaired balance, and other neurologic signs. The disorder results from an impaired innate immune response specifically to VZV DNA. Affected individuals do not have increased susceptibility to other infections. Treatment with acyclovir is effective (previous studies)." +MONDO_0054699,"Definition: Proteasome-associated autoinflammatory syndrome-3 is an autosomal recessive syndrome with onset in early infancy. Affected individuals present with nodular dermatitis, recurrent fever, myositis, panniculitis-induced lipodystrophy, lymphadenopathy, and dysregulation of the immune response, particularly associated with abnormal type I interferon-induced gene expression patterns. Additional features are highly variable, but may include joint contractures, hepatosplenomegaly, anemia, thrombocytopenia, recurrent infections, autoantibodies, and hypergammaglobulinemia. Some patients may have intracranial calcifications (summary by previous studies). + +For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (previous studies)." +Orphanet_30925,"Definition: Neurohypophyseal diabetes insipidus is an autosomal dominant disorder of free water conservation characterized by childhood onset of polyuria and polydipsia. Affected individuals are apparently normal at birth, but characteristically develop symptoms of vasopressin deficiency during childhood (summary by previous studies)." +MONDO_0007450,"Definition: Neurohypophyseal diabetes insipidus is an autosomal dominant disorder of free water conservation characterized by childhood onset of polyuria and polydipsia. Affected individuals are apparently normal at birth, but characteristically develop symptoms of vasopressin deficiency during childhood (summary by previous studies)." +MONDO_0001056,"Definition: In a review article on the genetic predisposition to gastric cancer, previous studies concluded that several genes may be associated with an increased risk of gastric cancer. + +Gastric cancer is a manifestation of a number of inherited cancer predisposition syndromes, including hereditary nonpolyposis colon cancer (HNPCC1; see previous studies), familial adenomatous polyposis (FAP; previous studies), Peutz-Jeghers syndrome (PJS; previous studies), Cowden disease (CD; previous studies), the Li-Fraumeni syndrome (previous studies), and diffuse gastric and lobular breast cancer syndrome (DGLBC; previous studies). + +previous studies provided a review of genetic susceptibility to gastric cancer in patients infected with Helicobacter pylori (see previous studies)." +EFO_0000178,"Definition: In a review article on the genetic predisposition to gastric cancer, previous studies concluded that several genes may be associated with an increased risk of gastric cancer. + +Gastric cancer is a manifestation of a number of inherited cancer predisposition syndromes, including hereditary nonpolyposis colon cancer (HNPCC1; see previous studies), familial adenomatous polyposis (FAP; previous studies), Peutz-Jeghers syndrome (PJS; previous studies), Cowden disease (CD; previous studies), the Li-Fraumeni syndrome (previous studies), and diffuse gastric and lobular breast cancer syndrome (DGLBC; previous studies). + +previous studies provided a review of genetic susceptibility to gastric cancer in patients infected with Helicobacter pylori (see previous studies)." +MONDO_0007403,"Definition: The human prion diseases occur in inherited, acquired, and sporadic forms. Approximately 15% are inherited and associated with coding mutations in the PRNP gene. Acquired prion diseases include iatrogenic CJD, kuru (previous studies), variant CJD (vCJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE) in cattle. Variant CJD is believed to be acquired from cattle infected with BSE. However, the majority of human cases of prion disease occur as sporadic CJD (sCJD) (previous studies; previous studies; previous studies). + +previous studies provided a comprehensive review of Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. + +previous studies described the characteristics of sporadic CJD as encapsulated by C. Miller Fisher in 1960." +MONDO_0007738,"Definition: Although patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture, and affected individuals may receive an initial clinical diagnosis of Larsen syndrome (see previous studies) or humerospinal dysostosis. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia become apparent, leading to arthritis of the hips and spine with intervertebral disc degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood; at this stage, the clinical features are those previously described as the Omani type of SED (summary by previous studies)." +Orphanet_263463,"Definition: Although patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture, and affected individuals may receive an initial clinical diagnosis of Larsen syndrome (see previous studies) or humerospinal dysostosis. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia become apparent, leading to arthritis of the hips and spine with intervertebral disc degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood; at this stage, the clinical features are those previously described as the Omani type of SED (summary by previous studies)." +MONDO_0007979,"Definition: Metachondromatosis is characterized by exostoses (osteochondromas), commonly of the hands and feet, and enchondromas of long bone metaphyses and iliac crests (summary by previous studies)." +MONDO_0009218,"Definition: Farber lipogranulomatosis is an autosomal recessive lysosomal storage disorder characterized by early-onset subcutaneous nodules, painful and progressively deformed joints, and hoarseness by laryngeal involvement. Based on the age of onset, the severity of symptoms, and the difference in organs affected, 6 clinical subtypes due to deficiency of acid ceramidase have been distinguished. The most severe form is subtype 4, a rare neonatal form of the disease with death occurring before 1 year of age (summary by previous studies)." +MONDO_0009397,"Definition: Neonatal severe hyperparathyroidism usually manifests in the first 6 months of life with severe hypercalcemia, bone demineralization, and failure to thrive. Early diagnosis is critical because untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. Some infants have milder hyperparathyroidism and a substantially milder clinical presentation and natural history (summary by previous studies)." +MONDO_0009505,"Definition: D-lactic aciduria is characterized by elevated D-lactate in plasma and urine. Patients show elevated serum uric acid concentrations and low urinary uric acid levels, due to reduced renal clearance of uric acid, and affected adults may experience episodes of gouty arthropathy (previous studies). + +For a discussion of genetic heterogeneity of serum uric acid concentration quantitative trait loci, see UAQTL1 (previous studies)." +MONDO_0009635,"Definition: Diarrhea-2 with microvillus atrophy, with or without cholestasis (DIAR2) is characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms are recognized: early-onset microvillus inclusion disease (MVID) with diarrhea beginning in the neonatal period, and late-onset, with first symptoms appearing after 3 or 4 months of life. Definite diagnosis is made by transmission electron microscopy demonstrating shortening or absence of apical microvilli with pathognomonic microvillus inclusions in mature enterocytes and peripheral accumulation of periodic acid-Schiff (PAS)-positive granules or vesicles in immature enterocytes (previous studies). The natural course of MVID is often fatal, but partial or total weaning from parenteral nutrition has been described. + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +MONDO_0019569,"Definition: Cockayne syndrome is characterized by abnormal and slow growth and development that becomes evident within the first few years after birth. 'Cachectic dwarfism' describes the outward appearance of afflicted individuals. Other features include cutaneous photosensitivity, thin, dry hair, a progeroid appearance, progressive pigmentary retinopathy, sensorineural hearing loss, dental caries, and a characteristic stance in the ambulatory patient. Patients often show disproportionately long limbs with large hands and feet, and flexion contractures of joints are usual skeletal features. Knee contractures result in a 'horse-riding stance.' There is delayed neural development and severe progressive neurologic degeneration resulting in mental retardation. The mean age at death in reported cases is 12.5 years, although a few affected individuals have lived into their late teens or twenties. Remarkably, in striking contrast with xeroderma pigmentosum, patients with CS have no significant increase in skin cancer or infection (previous studies). + +previous studies noted that there is an early-onset form of Cockayne syndrome in which patients may show abnormalities at birth and have a shorter survival. previous studies thus suggested that CS could be divided clinically into the more common type I, with classic CS symptoms that manifest within the first few years or life, and the less common type II, with more severe symptoms that manifest prenatally. previous studies found no correlation between genotype and phenotype among 16 patients with CS of varying severities, and concluded that clinical differences were based on other genetic backgrounds or the intrauterine environment. + + Genetic Heterogeneity of Cockayne Syndrome + +Cockayne syndrome is a genetically heterogeneous disorder, and certain types show some overlap with certain forms of xeroderma pigmentosum (XP), another disorder caused by defective DNA repair. See also Cockayne syndrome B (previous studies), caused by mutation in the ERCC6 gene (previous studies) on chromosome 10q11; XPG/CS (see previous studies), caused by mutation in the ERCC5 gene (previous studies) on chromosome 13q33; XPB/CS (see previous studies), caused by mutation in the ERCC3 gene (previous studies) on chromosome 2q21; and XPF/CS (see previous studies), caused by mutation in the ERCC4 gene (previous studies) on chromosome 16p13. + +previous studies reviewed the clinical, pathologic, and molecular features of Cockayne syndrome, xeroderma pigmentosum, and the XP-CS complex." +MONDO_0031068,"Definition: Axonal Charcot-Marie-Tooth disease type 2II (CMT2II) is an autosomal dominant neurologic disorder characterized by a slowly progressive sensorimotor peripheral neuropathy affecting mainly the lower limbs, resulting in distal muscle weakness and atrophy and subsequent walking difficulties. Some patients may have upper limb involvement with atrophy of the intrinsic hand muscles. The age at onset is highly variable, ranging from infancy to adulthood. Electrophysiologic studies are usually consistent with an axonal process, although some may show intermediate or even demyelinating values (previous studies; previous studies). One family with possible autosomal recessive inheritance has been reported (previous studies). + +For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0054801,"Definition: Familial erythrocytosis-6 is characterized by an increased oxygen affinity of hemoglobin (Hb), which results in decreased delivery of oxygen into the peripheral tissues and compensatory polycythemia. Patients are generally asymptomatic, as compensatory polycythemia assures normal oxygen tissue delivery. Patients have normal red cell morphology (summary by previous studies). previous studies noted that although high oxygen affinity hemoglobins are usually well tolerated in young patients, they can lead to thrombotic complications in older patients or when they are associated with another cause that increases thrombotic risk. previous studies also noted that the effect of increased oxygen affinity of Hb caused by an alpha chain variant (see previous studies) is usually milder than that caused by a beta chain variant." +Orphanet_217055,"Definition: Autosomal recessive intermediate Charcot-Marie-Tooth disease A (CMTRIA) is a peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. Onset is usually in early childhood (summary by previous studies). + + Genetic Heterogeneity of Recessive Intermediate Charcot-Marie-Tooth Disease + +See also CMTRIB (previous studies), caused by mutation in the KARS gene (previous studies) on chromosome 16q; CMTRIC (previous studies), caused by mutation in the PLEKHG5 gene (previous studies) on chromosome 1p36; and CMTRID (previous studies), caused by mutation in the COX6A1 gene (previous studies) on chromosome 12q24." +MONDO_0012014,"Definition: Autosomal recessive intermediate Charcot-Marie-Tooth disease A (CMTRIA) is a peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. Onset is usually in early childhood (summary by previous studies). + + Genetic Heterogeneity of Recessive Intermediate Charcot-Marie-Tooth Disease + +See also CMTRIB (previous studies), caused by mutation in the KARS gene (previous studies) on chromosome 16q; CMTRIC (previous studies), caused by mutation in the PLEKHG5 gene (previous studies) on chromosome 1p36; and CMTRID (previous studies), caused by mutation in the COX6A1 gene (previous studies) on chromosome 12q24." +Orphanet_300359,"Definition: Autoinflammation, antibody deficiency, and immune dysregulation (APLAID) is an autosomal dominant systemic disorder characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, the eye, and the gastrointestinal tract. Affected individuals have a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies (summary by previous studies)." +MONDO_0013944,"Definition: Autoinflammation, antibody deficiency, and immune dysregulation (APLAID) is an autosomal dominant systemic disorder characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, the eye, and the gastrointestinal tract. Affected individuals have a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies (summary by previous studies)." +EFO_0010566,"Definition: Autosomal dominant intellectual developmental disorder-60 with seizures is characterized by global developmental delay apparent in infancy, followed by onset of seizures in the first years of life. Patients have delayed walking, an ataxic gait, and moderately to severely impaired intellectual development with poor speech (summary by previous studies)." +EFO_1001306,"Definition: Diarrhea-9 (DIAR9) is a form of neonatal-onset chronic diarrhea characterized by an osmotic diarrhea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +MONDO_0008280,"Definition: Peutz-Jeghers syndrome is an autosomal dominant disorder characterized by melanocytic macules of the lips, buccal mucosa, and digits; multiple gastrointestinal hamartomatous polyps; and an increased risk of various neoplasms." +MONDO_0008411,"Definition: Ulnar-mammary syndrome (UMS) is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies (previous studies)." +MONDO_0008791,"Definition: Anencephaly is characterized by the absence of cranial vault and brain tissues in the fetus. It is considered an extreme form of neural tube defect (previous studies) (summary by previous studies). + + Genetic Heterogeneity of Anencephaly + +See also anencephaly-2 (ANPH2; previous studies), caused by mutation in the NUAK12 gene (previous studies) on chromosome 1q32." +Orphanet_1048,"Definition: Anencephaly is characterized by the absence of cranial vault and brain tissues in the fetus. It is considered an extreme form of neural tube defect (previous studies) (summary by previous studies). + + Genetic Heterogeneity of Anencephaly + +See also anencephaly-2 (ANPH2; previous studies), caused by mutation in the NUAK12 gene (previous studies) on chromosome 1q32." +MONDO_0009039,"Definition: The cardinal features of the Baller-Gerold syndrome are craniosynostosis and radial aplasia (previous studies). Cases reported as Baller-Gerold syndrome have phenotypic overlap with several other disorders, including Saethre-Chotzen syndrome (SCS; previous studies)." +MONDO_0009254,"Definition: Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex. + +Fucosidosis has been classified into 2 major types. Type 1 is characterized by rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life. Type 2 is characterized by milder psychomotor retardation and neurologic signs, the development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (previous studies)." +MONDO_0009284,"Definition: Two forms of glutathione synthetase deficiency have been described; a mild form, referred to as glutathione synthetase deficiency of erythrocytes, causing hemolytic anemia, and a more severe form causing 5-oxoprolinuria with secondary neurologic involvement (previous studies)." +Orphanet_32,"Definition: Two forms of glutathione synthetase deficiency have been described; a mild form, referred to as glutathione synthetase deficiency of erythrocytes, causing hemolytic anemia, and a more severe form causing 5-oxoprolinuria with secondary neurologic involvement (previous studies)." +MONDO_0009290,"Definition: Glycogen storage disease II (GSD2), an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form, cardiomyopathy and muscular hypotonia are the cardinal features; in the juvenile and adult forms, involvement of skeletal muscles dominates the clinical picture (previous studies)." +Orphanet_365,"Definition: Glycogen storage disease II (GSD2), an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form, cardiomyopathy and muscular hypotonia are the cardinal features; in the juvenile and adult forms, involvement of skeletal muscles dominates the clinical picture (previous studies)." +MONDO_0009656,"Definition: Sanfilippo syndrome B is an autosomal recessive lysosomal storage disorder characterized by the accumulation of heparan sulfate. Clinically, patients have progressive neurodegeneration, behavioral problems, mild skeletal changes, and shortened life span. The clinical severity ranges from mild to severe (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Sanfilippo syndrome, or mucopolysaccharidosis III, see MPS IIIA (previous studies)." +MONDO_0010649,"Definition: Megalocornea is an inherited eye disorder in which the corneal diameter is bilaterally enlarged (greater than 13 mm) without an increase in intraocular pressure. It may also be referred to as 'anterior megalophthalmos,' since the entire anterior segment is larger than normal. Features of megalocornea in addition to a deep anterior chamber include astigmatic refractive errors, atrophy of the iris stroma, miosis secondary to decreased function of the dilator muscle, iridodonesis, and tremulousness, subluxation, or dislocation of the lens. Whereas most affected individuals exhibit normal ocular function, complications include cataract development and glaucoma following lenticular dislocation or subluxation. X-linked recessive inheritance is the most common pattern, accounting for the male preponderance of the disorder (summary by previous studies). + +Megalocornea sometimes occurs as part of the Marfan syndrome (previous studies). + + Genetic Heterogeneity of Megalocornea + +Autosomal recessive megalocornea has been reported (previous studies)." +MONDO_0011640,"Definition: Genitopatellar syndrome is a rare disorder consisting of microcephaly, severe psychomotor retardation, and characteristic coarse facial features, including broad nose and small or retracted chin, associated with congenital flexion contractures of the lower extremities, abnormal or missing patellae, and urogenital anomalies (summary by previous studies)." +MONDO_0011749,"Definition: Oculocutaneous albinism type I is an autosomal recessive disorder characterized by absence of pigment in hair, skin, and eyes, and does not vary with race or age. Severe nystagmus, photophobia, and reduced visual acuity are common features. OCA type I is divided into 2 types: type IA, characterized by complete lack of tyrosinase activity due to production of an inactive enzyme, and type IB, characterized by reduced activity of tyrosinase. + +Although OCA caused by mutations in the TYR gene was classically known as 'tyrosinase-negative' OCA, previous studies noted that some patients with 'tyrosinase-positive' OCA may indeed have TYR mutations resulting in residual enzyme activity. These patients can be classified as having OCA1B." +MONDO_0013566,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0014261,"Definition: Combined oxidative phosphorylation deficiency-18 is an autosomal recessive disorder of mitochondrial function characterized by intrauterine growth retardation, hypotonia, visual impairment, speech delay, and lactic acidosis associated with decreased mitochondrial respiratory chain activity. Affected patients may also show hematologic abnormalities, mainly macrocytic anemia (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +EFO_0005546,"Definition: Congenital disorder of glycosylation type IIp (CDG2P) is an autosomal recessive metabolic disorder characterized by mild liver dysfunction, which may be found incidentally during adolescence. Laboratory abnormalities include elevated liver enzymes and alkaline phosphatase, coagulation factor deficiencies, hypercholesterolemia, and low ceruloplasmin. Serum isoelectric focusing of proteins shows a combined defect of N- and O-glycosylation, suggestive of a Golgi defect (summary by previous studies). + +For an overview of congenital disorders of glycosylation, see CDG1A (previous studies) and CDG2A (previous studies)." +MONDO_0014790,"Definition: Congenital disorder of glycosylation type IIp (CDG2P) is an autosomal recessive metabolic disorder characterized by mild liver dysfunction, which may be found incidentally during adolescence. Laboratory abnormalities include elevated liver enzymes and alkaline phosphatase, coagulation factor deficiencies, hypercholesterolemia, and low ceruloplasmin. Serum isoelectric focusing of proteins shows a combined defect of N- and O-glycosylation, suggestive of a Golgi defect (summary by previous studies). + +For an overview of congenital disorders of glycosylation, see CDG1A (previous studies) and CDG2A (previous studies)." +MONDO_0007187,"Definition: The basal cell nevus syndrome (BCNS) is characterized by numerous basal cell cancers and epidermal cysts of the skin, calcified dural folds, keratocysts of the jaws, palmar and plantar pits, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, fetal rhabdomyomas, and various stigmata of maldevelopment (e.g., rib and vertebral abnormalities, cleft lip or cleft palate, and cortical defects of bones) (summary by previous studies). + + Genetic Heterogeneity of Basal Cell Nevus Syndrome + +See also BCNS2, caused by mutation in the SUFU gene (previous studies) on chromosome 10q24." +MONDO_0007309,"Definition: For a general phenotypic description and a discussion of genetic heterogeneity of Charcot-Marie-Tooth disease type 1, see CMT1B (previous studies). + +CMT1A is the most common form of CMT. The average age of onset of clinical symptoms is 12.2 +/- 7.3 years. Slow nerve conduction velocity (NCV) less than 38 m/s is highly diagnostic and is a 100% penetrant phenotype independent of age (previous studies)." +MONDO_0007606,"Definition: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner, with most patients being confined to a wheelchair by the third decade of life and requiring lifelong care (summary by previous studies)." +MONDO_0007698,"Definition: Hand-foot-genital syndrome (HFGS) is an autosomal dominant condition characterized by distal limb and distal genitourinary tract malformations. The most striking limb abnormality is first-digit hypoplasia, comprising short, proximally placed thumbs with hypoplastic thenar eminences and short, medially deviated halluces. There is also ulnar deviation of the second fingers, clinodactyly/brachydactyly of the fifth fingers, brachydactyly of the second to fifth toes, and delayed ossification, fusion, and shortening of the carpals and tarsals. These abnormalities appear to be fully penetrant, bilateral, and symmetrical, with little variation in severity. In contrast, genitourinary tract abnormalities are incompletely penetrant and variably severe, and include hypospadias in males, Mullerian duct fusion defects in females, vesicoureteric reflux, and pelviureteric junction obstruction (summary by previous studies)." +MONDO_0009650,"Definition: Mucolipidosis type II alpha/beta is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. It is phenotypically more severe than the allelic disorder mucolipidosis type III alpha/beta (summary by previous studies)." +MONDO_0010183,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC (MAHCC; previous studies), cblD (MAHCD; previous studies), cblF, and cblJ (MAHCJ; previous studies)." +Orphanet_79284,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC (MAHCC; previous studies), cblD (MAHCD; previous studies), cblF, and cblJ (MAHCJ; previous studies)." +Orphanet_26,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC (MAHCC; previous studies), cblD (MAHCD; previous studies), cblF, and cblJ (MAHCJ; previous studies)." +MONDO_0011559,"Definition: Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without progression to liver failure. The cholestatic attacks vary in severity and duration and patients are asymptomatic between episodes, both clinically and biochemically (previous studies)." +MONDO_0011801,"Definition: Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is an autosomal recessive neurologic disorder characterized by onset of gait disturbances in the first or second decades of life. Affected individuals have cerebellar ataxia associated with cerebellar atrophy on brain imaging, as well as an axonal sensorimotor neuropathy with distal sensory impairment, hypo- or areflexia, pes cavus, and steppage gait (summary by previous studies). + + Genetic Heterogeneity of Spinocerebellar Ataxia with Axonal Neuropathy + +See also SCAN2 (previous studies), caused by mutation in the SETX gene (previous studies) on chromosome 9q34, and SCAN3 (previous studies), caused by mutation in the COA7 gene (previous studies) on chromosome 1p32." +Orphanet_94124,"Definition: Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is an autosomal recessive neurologic disorder characterized by onset of gait disturbances in the first or second decades of life. Affected individuals have cerebellar ataxia associated with cerebellar atrophy on brain imaging, as well as an axonal sensorimotor neuropathy with distal sensory impairment, hypo- or areflexia, pes cavus, and steppage gait (summary by previous studies). + + Genetic Heterogeneity of Spinocerebellar Ataxia with Axonal Neuropathy + +See also SCAN2 (previous studies), caused by mutation in the SETX gene (previous studies) on chromosome 9q34, and SCAN3 (previous studies), caused by mutation in the COA7 gene (previous studies) on chromosome 1p32." +MONDO_0012721,"Definition: Mutations in the KCTD7 gene cause a severe neurodegenerative phenotype characterized by onset of intractable myoclonic seizures before age 2 years and accompanied by developmental regression. The initial description was consistent with a form of progressive myoclonic epilepsy (designated here as EPM3), whereas a later report identified intracellular accumulation of autofluorescent lipopigment storage material, consistent with neuronal ceroid lipofuscinosis (designated CLN14). Ultrastructural findings on skin biopsies thus appear to be variable. However, clinical features are generally consistent between reports (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800). + +For a general phenotypic description and a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (previous studies)." +MONDO_0012864,"Definition: Glass syndrome is characterized by intellectual disability of variable severity and dysmorphic facial features, including micrognathia, downslanting palpebral fissures, cleft palate, and crowded teeth. Additional features may include seizures, joint laxity, arachnodactyly, and happy demeanor (summary by previous studies; previous studies; previous studies)." +MONDO_0013355,"Definition: Congenital dyserythropoietic anemia type IV (CDAN4) is an autosomal dominant red blood cell disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDAN4 also have increased levels of fetal hemoglobin (summary by previous studies). + +For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see CDAN1 (previous studies)." +Orphanet_293825,"Definition: Congenital dyserythropoietic anemia type IV (CDAN4) is an autosomal dominant red blood cell disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDAN4 also have increased levels of fetal hemoglobin (summary by previous studies). + +For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see CDAN1 (previous studies)." +MONDO_0014081,"Definition: Immunodeficiency-11A is an autosomal recessive primary immunodeficiency characterized by normal numbers of T and B lymphocytes, but defective intracellular signaling. There is a block in B-cell differentiation with increased numbers of transitional B cells and hypogammaglobulinemia, as well as decreased numbers of regulatory T cells and defects in T-cell function (summary by previous studies and previous studies)." +MONDO_0030361,"Definition: Aicardi-Goutieres syndrome-8 (AGS8) is a type I interferonopathy characterized by severe developmental delay and progressive neurologic deterioration ending in premature death. Brain imaging shows diffusely abnormal white matter, severe cerebral atrophy, and intracranial calcification (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (previous studies)." +MONDO_0044319,"Definition: IDDFSDA is an autosomal recessive severe multisystem disorder characterized by poor overall growth, developmental delay, early-onset seizures, intellectual disability, and dysmorphic features. There is phenotypic variability. The most severely affected patients have a neurodevelopmental disorder with microcephaly, absent speech, and inability to walk, and they require feeding tubes. Some patients have congenital heart defects or nonspecific abnormalities on brain imaging. Less severely affected individuals have mild to moderate intellectual disability with normal speech and motor development (summary by previous studies)." +MONDO_0100354,"Definition: Megacystis-microcolon-intestinal hypoperistalsis syndrome-1 (MMIHS1) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. A distended bladder (megacystis) may be detected on prenatal ultrasound. Intestinal malrotation has also been observed (summary by previous studies). + + Genetic Heterogeneity of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome + +See MMIHS2 (previous studies), caused by mutation in the MYH11 gene (previous studies) on chromosome 16p13; MMIHS3 (previous studies), caused by mutation in the LMOD1 gene (previous studies) on chromosome 1q32; MMIHS4 (previous studies), caused by mutation in the MYL9 gene (previous studies) on chromosome 20q11; and MMIHS5 (previous studies), caused by mutation in the ACTG2 gene (previous studies) on chromosome 2p13." +Orphanet_2253,"Definition: Foveal hypoplasia is defined as the lack of foveal depression with continuity of all neurosensory retinal layers in the presumed foveal area. Foveal hypoplasia as an isolated entity is a rare phenomenon; it is usually described in association with other ocular disorders, such as aniridia (previous studies), microphthalmia (see previous studies), albinism (see previous studies), or achromatopsia (see previous studies). All reported cases of foveal hypoplasia have been accompanied by decreased visual acuity and nystagmus (summary by previous studies). + + Genetic Heterogeneity of Foveal Hypoplasia + +Foveal hypoplasia-2 (FVH2; previous studies) is caused by mutation in the SLC38A8 gene (previous studies) on chromosome 16q23." +Orphanet_352577,"Definition: Bainbridge-Ropers syndrome (BRPS) is a developmental disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, hypotonia, feeding difficulties, poor growth, and dysmorphic facial features (summary by previous studies)." +MONDO_0014205,"Definition: Bainbridge-Ropers syndrome (BRPS) is a developmental disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, hypotonia, feeding difficulties, poor growth, and dysmorphic facial features (summary by previous studies)." +Orphanet_352654,"Definition: Spastic paraplegia-79B (SPG79B) is an autosomal recessive progressive neurologic disorder characterized by onset of spastic paraplegia and optic atrophy in the first decade of life. Additional features are variable, but may include peripheral neuropathy, cerebellar ataxia, and cognitive impairment (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0014209,"Definition: Spastic paraplegia-79B (SPG79B) is an autosomal recessive progressive neurologic disorder characterized by onset of spastic paraplegia and optic atrophy in the first decade of life. Additional features are variable, but may include peripheral neuropathy, cerebellar ataxia, and cognitive impairment (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +Orphanet_79293,"Definition: Lecithin:cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism and causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure." +MONDO_0009515,"Definition: Lecithin:cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism and causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure." +EFO_0000693,"Definition: Schwannomatosis-1 (SWN1) is characterized by the onset of multiple intracranial, spinal, or peripheral schwannomas, without involvement of the vestibular nerve. Affected individuals may also have multiple meningiomas (summary by previous studies). + +Schwannomatosis, also known as neurilemmomatosis, was first reported by previous studies as neurofibromatosis type 3. + + Genetic Heterogeneity of Schwannomatosis + +See also schwannomatosis-2 (previous studies), conferred by germline heterozygous mutation in the LZTR1 gene (previous studies) on chromosome 22q11. + +Individual schwannoma tumors from patients with schwannomatosis have been found to harbor somatic mutations in the SMARCB1." +EFO_0009137,"Definition: RHDA3 is an autosomal dominant disorder characterized by abnormal kidney development beginning in utero. The phenotype is highly variable, even within families, and there is evidence for incomplete penetrance. Some affected individuals have bilateral renal agenesis, which is usually fatal in utero or in the perinatal period, whereas others may have unilateral agenesis that is compatible with life, or milder manifestations, such as vesicoureteral reflux (VUR). Female mutation carriers may also have uterine or ovarian abnormalities, including uterovaginal and ovarian agenesis. Renal aplasia falls at the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT; see previous studies) (summary by previous studies, previous studies, and previous studies). + +For a discussion of genetic heterogeneity of renal hypodysplasia/aplasia, see RHDA1 (previous studies)." +EFO_0022485,"Definition: Paragangliomas, also referred to as 'glomus body tumors,' are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors (hence, the tumor name 'chemodectomas') and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (previous studies; previous studies). + +The triad of gastric leiomyosarcoma, pulmonary chondroma, and extraadrenal paraganglioma constitutes a syndrome that occurs mainly in young women and is known as the Carney triad (previous studies). This triad is not to be confused with the other Carney syndrome of myxoma, spotty pigmentation, and endocrinopathy (previous studies). + +previous studies provided a review of the molecular pathogenesis of hereditary paraganglioma. + + Genetic Heterogeneity of Paragangliomas + +See also PGL4 (previous studies), caused by mutation in the SDHB gene (previous studies) on chromosome 1p36; PGL3 (previous studies), caused by mutation in the SDHC gene (previous studies) on chromosome 1q21; PGL2 (previous studies), caused by mutation in the SDHAF2 gene (previous studies) on chromosome 11q13; PGL5 (previous studies), caused by mutation in the SDHA gene (previous studies) on chromosome 5p15; PGL6 (previous studies), caused by mutation in the SLC25A11 gene (previous studies) on chromosome 17p13; and PGL7 (previous studies), caused by mutation in the DLST gene (previous studies) on chromosome 14q24." +MONDO_0008192,"Definition: Paragangliomas, also referred to as 'glomus body tumors,' are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors (hence, the tumor name 'chemodectomas') and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (previous studies; previous studies). + +The triad of gastric leiomyosarcoma, pulmonary chondroma, and extraadrenal paraganglioma constitutes a syndrome that occurs mainly in young women and is known as the Carney triad (previous studies). This triad is not to be confused with the other Carney syndrome of myxoma, spotty pigmentation, and endocrinopathy (previous studies). + +previous studies provided a review of the molecular pathogenesis of hereditary paraganglioma. + + Genetic Heterogeneity of Paragangliomas + +See also PGL4 (previous studies), caused by mutation in the SDHB gene (previous studies) on chromosome 1p36; PGL3 (previous studies), caused by mutation in the SDHC gene (previous studies) on chromosome 1q21; PGL2 (previous studies), caused by mutation in the SDHAF2 gene (previous studies) on chromosome 11q13; PGL5 (previous studies), caused by mutation in the SDHA gene (previous studies) on chromosome 5p15; PGL6 (previous studies), caused by mutation in the SLC25A11 gene (previous studies) on chromosome 17p13; and PGL7 (previous studies), caused by mutation in the DLST gene (previous studies) on chromosome 14q24." +MONDO_0007307,"Definition: Charcot-Marie-Tooth disease is a sensorineural peripheral polyneuropathy. Affecting approximately 1 in 2,500 individuals, Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system (previous studies). Autosomal dominant, autosomal recessive, and X-linked forms have been recognized. + + Classification + +On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1, or HMSNI) and primary peripheral axonal (type 2, or HMSNII) neuropathies. The demyelinating neuropathies classified as CMT type 1 are characterized by severely reduced motor NCVs (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy. The axonal neuropathies classified as CMT type 2 are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (see CMT2A1; previous studies). Distal hereditary motor neuropathy (dHMN) (see previous studies), or spinal CMT, is characterized by exclusive motor involvement and sparing of sensory nerves (previous studies). + +previous studies proposed that the forms of CMT with very slow nerve conduction be given the gene symbol CMT1A (previous studies) and CMT1B, CMT1A being the gene on chromosome 17 and CMT1B being the gene on chromosome 1. CMT2 was the proposed symbol for the autosomal locus responsible for the moderately slow nerve conduction form of the disease (axonal). + +For a phenotypic description and discussion of genetic heterogeneity of the various subtypes of CMT, see CMTX1 (previous studies), CMT2A1 (previous studies), CMT3 (DSS; previous studies), CMT4A (previous studies), and CMTDIB (previous studies). + + Genetic Heterogeneity of Autosomal Dominant Demyelinating CMT1 + +Autosomal dominant demyelinating CMT1 is a genetically heterogeneous disorder and can be caused by mutations in different genes; see CMT1A (previous studies), CMT1C (previous studies), CMT1D (previous studies), CMT1E (previous studies), CMT1F (previous studies), CMT1G (previous studies), CMT1H (previous studies), CMT1I (previous studies), and CMT1J (previous studies). + +See also previous studies for a related phenotype characterized by isolated slowed nerve conduction velocities (NCVs)." +MONDO_0007436,"Definition: In dentin dysplasia type I, both primary and secondary dentitions are affected. The color and general morphology of the teeth are usually normal, although they may be slightly opalescent and blue or brown. Teeth may be very mobile and exfoliate spontaneously because of inadequate root formation. On radiographs, the roots are short and may be more pointed than normal. Pulp chambers are usually absent except for a chevron-shaped remnant in the crown (previous studies). Root canals are usually absent. Periapical radiolucencies may be present at the apices of affected teeth, for reasons unknown. On light microscopic examination of the permanent teeth, the coronal dentin is normal, but further apically becomes irregular, fills the pulp chamber, and has a 'sand-dune' morphology. Scanning electron microscopic studies of the deciduous and permanent teeth have been reported (previous studies; previous studies). + + Subclassification of Dentin Dysplasia Type I + +previous studies and previous studies reviewed dentin dysplasia and proposed 4 subtypes of dentin dysplasia type I, which they designated as DD1a-d. In DD1a, there is complete obliteration of pulp chambers and no root development, with many periapical radiolucent areas. In DD1b, there are horizontal crescent-shaped radiolucent pulpal remnants and a few millimeters of root development, with many periapical radiolucent areas. DD1c shows 2 horizontal crescent-shaped radiolucent lines and significant but incomplete root development, with or without periapical radiolucent areas. DD1d is characterized by visible pulp chambers and oval pulp stones in the coronal third of the root canal with bulging of the root around the stones and few if any periapical radiolucent areas. The authors noted that the distinctions between the subtypes of DD1 were primarily useful clinically in terms of treatment options." +MONDO_0009223,"Definition: Male patients with hypogonadotropic hypogonadism due to isolated luteinizing hormone (LH) deficiency have normal sexual differentiation but fail to develop spontaneous puberty. Absence of LH alters Leydig cell proliferation and maturation and impairs the onset of normal spermatogenesis, which requires high levels of intratesticular testosterone. Infertility and very low levels of spermatogenesis generally persist in affected men despite long-term exposure to gonadotropin therapy. Female patients exhibit normal pubertal development and menarche, followed by oligomenorrhea and anovulatory secondary amenorrhea (summary by previous studies). + +Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +For a general phenotypic description and discussion of genetic heterogeneity of hypogonadotropic hypogonadism, see previous studies. + + Reviews + +previous studies noted that the clinical manifestations of female patients with hypogonadotropic hypogonadism due to mutations in LHB are very similar to those of women with hypergonadotropic hypogonadism due to inactivating mutations of the LH receptor (see previous studies): all have female external genitalia, spontaneous development of normal pubic hair and breasts at puberty, and normal to late menarche followed by oligoamenorrhea and infertility. Pelvic ultrasound shows a small or normal uterus and normal or enlarged ovaries with cysts. However, women with LHB mutations can be treated with luteinizing hormone or chorionic gonadotropin (CG; previous studies) replacement therapy; women with LH receptor mutations are resistant to LH, and no treatment is effective in recovering their fertility." +MONDO_0009485,"Definition: Kaufman oculocerebrofacial syndrome (KOS) is a rare autosomal recessive disorder characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability (summary by previous studies)." +MONDO_0009612,"Definition: Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. This form is unresponsive to B12 therapy. Various forms of isolated methylmalonic aciduria also occur in a subset of patients with defects in the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl) and are classified according to complementation group: cblA (previous studies), caused by mutation in the MMAA gene (previous studies) on chromosome 4q31, and cblB (previous studies), caused by mutation in the MMAB gene (previous studies) on 12q24. + +Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (previous studies), cblD (previous studies), and cblF (previous studies). + +See the comprehensive review of previous studies." +MONDO_0009762,"Definition: Autosomal recessive congenital nystagmus-8 (NYS8) is characterized by the presence of bilateral horizontal nystagmus in the absence of other neurologic signs or symptoms. Brain imaging is normal (previous studies). + +For a discussion of genetic heterogeneity of congenital nystagmus, see NYS1 (previous studies)." +MONDO_0010246,"Definition: Developmental and epileptic encephalopathy-9 (DEE9) is an X-linked disorder characterized by seizure onset in infancy and mild to severe intellectual impairment. Autistic and psychiatric features have been reported in some individuals. The disorder affects heterozygous females only; transmitting males are unaffected (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see previous studies." +Orphanet_2076,"Definition: Developmental and epileptic encephalopathy-9 (DEE9) is an X-linked disorder characterized by seizure onset in infancy and mild to severe intellectual impairment. Autistic and psychiatric features have been reported in some individuals. The disorder affects heterozygous females only; transmitting males are unaffected (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see previous studies." +MONDO_0010472,"Definition: Developmental and epileptic encephalopathy-36 (DEE36) is an X-linked neurodevelopmental disorder characterized by the onset of seizures at a mean age of 6.5 months. Most patients present with infantile spasms associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome. The seizures tend to be refractory to treatment, although some patients may respond to benzodiazepines or a ketogenic diet. Affected individuals have severely delayed psychomotor development with poor motor function, severe intellectual disability, poor or absent speech, and limited eye contact. More variable features include feeding difficulties sometimes requiring tube feeding, ocular defects including cortical visual impairment, dysmorphic facial features, and scoliosis or osteopenia. The vast majority of patients reported have been females, although rare affected males with a similar phenotype have been described. Most patients show normal N-glycosylation on transferrin isoelectric focusing, but some show abnormal N-glycosylation consistent with CDG type I (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies. + +For a discussion of the classification of CDGs, see CDG1A (previous studies)." +Orphanet_324422,"Definition: Developmental and epileptic encephalopathy-36 (DEE36) is an X-linked neurodevelopmental disorder characterized by the onset of seizures at a mean age of 6.5 months. Most patients present with infantile spasms associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome. The seizures tend to be refractory to treatment, although some patients may respond to benzodiazepines or a ketogenic diet. Affected individuals have severely delayed psychomotor development with poor motor function, severe intellectual disability, poor or absent speech, and limited eye contact. More variable features include feeding difficulties sometimes requiring tube feeding, ocular defects including cortical visual impairment, dysmorphic facial features, and scoliosis or osteopenia. The vast majority of patients reported have been females, although rare affected males with a similar phenotype have been described. Most patients show normal N-glycosylation on transferrin isoelectric focusing, but some show abnormal N-glycosylation consistent with CDG type I (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies. + +For a discussion of the classification of CDGs, see CDG1A (previous studies)." +MONDO_0013062,"Definition: Congenital long QT syndrome (LQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (previous studies). + +For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (previous studies)." +MONDO_0013775,"Definition: The role of thrombomodulin in thrombosis is controversial. Although there have been several reports of THBD mutations in patients with venous thrombosis, clear functional evidence for the pathogenicity of these mutations is lacking. In a review, previous studies noted that thrombomodulin has a major role in capillary beds and that THBD variation may not be associated with large vessel thrombosis. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis. However, variation in the THBD gene may be associated with increased risk for arterial thrombosis and myocardial infarction. This association may be attributed to the fact that thrombomodulin can modulate inflammatory processes, complement activity, and fibrinolysis." +MONDO_0016163,"Definition: Spinocerebellar ataxia-7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia associated with pigmental macular dystrophy. In her classification of ataxia, previous studies referred to progressive cerebellar ataxia with pigmentary macular degeneration as type II ADCA (autosomal dominant cerebellar ataxia). The age at onset, degree of severity, and rate of progression vary among and within families. Associated neurologic signs, such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss, or dementia, are also variable. Genetic anticipation is observed and is greater in paternal than in maternal transmissions (previous studies; summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0029131,"Definition: Autosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (summary by previous studies)." +MONDO_0030839,"Definition: Abnormal thyroid hormone metabolism-2 (THMA2) is characterized by elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. Some patients exhibit resistance to thyroid-stimulating hormone (TSH; see previous studies) with mildly elevated TSH levels, and elevated cholesterol levels have been observed (previous studies). + +For a discussion of genetic heterogeneity of abnormal thyroid hormone metabolism, see THMA1 (previous studies)." +MONDO_0030871,"Definition: Vertebral hypersegmentation and orofacial anomalies (VHO) is characterized by supernumerary cervical, thoracic, and/or lumbar vertebrae, in association with supernumerary ribs. Most patients also exhibit orofacial clefting and ear anomalies (previous studies)." +MONDO_0030877,"Definition: Cardioacrofacial dysplasia-2 (CAFD2) is characterized by congenital cardiac defects, primarily common atrium or atrioventricular septal defect; limb anomalies, including short limbs, brachydactyly, and postaxial polydactyly; and dysmorphic facial features. Developmental delay of variable severity has also been observed (previous studies). + +For a discussion of genetic heterogeneity of CAFD, see CAFD1 (previous studies)." +MONDO_0032685,"Definition: Aside from the clinical features of infantile cataract, skin abnormalities, and impaired intellectual development, CASGID is characterized by strikingly high intracerebral and urinary glutamate excess with almost undetectable glutamine. A gain-of-function mutation in the GLS gene was found (see MOLECULAR GENETICS) (previous studies). GLS loss of function is implicated in developmental and epileptic encephalopathy-71 (DEE71; previous studies) and a syndrome of global developmental delay and progressive ataxia (GDPAG; previous studies)." +MONDO_0054591,"Definition: Stankiewicz-Isidor syndrome (STISS) is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral disorders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems (summary by previous studies)." +Orphanet_264675,"Definition: Inborn errors of pulmonary surfactant metabolism are genetically heterogeneous disorders resulting in severe respiratory insufficiency or failure in full-term neonates or infants. These disorders are associated with various pathologic entities, including pulmonary alveolar proteinosis (PAP), desquamative interstitial pneumonitis (DIP), or cellular nonspecific interstitial pneumonitis (NSIP) (previous studies). + +A clinically similar disorder characterized by respiratory distress (previous studies) can affect preterm infants, who show developmental deficiency of surfactant. + +Acquired PAP (previous studies) is an autoimmune disorder characterized by the presence of autoantibodies to CSF2 (previous studies). + + Genetic Heterogeneity of Pulmonary Surfactant Metabolism Dysfunction + +See also SMDP2 (previous studies), caused by mutation in the SPTPC gene (previous studies) on 8p21; SMDP3 (previous studies), caused by mutation in the ABCA3 gene (previous studies) on 16p13; SMDP4 (previous studies), caused by mutation in the CSF2RA gene (previous studies) on Xp22; and SMDP5 (previous studies), caused by mutation in the CSF2RB gene (previous studies) on 22q12." +MONDO_0009929,"Definition: Inborn errors of pulmonary surfactant metabolism are genetically heterogeneous disorders resulting in severe respiratory insufficiency or failure in full-term neonates or infants. These disorders are associated with various pathologic entities, including pulmonary alveolar proteinosis (PAP), desquamative interstitial pneumonitis (DIP), or cellular nonspecific interstitial pneumonitis (NSIP) (previous studies). + +A clinically similar disorder characterized by respiratory distress (previous studies) can affect preterm infants, who show developmental deficiency of surfactant. + +Acquired PAP (previous studies) is an autoimmune disorder characterized by the presence of autoantibodies to CSF2 (previous studies). + + Genetic Heterogeneity of Pulmonary Surfactant Metabolism Dysfunction + +See also SMDP2 (previous studies), caused by mutation in the SPTPC gene (previous studies) on 8p21; SMDP3 (previous studies), caused by mutation in the ABCA3 gene (previous studies) on 16p13; SMDP4 (previous studies), caused by mutation in the CSF2RA gene (previous studies) on Xp22; and SMDP5 (previous studies), caused by mutation in the CSF2RB gene (previous studies) on 22q12." +Orphanet_217563,"Definition: Inborn errors of pulmonary surfactant metabolism are genetically heterogeneous disorders resulting in severe respiratory insufficiency or failure in full-term neonates or infants. These disorders are associated with various pathologic entities, including pulmonary alveolar proteinosis (PAP), desquamative interstitial pneumonitis (DIP), or cellular nonspecific interstitial pneumonitis (NSIP) (previous studies). + +A clinically similar disorder characterized by respiratory distress (previous studies) can affect preterm infants, who show developmental deficiency of surfactant. + +Acquired PAP (previous studies) is an autoimmune disorder characterized by the presence of autoantibodies to CSF2 (previous studies). + + Genetic Heterogeneity of Pulmonary Surfactant Metabolism Dysfunction + +See also SMDP2 (previous studies), caused by mutation in the SPTPC gene (previous studies) on 8p21; SMDP3 (previous studies), caused by mutation in the ABCA3 gene (previous studies) on 16p13; SMDP4 (previous studies), caused by mutation in the CSF2RA gene (previous studies) on Xp22; and SMDP5 (previous studies), caused by mutation in the CSF2RB gene (previous studies) on 22q12." +Orphanet_363700,"Definition: Neurofibromatosis type I (NF1) is an autosomal dominant disorder characterized by cafe-au-lait spots, Lisch nodules in the eye, and fibromatous tumors of the skin. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. NF1 is sometimes referred to as 'peripheral neurofibromatosis.' The worldwide incidence of NF1 is 1 in 2,500 to 1 in 3,000 individuals (reviews by previous studies and previous studies). + +Type II neurofibromatosis (NF2; previous studies) is a genetically distinct disorder caused by mutation in the gene encoding merlin (NF2; previous studies) on chromosome 22q12. NF2, sometimes known as 'central neurofibromatosis,' is characterized by bilateral acoustic neuroma and meningioma, but few skin lesions or neurofibromas (previous studies). + +Some patients with homozygous or compound heterozygous mutations in mismatch repair genes (see, e.g., MLH1; previous studies and MSH2; previous studies) have a phenotype characterized by early onset malignancies and mild features of NF1, especially cafe-au-lait spots; this is known as the mismatch repair cancer syndrome (see MMRCS1, previous studies), sometimes referred to as brain tumor-polyposis syndrome-1 or Turcot syndrome. These patients typically do not have germline mutations in the NF1 gene, although a study by previous studies suggested that biallelic mutations in mismatch repair genes may cause somatic mutations in the NF1 gene, perhaps resulting in isolated features resembling NF1. + +See also Legius syndrome (previous studies), a genetically distinct disorder with a similar phenotype to NF1." +MONDO_0018975,"Definition: Neurofibromatosis type I (NF1) is an autosomal dominant disorder characterized by cafe-au-lait spots, Lisch nodules in the eye, and fibromatous tumors of the skin. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. NF1 is sometimes referred to as 'peripheral neurofibromatosis.' The worldwide incidence of NF1 is 1 in 2,500 to 1 in 3,000 individuals (reviews by previous studies and previous studies). + +Type II neurofibromatosis (NF2; previous studies) is a genetically distinct disorder caused by mutation in the gene encoding merlin (NF2; previous studies) on chromosome 22q12. NF2, sometimes known as 'central neurofibromatosis,' is characterized by bilateral acoustic neuroma and meningioma, but few skin lesions or neurofibromas (previous studies). + +Some patients with homozygous or compound heterozygous mutations in mismatch repair genes (see, e.g., MLH1; previous studies and MSH2; previous studies) have a phenotype characterized by early onset malignancies and mild features of NF1, especially cafe-au-lait spots; this is known as the mismatch repair cancer syndrome (see MMRCS1, previous studies), sometimes referred to as brain tumor-polyposis syndrome-1 or Turcot syndrome. These patients typically do not have germline mutations in the NF1 gene, although a study by previous studies suggested that biallelic mutations in mismatch repair genes may cause somatic mutations in the NF1 gene, perhaps resulting in isolated features resembling NF1. + +See also Legius syndrome (previous studies), a genetically distinct disorder with a similar phenotype to NF1." +Orphanet_88632,"Definition: Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by previous studies)." +MONDO_0009617,"Definition: Primary microcephaly refers to the clinical finding of a head circumference more than than 3 standard deviations (SD) below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which refers to a progressive neurodegenerative condition. Microcephaly is a disorder of fetal brain growth; individuals with microcephaly have small brains and almost always have mental retardation, although rare individuals with mild microcephaly (-3 SD) and normal intelligence have been reported. Additional clinical features may include short stature or mild seizures. MCPH is associated with a simplification of the cerebral cortical gyral pattern and a slight reduction in the volume of the white matter, consistent with the small size of the brain, but the architecture of the brain in general is normal, with no evidence of a neuronal migration defect (review by previous studies). + +Most cases of primary microcephaly show an autosomal recessive mode of inheritance. Because MCPH directly affects neurogenesis, or neurogenic mitosis, rather than growth of the skull, some prefer the term 'micrencephaly' (previous studies). + +MCPH1 in particular is associated with premature chromosome condensation in cell studies (previous studies). + + Genetic Heterogeneity of Primary Microcephaly + +Primary microcephaly is a genetically heterogeneous disorder. See MCPH2 (previous studies), caused by mutation in the WDR62 gene (previous studies) on chromosome 19q13; MCPH3 (previous studies), caused by mutation in the CDK5RAP2 gene (previous studies) on 9q33; MCPH4 (previous studies), caused by mutation in the CASC5 gene (previous studies) on 15q14; MCPH5 (previous studies), caused by mutation in the ASPM gene (previous studies) on 1q31; MCPH6 (previous studies), caused by mutation in the CENPJ gene (previous studies) on 13q12; MCPH7 (previous studies), caused by mutation in the STIL gene (previous studies) on 1p33; MCPH8 (previous studies), caused by mutation in the CEP135 gene (previous studies) on 4q12; MCPH9 (previous studies), caused by mutation in the CEP152 gene (previous studies) on 15q21; MCPH10 (previous studies), caused by mutation in the ZNF335 gene (previous studies) on 20q13; MCPH11 (previous studies), caused by mutation in the PHC1 gene (previous studies) on 12p13; MCPH12 (previous studies), caused by mutation in the CDK6 gene (previous studies) on 7q21; MCPH13 (previous studies), caused by mutation in the CENPE gene (previous studies) on 4q24; MCPH14 (previous studies), caused by mutation in the SASS6 gene (previous studies) on 1p21; MCPH15 (previous studies), caused by mutation in the MFSD2A gene (previous studies) on 1p34; MCPH16 (previous studies), caused by mutation in the ANKLE2 gene (previous studies) on 12q24; MCPH17 (previous studies), caused by mutation in the CIT gene (previous studies) on 12q24; MCPH18 (previous studies), caused by mutation in the WDFY3 gene (previous studies) on 4q21; MCPH19 (previous studies), caused by mutation in the COPB2 gene (previous studies) on 3q23; MCPH20 (previous studies), caused by mutation in the KIF14 gene (previous studies) on 1q31; MCPH21 (previous studies), caused by mutation in the NCAPD2 gene (previous studies) on 12p13; MCPH22 (previous studies), caused by mutation in the NCAPD3 gene (previous studies) on 11q25; MCPH23 (previous studies), caused by mutation in the NCAPH gene (previous studies) on 2q11; MCPH24 (previous studies), caused by mutation in the NUP37 gene (previous studies) on 12q23; MCPH25 (previous studies), caused by mutation in the MAP11 gene (previous studies) on 7q22; MCPH26 (previous studies), caused by mutation in the LMNB1 gene (previous studies) on 5q23; MCPH27 (previous studies), caused by mutation in the LMNB2 gene (previous studies) on 19p13; MCPH28 (previous studies), caused by mutation in the RRP7A gene (previous studies) on 22q13; MCPH29 (previous studies), caused by mutation in the PDCD6IP gene (previous studies) on 3p22; and MCPH30 (previous studies), caused by mutation in the BUB1 gene (previous studies) on 2q14." +MONDO_0009636,"Definition: Mitochondrial DNA depletion syndrome-3 is a severe autosomal recessive disorder characterized by onset in infancy of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, and V) and mtDNA depletion (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +Orphanet_279934,"Definition: Mitochondrial DNA depletion syndrome-3 is a severe autosomal recessive disorder characterized by onset in infancy of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, and V) and mtDNA depletion (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0009665,"Definition: Multiple carboxylase deficiency (MCD) is an autosomal recessive metabolic disorder characterized primarily by cutaneous and neurologic abnormalities. Symptoms result from the patient's inability to reutilize biotin, a necessary nutrient. previous studies recognized that multiple carboxylase deficiency could be classified into early (see previous studies) and late forms. The early form showed higher urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxypropionic acid than the late form and was associated with normal plasma biotin concentrations. previous studies proposed a defect in holocarboxylase synthetase and intestinal biotin absorption, respectively. + +Some patients with biotinidase deficiency present in infancy (previous studies; previous studies), and some individuals with this deficiency are asymptomatic (previous studies)." +MONDO_0010209,"Definition: Xanthinuria, which was first described by previous studies, is characterized by excretion of large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. Two clinically similar but distinct forms of xanthinuria are recognized. In type I there is an isolated deficiency of xanthine dehydrogenase, and in type II (XAN2; previous studies) there is a dual deficiency of xanthine dehydrogenase and aldehyde oxidase (previous studies). Type I patients can metabolize allopurinol, whereas type II patients cannot (previous studies). Xanthinuria also occurs in molybdenum cofactor deficiency (previous studies). + +Type II xanthinuria is caused by mutation in the MOCOS gene (previous studies), which encodes the enzyme that sulfurates the molybdenum cofactor for XDH and AOX1 (previous studies)." +MONDO_0010306,"Definition: The Cabezas type of X-linked syndromic intellectual developmental disorder is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (previous studies)." +MONDO_0010421,"Definition: X-linked agammaglobulinemia is an immunodeficiency characterized by failure to produce mature B lymphocytes and associated with a failure of Ig heavy chain rearrangement. The defect in this disorder resides in BTK, also known as BPK or ATK, a key regulator in B-cell development (previous studies). The X-linked form accounts for approximately 85 to 90% of cases of the disorder. Also see previous studies. The remaining 15% of cases constitute a heterogeneous group of autosomal disorders (previous studies; previous studies). + + Genetic Heterogeneity of Agammaglobulinemia/Hypogammaglobulinemia + +A form of X-linked hypogammaglobulemia (IMD61; previous studies) is caused by mutation in the SH3KBP1 gene (previous studies) on chromosome Xq22. + +See agammaglobulinemia-1 (AGM1; previous studies) for a discussion of genetic heterogeneity of autosomal forms of agammaglobulinemia." +MONDO_0012074,"Definition: Mandibuloacral dysplasia with type B lipodystrophy (MADB) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies such as mandibular hypoplasia, skeletal anomalies such as progressive osteolysis of the terminal phalanges and clavicles, and skin changes such as mottled hyperpigmentation and atrophy. The lipodystrophy is characterized by generalized loss of subcutaneous fat involving the face, trunk, and extremities. Some patients have a progeroid appearance. Metabolic complications associated with insulin resistance have been reported (previous studies; summary by previous studies). + +For a general phenotypic description of lipodystrophy associated with mandibuloacral dysplasia, see MADA (previous studies)." +MONDO_0012669,"Definition: Legius syndrome (LGSS) is an autosomal dominant disorder that shows some similarities to neurofibromatosis type I (NF1; previous studies), which is caused by mutation in the neurofibromin gene (previous studies); however, Legius syndrome is less severe. Individuals with Legius syndrome typically have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. Legius syndrome is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin, and thus may be considered a RASopathy (review by previous studies)." +MONDO_0013601,"Definition: Several documented cases of glutathione peroxidase (GPX1; previous studies) deficiency in association with hemolytic anemia have been reported. However, previous studies stated: 'To date, no defects in glutathione peroxidase have been unequivocally incriminated in the pathogenesis of hemolytic syndromes, although several instances of partial deficiency have been reported in patients with anemias of unknown etiology. This association may be coincidental, since there is a broad range of ethnic variation in the erythrocyte enzyme' (previous studies)." +MONDO_0030049,"Definition: SRXX5 is characterized by genital virilization in 46,XX individuals, associated with congenital heart disease and variable somatic anomalies including blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and congenital diaphragmatic hernia (previous studies)." +MONDO_0030088,"Definition: Permanent neonatal diabetes mellitus-3 (PNDM3) is characterized by the onset of mild to severe hyperglycemia within the first months of life, and requires lifelong therapy (summary by previous studies). Some patients also have neurologic features, including developmental delay and epilepsy (previous studies; previous studies). The triad of developmental delay, epilepsy, and neonatal diabetes is known as DEND. + +For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (previous studies)." +MONDO_0030355,"Definition: Facioscapulohumeral muscular dystrophy (FSHD) is a skeletal muscle disorder characterized by adult onset of progressive muscle weakness of the face and upper extremity muscles. With disease progression, other muscles also may become affected. There is significant clinical variability and incomplete penetrance (summary by previous studies). + +For a discussion of genetic heterogeneity of FSHD, see FSHD1 (previous studies)." +MONDO_0032837,"Definition: Abdominal obesity-metabolic syndrome-4 (AOMS4) is characterized by obesity, hypertension, and early-onset coronary artery disease. Most affected individuals meet the criteria for metabolic syndrome, including elevated triglyceride and low high-density lipoprotein levels, and type 2 diabetes (previous studies). + +For a discussion of the genetic heterogeneity of abdominal obesity-metabolic syndrome, see AOMS1 (previous studies)." +Orphanet_1071,"Definition: Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC) is an autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon, and cleft lip and/or palate (summary by previous studies)." +MONDO_0007124,"Definition: Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC) is an autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon, and cleft lip and/or palate (summary by previous studies)." +EFO_0003108,"Definition: Essential tremor may be the most common human movement disorder. The main feature of essential tremor is postural tremor of the arms, but the head, legs, trunk, voice, jaw, and facial muscles also may be involved. Aggravated by emotions, hunger, fatigue, and temperature extremes, the condition may cause a functional disability or even incapacitation. Autosomal dominant inheritance can be demonstrated in most families (summary by previous studies). + +previous studies provided a detailed review of the genetics of essential tremor. + + Genetic Heterogeneity of Essential Tremor + +Other forms of hereditary essential tremor include ETM2 (previous studies), mapped to chromosome 2p25-p22; ETM3 (previous studies), mapped to chromosome 6p23; ETM4 (previous studies), caused by mutation in the FUS gene (previous studies) on chromosome 16p11; ETM5 (previous studies), caused by mutation in the TENM4 gene (previous studies) on chromosome 11q14; and ETM6 (previous studies), caused by mutation in the NOTCH2NLC gene (previous studies) on chromosome 1q21." +EFO_0009030,"Definition: Cerebellofaciodental syndrome is an autosomal recessive neurodevelopmental disorder characterized by delayed development, intellectual disability, abnormal facial and dental findings, and cerebellar hypoplasia (summary by previous studies)." +MONDO_0008492,"Definition: Stiff skin syndrome is characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness (previous studies). + +Patients with similar phenotypes involving stiff skin have been described; see, e.g., familial progressive scleroderma (previous studies), symmetric lipomatosis (previous studies), and congenital fascial dystrophy (previous studies)." +MONDO_0008759,"Definition: Oxoglutarate dehydrogenase deficiency (OGDHD) is an autosomal recessive disorder associated with features of infantile- and pediatric-onset basal ganglia-associated movement disorders, hypotonia, developmental delays, ataxia, and seizures (summary by previous studies)." +MONDO_0009662,"Definition: Mucopolysaccharidosis type VII is an autosomal recessive lysosomal storage disease characterized by the inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (previous studies). MPS VII was the first autosomal mucopolysaccharidosis for which chromosomal assignment was achieved." +MONDO_0009720,"Definition: Keipert syndrome (KPTS) is characterized by craniofacial and digital abnormalities and variable learning difficulties. The distinctive facial appearance includes broad forehead, hypertelorism, prominent nose, wide mouth, and prominent upper lip with cupid bow configuration. Digital anomalies are also distinctive, with widening of all distal phalanges, particularly of the thumbs and great toes (previous studies)." +MONDO_0010200,"Definition: Wilson disease is an autosomal recessive disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neurologic abnormalities. + +previous studies provided a detailed review of the molecular pathogenesis of Wilson disease." +MONDO_0010502,"Definition: Female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F) is an X-linked dominant neurodevelopmental disorder characterized by delayed psychomotor development and mild to moderate intellectual disability. Affected females can have a wide range of additional congenital anomalies, including scoliosis, postaxial polydactyly, mild cardiac or urogenital anomalies, dysmorphic facial features, and mild structural brain abnormalities (summary by previous studies)." +MONDO_0011732,"Definition: Individuals with familial digital arthropathy-brachydactyly appear normal at birth, with no clinical or radiographic evidence of a developmental skeletal dysplasia. The earliest changes appear during the first decade of life and involve irregularities in the proximal articular surfaces of the distal interphalangeal joints of the hand. By adulthood, all interphalangeal, metacarpophalangeal, and metatarsophalangeal joints are affected by a deforming, painful osteoarthritis. The remainder of the skeleton is clinically and radiographically unaffected, thus distinguishing this disorder from other TRPV4 skeletal dysplasias, the cardinal features of which include abnormalities of the spine and disproportionate short stature (previous studies)." +MONDO_0014731,"Definition: Seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, behavioral problems, poor or absent speech, seizures, dysmorphic facial features with macro- or microcephaly, and skeletal abnormalities, including scoliosis and delayed bone age. Other features may include hypotonia, gastrointestinal problems, and exostoses (summary by previous studies)." +MONDO_0030987,"Definition: VCTERL syndrome is characterized by anomalies of the vertebrae, heart, trachea, esophagus, kidneys, and limbs. Some patients also exhibit craniofacial abnormalities. Incomplete penetrance and markedly variable disease expression have been observed, including intrafamilial variability (previous studies)." +MONDO_0032565,"Definition: External ophthalmoplegia with rib and vertebral anomalies (EORVA) is characterized by congenital nonprogressive external ophthalmoplegia and ptosis, with torticollis and scoliosis developing during childhood. In addition, patients exhibit hypoplastic or missing ribs with fusion anomalies (previous studies)." +Orphanet_100984,"Definition: The hereditary spastic paraplegias are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of previous studies and previous studies. + +SPG is classified according to both the mode of inheritance (autosomal dominant, autosomal recessive (see previous studies), and X-linked (see previous studies)) and whether progressive spasticity occurs in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, and deafness. The major neuropathologic feature of autosomal dominant, uncomplicated SPG is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts (crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis, respectively). Spinocerebellar fibers are involved to a lesser extent. Since the description of 'pure' hereditary spastic paraparesis of late onset by previous studies, many 'complicated' forms of the disorder have been reported and the question as to whether a 'pure' form exists has been raised off and on. Probably in large part because of their exceptional length, the pyramidal tracts are unusually vulnerable to both acquired and genetic derangement. Although a majority of reported families have displayed recessive inheritance, 10 to 30% of families have a dominant pattern and in fact recessive inheritance of a 'pure' spastic paraplegia may be rare. + + Genetic Heterogeneity of Autosomal Dominant Spastic Paraplegia + +In addition to SPG3A, other forms of autosomal dominant spastic paraplegia for which the molecular basis is known include SPG4 (previous studies), caused by mutation in the SPAST gene (previous studies) on 2p22; SPG6 (previous studies), caused by mutation in the NIPA1 gene (previous studies) on 15q11; SPG8 (previous studies), caused by mutation in the WASHC5 gene (previous studies) on 8q24; SPG9A (previous studies), caused by mutation in the ALDH18A1 gene (previous studies) on 10q24; SPG10 (previous studies), caused by mutation in the KIF5A gene (previous studies) on 12q13; SPG12 (previous studies), caused by mutation in the RTN2 gene (previous studies) on 19q13; SPG13 (previous studies), caused by mutation in the SSPD1 gene (previous studies) on 2q33.1; SPG31 (previous studies), caused by mutation in the REEP1 gene (previous studies) on 2p11; SPG30 (previous studies), caused by mutation in the KIF1A gene (previous studies) on 2q37; SPG33 (previous studies), caused by mutation in the ZFYVE27 gene (previous studies) on 10q24; SPG72 (previous studies), caused by mutation in the REEP2 gene (previous studies) on 5q31; SPG73 (previous studies), caused by mutation in the CPT1C gene (previous studies) on 19q13; SPG80 (previous studies), caused by mutation in the UBAP1 gene (previous studies) on chromosome 9p13; SPG88 (previous studies), caused by mutation in the KPNA3 gene (previous studies) on chromosome 13q14; and SPG90A (previous studies), caused by mutation in the SPTSSA gene (previous studies) on chromosome 14q13. + +Autosomal dominant spastic paraplegia has been mapped to chromosomes 9q (SPG19; previous studies), 1p31-p21 (SPG29; previous studies), 12q23-q24 (SPG36; previous studies), 8p21.1-q13.3 (SPG37; previous studies), 4p16-p15 (SPG38; previous studies), and 11p14.1-p11.2 (SPG41; previous studies)." +MONDO_0008437,"Definition: The hereditary spastic paraplegias are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of previous studies and previous studies. + +SPG is classified according to both the mode of inheritance (autosomal dominant, autosomal recessive (see previous studies), and X-linked (see previous studies)) and whether progressive spasticity occurs in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, and deafness. The major neuropathologic feature of autosomal dominant, uncomplicated SPG is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts (crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis, respectively). Spinocerebellar fibers are involved to a lesser extent. Since the description of 'pure' hereditary spastic paraparesis of late onset by previous studies, many 'complicated' forms of the disorder have been reported and the question as to whether a 'pure' form exists has been raised off and on. Probably in large part because of their exceptional length, the pyramidal tracts are unusually vulnerable to both acquired and genetic derangement. Although a majority of reported families have displayed recessive inheritance, 10 to 30% of families have a dominant pattern and in fact recessive inheritance of a 'pure' spastic paraplegia may be rare. + + Genetic Heterogeneity of Autosomal Dominant Spastic Paraplegia + +In addition to SPG3A, other forms of autosomal dominant spastic paraplegia for which the molecular basis is known include SPG4 (previous studies), caused by mutation in the SPAST gene (previous studies) on 2p22; SPG6 (previous studies), caused by mutation in the NIPA1 gene (previous studies) on 15q11; SPG8 (previous studies), caused by mutation in the WASHC5 gene (previous studies) on 8q24; SPG9A (previous studies), caused by mutation in the ALDH18A1 gene (previous studies) on 10q24; SPG10 (previous studies), caused by mutation in the KIF5A gene (previous studies) on 12q13; SPG12 (previous studies), caused by mutation in the RTN2 gene (previous studies) on 19q13; SPG13 (previous studies), caused by mutation in the SSPD1 gene (previous studies) on 2q33.1; SPG31 (previous studies), caused by mutation in the REEP1 gene (previous studies) on 2p11; SPG30 (previous studies), caused by mutation in the KIF1A gene (previous studies) on 2q37; SPG33 (previous studies), caused by mutation in the ZFYVE27 gene (previous studies) on 10q24; SPG72 (previous studies), caused by mutation in the REEP2 gene (previous studies) on 5q31; SPG73 (previous studies), caused by mutation in the CPT1C gene (previous studies) on 19q13; SPG80 (previous studies), caused by mutation in the UBAP1 gene (previous studies) on chromosome 9p13; SPG88 (previous studies), caused by mutation in the KPNA3 gene (previous studies) on chromosome 13q14; and SPG90A (previous studies), caused by mutation in the SPTSSA gene (previous studies) on chromosome 14q13. + +Autosomal dominant spastic paraplegia has been mapped to chromosomes 9q (SPG19; previous studies), 1p31-p21 (SPG29; previous studies), 12q23-q24 (SPG36; previous studies), 8p21.1-q13.3 (SPG37; previous studies), 4p16-p15 (SPG38; previous studies), and 11p14.1-p11.2 (SPG41; previous studies)." +Orphanet_1578,"Definition: Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) D is an autosomal recessive disorder characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported (previous studies). Patients may also develop hypomagnesemia and nonautoimmune diabetes mellitus during puberty (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (previous studies)." +MONDO_0009908,"Definition: Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) D is an autosomal recessive disorder characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported (previous studies). Patients may also develop hypomagnesemia and nonautoimmune diabetes mellitus during puberty (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (previous studies)." +Orphanet_2072,"Definition: Gaucher disease type IIIc (GD3C) is a rare variant of subacute neuronopathic Gaucher disease type III (previous studies), but is considered distinct because of its association with cardiovascular calcifications (previous studies)." +MONDO_0009268,"Definition: Gaucher disease type IIIc (GD3C) is a rare variant of subacute neuronopathic Gaucher disease type III (previous studies), but is considered distinct because of its association with cardiovascular calcifications (previous studies)." +Orphanet_30,"Definition: Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by previous studies). + +previous studies stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported." +MONDO_0009797,"Definition: Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by previous studies). + +previous studies stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported." +Orphanet_79311,"Definition: Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Different forms of isolated methylmalonic aciduria have been classified according to complementation groups of cells in vitro. Patients with defects in the synthesis of AdoCbl are usually responsive to vitamin B12 therapy and are classified as 'cbl' type: these include cblB and cblA (previous studies). The cblA type is caused by mutation in the MMAA gene (previous studies). The 'mut' type (previous studies) is caused by mutation in the MUT gene; in general, the mut form of MMA is unresponsive to vitamin B12 therapy. + +Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (previous studies), cblD (previous studies), and cblF (previous studies)." +MONDO_0009614,"Definition: Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Different forms of isolated methylmalonic aciduria have been classified according to complementation groups of cells in vitro. Patients with defects in the synthesis of AdoCbl are usually responsive to vitamin B12 therapy and are classified as 'cbl' type: these include cblB and cblA (previous studies). The cblA type is caused by mutation in the MMAA gene (previous studies). The 'mut' type (previous studies) is caused by mutation in the MUT gene; in general, the mut form of MMA is unresponsive to vitamin B12 therapy. + +Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (previous studies), cblD (previous studies), and cblF (previous studies)." +EFO_0000762,"Definition: Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (previous studies)." +HP_0000598,"Definition: previous studies was the first to describe a congenital aural atresia (CAA) classification, which has been modified over the years (previous studies; previous studies; previous studies). In CAA type I, there is bony or fibrous atresia of the lateral part of the external auditory canal and an almost normal medial part and middle ear. CAA type II is the most frequent type and is characterized by partial or total aplasia of the external auditory canal. CAA type IIA involves an external auditory canal with either complete bony atresia of the medial part or partial aplasia that ends blindly in a fistula leading to a rudimentary tympanic membrane. CAA type IIB is characterized by bony stenosis of the total length of the external auditory canal. CAA type III involves bony atresia of the external auditory canal and a very small or absent middle-ear cavity (summary by previous studies)." +MONDO_0009866,"Definition: Cytosolic phosphoenolpyruvate carboxykinase deficiency causes a defect in gluconeogenesis that results in a 'biochemical signature' of fasting hypoglycemia with high tricarboxylic acid cycle intermediate excretion, particularly of fumarate. Other biochemical anomalies that may be seen during metabolic crisis include ketonuria, dicarboxylic aciduria, and urea cycle dysfunction (previous studies). + +See PCKDM (previous studies) for a discussion of mitochondrial PCK (PEPCK2; previous studies) deficiency." +MONDO_0009973,"Definition: Reticular dysgenesis, the most severe form of inborn severe combined immunodeficiency (SCID), is characterized by absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immune functions, leading to fatal septicemia within days after birth (summary by previous studies)." +MONDO_0010275,"Definition: X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL) is an X-linked recessive developmental disorder characterized by slowly progressive skeletal and neurologic abnormalities, including short stature, large and deformed joints, significant motor impairment, visual defects, and sometimes cognitive deficits. Affected individuals typically have normal early development in the first year or so of life, followed by development regression and the development of symptoms. Brain imaging shows white matter abnormalities consistent with hypomyelinating leukodystrophy (summary by previous studies)." +MONDO_0011469,"Definition: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies (previous studies). + +previous studies proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type I (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type II (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later." +MONDO_0011725,"Definition: The hereditary hyperbilirubinemias (previous studies) include (1) those resulting in predominantly unconjugated hyperbilirubinemia: Gilbert or Arias syndrome, Crigler-Najjar syndrome type I, and Crigler-Najjar syndrome type II; and (2) those resulting in predominantly conjugated hyperbilirubinemia: Dubin-Johnson syndrome (previous studies), Rotor syndrome (previous studies), and several forms of intrahepatic cholestasis (previous studies, previous studies, previous studies, previous studies). Detailed studies show that patients with Crigler-Najjar syndrome type II have reduced activity of bilirubin glucuronosyltransferase (previous studies, previous studies)." +MONDO_0012243,"Definition: BILU syndrome is an autosomal dominant complex disorder characterized by humoral immunodeficiency with undetectable B cells, distal limb anomalies, dysmorphic facial features, and urogenital malformations (summary by previous studies)." +MONDO_0012282,"Definition: Al-Gazali syndrome (ALGAZ) is characterized by prenatal growth retardation, skeletal anomalies including joint contractures, camptodactyly, and bilateral talipes equinovarus, small mouth, anterior segment eye anomalies, and early lethality (summary by previous studies)." +MONDO_0014024,"Definition: Spastic paraplegia-43 (SPG43) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive spasticity affecting the lower and upper limbs (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +Orphanet_320370,"Definition: Spastic paraplegia-43 (SPG43) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive spasticity affecting the lower and upper limbs (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see previous studies." +MONDO_0054565,"Definition: Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by previous studies and previous studies). + +There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, previous studies). + +For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (previous studies)." +MONDO_0054728,"Definition: Spermatogenic failure-24 is characterized by multiple morphologic abnormalities of the flagella (MMAF), including absent, short, coiled, bent, and irregular-caliber flagella. Malformations of the sperm head have also been observed. In addition, patients exhibit very low sperm concentrations and total sperm counts per ejaculate (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0060596,"Definition: NEDDFL is a neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability, poor growth with small head size, dysmorphic facial features, and mild abnormalities of the hands and feet (summary by previous studies)." +EFO_0004911,"Definition: Familial hypercholesterolemia-3 (FHCL3) is an autosomal dominant disorder of lipid metabolism characterized by a selective increase of low density lipoprotein particles in plasma, giving rise to tendon and skin xanthomas, arcus corneae, and coronary artery disease (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of hypercholesterolemia, see previous studies. + +previous studies reported a large 3-generation French family (HC2) in which 7 individuals had hypercholesterolemia. All affected members had levels of total cholesterol above the 97th percentile when compared with age- and sex-matched French individuals. The proband was a 36-year-old woman, ascertained at age 17 years with 3.32 g/l total cholesterol, 2.36 g/l LDL-C, 0.48 g/l HDL-C, 0.61 g/l triglycerides, and arcus corneae. Her sister, aged 40 years, was ascertained at age 20 years with similar lipid levels, arcus corneae, tendon xanthomas, and xanthelasmas. + +previous studies reported a large Utah kindred (K1173) segregating hypercholesterolemia. In this pedigree, the LDL levels (mean, 237 +/-70) were similar to those of familial hypercholesterolemia pedigrees with mutations in the LDL receptor gene (FHCL1; previous studies), and penetrance was complete even at young ages. Triglyceride levels were significantly lower than in FHCL1 pedigrees, but mean age and body mass index were also lower. There were no differences in the frequency of tendon xanthomas or coronary artery disease." +MONDO_0011369,"Definition: Familial hypercholesterolemia-3 (FHCL3) is an autosomal dominant disorder of lipid metabolism characterized by a selective increase of low density lipoprotein particles in plasma, giving rise to tendon and skin xanthomas, arcus corneae, and coronary artery disease (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of hypercholesterolemia, see previous studies. + +previous studies reported a large 3-generation French family (HC2) in which 7 individuals had hypercholesterolemia. All affected members had levels of total cholesterol above the 97th percentile when compared with age- and sex-matched French individuals. The proband was a 36-year-old woman, ascertained at age 17 years with 3.32 g/l total cholesterol, 2.36 g/l LDL-C, 0.48 g/l HDL-C, 0.61 g/l triglycerides, and arcus corneae. Her sister, aged 40 years, was ascertained at age 20 years with similar lipid levels, arcus corneae, tendon xanthomas, and xanthelasmas. + +previous studies reported a large Utah kindred (K1173) segregating hypercholesterolemia. In this pedigree, the LDL levels (mean, 237 +/-70) were similar to those of familial hypercholesterolemia pedigrees with mutations in the LDL receptor gene (FHCL1; previous studies), and penetrance was complete even at young ages. Triglyceride levels were significantly lower than in FHCL1 pedigrees, but mean age and body mass index were also lower. There were no differences in the frequency of tendon xanthomas or coronary artery disease." +EFO_0009019,"Definition: Spastic paraplegia-76 is an autosomal recessive neurologic disorder characterized by young-adult onset of slowly progressive spasticity of the lower limbs resulting in gait difficulties. Most affected individuals have upper limb involvement and additional features such as foot deformities and dysarthria. Cognition is unaffected (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0009123,"Definition: Orthostatic hypotension-1 (ORTHYP1) is an autosomal recessive disorder characterized by profound autonomic failure. In addition to severe orthostatic hypotension, ptosis, nasal stuffiness, impaired ejaculation, and a neonatal history of delayed eye opening are frequent findings. Biochemical features include undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and undetectable levels of dopamine beta-hydroxylase (summary by previous studies). + + Genetic Heterogeneity of Orthostatic Hypotension + +See also ORTHYP2 (previous studies), caused by mutation in the CYB561 gene (previous studies) on chromosome 17q11." +MONDO_0009734,"Definition: Familial hyperinsulinism, also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur (previous studies). + + Genetic Heterogeneity of Hyperinsulinemic Hypoglycemia + +HHF2 (previous studies) is caused by mutation in the KCNJ11 gene (previous studies) on chromosome 11p15. HHF3 (previous studies) is caused by mutation in the glucokinase gene (GCK; previous studies) on chromosome 7p13. HHF4 (previous studies) is caused by mutation in the HADH gene (previous studies) on chromosome 4q25. HHF5 (previous studies) is caused by mutation in the insulin receptor gene (INSR; previous studies) on chromosome 19p13. HHF6 (previous studies) is caused by mutation in the GLUD1 gene (previous studies) on chromosome 10q23. HHF7 (previous studies) is caused by mutation in the SLC16A1 (previous studies) on chromosome 1p13. There is evidence of further genetic heterogeneity of HHF." +MONDO_0010823,"Definition: Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 is the most frequent form of RCDP (summary by previous studies). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP3 is classified as a single peroxisome enzyme deficiency (previous studies). + +For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see previous studies." +MONDO_0012738,"Definition: Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (previous studies)." +Orphanet_101016,"Definition: Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (previous studies)." +MONDO_0013421,"Definition: Patients with deficiency of C8 suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes. Most such patients are discovered among those having their first episode of meningitis at ages older than 10 years (previous studies). + +Two types of inherited C8 deficiency have been reported in humans: type I (previous studies), in which only C8 alpha (C8A, previous studies) and C8 gamma (C8G; previous studies) are deficient, and type II, in which only C8 beta is deficient (previous studies; previous studies). The 2 types are clinically indistinguishable (previous studies)." +MONDO_0013737,"Definition: Autosomal recessive spastic paraplegia-46 (SPG46) is a neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +Orphanet_320391,"Definition: Autosomal recessive spastic paraplegia-46 (SPG46) is a neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0013991,"Definition: Leptin deficiency is characterized by severe early-onset obesity, hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (previous studies)." +MONDO_0014132,"Definition: MMDS3 is an autosomal recessive severe neurodegenerative disorder characterized by loss of previously acquired developmental milestones in the first months or years of life. Some affected patients have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some patients die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some patients may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable. There may be additional biochemical evidence of mitochondrial dysfunction (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (previous studies)." +Orphanet_363424,"Definition: MMDS3 is an autosomal recessive severe neurodegenerative disorder characterized by loss of previously acquired developmental milestones in the first months or years of life. Some affected patients have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some patients die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some patients may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable. There may be additional biochemical evidence of mitochondrial dysfunction (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (previous studies)." +MONDO_0014286,"Definition: Hereditary sensory neuropathy type IF is an autosomal dominant sensory neuropathy affecting the lower limbs. Distal sensory impairment becomes apparent during the second or third decade of life, resulting in painless ulceration of the feet with poor healing, which can progress to osteomyelitis, bone destruction, and amputation. There is no autonomic involvement, spasticity, or cognitive impairment (summary by previous studies). + +For a discussion of genetic heterogeneity of HSN, see HSAN1A (previous studies)." +MONDO_0014975,"Definition: Autosomal recessive spastic paraplegia-78 is an adult-onset neurodegenerative disorder characterized predominantly by spasticity and muscle weakness of the lower limbs, resulting in gait difficulties and loss of ambulation in some patients. Affected individuals also have cerebellar signs, such as dysarthria, oculomotor disturbances, and limb and gait ataxia; brain imaging shows cerebellar atrophy. Some patients may have mild cognitive impairment or frank dementia. The phenotype is highly variable (summary by previous studies). + +Biallelic mutation in the ATP13A2 gene also causes Kufor-Rakeb syndrome (KRS; previous studies), a neurodegenerative disorder with overlapping features. Patients with KRS have earlier onset and prominent parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by previous studies)." +MONDO_0030819,"Definition: Meckel syndrome-14 (MKS14) is a lethal disorder characterized by occipital encephalocele, postaxial polydactyly of the hands and feet, and polycystic kidneys. Stillbirth has been reported, as well as death within hours in a live-born affected individual (previous studies; previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (previous studies)." +MONDO_0032897,"Definition: Intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA) is a neurodevelopmental disorder characterized by onset of hypotonia and variably impaired global developmental delay in infancy. Affected individuals tend to have learning disability, usually requiring special schooling, as well as behavioral abnormalities, such as autistic features and attention deficit-hyperactivity disorder (ADHD). Additional more variable features may include nonspecific dysmorphic facial features, congenital heart defects, visual or ocular movement anomalies, and poor feeding and/or gastroesophageal reflux (summary by previous studies)." +MONDO_0100157,"Definition: Imerslund-Grasbeck syndrome-2 (IGS2) is an autosomal recessive disorder characterized by onset of megaloblastic anemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Low molecular weight (LMW) proteinuria is frequently present, but usually occurs later and is usually mild or subclinical. Patients often present with vague symptoms, including failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Treatment with vitamin B12 results in sustained clinical improvement of the anemia. The proteinuria is nonprogressive, and affected individuals do not have deterioration of kidney function; correct diagnosis is important to prevent unnecessary treatment. The disorder results from a combination of vitamin B12 deficiency due to selective malabsorption of the vitamin, and impaired reabsorption of LMW proteins in the proximal renal tubule. These defects are caused by disruption of the AMN/CUBN (previous studies) complex that forms the 'cubam' receptor responsible for intestinal uptake of B12/GIF (CBLIF; previous studies). In the kidney, AMN/CUBN interacts with the endocytic receptor megalin (LRP2; previous studies), which is important for the reabsorption of plasma proteins (summary by previous studies, previous studies, and previous studies). + +For a discussion of genetic heterogeneity of Imerslund-Grasbeck syndrome, see previous studies." +Orphanet_137681,"Definition: Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by previous studies). + + Genetic Heterogeneity of Combined Oxidative Phosphorylation Deficiency + +See also COXPD2 (previous studies), caused by mutation in the MRPS16 gene (previous studies) on 10q22; COXPD3 (previous studies), caused by mutation in the TSFM gene (previous studies) on 12q14; COXPD4 (previous studies), caused by mutation in the TUFM gene (previous studies) on 16p11; COXPD5 (previous studies), caused by mutation in the MRPS22 gene (previous studies) on 3q23; COXPD6 (previous studies), caused by mutation in the AIFM1 gene (previous studies) on Xq26; COXPD7 (previous studies), caused by mutation in the MTRFR gene (previous studies) on 12q24; COXPD8 (previous studies), caused by mutation in the AARS2 gene (previous studies) on 6p21; COXPD9 (previous studies), caused by mutation in the MRPL3 gene (previous studies) on 3q22; COXPD10 (previous studies), caused by mutation in the MTO1 gene (previous studies) on 6q13; COXPD11 (previous studies), caused by mutation in the RMND1 gene (previous studies) on 6q25; COXPD12 (previous studies), caused by mutation in the EARS2 gene (previous studies) on 16p13; COXPD13 (previous studies), caused by mutation in the PNPT1 gene (previous studies) on 2p16; COXPD14 (previous studies), caused by mutation in the FARS2 gene (previous studies) on 6p25; COXPD15 (previous studies), caused by mutation in the MTFMT gene (previous studies) on 15q; COXPD16 (previous studies), caused by mutation in the MRPL44 gene (previous studies) on 2q36; COXPD17 (previous studies), caused by mutation in the ELAC2 gene (previous studies) on 17p11; COXPD18 (previous studies), caused by mutation in the SFXN4 gene (previous studies) on 10q26; COXPD19 (previous studies), caused by mutation in the LYRM4 gene (previous studies) on 6p25; COXPD20 (previous studies), caused by mutation in the VARS2 gene (previous studies) on 6p21; COXPD21 (previous studies), caused by mutation in the TARS2 gene (previous studies) on 1q21; COXPD22 (previous studies), caused by mutation in the ATP5A1 gene (previous studies) on 18q12; COXPD23 (previous studies), caused by mutation in the GTPBP3 (previous studies) gene on 19p13; COXPD24 (previous studies), caused by mutation in the NARS2 gene (previous studies) on 11q14; COXPD25 (previous studies), caused by mutation in the MARS2 gene (previous studies) on 2q33; COXPD26 (previous studies), caused by mutation in the TRMT5 gene (previous studies) on 14q23; COXPD27 (previous studies), caused by mutation in the CARS2 gene (previous studies) on 13q34; COXPD28 (previous studies), caused by mutation in the SLC25A26 gene (previous studies) on 3p14; COXPD29 (previous studies), caused by mutation in the TXN2 gene (previous studies) on 22q12; COXPD30 (previous studies), caused by mutation in the TRMT10C gene (previous studies) on 3q12; and COXPD31 (previous studies), caused by mutation in the MIPEP gene (previous studies) on 13q12; COXPD32 (previous studies), caused by mutation in the MRPS34 gene (previous studies) on 16q13; COXPD33 (previous studies), caused by mutation in the C1QBP gene (previous studies) on 17p13; and COXPD34 (previous studies), caused by mutation in the MRPS7 gene (previous studies) on 17q25; COXPD35 (previous studies), caused by mutation in the TRIT1 gene (previous studies) on 1p34; COXPD36 (previous studies), caused by mutation in the MRPS2 gene (previous studies) on 9q34; COXPD37 (previous studies), caused by mutation in the MICOS13 gene (previous studies) on 19p13; COXPD38 (previous studies), caused by mutation in the MRPS14 gene (previous studies) on 1q23; COXPD39 (previous studies), caused by mutation in the GFM2 gene (previous studies) on 5q13; COXPD40 (previous studies), caused by mutation in the QRSL1 gene (previous studies) on 6q21; COXPD41 (previous studies), caused by mutation in the GATB gene (previous studies) on 4q31; COXPD42 (previous studies), caused by mutation in the GATC gene (previous studies) on 12q24; COXPD43 (previous studies), caused by mutation in the TIMM22 gene (previous studies) on 17p13; COXPD44 (previous studies), caused by mutation in the FASTKD2 gene (previous studies) on 2q33; COXPD45 (previous studies), caused by mutation in the MRPL12 gene (previous studies) on 17q25; COXPD46 (previous studies), caused by mutation in the MRPS23 gene (previous studies) on 17q22; COXPD47 (previous studies), caused by mutation in the MRPS28 gene (previous studies) on 8q21; COXPD48 (previous studies), caused by mutation in the NSUN3 gene (previous studies) on 3q11; COXPD49 (previous studies), caused by mutation in the MIEF2 gene (previous studies) on 17p11; COXPD50 (previous studies), caused by mutation in the MRPS25 gene (previous studies) on 3p25; COXPD51 (previous studies), caused by mutation in the PTCD3 gene (previous studies) on 2p11; COXPD52 (previous studies), caused by mutation in the NFS1 gene (previous studies) on 20q11; COXPD53 (previous studies), caused by mutation in the C2ORF69 gene (previous studies) on 2q33; and COXPD54 (previous studies), caused by mutation in the PRORP gene (previous studies) on 14q13.; COXPD55 (previous studies), caused by mutation in the POLRMT gene (previous studies) on 19p13; COXPD56 (previous studies), caused by mutation in the TAMM41 gene (previous studies) on 3p25; and COXPD57 (previous studies), caused by mutation in the CRLS1 gene (previous studies) on 20p12." +MONDO_0012191,"Definition: Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by previous studies). + + Genetic Heterogeneity of Combined Oxidative Phosphorylation Deficiency + +See also COXPD2 (previous studies), caused by mutation in the MRPS16 gene (previous studies) on 10q22; COXPD3 (previous studies), caused by mutation in the TSFM gene (previous studies) on 12q14; COXPD4 (previous studies), caused by mutation in the TUFM gene (previous studies) on 16p11; COXPD5 (previous studies), caused by mutation in the MRPS22 gene (previous studies) on 3q23; COXPD6 (previous studies), caused by mutation in the AIFM1 gene (previous studies) on Xq26; COXPD7 (previous studies), caused by mutation in the MTRFR gene (previous studies) on 12q24; COXPD8 (previous studies), caused by mutation in the AARS2 gene (previous studies) on 6p21; COXPD9 (previous studies), caused by mutation in the MRPL3 gene (previous studies) on 3q22; COXPD10 (previous studies), caused by mutation in the MTO1 gene (previous studies) on 6q13; COXPD11 (previous studies), caused by mutation in the RMND1 gene (previous studies) on 6q25; COXPD12 (previous studies), caused by mutation in the EARS2 gene (previous studies) on 16p13; COXPD13 (previous studies), caused by mutation in the PNPT1 gene (previous studies) on 2p16; COXPD14 (previous studies), caused by mutation in the FARS2 gene (previous studies) on 6p25; COXPD15 (previous studies), caused by mutation in the MTFMT gene (previous studies) on 15q; COXPD16 (previous studies), caused by mutation in the MRPL44 gene (previous studies) on 2q36; COXPD17 (previous studies), caused by mutation in the ELAC2 gene (previous studies) on 17p11; COXPD18 (previous studies), caused by mutation in the SFXN4 gene (previous studies) on 10q26; COXPD19 (previous studies), caused by mutation in the LYRM4 gene (previous studies) on 6p25; COXPD20 (previous studies), caused by mutation in the VARS2 gene (previous studies) on 6p21; COXPD21 (previous studies), caused by mutation in the TARS2 gene (previous studies) on 1q21; COXPD22 (previous studies), caused by mutation in the ATP5A1 gene (previous studies) on 18q12; COXPD23 (previous studies), caused by mutation in the GTPBP3 (previous studies) gene on 19p13; COXPD24 (previous studies), caused by mutation in the NARS2 gene (previous studies) on 11q14; COXPD25 (previous studies), caused by mutation in the MARS2 gene (previous studies) on 2q33; COXPD26 (previous studies), caused by mutation in the TRMT5 gene (previous studies) on 14q23; COXPD27 (previous studies), caused by mutation in the CARS2 gene (previous studies) on 13q34; COXPD28 (previous studies), caused by mutation in the SLC25A26 gene (previous studies) on 3p14; COXPD29 (previous studies), caused by mutation in the TXN2 gene (previous studies) on 22q12; COXPD30 (previous studies), caused by mutation in the TRMT10C gene (previous studies) on 3q12; and COXPD31 (previous studies), caused by mutation in the MIPEP gene (previous studies) on 13q12; COXPD32 (previous studies), caused by mutation in the MRPS34 gene (previous studies) on 16q13; COXPD33 (previous studies), caused by mutation in the C1QBP gene (previous studies) on 17p13; and COXPD34 (previous studies), caused by mutation in the MRPS7 gene (previous studies) on 17q25; COXPD35 (previous studies), caused by mutation in the TRIT1 gene (previous studies) on 1p34; COXPD36 (previous studies), caused by mutation in the MRPS2 gene (previous studies) on 9q34; COXPD37 (previous studies), caused by mutation in the MICOS13 gene (previous studies) on 19p13; COXPD38 (previous studies), caused by mutation in the MRPS14 gene (previous studies) on 1q23; COXPD39 (previous studies), caused by mutation in the GFM2 gene (previous studies) on 5q13; COXPD40 (previous studies), caused by mutation in the QRSL1 gene (previous studies) on 6q21; COXPD41 (previous studies), caused by mutation in the GATB gene (previous studies) on 4q31; COXPD42 (previous studies), caused by mutation in the GATC gene (previous studies) on 12q24; COXPD43 (previous studies), caused by mutation in the TIMM22 gene (previous studies) on 17p13; COXPD44 (previous studies), caused by mutation in the FASTKD2 gene (previous studies) on 2q33; COXPD45 (previous studies), caused by mutation in the MRPL12 gene (previous studies) on 17q25; COXPD46 (previous studies), caused by mutation in the MRPS23 gene (previous studies) on 17q22; COXPD47 (previous studies), caused by mutation in the MRPS28 gene (previous studies) on 8q21; COXPD48 (previous studies), caused by mutation in the NSUN3 gene (previous studies) on 3q11; COXPD49 (previous studies), caused by mutation in the MIEF2 gene (previous studies) on 17p11; COXPD50 (previous studies), caused by mutation in the MRPS25 gene (previous studies) on 3p25; COXPD51 (previous studies), caused by mutation in the PTCD3 gene (previous studies) on 2p11; COXPD52 (previous studies), caused by mutation in the NFS1 gene (previous studies) on 20q11; COXPD53 (previous studies), caused by mutation in the C2ORF69 gene (previous studies) on 2q33; and COXPD54 (previous studies), caused by mutation in the PRORP gene (previous studies) on 14q13.; COXPD55 (previous studies), caused by mutation in the POLRMT gene (previous studies) on 19p13; COXPD56 (previous studies), caused by mutation in the TAMM41 gene (previous studies) on 3p25; and COXPD57 (previous studies), caused by mutation in the CRLS1 gene (previous studies) on 20p12." +Orphanet_163956,"Definition: The Nascimento type of X-linked syndromic intellectual developmental disorder (MRXSN) is characterized by dysmorphic features, including large head, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, abnormal hair whorls, micropenis, and onychodystrophy. Female carriers have normal cognition, but may show subtle facial features (summary by previous studies)." +MONDO_0010461,"Definition: The Nascimento type of X-linked syndromic intellectual developmental disorder (MRXSN) is characterized by dysmorphic features, including large head, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, abnormal hair whorls, micropenis, and onychodystrophy. Female carriers have normal cognition, but may show subtle facial features (summary by previous studies)." +Orphanet_300333,"Definition: Epidermolysis bullosa simplex-7 with nephropathy and deafness (EBS7) is characterized by the presence of skin blistering at birth, particularly in the tibial area but also scattered on other parts of the body, particularly those exposed to trauma. Nephropathy manifests with proteinuria (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0012190,"Definition: Epidermolysis bullosa simplex-7 with nephropathy and deafness (EBS7) is characterized by the presence of skin blistering at birth, particularly in the tibial area but also scattered on other parts of the body, particularly those exposed to trauma. Nephropathy manifests with proteinuria (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +Orphanet_394,"Definition: Classic homocystinuria is an autosomal recessive metabolic disorder of sulfur metabolism. The clinical features of untreated homocystinuria due to CBS deficiency usually manifest in the first or second decade of life and include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome (MFS; previous studies), and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine. There are 2 main phenotypes of the classic disorder: a milder pyridoxine (vitamin B6)-responsive form, and a more severe pyridoxine-nonresponsive form. Pyridoxine is a cofactor for the CBS enzyme, and can aid in the conversion of homocysteine to cysteine (summary by previous studies and previous studies). + +Some patients have been reported to have a milder form of homocystinuria, which is characterized by increased plasma homocysteine and increased risk for thrombotic events in young adulthood, but without the other skeletal, ocular, or nervous system manifestations observed in classic homocystinuria (previous studies)." +MONDO_0009352,"Definition: Classic homocystinuria is an autosomal recessive metabolic disorder of sulfur metabolism. The clinical features of untreated homocystinuria due to CBS deficiency usually manifest in the first or second decade of life and include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome (MFS; previous studies), and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine. There are 2 main phenotypes of the classic disorder: a milder pyridoxine (vitamin B6)-responsive form, and a more severe pyridoxine-nonresponsive form. Pyridoxine is a cofactor for the CBS enzyme, and can aid in the conversion of homocysteine to cysteine (summary by previous studies and previous studies). + +Some patients have been reported to have a milder form of homocystinuria, which is characterized by increased plasma homocysteine and increased risk for thrombotic events in young adulthood, but without the other skeletal, ocular, or nervous system manifestations observed in classic homocystinuria (previous studies)." +Orphanet_79396,"Definition: Generalized severe epidermolysis bullosa simplex-1A (EBS1A) is an autosomal dominant skin disorder characterized by generalized intraepidermal skin blistering from minimal mechanical trauma beginning at birth. A herpetiform (arcuate) pattern of blisters, a crusting-necrotic aspect of the lesions that is often associated with inflammatory plaques, and clumping of keratin intermediate filaments seen on electron microscopy define the severe subtype of EBS. Skin fragility is very prominent at birth, and large tense blisters can occur after minimal trauma or spontaneously; the disorder may be life-threatening in the first year of life. Congenital ulcerated areas on hands and feet as well as nail involvement are common. Blistering is exacerbated by heat, humidity, and sweating. Tendency to blistering diminishes in adolescence (summary by previous studies). + +Epidermolysis bullosa simplex (EBS) comprises a group of clinically and genetically heterogeneous skin disorders characterized by recurrent blistering of the skin following minor physical trauma as a result of cytolysis within basal epidermal cells. Most forms show autosomal dominant inheritance. The severe subtype of EBS was previously known as the Dowling-Meara type. The other 2 main subtypes of EBS are the generalized intermediate, previously known as Koebner, type (see previous studies) and the localized, previously known as Weber-Cockayne, type (see previous studies) (previous studies). All 3 of these main subtypes can be caused by mutation in either the KRT5 or the KRT14 gene. Rare EBS subtypes are clinically and genetically heterogeneous and include several syndromic types. + +Other types of epidermis bullosa (EB), classified by the level of skin cleavage and other ultrastructural laboratory findings in addition to clinical features, are junctional EB (JEB; see previous studies) and dystrophic EB (DEB; see previous studies). + + Genetic Heterogeneity of Epidermolysis Bullosa Simplex + +Other forms of EBS that are caused by mutation in the KRT14 gene are generalized intermediate EBS1B (previous studies), previously known as the Koebner type; localized EBS1C (previous studies), previously known as the Weber-Cockayne type; and autosomal recessive generalized EBS1D (previous studies). + +Forms of EBS caused by mutation in the KRT5 gene are generalized severe EBS2A (previous studies); generalized intermediate EBS2B (previous studies); localized EBS2C (previous studies); generalized autosomal recessive EBS2D (previous studies); EBS2E (previous studies), with migratory circinate erythema; and EBS2F (previous studies), with mottled pigmentation. + +EBS3 (previous studies) is caused by mutation in the DST gene (previous studies). EBS4 (previous studies) is caused by mutation in the EXPH5 gene (previous studies). + +Forms of EBS caused by mutation in the PLEC gene (previous studies) are EBS5A (previous studies), Ogna type; EBS5B (previous studies), with muscular dystrophy; EBS5C (previous studies), with pyloric atresia; and EBS5D (previous studies), autosomal recessive generalized intermediate. + +EBS6 (previous studies), with scarring and hair loss, is caused by mutation in the KLHL24 gene (previous studies). + +EBS7 (previous studies), with nephropathy and deafness, is caused by mutation in the CD151 gene (previous studies). + + Reviews + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility. + +previous studies reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system." +MONDO_0007550,"Definition: Generalized severe epidermolysis bullosa simplex-1A (EBS1A) is an autosomal dominant skin disorder characterized by generalized intraepidermal skin blistering from minimal mechanical trauma beginning at birth. A herpetiform (arcuate) pattern of blisters, a crusting-necrotic aspect of the lesions that is often associated with inflammatory plaques, and clumping of keratin intermediate filaments seen on electron microscopy define the severe subtype of EBS. Skin fragility is very prominent at birth, and large tense blisters can occur after minimal trauma or spontaneously; the disorder may be life-threatening in the first year of life. Congenital ulcerated areas on hands and feet as well as nail involvement are common. Blistering is exacerbated by heat, humidity, and sweating. Tendency to blistering diminishes in adolescence (summary by previous studies). + +Epidermolysis bullosa simplex (EBS) comprises a group of clinically and genetically heterogeneous skin disorders characterized by recurrent blistering of the skin following minor physical trauma as a result of cytolysis within basal epidermal cells. Most forms show autosomal dominant inheritance. The severe subtype of EBS was previously known as the Dowling-Meara type. The other 2 main subtypes of EBS are the generalized intermediate, previously known as Koebner, type (see previous studies) and the localized, previously known as Weber-Cockayne, type (see previous studies) (previous studies). All 3 of these main subtypes can be caused by mutation in either the KRT5 or the KRT14 gene. Rare EBS subtypes are clinically and genetically heterogeneous and include several syndromic types. + +Other types of epidermis bullosa (EB), classified by the level of skin cleavage and other ultrastructural laboratory findings in addition to clinical features, are junctional EB (JEB; see previous studies) and dystrophic EB (DEB; see previous studies). + + Genetic Heterogeneity of Epidermolysis Bullosa Simplex + +Other forms of EBS that are caused by mutation in the KRT14 gene are generalized intermediate EBS1B (previous studies), previously known as the Koebner type; localized EBS1C (previous studies), previously known as the Weber-Cockayne type; and autosomal recessive generalized EBS1D (previous studies). + +Forms of EBS caused by mutation in the KRT5 gene are generalized severe EBS2A (previous studies); generalized intermediate EBS2B (previous studies); localized EBS2C (previous studies); generalized autosomal recessive EBS2D (previous studies); EBS2E (previous studies), with migratory circinate erythema; and EBS2F (previous studies), with mottled pigmentation. + +EBS3 (previous studies) is caused by mutation in the DST gene (previous studies). EBS4 (previous studies) is caused by mutation in the EXPH5 gene (previous studies). + +Forms of EBS caused by mutation in the PLEC gene (previous studies) are EBS5A (previous studies), Ogna type; EBS5B (previous studies), with muscular dystrophy; EBS5C (previous studies), with pyloric atresia; and EBS5D (previous studies), autosomal recessive generalized intermediate. + +EBS6 (previous studies), with scarring and hair loss, is caused by mutation in the KLHL24 gene (previous studies). + +EBS7 (previous studies), with nephropathy and deafness, is caused by mutation in the CD151 gene (previous studies). + + Reviews + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility. + +previous studies reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system." +MONDO_0000902,"Definition: Andermann syndrome is an autosomal recessive motor and sensory neuropathy with agenesis of the corpus callosum associated with developmental and neurodegenerative defects and dysmorphic features. It has a high prevalence in the French Canadian population in the Charlevoix and Saguenay-Lac-Saint-Jean region of Quebec (previous studies). + +previous studies provided a comprehensive review of the disorder. previous studies reviewed the many genetic causes of agenesis of the corpus callosum." +Orphanet_1496,"Definition: Andermann syndrome is an autosomal recessive motor and sensory neuropathy with agenesis of the corpus callosum associated with developmental and neurodegenerative defects and dysmorphic features. It has a high prevalence in the French Canadian population in the Charlevoix and Saguenay-Lac-Saint-Jean region of Quebec (previous studies). + +previous studies provided a comprehensive review of the disorder. previous studies reviewed the many genetic causes of agenesis of the corpus callosum." +MONDO_0007509,"Definition: Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. + +Hypohidrotic, or anhidrotic, ectodermal dysplasia is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia), and inability to sweat (anhidrosis or hypohidrosis). Typical clinical manifestations also include dryness of the skin, eyes, airways, and mucous membranes presumably due to the defective development of several exocrine glands. Hypohidrotic ectodermal dysplasia can be associated with dysmorphic features (forehead bumps, rings under the eyes, everted nose, and prominent lips) and occasionally with absent nipples (summary by previous studies)." +MONDO_0008717,"Definition: Acromesomelic dysplasia-2C (AMD2C) is characterized by skeletal abnormalities restricted to the limbs; the craniofacial skeleton and axial skeletal structures are normal. The severity of the long bone shortening progresses in a proximal to distal direction. The hands and feet are most severely affected, but the distal phalanges are relative normal. Affected individuals have joint dislocations but the number of joints involved is not constant (summary by previous studies). + +For a discussion of genetic heterogeneity of acromesomelic dysplasia, see AMD1 (previous studies)." +Orphanet_968,"Definition: Acromesomelic dysplasia-2C (AMD2C) is characterized by skeletal abnormalities restricted to the limbs; the craniofacial skeleton and axial skeletal structures are normal. The severity of the long bone shortening progresses in a proximal to distal direction. The hands and feet are most severely affected, but the distal phalanges are relative normal. Affected individuals have joint dislocations but the number of joints involved is not constant (summary by previous studies). + +For a discussion of genetic heterogeneity of acromesomelic dysplasia, see AMD1 (previous studies)." +MONDO_0010268,"Definition: X-linked lissencephaly-2 (LISX2) is a developmental disorder characterized by structural brain anomalies, early-onset intractable seizures, severe psychomotor retardation, and ambiguous genitalia. Males are severely affected and often die within the first days or months of life, whereas females may be unaffected or have a milder phenotype (previous studies). LISX2 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from hydranencephaly and lissencephaly to Proud syndrome (previous studies) to infantile spasms without brain malformations (DEE1; previous studies) to syndromic (previous studies) and nonsyndromic (previous studies) mental retardation (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (previous studies)." +MONDO_0010526,"Definition: Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body (previous studies). The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions, among other abnormalities (previous studies). + +An atypical variant of Fabry disease has been reported in which cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, develops in the sixth decade of life. These patients have residual GLA activity (previous studies; previous studies). + +Although Fabry disease was previously considered to be an X-linked recessive disorder, previous studies found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients. + +previous studies and previous studies provided detailed reviews of Fabry disease." +MONDO_0012248,"Definition: Limb-girdle muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies) represent the mildest end of the phenotypic spectrum of muscular dystrophies collectively known as dystroglycanopathies. The limb-girdle phenotype is characterized by onset of muscular weakness apparent after ambulation is achieved; mental retardation and mild brain anomalies are variable (previous studies; review by previous studies). The most severe end of the phenotypic spectrum of dystroglycanopathies is represented by congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A; see MDDGA1, previous studies), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and the intermediate range of the spectrum is represented by congenital muscular dystrophy-dystroglycanopathy with or without mental retardation (type B; see MDDGB1, previous studies). + + Genetic Heterogeneity of Limb-Girdle Muscular Dystrophy-Dystroglycanopathy (Type C) + +Limb-girdle muscular dystrophy due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGC2 (previous studies), caused by mutation in the POMT2 gene (previous studies); MDDGC3 (previous studies), caused by mutation in the POMGNT1 gene (previous studies); MDDGC4 (previous studies), caused by mutation in the FKTN gene (previous studies); MDDGC5 (previous studies), caused by mutation in the FKRP gene (previous studies); MDDGC7 (previous studies), caused by mutation in the ISPD gene (CRPPA; previous studies); MDDGC8 (previous studies), caused by mutation in the POMGNT2 gene (previous studies); MDDGC9 (previous studies) caused by mutation in the DAG1 gene (previous studies); MDDGC12 (previous studies), caused by mutation in the POMK gene (previous studies); MDDGC14 (previous studies) caused by mutation in the GMPPB gene (previous studies); and MDDGC15 (previous studies), caused by mutation in the DPM3 gene (previous studies)." +MONDO_0014071,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0014891,"Definition: Autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5) is characterized by the onset of progressive chronic renal disease in the first decades of life. Mild hyperuricemia may be present, but gout, hypertension, and proteinuria are usually absent. The disease may be associated with anemia or neutropenia. Some patients may have additional findings, including poor overall growth and impaired cognitive function. Renal biopsy shows tubulointerstitial abnormalities with atrophic tubules and fibrosis; secondary glomerular abnormalities and simple cysts may also be present (summary by previous studies). + +For a discussion of genetic heterogeneity and revised nomenclature of ADTKD, see ADTKD1 (previous studies)." +MONDO_0030634,"Definition: Hereditary diffuse leukoencephalopathy with spheroids-2 (HDLS2) is an autosomal dominant neurodegenerative disorder characterized by progressive cognitive and executive dysfunction, psychiatric disturbances, and neurologic symptoms, such as gait abnormalities, paresis, seizures, and rigidity. Symptom onset is usually in adulthood, although earlier onset has been reported. Some patients have an acute encephalopathic course with severe neurologic decline resulting in early death, whereas other patients have a more protracted and chronic disease course. Neuropathologic examination shows a leukoencephalopathy with axonal spheroids and myelination defects (summary by previous studies). + +For a discussion of genetic heterogeneity of HDLS, see HDLS1 (previous studies)." +MONDO_0030849,"Definition: Intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN) is an autosomal recessive neurologic disorder characterized by mild global developmental delay with motor impairment and severe speech delay apparent in the first years of life. Affected individuals begin to walk independently between 3 and 4 years of age, but often have an unsteady or ataxic gait. Most patients have progressive distal muscle weakness and atrophy of the lower limbs, foot or hand deformities, and dysarthria, consistent with a peripheral neuropathy. There is mildly impaired intellectual development. Some patients may have behavioral anomalies, such as autistic features or attention deficit-hyperactivity disorder (ADHD), and some can attend special schools. The overall clinical features indicate involvement of both the central and peripheral nervous systems (summary by previous studies and previous studies)" +MONDO_0032901,"Definition: CATIFA syndrome is characterized by global developmental delay and impaired intellectual development ranging from mild to severe, with most patients exhibiting attention-deficit hyperactivity disorder (ADHD). Patients show an elongated face with long philtrum and small ears. Ocular anomalies include congenital cataracts, strabismus, and amblyopia, which may be associated with reduced vision; other anomalies include cleft lip and/or palate and misaligned teeth with extensive caries (previous studies)." +MONDO_0032920,"Definition: Juvenile arthritis (JUVAR) is characterized by onset in early childhood of symmetric arthritis in multiple joints, associated with a marked increase in inflammatory markers. Some patients exhibit systemic symptoms, including quotidian fever, erythematous rash, generalized lymphadenopathy, hepatomegaly, and/or splenomegaly. There is high clinical variability, even within the same family (previous studies)." +MONDO_0032938,"Definition: Autosomal recessive idiopathic basal ganglia calcification-8 (IBGC8) is a progressive neurologic disorder with insidious onset of motor symptoms in adulthood. Affected individuals develop gait difficulties, parkinsonism, pyramidal signs, and dysarthria. Some may demonstrate cognitive decline or memory impairment. Brain imaging shows extensive calcifications in various brain regions including the basal ganglia, thalamus, and cerebellum. Because serum calcium and phosphate are normal, the disorder is thought to result from defects in the integrity of the neurovascular unit in the brain (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (previous studies)." +MONDO_0033614,"Definition: Autosomal recessive spastic paraplegia-83 (SPG83) is a neurologic disorder characterized by progressive lower limb spasticity resulting in gait instability. Patients develop symptoms in the second decade, consistent with juvenile onset. Some patients may have myalgia or mild dysarthria, but the phenotype is considered to be a pure type of SPG with no additional neurologic abnormalities (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0054833,"Definition: Charcot-Marie-Tooth disease type 2DD is an autosomal dominant peripheral sensorimotor neuropathy mainly affecting the lower limbs. Affected individuals have gait impairment due to distal muscle weakness and atrophy. Some patients may also have involvement of the distal upper limbs, resulting in atrophy of the intrinsic hand muscles. The age at onset and severity of the disorder is highly variable, even within families, and those with earlier onset in late childhood or the teenage years tend to have a more severe disease course. Patients remain ambulatory even late in the disease, although some may require orthotic devices (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (previous studies)." +Orphanet_1377,"Definition: Mutations in the GJA8 gene have been found to cause several types of autosomal dominant cataract, which have been described as congenital, zonular pulverulent, nuclear progressive, nuclear pulverulent, stellate nuclear, nuclear total, total, and posterior subcapsular. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the GJA8 gene. + +Before it was known that mutation in the GJB8 gene caused multiple types of cataract, this entry was titled 'Cataract, zonular pulverulent, 1,' with the symbols CZP1, CZP, and CAE1." +Orphanet_254905,"Definition: Mitochondrial complex IV deficiency nuclear type 1 (MC4DN1) is an autosomal recessive metabolic disorder characterized by rapidly progressive neurodegeneration and encephalopathy with loss of motor and cognitive skills between about 5 and 18 months of age after normal early development. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, and poor eye contact. Other features may include oculomotor abnormalities, including slow saccades, strabismus, ophthalmoplegia, and nystagmus, as well as deafness, apneic episodes, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see previous studies). Some patients may also have abnormalities in the brainstem and cerebellum. Laboratory studies usually show increased serum and CSF lactate and decreased levels and activity of mitochondrial respiratory complex IV in patient tissues. There is phenotypic variability, but death in childhood, often due to central respiratory failure, is common (summary by previous studies; previous studies; previous studies; previous studies) + + Genetic Heterogeneity of Mitochondrial Complex IV Deficiency + +Most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare (previous studies; previous studies). + +Mitochondrial complex IV deficiency caused by mutation in nuclear-encoded genes, in addition to MC4DN1, include MC4DN2 (previous studies), caused by mutation in the SCO2 gene (previous studies); MC4DN3 (previous studies), caused by mutation in the COX10 gene (previous studies); MC4DN4 (previous studies), caused by mutation in the SCO1 gene (previous studies); MC4DN5 (previous studies), caused by mutation in the LRPPRC gene (previous studies); MC4DN6 (previous studies), caused by mutation in the COX15 gene (previous studies); MC4DN7 (previous studies), caused by mutation in the COX6B1 gene (previous studies); MC4DN8 (previous studies), caused by mutation in the TACO1 gene (previous studies); MC4DN9 (previous studies), caused by mutation in the COA5 gene (previous studies); MC4DN10 (previous studies), caused by mutation in the COX14 gene (previous studies); MC4DN11 (previous studies), caused by mutation in the COX20 gene (previous studies); MC4DN12 (previous studies), caused by mutation in the PET100 gene (previous studies); MC4DN13 (previous studies), caused by mutation in the COA6 gene (previous studies); MC4DN14 (previous studies), caused by mutation in the COA3 gene (previous studies); MC4DN15 (previous studies), caused by mutation in the COX8A gene (previous studies); MC4DN16 (previous studies), caused by mutation in the COX4I1 gene (previous studies); MC4DN17 (previous studies), caused by mutation in the APOPT1 gene (previous studies); MC4DN18 (previous studies), caused by mutation in the COX6A2 gene (previous studies); MC4DN19 (previous studies), caused by mutation in the PET117 gene (previous studies); MC4DN20 (previous studies), caused by mutation in the COX5A gene (previous studies); MC4DN21 (previous studies), caused by mutation in the COXFA4 gene (previous studies); MC4DN22 (previous studies), caused by mutation in the COX16 gene (previous studies); and MC4DN23 (previous studies), caused by mutation in the COX11 gene (previous studies). + +Mitochondrial complex IV deficiency has been associated with mutations in several mitochondrial genes, including MTCO1 (previous studies), MTCO2 (previous studies), MTCO3 (previous studies), MTTS1 (previous studies), MTTL1 (previous studies), and MTTN (previous studies)." +MONDO_0009068,"Definition: Mitochondrial complex IV deficiency nuclear type 1 (MC4DN1) is an autosomal recessive metabolic disorder characterized by rapidly progressive neurodegeneration and encephalopathy with loss of motor and cognitive skills between about 5 and 18 months of age after normal early development. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, and poor eye contact. Other features may include oculomotor abnormalities, including slow saccades, strabismus, ophthalmoplegia, and nystagmus, as well as deafness, apneic episodes, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see previous studies). Some patients may also have abnormalities in the brainstem and cerebellum. Laboratory studies usually show increased serum and CSF lactate and decreased levels and activity of mitochondrial respiratory complex IV in patient tissues. There is phenotypic variability, but death in childhood, often due to central respiratory failure, is common (summary by previous studies; previous studies; previous studies; previous studies) + + Genetic Heterogeneity of Mitochondrial Complex IV Deficiency + +Most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare (previous studies; previous studies). + +Mitochondrial complex IV deficiency caused by mutation in nuclear-encoded genes, in addition to MC4DN1, include MC4DN2 (previous studies), caused by mutation in the SCO2 gene (previous studies); MC4DN3 (previous studies), caused by mutation in the COX10 gene (previous studies); MC4DN4 (previous studies), caused by mutation in the SCO1 gene (previous studies); MC4DN5 (previous studies), caused by mutation in the LRPPRC gene (previous studies); MC4DN6 (previous studies), caused by mutation in the COX15 gene (previous studies); MC4DN7 (previous studies), caused by mutation in the COX6B1 gene (previous studies); MC4DN8 (previous studies), caused by mutation in the TACO1 gene (previous studies); MC4DN9 (previous studies), caused by mutation in the COA5 gene (previous studies); MC4DN10 (previous studies), caused by mutation in the COX14 gene (previous studies); MC4DN11 (previous studies), caused by mutation in the COX20 gene (previous studies); MC4DN12 (previous studies), caused by mutation in the PET100 gene (previous studies); MC4DN13 (previous studies), caused by mutation in the COA6 gene (previous studies); MC4DN14 (previous studies), caused by mutation in the COA3 gene (previous studies); MC4DN15 (previous studies), caused by mutation in the COX8A gene (previous studies); MC4DN16 (previous studies), caused by mutation in the COX4I1 gene (previous studies); MC4DN17 (previous studies), caused by mutation in the APOPT1 gene (previous studies); MC4DN18 (previous studies), caused by mutation in the COX6A2 gene (previous studies); MC4DN19 (previous studies), caused by mutation in the PET117 gene (previous studies); MC4DN20 (previous studies), caused by mutation in the COX5A gene (previous studies); MC4DN21 (previous studies), caused by mutation in the COXFA4 gene (previous studies); MC4DN22 (previous studies), caused by mutation in the COX16 gene (previous studies); and MC4DN23 (previous studies), caused by mutation in the COX11 gene (previous studies). + +Mitochondrial complex IV deficiency has been associated with mutations in several mitochondrial genes, including MTCO1 (previous studies), MTCO2 (previous studies), MTCO3 (previous studies), MTTS1 (previous studies), MTTL1 (previous studies), and MTTN (previous studies)." +Orphanet_79091,"Definition: Congenital myopathy-6 with ophthalmoplegia (CMYP6) is a relatively mild muscle disorder characterized by childhood onset of symptoms. The disorder is either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity. CMYP6 can show both autosomal dominant and autosomal recessive inheritance; the phenotype is similar in both forms (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0011577,"Definition: Congenital myopathy-6 with ophthalmoplegia (CMYP6) is a relatively mild muscle disorder characterized by childhood onset of symptoms. The disorder is either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity. CMYP6 can show both autosomal dominant and autosomal recessive inheritance; the phenotype is similar in both forms (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +EFO_0004143,"Definition: Carpal tunnel syndrome-1 (CTS1) is characterized by hand pain and numbness in the distribution of the median nerve, with onset in the sixth decade of life. Amyloid deposits are observed in synovial tissue of the wrist and in the transverse carpal ligament (previous studies). + + Genetic Heterogeneity of Carpal Tunnel Syndrome + +CTS2 (previous studies) is caused by mutation in the COMP gene (previous studies) on chromosome 19p13. + +Susceptibility to the development of mononeuropathy of the median (MNMN; previous studies) may also be conferred by heterozygous mutation in the SH3TC2 gene (previous studies) on chromosome 5q32." +MONDO_0007495,"Definition: Autosomal dominant dopa-responsive dystonia (DRD) is characterized by generalized dystonia, diurnal fluctuation of symptoms, and a dramatic therapeutic response to L-dopa. The clinical spectrum can range from subtle neurologic signs and symptoms (e.g., abnormal writing tests) to orthopedic signs (e.g., pes equinovarus), parkinsonism, and even psychiatric manifestations (summary by previous studies)." +MONDO_0008919,"Definition: Primary systemic carnitine deficiency is due to a defect in the high-affinity carnitine transporter expressed in muscle, heart, kidney, lymphoblasts, and fibroblasts. This results in impaired fatty acid oxidation in skeletal and heart muscle. In addition, renal wasting of carnitine results in low serum levels and diminished hepatic uptake of carnitine by passive diffusion, which impairs ketogenesis (previous studies). If diagnosed early, all clinical manifestations of the disorder can be completely reversed by supplementation of carnitine. However, if left untreated, patients will develop lethal heart failure (summary by previous studies). + +See also myopathic carnitine deficiency (previous studies), which is restricted to skeletal muscle." +Orphanet_158,"Definition: Primary systemic carnitine deficiency is due to a defect in the high-affinity carnitine transporter expressed in muscle, heart, kidney, lymphoblasts, and fibroblasts. This results in impaired fatty acid oxidation in skeletal and heart muscle. In addition, renal wasting of carnitine results in low serum levels and diminished hepatic uptake of carnitine by passive diffusion, which impairs ketogenesis (previous studies). If diagnosed early, all clinical manifestations of the disorder can be completely reversed by supplementation of carnitine. However, if left untreated, patients will develop lethal heart failure (summary by previous studies). + +See also myopathic carnitine deficiency (previous studies), which is restricted to skeletal muscle." +MONDO_0009161,"Definition: Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (previous studies). previous studies reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human." +MONDO_0009239,"Definition: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +For a general phenotypic description and a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see previous studies." +Orphanet_52901,"Definition: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +For a general phenotypic description and a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see previous studies." +MONDO_0010518,"Definition: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by thrombocytopenia, eczema, and recurrent infections (previous studies). + + Genetic Heterogeneity of Wiskott-Aldrich Syndrome + +See Wiskott-Aldrich syndrome-2 (WAS2; previous studies), caused by mutation in the WIPF1 gene (previous studies). Also see previous studies for a possible autosomal dominant form of the disorder." +MONDO_0011579,"Definition: Late-onset retinal degeneration (LORD) is an autosomal dominant disorder characterized by onset in the fifth to sixth decade with night blindness and punctate yellow-white deposits in the retinal fundus, progressing to severe central and peripheral degeneration, with choroidal neovascularization and chorioretinal atrophy (previous studies)." +MONDO_0013302,"Definition: Nephronophthisis-11 (NPHP11) is an autosomal recessive kidney disease characterized histologically by renal interstitial infiltration with fibrosis, tubular atrophy with basement membrane disruption, and cyst development at the corticomedullary border. Hepatic fibrosis is also present. The clinical presentation includes polyuria, polydipsia, anemia, and growth retardation. End-stage renal disease develops in the first or second decade of life (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of NPHP, see NPHP1 (previous studies)." +MONDO_0013599,"Definition: IMD31C is a disorder of immunologic dysregulation with highly variable manifestations resulting from autosomal dominant gain-of-function mutations in STAT1 (previous studies). Most patients present in infancy or early childhood with chronic mucocutaneous candidiasis (CMC). Other highly variable features include recurrent bacterial, viral, fungal, and mycoplasmal infections, disseminated dimorphic fungal infections, enteropathy with villous atrophy, and autoimmune disorders, such as hypothyroidism or diabetes mellitus. A subset of patients show apparently nonimmunologic features, including osteopenia, delayed puberty, and intracranial aneurysms. Laboratory studies show increased activation of gamma-interferon (IFNG; previous studies)-mediated inflammation (summary by previous studies and previous studies)." +MONDO_0013800,"Definition: Ehlers-Danlos syndrome kyphoscoliotic type 2 is characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine (previous studies). + +For a discussion of genetic heterogeneity of the kyphoscoliotic type of EDS, see previous studies." +MONDO_0013990,"Definition: Pontocerebellar hypoplasia type 8 is an autosomal recessive neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased cerebral white matter, and a thin corpus callosum (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (previous studies)." +MONDO_0014510,"Definition: Peroxisomal fatty acyl-CoA reductase-1 disorder (PFCRD) is an autosomal recessive disorder characterized by onset in infancy of severely delayed psychomotor development, growth retardation with microcephaly, and seizures. Some patients may have congenital cataracts and develop spasticity later in childhood. Biochemical studies tend to show decreased plasmalogen, consistent with a peroxisomal defect. The disorder is reminiscent of rhizomelic chondrodysplasia punctata (see, e.g., RCDP1, previous studies), although the characteristic skeletal abnormalities observed in RCDP are absent (previous studies)." +MONDO_0014601,"Definition: Autosomal recessive spinocerebellar ataxia-20 is a neurodevelopmental disorder characterized by severely delayed psychomotor development with poor or absent speech, wide-based or absent gait, coarse facies, and cerebellar atrophy (summary by previous studies)." +Orphanet_397709,"Definition: Autosomal recessive spinocerebellar ataxia-20 is a neurodevelopmental disorder characterized by severely delayed psychomotor development with poor or absent speech, wide-based or absent gait, coarse facies, and cerebellar atrophy (summary by previous studies)." +MONDO_0018023,"Definition: Methemoglobinemia is a clinical condition in which more than 1% of hemoglobin is oxidized to methemoglobin, a type of hemoglobin that contains the ferric (Fe3+) form of iron. Patients with hemoglobin M are cyanotic but otherwise asymptomatic. If the mutation occurs in the hemoglobin alpha subunit (previous studies), cyanosis is apparent at birth, whereas if the beta chain is affected, cyanosis appears later or intensifies when beta subunit production increases. If a newborn carries a fetal M hemoglobin (gamma subunit; previous studies), cyanosis disappears when the complete gamma-beta-switch occurs (summary by previous studies)." +MONDO_0030869,"Definition: Spermatogenic failure-50 (SPGF50) is characterized by male infertility due to azoospermia resulting from meiotic arrest at prophase I (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +Orphanet_166078,"Definition: Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. The disorder results from a defect in platelet aggregation due to defects in the von Willebrand factor protein. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; previous studies). F8 is mutated in hemophilia A (summary by previous studies). + +For a review of the various forms of von Willebrand disease, see previous studies. + + Classification of von Willebrand Disease + +The classification of von Willebrand disease has a long and complex history. The current classification is based on that described by previous studies and updated by previous studies, which delineates 3 main subtypes according to the mutant protein phenotype. An earlier classification developed by a working party of the European Thrombosis Research Organization was provided by previous studies. + +Von Willebrand Disease Type 1 + +VWD type 1 is a quantitative partial deficiency of circulating VWF. In this type of VWD, there is a normal ratio of functional VWF activity (VWF:RCo, ristocetin cofactor activity) relative to VWF antigen level (VWF:Ag) (previous studies, previous studies). previous studies stated that type 1 VWD accounts for 60 to 80% of all VWD cases and is characterized by mild to moderate quantitative deficiencies of VWF and factor VIII, which are coordinately reduced to 5 to 30% of normal plasma levels (pathogenic levels of 5 to 30 IU/dL). In an updated consensus statement, previous studies noted that (1) some cases of VWF type 1 may have subtle abnormal VWF multimer patterns, but still retain normal functional activity, and (2) that loci other than VWF may be responsible for some cases of VWD. + +In reviews, previous studies and previous studies stated that the knowledge of the pathogenesis and molecular basis of type 1 VWD is still in its infancy and still evolving. Population studies have indicated that type 1 VWD is a complex genetic trait associated with a variety of genetic and environmental factors, and that additional loci in addition to VWF are likely involved. There is still uncertainty about the pathogenicity of many identified putative VWF variants, and the incomplete penetrance and variable expressivity of type 1 disease contributes to complexity in diagnosis and understanding of disease pathogenesis. + +Von Willebrand Disease Type 2 + +VWD type 2 (previous studies), which accounts for 10 to 30% of cases, is characterized by qualitative abnormalities of VWF; it is further divided into subtypes 2A, 2B, 2M, and 2N. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8 (previous studies; previous studies; previous studies). + +Von Willebrand Disease Type 3 + +VWD type 3 (previous studies), which accounts for 1 to 5% of cases, is characterized by a severe quantitative defect of VWF in plasma (less than 1% of normal plasma levels), with low but usually detectable levels of factor VIII (1 to 10% of normal plasma levels). In the rare type 3 disease (1 in 1 million people), symptoms are more frequent and severe (previous studies, previous studies)." +MONDO_0008668,"Definition: Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. The disorder results from a defect in platelet aggregation due to defects in the von Willebrand factor protein. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; previous studies). F8 is mutated in hemophilia A (summary by previous studies). + +For a review of the various forms of von Willebrand disease, see previous studies. + + Classification of von Willebrand Disease + +The classification of von Willebrand disease has a long and complex history. The current classification is based on that described by previous studies and updated by previous studies, which delineates 3 main subtypes according to the mutant protein phenotype. An earlier classification developed by a working party of the European Thrombosis Research Organization was provided by previous studies. + +Von Willebrand Disease Type 1 + +VWD type 1 is a quantitative partial deficiency of circulating VWF. In this type of VWD, there is a normal ratio of functional VWF activity (VWF:RCo, ristocetin cofactor activity) relative to VWF antigen level (VWF:Ag) (previous studies, previous studies). previous studies stated that type 1 VWD accounts for 60 to 80% of all VWD cases and is characterized by mild to moderate quantitative deficiencies of VWF and factor VIII, which are coordinately reduced to 5 to 30% of normal plasma levels (pathogenic levels of 5 to 30 IU/dL). In an updated consensus statement, previous studies noted that (1) some cases of VWF type 1 may have subtle abnormal VWF multimer patterns, but still retain normal functional activity, and (2) that loci other than VWF may be responsible for some cases of VWD. + +In reviews, previous studies and previous studies stated that the knowledge of the pathogenesis and molecular basis of type 1 VWD is still in its infancy and still evolving. Population studies have indicated that type 1 VWD is a complex genetic trait associated with a variety of genetic and environmental factors, and that additional loci in addition to VWF are likely involved. There is still uncertainty about the pathogenicity of many identified putative VWF variants, and the incomplete penetrance and variable expressivity of type 1 disease contributes to complexity in diagnosis and understanding of disease pathogenesis. + +Von Willebrand Disease Type 2 + +VWD type 2 (previous studies), which accounts for 10 to 30% of cases, is characterized by qualitative abnormalities of VWF; it is further divided into subtypes 2A, 2B, 2M, and 2N. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8 (previous studies; previous studies; previous studies). + +Von Willebrand Disease Type 3 + +VWD type 3 (previous studies), which accounts for 1 to 5% of cases, is characterized by a severe quantitative defect of VWF in plasma (less than 1% of normal plasma levels), with low but usually detectable levels of factor VIII (1 to 10% of normal plasma levels). In the rare type 3 disease (1 in 1 million people), symptoms are more frequent and severe (previous studies, previous studies)." +Orphanet_314051,"Definition: COXPD12 is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0013971,"Definition: COXPD12 is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +Orphanet_79395,"Definition: Variant Vohwinkel syndrome is a rare genodermatosis characterized by hyperkeratosis of the palms and soles, with a honeycomb appearance; constricting bands encircling the digits of the hands and feet, which frequently lead to autoamputation of the fifth digits; starfish-shaped, salmon-colored hyperkeratotic lesions, or knuckle pads, on the dorsal surface of the hands; and ichthyosiform dermatosis. The pathognomonic histologic finding is markedly thickened stratum corneum, hypergranulosis, and particularly, hyperkeratosis with round nuclei retained in the stratum corneum. Unlike classic Vohwinkel syndrome, hearing loss is not a feature (summary by previous studies)." +MONDO_0011396,"Definition: Variant Vohwinkel syndrome is a rare genodermatosis characterized by hyperkeratosis of the palms and soles, with a honeycomb appearance; constricting bands encircling the digits of the hands and feet, which frequently lead to autoamputation of the fifth digits; starfish-shaped, salmon-colored hyperkeratotic lesions, or knuckle pads, on the dorsal surface of the hands; and ichthyosiform dermatosis. The pathognomonic histologic finding is markedly thickened stratum corneum, hypergranulosis, and particularly, hyperkeratosis with round nuclei retained in the stratum corneum. Unlike classic Vohwinkel syndrome, hearing loss is not a feature (summary by previous studies)." +MONDO_0007797,"Definition: HDR syndrome (HDRS), also known as Barakat syndrome, is a heterogeneous disorder characterized by the triad of Hypoparathyroidism (H), nerve Deafness (D) and/or Renal disease (R). Variable clinical features include hypogonadotrophic hypogonadism, polycystic ovaries, congenital heart disease, retinitis pigmentosa, and cognitive disability (previous studies)." +Orphanet_2237,"Definition: HDR syndrome (HDRS), also known as Barakat syndrome, is a heterogeneous disorder characterized by the triad of Hypoparathyroidism (H), nerve Deafness (D) and/or Renal disease (R). Variable clinical features include hypogonadotrophic hypogonadism, polycystic ovaries, congenital heart disease, retinitis pigmentosa, and cognitive disability (previous studies)." +MONDO_0008922,"Definition: Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by previous studies). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (previous studies)." +MONDO_0009260,"Definition: GM1-gangliosidosis is an autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes. Clinically, patients show variable degrees of neurodegeneration and skeletal abnormalities. There are 3 main clinical variants categorized by severity and variable residual beta-galactosidase activity. Type I, or infantile form, shows rapid psychomotor deterioration beginning within 6 months of birth, generalized central nervous system involvement, hepatosplenomegaly, facial dysmorphism, macular cherry-red spots, skeletal dysplasia, and early death. Type II, or late-infantile/juvenile form (GM1G2; previous studies), has onset between 7 months and 3 years, shows generalized central nervous system involvement with psychomotor deterioration, seizures, localized skeletal involvement, and survival into childhood. Hepatosplenomegaly and cherry-red spots are usually not present. Type III, or adult/chronic form (GM1G3; previous studies), shows onset from 3 to 30 years and is characterized by localized skeletal involvement and localized central nervous system involvement, such as dystonia or gait or speech disturbance. There is an inverse correlation between disease severity and residual enzyme activity (previous studies). + +See also Morquio B disease (previous studies), an allelic disorder with skeletal anomalies and no neurologic involvement. + +The GM2-gangliosidoses include Tay-Sachs disease (previous studies) and Sandhoff disease (previous studies)." +MONDO_0010382,"Definition: previous studies provided a review of fragile X syndrome, which they characterized as a neurodevelopmental disorder, and FXTAS, which they characterized as a neurodegenerative disorder. previous studies provided a review of FXTAS and noted that the pathogenesis of the disorder is distinct from that in fragile X syndrome. FXTAS results form a toxic gain of function of FMR1 RNA, whereas fragile X syndrome results from a loss of FMR1 function. + +The penetrance of FXTAS in male carriers aged 50 years and over, ascertained through families with a fragile X syndrome proband, is at least 33% (previous studies); its penetrance in female carriers is approximately 5-10% (previous studies)." +MONDO_0010665,"Definition: Wilson-Turner syndrome (WTS) is an X-linked recessive neurologic disorder characterized by intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Females are unaffected (previous studies)." +MONDO_0011017,"Definition: In Naxos disease, abnormalities of the skin, hair, and nails are associated with arrhythmogenic right ventricular cardiomyopathy. The ectodermal features are evident from birth or early childhood, whereas the cardiac symptoms develop in young adulthood or later. Clinical variability of ectodermal features has been observed, with hair anomalies ranging from woolly hair to alopecia, and skin abnormalities ranging from mild focal palmoplantar keratoderma to generalized skin fragility or even lethal neonatal epidermolysis bullosa (previous studies; previous studies; previous studies; previous studies; previous studies). + +Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (Carvajal syndrome; previous studies) is caused by mutation in the desmoplakin gene (DSP; previous studies). Also see previous studies for a similar disorder caused by homozygous mutation in the DSC2 gene (previous studies)." +MONDO_0011759,"Definition: The mucopolysaccharidoses are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function. + +Deficiency of alpha-L-iduronidase can result in a wide range of phenotypic involvement with 3 major recognized clinical entities: Hurler (MPS IH; previous studies), Scheie (MPS IS; previous studies), and Hurler-Scheie (MPS IH/S) syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression (previous studies). + +previous studies presented 5 patients with alpha-L-iduronidase deficiency and a phenotype atypical for both Hurler and Scheie syndromes. They felt that the genetic compound explanation was acceptable for some cases, but that others must represent different mutations." +MONDO_0012415,"Definition: Progressive external ophthalmoplegia-4 is an autosomal dominant form of mitochondrial disease that variably affects skeletal muscle, the nervous system, the liver, and the gastrointestinal tract. Age at onset ranges from infancy to adulthood. The phenotype ranges from relatively mild, with adult-onset skeletal muscle weakness and weakness of the external eye muscles, to severe, with a multisystem disorder characterized by delayed psychomotor development, lactic acidosis, constipation, and liver involvement (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (previous studies)." +MONDO_0012651,"Definition: Autosomal recessive spastic ataxia is a neurologic disorder characterized by onset in the first 2 decades of cerebellar ataxia, dysarthria, and variable spasticity of the lower limbs. Cognition is not affected (summary by previous studies). + +For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (previous studies)." +MONDO_0013942,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 9 (CG9, equivalent to CGD) have mutations in the PEX16 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0014292,"Definition: Leukoencephalopathy with ataxia is an autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles. The findings suggest myelin microvacuolation restricted to certain brain regions. Clinical features include ataxia and unstable gait; more variable abnormalities may include visual field defects, headaches, and learning disabilities (summary by previous studies)." +MONDO_0030797,"Definition: Retinitis pigmentosa-93 (RP93) is characterized by mild to moderate rod-cone dystrophy with onset in the second or third decade of life. Patients have constricted visual fields with macular sparing and show mildly reduced visual acuity with mild to high myopia (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see previous studies." +MONDO_0030861,"Definition: Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (previous studies)." +Orphanet_67041,"Definition: Mucopolysaccharidosis type IX (MPS9) is a rare progressive lysosomal storage disorder caused by the deficiency of the enzyme hyaluronoglucosaminidase-1, which degrades hyaluronan (summary by previous studies)." +MONDO_0011093,"Definition: Mucopolysaccharidosis type IX (MPS9) is a rare progressive lysosomal storage disorder caused by the deficiency of the enzyme hyaluronoglucosaminidase-1, which degrades hyaluronan (summary by previous studies)." +EFO_0009033,"Definition: Combined oxidative phosphorylation deficiency-23 is an autosomal recessive disorder characterized by early childhood onset of hypertrophic cardiomyopathy and/or neurologic symptoms, including hypotonia and delayed psychomotor development. Laboratory investigations are consistent with a defect in mitochondrial function resulting in lactic acidosis, impaired activities of respiratory complexes I and IV, and defective translation of mitochondrial proteins. Brain imaging shows abnormal lesions in the basal ganglia, thalamus, and brainstem. The severity of the disorder is variable, ranging from death in early infancy to survival into the second decade (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +EFO_0009158,"Definition: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions (summary by previous studies). + + Genetic Heterogeneity of PEBEL + +See also PEBEL2 (previous studies), caused by mutation in the NAXD gene (previous studies) on chromosome 13q34." +EFO_0010255,"Definition: Recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN) is an autosomal recessive metabolic disorder with a highly variable phenotype. Most affected individuals present in the first years of life with episodic lactic acidosis associated with illness or stress, resulting in transient or permanent neurologic dysfunction. Some patients may recover, whereas others show subsequent variable developmental regression of motor and cognitive skills. Other features may include dystonia, hypotonia with inability to sit or walk, seizures, and abnormal signals in the basal ganglia. There is significant phenotypic heterogeneity, even among patients with the same mutation (summary by previous studies)." +EFO_0010656,"Definition: Mitochondrial complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is an autosomal recessive progressive and degenerative disorder characterized by episodic regression of gross motor skills beginning in early childhood. The episodes are associated with metabolic stress, including fever, illness, and general anesthesia. Patients develop gait difficulties or loss of ambulation, as well as other variable abnormalities, including abnormal movements, hemiplegia, and persistent lethargy. Brain imaging shows degenerative features in the basal ganglia and brainstem consistent with a diagnosis of Leigh syndrome (see previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see MC5DN1 (previous studies)." +MONDO_0032869,"Definition: Mitochondrial complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is an autosomal recessive progressive and degenerative disorder characterized by episodic regression of gross motor skills beginning in early childhood. The episodes are associated with metabolic stress, including fever, illness, and general anesthesia. Patients develop gait difficulties or loss of ambulation, as well as other variable abnormalities, including abnormal movements, hemiplegia, and persistent lethargy. Brain imaging shows degenerative features in the basal ganglia and brainstem consistent with a diagnosis of Leigh syndrome (see previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see MC5DN1 (previous studies)." +MONDO_0007334,"Definition: Popliteal pterygium syndrome (PPS) is an autosomal dominant disorder with diverse clinical features including orofacial anomalies such as lower lip pits, cleft lip and/or palate, and syngnathia, and skin and genital abnormalities including webbing of the lower limbs, syndactyly, hypoplasia of the labia majora, and bifid or absent scrotum (summary by previous studies)." +MONDO_0007793,"Definition: Hypochondroplasia (HCH) is an autosomal dominant disorder characterized by short-limbed dwarfism, lumbar lordosis, short and broad bones, and caudad narrowing of the interpediculate distance of the lumbar spine. It shows some resemblance to achondroplasia, but is much milder and can be distinguished on clinical and radiographic grounds (previous studies)." +MONDO_0007934,"Definition: Retinitis pigmentosa-91 (R91) is characterized by night blindness and constriction of visual fields, with bone-spicule pigmentation, attenuation of retinal vessels, and optic disc pallor on funduscopy. Patients may also experience early macular involvement, with photophobia and reduced visual acuity, and some show a bull's eye pattern of macular atrophy (previous studies)." +MONDO_0010279,"Definition: Terminal osseous dysplasia is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma during infancy (previous studies)." +Orphanet_88630,"Definition: Terminal osseous dysplasia is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma during infancy (previous studies)." +MONDO_0010480,"Definition: G6PD deficiency is the most common genetic cause of chronic and drug-, food-, or infection-induced hemolytic anemia. G6PD catalyzes the first reaction in the pentose phosphate pathway, which is the only NADPH-generation process in mature red cells; therefore, defense against oxidative damage is dependent on G6PD. Most G6PD-deficient patients are asymptomatic throughout their life, but G6PD deficiency can be life-threatening. The most common clinical manifestations of G6PD deficiency are neonatal jaundice and acute hemolytic anemia, which in most patients is triggered by an exogenous agent, e.g., primaquine or fava beans. Acute hemolysis is characterized by fatigue, back pain, anemia, and jaundice. Increased unconjugated bilirubin, lactate dehydrogenase, and reticulocytosis are markers of the disorder. The striking similarity between the areas where G6PD deficiency is common and Plasmodium falciparum malaria (see previous studies) is endemic provided evidence that G6PD deficiency confers resistance against malaria (summary by previous studies)." +EFO_0004272,"Definition: G6PD deficiency is the most common genetic cause of chronic and drug-, food-, or infection-induced hemolytic anemia. G6PD catalyzes the first reaction in the pentose phosphate pathway, which is the only NADPH-generation process in mature red cells; therefore, defense against oxidative damage is dependent on G6PD. Most G6PD-deficient patients are asymptomatic throughout their life, but G6PD deficiency can be life-threatening. The most common clinical manifestations of G6PD deficiency are neonatal jaundice and acute hemolytic anemia, which in most patients is triggered by an exogenous agent, e.g., primaquine or fava beans. Acute hemolysis is characterized by fatigue, back pain, anemia, and jaundice. Increased unconjugated bilirubin, lactate dehydrogenase, and reticulocytosis are markers of the disorder. The striking similarity between the areas where G6PD deficiency is common and Plasmodium falciparum malaria (see previous studies) is endemic provided evidence that G6PD deficiency confers resistance against malaria (summary by previous studies)." +MONDO_0011971,"Definition: Hyper-IgM syndrome is a condition characterized by normal or increased serum IgM concentrations associated with low or absent serum IgG, IgA, and IgE concentrations, indicating a defect in the class-switch recombination (CSR) process. + +For a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (previous studies)." +MONDO_0014062,"Definition: PEOA6 is characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA (mtDNA) deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (previous studies)." +MONDO_0014940,"Definition: Childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP) is an autosomal recessive progressive disorder characterized by onset of gait ataxia, cognitive decline, and gaze palsy in the first or second decades. Additional features include dysarthria, dystonia, and athetoid movements. Some patients may become wheelchair-bound as young adults (summary by previous studies)." +MONDO_0018544,"Definition: Adrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes. + +ABCD1 is an ATPase binding cassette protein in the same category of transporter proteins such as the CFTR and MDR proteins. + +Identification of X-ALD as a lipid-storage disease, as a defect in the capacity to degrade VLCFAs, and its characterization as a peroxisomal disorder was reviewed by previous studies. + +previous studies provided a clinical review of ALD." +MONDO_0031021,"Definition: Developmental and epileptic encephalopathy-104 (DEE104) is an autosomal dominant disorder characterized by developmental delay in the first few months of life and drug-resistant focal and generalized tonic-clonic seizures (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0054852,"Definition: Peeling skin syndrome-6 (PSS6) is characterized by generalized ichthyotic dry skin and bullous peeling lesions on the trunk and limbs at sites of minor trauma. There is residual hyperpigmentation in areas of healing, but no scarring. Skin symptoms are exacerbated by warmth and humidity; however, the disorder improves markedly with age (previous studies; previous studies). + +For a discussion of genetic heterogeneity of peeling skin syndrome, see PSS1 (previous studies)." +Orphanet_101078,"Definition: X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4) is a mitochondrial disorder manifest as progressive neurologic dysfunction with highly variable features. The age at onset ranges from infancy to young adulthood, and patients can present with different features, including hearing loss, delayed motor development, or difficulty walking due to peripheral neuropathy and/or cerebellar ataxia. Most patients develop all features, including a progressive sensorimotor axonal neuropathy and deafness due to auditory neuropathy. Additional more variable features can include cognitive impairment, cerebellar atrophy on brain imaging, cerebellar signs, such as dysarthria, abnormal extraocular movements, tremor, and dysmetria, as well as spasticity. There is significant intrafamilial variability: the variable features are consistent with mitochondrial dysfunction. Prolonged treatment with riboflavin may result in some mild improvement in the ataxia (summary by previous studies, previous studies, previous studies)." +MONDO_0010689,"Definition: X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4) is a mitochondrial disorder manifest as progressive neurologic dysfunction with highly variable features. The age at onset ranges from infancy to young adulthood, and patients can present with different features, including hearing loss, delayed motor development, or difficulty walking due to peripheral neuropathy and/or cerebellar ataxia. Most patients develop all features, including a progressive sensorimotor axonal neuropathy and deafness due to auditory neuropathy. Additional more variable features can include cognitive impairment, cerebellar atrophy on brain imaging, cerebellar signs, such as dysarthria, abnormal extraocular movements, tremor, and dysmetria, as well as spasticity. There is significant intrafamilial variability: the variable features are consistent with mitochondrial dysfunction. Prolonged treatment with riboflavin may result in some mild improvement in the ataxia (summary by previous studies, previous studies, previous studies)." +MONDO_0008493,"Definition: Overhydrated hereditary stomatocytosis is a variably compensated macrocytic hemolytic anemia of fluctuating severity, characterized by circulating erythrocytes with slit-like lucencies (stomata) evident on peripheral blood smears. OHST red cells exhibit cation leak, resulting in elevated cell Na+ content with reduced K+ content, with increased ouabain-resistant cation leak fluxes in the presence of presumably compensatory increases in ouabain-sensitive Na(+)-K(+) ATPase activity, and red cell age-dependent loss of stomatin/EBP7.2 (EBP72; previous studies) from the erythroid membrane. Clinically, patients with OHST exhibit overhydrated erythrocytes and a temperature-dependent red cell cation leak. The temperature dependence of the leak is 'monotonic' and has a steep slope, reflecting the very large leak at 37 degrees centigrade (summary by previous studies and previous studies). + +For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see previous studies." +MONDO_0008918,"Definition: Carnitine-acylcarnitine translocase deficiency is a rare autosomal recessive metabolic disorder of long-chain fatty acid oxidation. Metabolic consequences include hypoketotic hypoglycemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have been reported (summary by previous studies)." +MONDO_0010088,"Definition: Multiple sulfatase deficiency is an autosomal recessive inborn error of metabolism resulting in tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. The enzymatic defect affects the whole family of sulfatase enzymes; thus, the disorder combines features of metachromatic leukodystrophy (previous studies) and of various mucopolysaccharidoses (see, e.g., MPS6; previous studies). Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and ichthyosis. Different types of MSD can be distinguished according to the age of onset: neonatal, late infantile (0 to 2 years), and juvenile (2 to 4 years). Neonatal MSD is the most severe form with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. Late-infantile MSD, which includes the majority of cases, resembles late-infantile metachromatic leukodystrophy with progressive loss of mental and motor abilities and skeletal changes. There is also an attenuated form of late-infantile MSD with onset beyond the second year of life. Rare cases of juvenile-onset MSD have been reported with onset of symptoms in late childhood and slower progression (previous studies) (summary by previous studies)." +Orphanet_585,"Definition: Multiple sulfatase deficiency is an autosomal recessive inborn error of metabolism resulting in tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. The enzymatic defect affects the whole family of sulfatase enzymes; thus, the disorder combines features of metachromatic leukodystrophy (previous studies) and of various mucopolysaccharidoses (see, e.g., MPS6; previous studies). Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and ichthyosis. Different types of MSD can be distinguished according to the age of onset: neonatal, late infantile (0 to 2 years), and juvenile (2 to 4 years). Neonatal MSD is the most severe form with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. Late-infantile MSD, which includes the majority of cases, resembles late-infantile metachromatic leukodystrophy with progressive loss of mental and motor abilities and skeletal changes. There is also an attenuated form of late-infantile MSD with onset beyond the second year of life. Rare cases of juvenile-onset MSD have been reported with onset of symptoms in late childhood and slower progression (previous studies) (summary by previous studies)." +MONDO_0010717,"Definition: Genetic defects in the pyruvate dehydrogenase complex are one of the most common causes of primary lactic acidosis in children. Most cases are caused by mutation in the E1-alpha subunit gene on the X chromosome. X-linked PDH deficiency is one of the few X-linked diseases in which a high proportion of heterozygous females manifest severe symptoms. The clinical spectrum of PDH deficiency is broad, ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis (previous studies; previous studies). + + Genetic Heterogeneity of Pyruvate Dehydrogenase Complex Deficiency + +PDH deficiency can also be caused by mutation in other subunits of the PDH complex, including a form (PDHXD; previous studies) caused by mutation in the component X gene (PDHX; previous studies) on chromosome 11p13; a form (PDHBD; previous studies) caused by mutation in the PDHB gene (previous studies) on chromosome 3p14; a form (PDHDD; previous studies) caused by mutation in the DLAT gene (previous studies) on chromosome 11q23; a form (PDHPD; previous studies) caused by mutation in the PDP1 gene (previous studies) on chromosome 8q22; and a form (PDHLD; previous studies) caused by mutation in the LIAS gene (previous studies) on chromosome 4p14." +MONDO_0011365,"Definition: Say-Barber-Biesecker-Young-Simpson syndrome, a variant of Ohdo syndrome (previous studies), is characterized by distinctive facial appearance with severe blepharophimosis, an immobile mask-like face, a bulbous nasal tip, and a small mouth with a thin upper lip. The condition presents in infancy with severe hypotonia and feeding problems. Associated skeletal problems include joint laxity, abnormally long thumbs and great toes, and dislocated or hypoplastic patellae. Structural cardiac defects are present in around 50% of cases, and dental anomalies, including small and pointed teeth, are common. Many affected individuals have abnormalities of thyroid structure or function. YSS is usually associated with severe mental retardation, delayed motor milestones, and significantly impaired speech (summary by previous studies). + +Genitopatellar syndrome (previous studies) is an allelic disorder with overlapping features." +Orphanet_3047,"Definition: Say-Barber-Biesecker-Young-Simpson syndrome, a variant of Ohdo syndrome (previous studies), is characterized by distinctive facial appearance with severe blepharophimosis, an immobile mask-like face, a bulbous nasal tip, and a small mouth with a thin upper lip. The condition presents in infancy with severe hypotonia and feeding problems. Associated skeletal problems include joint laxity, abnormally long thumbs and great toes, and dislocated or hypoplastic patellae. Structural cardiac defects are present in around 50% of cases, and dental anomalies, including small and pointed teeth, are common. Many affected individuals have abnormalities of thyroid structure or function. YSS is usually associated with severe mental retardation, delayed motor milestones, and significantly impaired speech (summary by previous studies). + +Genitopatellar syndrome (previous studies) is an allelic disorder with overlapping features." +MONDO_0011581,"Definition: Dilated cardiomyopathy with woolly hair and keratoderma (DCWHK) is characterized by the presence of woolly or sparse hair from birth. Some patients exhibit fragile skin with blisters/erosions after minor mechanical trauma, with hyperkeratosis and epidermolytic keratoderma developing in early childhood. Cardiomyopathy may become apparent in the first decade of life, and early death due to heart failure has been reported, but patients may remain asymptomatic into the fourth decade of life. Some patients exhibit an arrhythmogenic form of cardiomyopathy, with sudden death in early adulthood (previous studies; previous studies; previous studies; previous studies). + +Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (Naxos disease; previous studies) is caused by mutation in the plakoglobin gene (JUP; previous studies). Also see previous studies for a similar disorder caused by homozygous mutation in the DSC2 gene (previous studies). + +Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (DCWHKTA; previous studies) is caused by heterozygous mutation in DSP. An isolated form of striated PPK (PPKS2; previous studies) is also caused by heterozygous mutation in DSP. + + Reviews + +In a review of cardiocutaneous syndromes and arrhythmogenic cardiomyopathy, previous studies stated that although the cardiac component of Carvajal syndrome was originally considered dilated cardiomyopathy, many of its features resemble those of arrhythmogenic cardiomyopathy (see previous studies). In addition, they noted that different disease subtypes have been found to coexist within the same kindred, suggesting a role for modifier genes and/or environmental influences." +MONDO_0011730,"Definition: Fumarase deficiency (FMRD) is a severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy (summary by previous studies and previous studies)." +MONDO_0011933,"Definition: Congenital disorder of glycosylation type Ii (CDG1I) is a rare autosomal recessive disorder characterized by neurologic involvement, including a convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression (summary by previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies)." +MONDO_0012436,"Definition: Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (previous studies)." +MONDO_0032941,Definition: Myopia-27 (MYP27) is characterized by early-onset high myopia with increased axial lengths. Fundus changes include optic nerve head crescent and tigroid appearance of the posterior retina (previous studies). +MONDO_0033541,"Definition: Immunodeficiency-69 (IMD69) is an autosomal recessive disorder characterized by increased susceptibility to disseminated mycobacterial infection, including after BCG (bacille Calmette-Guerin) vaccination. Affected individuals develop fever, hepatosplenomegaly, leukocytosis, and thrombocytosis during the acute infection. There appears to be normal immunologic function against other pathogens, including viruses and bacteria. Immunologic work-up shows normal parameters, but patient T and NK cells fail to produce gamma-interferon (IFNG) when stimulated in vitro (summary by previous studies). + +IMD69 is a form of mendelian susceptibility to mycobacterial disease (MSMD) (see, e.g., IMD27A; previous studies)." +Orphanet_135,"Definition: Leukoencephalopathy with vanishing white matter is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. Age at onset ranges from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may additionally develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (summary by previous studies and previous studies). The association of vanishing white matter leukodystrophy with ovarian failure had been referred to as 'ovarioleukodystrophy.' + + Genetic Heterogeneity of Leukoencephalopathy with Vanishing White Matter + +Leukoencephalopathy with vanishing white matter may be caused by mutations in any of the 5 genes encoding the subunits of the eukaryotic translation factor initiation factor 2B. VWM2 (previous studies) is caused by mutation in the EIF2B2 gene (previous studies) on chromosome 14q24; VWM3 (previous studies) is caused by mutation in the EIF2B3 gene (previous studies) on chromosome 1p34; VWM4 (previous studies) is caused by mutation in the EIF2B4 gene (previous studies) on chromosome 2p23; and VWM5 (previous studies) is caused by mutation in the EIF2B5 gene (previous studies) on chromosome 3q27." +MONDO_0020507,"Definition: Leukoencephalopathy with vanishing white matter is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. Age at onset ranges from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may additionally develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (summary by previous studies and previous studies). The association of vanishing white matter leukodystrophy with ovarian failure had been referred to as 'ovarioleukodystrophy.' + + Genetic Heterogeneity of Leukoencephalopathy with Vanishing White Matter + +Leukoencephalopathy with vanishing white matter may be caused by mutations in any of the 5 genes encoding the subunits of the eukaryotic translation factor initiation factor 2B. VWM2 (previous studies) is caused by mutation in the EIF2B2 gene (previous studies) on chromosome 14q24; VWM3 (previous studies) is caused by mutation in the EIF2B3 gene (previous studies) on chromosome 1p34; VWM4 (previous studies) is caused by mutation in the EIF2B4 gene (previous studies) on chromosome 2p23; and VWM5 (previous studies) is caused by mutation in the EIF2B5 gene (previous studies) on chromosome 3q27." +Orphanet_271861,"Definition: Hereditary amyloidoses are a clinically and genetically heterogeneous group of autosomal dominantly inherited diseases characterized by the deposit of unsoluble protein fibrils in the extracellular matrix (summary by previous studies). Patients with transthyretin amyloidosis typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. In later stages of the disease severe diarrhea with malabsorption, cachexia, incapacitating neuropathy, severe cardiac disturbances, and marked orthostatic hypotension dominate the clinical picture. Death usually occurs 5 to 15 years after onset of symptoms. + +Before the emergence of molecular genetics, hereditary amyloidoses were classified into 4 subtypes according to symptom constellation and ethnic origin (summary by previous studies). The course of disease beginning with sensorimotor polyneuropathy that starts in early adulthood symmetrically at the legs and progresses rather rapidly to incapacitate the patient within a few years has been labeled familial amyloid polyneuropathy type I (FAP I), also known as Portuguese, Portuguese-Swedish-Japanese, or Andrade type. FAP I can be considered the prototype of the manifestation of hereditary TTR amyloidosis. The overwhelming majority of cases of FAP I result from a val30-to-met (V30M; previous studies) substitution. A course of disease with neuropathy beginning at the hands and frequent carpal tunnel operations has been designated FAP II, also known as the Indiana/Swiss (previous studies) or Maryland/German (previous studies) type. Vitreous opacities occur early in the disease course, whereas impotence and renal insufficiency are rare. Amyloidosis due to mutations in the APOA1 gene (previous studies) has been referred to as FAP III or Iowa type (see previous studies and previous studies). The Finnish type of amyloidosis (previous studies) has been referred to as FAP IV and is caused by mutations in gelsolin (previous studies). + +Systems based on clinical phenotypes have historically been used to classify the amyloidoses, but emphasis on the characterization of the amyloid fibril protein has proved more useful (previous studies). In addition to hereditary amyloidosis, 2 other major forms of systemic amyloidosis exist. Immunoglobulin (AL) amyloidosis, formerly known as primary amyloidosis, is caused by the accumulation of monoclonal immunoglobulin (Ig) light chains as amyloid fibrils. Reactive (AA) amyloidosis, formerly known as secondary amyloidosis, is associated with chronic inflammatory diseases (e.g., rheumatoid arthritis, previous studies; familial Mediterranean fever, previous studies), and fibrils are derived from the circulating acute-phase reactant serum amyloid A protein (see previous studies). + +previous studies provided a review of transthyretin-related familial amyloid polyneuropathy. The authors stated that the phenotypes can be classified into neuropathic, oculoleptomeningeal, and cardiac." +Orphanet_51,"Definition: Aicardi-Goutieres syndrome is a genetically heterogeneous encephalopathy characterized in its most severe form by cerebral atrophy, leukodystrophy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon (IFNA1; previous studies), and negative serologic investigations for common prenatal infections (previous studies). AGS is phenotypically similar to in utero viral infection. Severe neurologic dysfunction becomes clinically apparent in infancy, and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood. Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated hepatic transaminases along with intermittent fever may also erroneously suggest an infective process (previous studies). + +In a review of AGS, previous studies noted that an expanded phenotypic spectrum has been recognized and that most of the original criteria for diagnosis no longer apply: affected individuals may show later onset and may not have severe or progressive neurologic dysfunction, calcification of the basal ganglia, or CSF lymphocytosis. The appearance of chilblains is an important clinical sign for correct diagnosis. The most severe neonatal form of AGS is typically due to mutation in the TREX1 gene. + +Cree encephalitis was originally considered a separate disorder, but genetic evidence has shown that it is the same as AGS1. See also pseudo-TORCH syndrome (previous studies), which shows phenotypic overlap and may in some cases represent AGS (previous studies; previous studies). AGS is distinct from the similarly named Aicardi syndrome (previous studies), which is characterized by agenesis of the corpus callosum, spinal skeletal abnormalities, and chorioretinal abnormalities. + + Genetic Heterogeneity of Aicardi-Goutieres Syndrome + +See also AGS2 (previous studies), caused by mutation in the gene encoding subunit B of ribonuclease H2 (RNASEH2B; previous studies) on chromosome 13q14; AGS3 (previous studies), caused by mutation in the RNASEH2C gene (previous studies) on chromosome 11q13; AGS4 (previous studies), caused by mutation in the RNASEH2A gene (previous studies) on chromosome 19p13; AGS5 (previous studies), caused by mutation in the SAMHD1 gene (previous studies) on chromosome 20q11; AGS6 (previous studies), caused by mutation in the ADAR1 gene (previous studies) on chromosome 1q21; AGS7 (previous studies), caused by mutation in the IFIH1 gene (previous studies) on chromosome 2q24; AGS8 (previous studies), caused by mutation in the LSM11 gene (previous studies) on chromosome 5q33; and AGS9 (previous studies), caused by mutation in the RNU7-1 gene (previous studies) on chromosome 12p13." +EFO_0010635,"Definition: Weiss-Kruszka syndrome (WSKA) is an autosomal dominant multiple congenital anomaly syndrome characterized by variable but usually mild global developmental delay and common craniofacial abnormalities, including ptosis, abnormal head shape, downslanting palpebral fissures, epicanthal folds, arched eyebrows, and short upturned nose. Many patients have hypotonia and feeding difficulties. A few patients show agenesis of the corpus callosum on brain imaging. Most cases occur sporadically, but there are rare familial cases that show highly variable expressivity in the phenotypic manifestations (summary by previous studies)." +EFO_0010651,"Definition: Intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF) is an autosomal dominant disorder characterized by global developmental delay apparent from infancy, impaired language development, and dysmorphic facial features, including hypertelorism, epicanthal folds, and abnormal palpebral fissures. Some patients may have additional findings, including feeding difficulties, mild cardiac or genitourinary defects, and distal skeletal anomalies (summary by previous studies)." +MONDO_0007885,"Definition: Legg-Calve-Perthes disease (LCPD) is characterized by loss of circulation to the femoral head, resulting in avascular necrosis in a growing child. Clinical pictures of the disease vary, depending on the phase of disease progression through ischemia, revascularization, fracture and collapse, and repair and remodeling of the bone. The disease occurs more frequently in boys, and most patients tend to be shorter than their peers. Both familial and isolated cases of LCPD have been reported (summary by previous studies)." +Orphanet_2380,"Definition: Legg-Calve-Perthes disease (LCPD) is characterized by loss of circulation to the femoral head, resulting in avascular necrosis in a growing child. Clinical pictures of the disease vary, depending on the phase of disease progression through ischemia, revascularization, fracture and collapse, and repair and remodeling of the bone. The disease occurs more frequently in boys, and most patients tend to be shorter than their peers. Both familial and isolated cases of LCPD have been reported (summary by previous studies)." +MONDO_0008393,"Definition: Rubinstein-Taybi syndrome is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile. Affected individuals also have an increased risk of tumor formation (previous studies; review by previous studies). + +Floating-Harbor syndrome (previous studies), which shows phenotypic overlap with Rubinstein-Taybi syndrome, is caused by mutation in the SRCAP gene (previous studies), a coactivator for CREBBP. + + Genetic Heterogeneity of Rubinstein-Taybi Syndrome + +Rubinstein-Taybi syndrome-1 (RSTS1) constitutes about 50 to 70% of patients with the disorder. Rubinstein-Taybi syndrome-2 (RSTS2; previous studies) comprises about 3% of patients and is primarily due to de novo heterozygous mutation in the EP300 gene (previous studies) on chromosome 22q13 (previous studies). + +See also chromosome 16p13.3 deletion syndrome (previous studies), a severe form of Rubinstein-Taybi syndrome resulting from a contiguous gene deletion involving the CREBBP gene as well as other neighboring genes." +MONDO_0008397,"Definition: Autosomal dominant aplasia of lacrimal and salivary glands is a rare condition characterized by irritable eyes, epiphora (constant tearing), and xerostomia (dryness of the mouth), which increases risk of dental erosion, dental caries, periodontal disease, and oral infections. ALSG has variable expressivity, and affected individuals may have aplasia or hypoplasia of the lacrimal, parotid, submandibular, and sublingual glands and absence of the lacrimal puncta. In affected individuals, the misdiagnosis is often made of the more prevalent disorder Sjogren syndrome (previous studies), an autoimmune condition characterized by keratoconjunctivitis sicca and xerostomia. Both sporadic and familial cases of ALSG have been described (summary by previous studies)." +MONDO_0010193,"Definition: Weaver syndrome (WVS) comprises pre- and postnatal overgrowth, accelerated osseous maturation, characteristic craniofacial appearance, and developmental delay. Most cases are sporadic, although autosomal dominant inheritance has been reported. Although there is phenotypic overlap between Weaver syndrome and Sotos syndrome (previous studies), distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand in Weaver syndrome, whereas in Sotos syndrome carpal bone development is at or behind that of the rest of the hand (summary by previous studies). + +Sotos syndrome (previous studies), which shows considerable phenotypic overlap with Weaver syndrome, is caused by mutation in the NSD1 gene (previous studies) on chromosome 5q35. Other 'Weaver-like' syndromes include Cohen-Gibson syndrome (COGIS; previous studies), caused by heterozygous mutation in the EED gene (previous studies) on chromosome 11q14; and Imagawa-Matsumoto syndrome (IMMAS; previous studies), caused by heterozygous mutation in the SUZ12 gene (previous studies) on chromosome 17q11. + +The 'Weaver-like' syndrome reported by previous studies in a mother and son may be a separate entity." +MONDO_0011614,"Definition: Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting (summary by previous studies)." +MONDO_0013128,"Definition: Autosomal dominant tubulointerstitial kidney disease-4 (ADTKD4) is a progressive renal disorder characterized by early-onset anemia and increased serum uric acid with a bland urinalysis and without proteinuria. Although the anemia tends to improve with age, progressive renal insufficiency results in end-stage kidney disease between 40 and 70 years. Renal ultrasound may show small echogenic kidneys, and biopsy shows tubular atrophy and interstitial fibrosis, sometimes with cysts and secondary glomerulosclerosis (summary by previous studies). + +For discussion of the revised nomenclature and genetic heterogeneity of ADTKD, see ADTKD1 (previous studies)." +Orphanet_217330,"Definition: Autosomal dominant tubulointerstitial kidney disease-4 (ADTKD4) is a progressive renal disorder characterized by early-onset anemia and increased serum uric acid with a bland urinalysis and without proteinuria. Although the anemia tends to improve with age, progressive renal insufficiency results in end-stage kidney disease between 40 and 70 years. Renal ultrasound may show small echogenic kidneys, and biopsy shows tubular atrophy and interstitial fibrosis, sometimes with cysts and secondary glomerulosclerosis (summary by previous studies). + +For discussion of the revised nomenclature and genetic heterogeneity of ADTKD, see ADTKD1 (previous studies)." +MONDO_0014953,"Definition: Intellectual developmental disorder with cardiac arrhythmia is an autosomal recessive multisystem disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, and bradycardia and/or cardiac sinus arrhythmias. Additional features include visual abnormalities, seizures, hypotonia, and gastric reflux (summary by previous studies)." +MONDO_0017790,"Definition: Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is characterized by autosomal dominant transmission of fundic gland polyposis (FGP) with occasional hyperplastic and adenomatous polyps, sparing of the gastric antrum, and the development of intestinal-type gastric adenocarcinoma. Colorectal polyposis is not observed, and family history does not include colorectal cancer (previous studies)." +MONDO_0030858,"Definition: Immunodeficiency-75 with lymphoproliferation (IMD75) is an autosomal recessive immunologic disorder characterized by immunodeficiency, immune dysregulation, and the development of lymphoproliferative disorders, including lymphoma. Affected individuals usually present in infancy with severe and recurrent infections, mainly viral and affecting the respiratory tract. Some patients may have autoimmune cytopenias, anemia, or thrombocytopenia. Patients also develop hepatosplenomegaly, lymphadenopathy, lymphoproliferative disorders, and various types of T- or B-cell lymphomas. Immunologic work-up shows decreased class-switched B cells, impaired B-cell terminal differentiation, and hypo- or hypergammaglobulinemia. There is skewed differentiation and dysregulation of T cells, as well as possibly disrupted hematopoiesis. Additional features include failure to thrive and global developmental delay. The phenotype may be reminiscent of ALPS (previous studies), including laboratory evidence of impaired Fas-dependent T-cell apoptosis. Although hematopoietic stem cell transplantation may be effective treatment, many patients die in childhood (summary by previous studies)." +MONDO_0030898,"Definition: Immunodeficiency-76 (IMD76) is an autosomal recessive primary immunologic disorder characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. More variable features found in some patients include lymphoma and neurologic features. Although bone marrow transplantation may be curative, many patients die in childhood (summary by previous studies)." +MONDO_0032923,"Definition: Autosomal recessive spinocerebellar ataxia-28 (SCAR28) is a neurologic disorder characterized by onset in early childhood of mildly delayed motor development, gait ataxia, incoordination of fine motor movements, and dysarthria. Affected individuals may have features of spasticity and may show mildly impaired cognitive function. Brain imaging shows cerebellar vermis hypoplasia (summary by previous studies)." +MONDO_0859171,"Definition: Luo-Schoch-Yamamoto syndrome (LUSYAM) is a neurodevelopmental disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have delayed walking, early-onset seizures, hypotonia, dysmorphic facial features, and white matter abnormalities on brain imaging (previous studies)." +MONDO_0007574,"Definition: Spinocerebellar ataxia-34 is an autosomal dominant disorder characterized by slowly progressive cerebellar ataxia. The age at onset is usually during the young adult years, and most patients remain ambulatory until late in life. One family with SCA34 also had onset of erythema and hyperkeratosis in early childhood (previous studies), whereas other families have additional neurologic signs, including ocular movement disturbances and pyramidal tract signs (previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0009885,"Definition: Scott syndrome is a mild platelet-type bleeding disorder characterized by impaired surface exposure of procoagulant phosphatidylserine (PS) on platelets and other blood cells, following activation with Ca(2+)-elevating agents (previous studies)." +MONDO_0010225,"Definition: The term 'X-linked hypercalciuric nephrolithiasis' comprises several related forms of hereditary renal tubular disorders caused by mutations in the CLCN5 gene, including Dent disease, X-linked recessive nephrolithiasis (previous studies), X-linked recessive hypophosphatemic rickets (previous studies), and low molecular weight proteinuria (previous studies). Although these disorders are allelic and are all characterized by progressive proximal renal tubulopathy with hypercalciuria, low molecular weight proteinuria, and nephrocalcinosis, they vary in degree of severity and were originally reported as separate disorders. Some have considered these disorders as phenotypic variants of a single disease, referred to as the 'Dent disease complex' (previous studies; previous studies). + +previous studies provided a comprehensive review of genetic disorders of renal electrolyte transport. + + Genetic Heterogeneity of Dent Disease + +See also Dent disease-2 (DENT2; previous studies), caused by mutation in the OCRL gene (previous studies) on chromosome Xq26." +MONDO_0010265,"Definition: Simpson-Golabi-Behmel syndrome type 2 (SGBS2) is an X-linked recessive disorder in which affected males have severely impaired intellectual development, ciliary dyskinesia, and macrocephaly (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Simpson-Golabi-Behmel syndrome, see previous studies." +MONDO_0012205,"Definition: Autosomal dominant striatal degeneration is a neurologic disorder characterized by variable movement abnormalities due to dysfunction in the striatal part of the basal ganglia (summary by previous studies). + + Genetic Heterogeneity of Autosomal Dominant Striatal Degeneration + +See also ADSD2 (previous studies), caused by mutation in the PDE10A gene (previous studies) on chromosome 6q27." +MONDO_0012806,"Definition: EDAID2 is characterized by variable features of ectodermal dysplasia (e.g., hypo/anhidrosis, sparse hair, tooth anomalies) and various immunologic and infectious phenotypes of differing severity (summary by previous studies). + +Mutations in the NFKBIA gene result in functional impairment of NFKB (see previous studies), a master transcription factor required for normal activation of immune responses. Interruption of NFKB signaling results in decreased production of proinflammatory cytokines and certain interferons, rendering patients susceptible to infection (previous studies). + +For discussion of genetic heterogeneity of ectodermal dysplasia and immune deficiency, see previous studies." +MONDO_0013006,"Definition: IGHD type IB is an autosomal recessive disorder characterized by low but detectable levels of GH, short stature (more than 2 SD below the mean for age and sex), delayed bone age, and a good response to rhGH treatment without antibody formation (summary by previous studies). + +For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see previous studies." +MONDO_0030974,Definition: Mitochondrial complex II deficiency nuclear type 4 (MC2DN4) is a severe autosomal recessive disorder characterized by early-onset progressive neurodegeneration with leukoencephalopathy. Acute episodes of neurodegeneration are often triggered by catabolic stress such as infection or fasting. +MONDO_0031002,"Definition: Baralle-Macken syndrome (BARMACS) is an autosomal recessive disorder characterized by global developmental delay apparent from infancy, difficulty walking or inability to walk, and impaired intellectual development with poor or absent speech. Affected individuals develop early-onset cataracts; some may have microcephaly. Additional more variable features may include dysmorphic facial features, metabolic abnormalities, spasticity, and lymphopenia (summary by previous studies)." +Orphanet_2209,"Definition: Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH; previous studies), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (previous studies). + +See previous studies and previous studies for detailed reviews of PKU." +MONDO_0009861,"Definition: Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH; previous studies), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (previous studies). + +See previous studies and previous studies for detailed reviews of PKU." +Orphanet_2891,"Definition: Abnormal hair, joint laxity, and developmental delay (HJDD) is characterized by normal hair at birth that gradually becomes sparse, twisted, brittle, and easily broken, with pili torti and trichorrhexis nodosa observed on light microscopy. Other features include increased joint mobility and cognitive delay (previous studies)." +MONDO_0009871,"Definition: Abnormal hair, joint laxity, and developmental delay (HJDD) is characterized by normal hair at birth that gradually becomes sparse, twisted, brittle, and easily broken, with pili torti and trichorrhexis nodosa observed on light microscopy. Other features include increased joint mobility and cognitive delay (previous studies)." +MONDO_0007669,"Definition: Renal cysts and diabetes syndrome (RCAD) is an autosomal dominant multisystemic disorder with significant phenotypic heterogeneity. It is characterized by (1) nondiabetic renal disease resulting from abnormal renal development, and (2) diabetes, which in some cases occurs earlier than age 25 years and is thus consistent with a diagnosis of maturity-onset diabetes of the young (MODY). The renal disease is highly variable and includes renal cysts, glomerular tufts, aberrant nephrogenesis, primitive tubules, irregular collecting systems, oligomeganephronia, enlarged renal pelvises, abnormal calyces, small kidney, single kidney, and horseshoe kidney. Some patients with renal disease have hyperuricemic nephropathy with tubulointerstitial changes on biopsy, consistent with autosomal dominant tubulointerstitial kidney disease (ADTKD). Affected individuals may also have abnormalities of the genital tract, including vaginal aplasia, rudimentary uterus, bicornuate uterus, epididymal cysts, and atresia of the vas deferens (previous studies; previous studies; previous studies; previous studies; summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of MODY, see previous studies. + +For a discussion of genetic heterogeneity of ADTKD and a discussion of the revised nomenclature of these disorders, see ADTKD1 (previous studies). + +The renal abnormalities are part of a spectrum of malformations known as congenital anomalies of the kidney and urinary tract (CAKUT; see previous studies) (summary by previous studies)." +MONDO_0007859,"Definition: Striate palmoplantar keratoderma belongs to a group of skin diseases in which there is thickening of the skin on the palms and soles. The striate form is characterized by longitudinal hyperkeratotic lesions extending the length of each finger to the palm, and hyperkeratotic lesions are restricted to regions of the body where pressure and abrasion are greatest (summary by previous studies). Patients with diffuse or focal forms of keratoderma associated with mutation in the DSG1 gene have also been reported (previous studies; previous studies). + + Genetic Heterogeneity of Keratosis Palmoplantaris Striata + +Type II PPKS (PPKS2; previous studies) is caused by mutation in the DSP gene (previous studies) on chromosome 6. + +Type III PPKS (PPKS3; previous studies) is caused by mutation in the keratin-1 gene (KRT1; previous studies) on chromosome 12q. + +For a general phenotypic description and a discussion of genetic heterogeneity of palmoplantar keratoderma (PPK), see epidermolytic PPK (previous studies). + +previous studies reviewed desmosome biology in cardiocutaneous syndromes and inherited skin disease, including discussion of the involvement of the DSG1 and DSP genes." +MONDO_0008426,"Definition: Shprintzen-Goldberg syndrome is a disorder comprising craniosynostosis, a marfanoid habitus, and skeletal, neurologic, cardiovascular, and connective tissue anomalies. There appears to be a characteristic facies involving hypertelorism, downslanting palpebral fissures, high-arched palate, micrognathia, and low-set posteriorly rotated ears. Other commonly reported manifestations include hypotonia, developmental delay, and inguinal or umbilical hernia; the most common skeletal manifestations are arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility (summary by previous studies). + +There is considerable phenotypic overlap between SGS and Marfan syndrome (MFS; previous studies) and Loeys-Dietz syndrome (LDS; see previous studies): SGS includes virtually all of the craniofacial, skeletal, skin, and cardiovascular manifestations of MFS and LDS, with the additional findings of mental retardation and severe skeletal muscle hypotonia (summary by previous studies)." +MONDO_0008818,"Definition: Arterial tortuosity syndrome is a rare connective tissue disorder characterized by generalized tortuosity, elongation, stenosis, and aneurysms of the major arteries. Skin and joint abnormalities, including hyperextensibility or hyperlaxity of the skin, joint laxity or contractures, and inguinal hernias, may also be observed. Other abnormalities include micrognathia, elongated face, high palate, beaked nose, sliding hernia, and ventricular hypertrophy (summary by previous studies)." +MONDO_0009841,"Definition: PEHO is a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy due to almost total loss of granule neurons. Affected individuals present in early infancy with hypotonia, profoundly delayed psychomotor development, optic atrophy, progressive atrophy of the cerebellum and brainstem, and dysmyelination. Most patients also develop infantile seizures that are often associated with hypsarrhythmia on EEG, and many have peripheral edema (summary by previous studies)." +MONDO_0010437,"Definition: Combined oxidative phosphorylation deficiency-6 (COXPD6) is an X-linked recessive severe encephalomyopathic disorder with onset in utero or in infancy. Affected patients have hypotonia and severely impaired psychomotor development associated with variably decreased enzymatic activity of mitochondrial respiratory complexes in skeletal muscle or fibroblasts. More variable features may include sensorimotor neuropathy, seizures, severe muscle weakness, abnormal signals in the basal ganglia, hypertrophic cardiomyopathy, deafness, swallowing difficulties, and respiratory insufficiency. Death in childhood may occur (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0010654,"Definition: Partington syndrome (PRTS) is an X-linked developmental disorder characterized by mental retardation and variable movement disturbances. Partington syndrome is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from hydranencephaly and lissencephaly (LISX2; previous studies) to Proud syndrome (previous studies) to infantile spasms without brain malformations (see previous studies) to nonsyndromic mental retardation (previous studies). Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (previous studies; previous studies)." +MONDO_0010857,"Definition: Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; previous studies) (reviews by previous studies and previous studies). previous studies provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). + + Clinical Variability of Tauopathies + +Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (previous studies). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (previous studies); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (previous studies); frontotemporal dementia with parkinsonism (FLDEM) (previous studies); and multiple system tauopathy with presenile dementia (MSTD) (previous studies). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. + +Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (previous studies) and progressive supranuclear palsy (PSP; previous studies), + +Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (previous studies). + +previous studies suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. + + Genetic Heterogeneity of Frontotemporal Lobar Degeneration + +Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (previous studies), caused by mutation in the GRN gene (previous studies) on chromosome 17q21; FTLALS7 (previous studies), caused by mutation in the CHMP2B gene (previous studies) on chromosome 3p11; inclusion body myopathy with Paget disease and FTD (IBMPFD; previous studies), caused by mutation in the VCP gene (previous studies) on chromosome 9p13; ALS6 (previous studies), caused by mutation in the FUS gene (previous studies) on 16p11; ALS10 (previous studies), caused by mutation in the TARDBP gene (previous studies) on 1p36; and FTDALS1 (previous studies), caused by mutation in the C9ORF72 gene (previous studies) on 9p21. + +In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; previous studies) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; previous studies)." +MONDO_0012994,"Definition: SPR deficiency results in neurologic deterioration due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Clinically, affected individuals show an L-DOPA-responsive, diurnally fluctuating movement disorder usually associated with cognitive delay and severe neurologic dysfunction. BH4 is a required cofactor for the synthesis of the neurotransmitters dopamine and serotonin. BH4 is also a required cofactor for phenylalanine hydroxylase (PAH; previous studies), but patients with SPR deficiency do not exhibit overt hyperphenylalaninemia. The lack of hyperphenylalaninemia distinguishes SPR deficiency from other disorders of BH4 synthesis (see, e.g., HPABH4A, previous studies). However, the neurologic phenotype of SPR deficiency resembles the other BH4-deficient disorders (summary by previous studies and previous studies). + +Another form of dopa-responsive dystonia (DTY5; previous studies) is caused by mutation in the gene encoding GTP cyclohydrolase I (GCH1; previous studies), which is also a component of the biopterin synthetic pathway." +MONDO_0013456,"Definition: Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (previous studies) to childhood absence epilepsy with learning difficulties to lack of symptoms (previous studies). Treatment with folinic acid can ameliorate some of the symptoms." +MONDO_0014452,"Definition: Inherited disorders of fibrinogen affect either the quantity (afibrinogenemia and hypofibrinogenemia; previous studies) or the quality (dysfibrinogenemia) of the circulating fibrinogen, or both (hypodysfibrinogenemia). Patients with dysfibrinogenemia are frequently asymptomatic, but some patients have bleeding diathesis, thromboembolic complications, or both (summary by previous studies). Reports (e.g., previous studies) on approximately 350 families with dysfibrinogenemia revealed that approximately half of cases are clinically silent, a quarter show a tendency toward bleeding, and another quarter show a predisposition for thrombosis with or without bleeding (summary by previous studies)." +MONDO_0018875,"Definition: Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. LFS is characterized by autosomal dominant inheritance and early onset of tumors, multiple tumors within an individual, and multiple affected family members. In contrast to other inherited cancer syndromes, which are predominantly characterized by site-specific cancers, LFS presents with a variety of tumor types. The most common types are soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma. Classic LFS is defined as a proband with a sarcoma before the age of 45 years and a first-degree relative with any cancer before the age of 45 years and 1 additional first- or second-degree relative in the same lineage with any cancer before the age of 45 years or a sarcoma at any age (previous studies). Li-Fraumeni-like syndrome (LFL) is defined as a proband with any childhood cancer, or a sarcoma, brain tumor, or adrenocortical tumor before the age of 45 years, plus a first- or second-degree relative in the same lineage with a typical LFS tumor at any age, and an additional first- or second-degree relative in the same lineage with any cancer before the age of 60 years (previous studies). A less restrictive definition of LFL is 2 different LFS-related tumors in first- or second-degree relatives at any age (previous studies). Approximately 70% of LFS cases and 40% of LFL cases contain germline mutations in the p53 gene on chromosome 17p13.1 (previous studies). + + Genetic Heterogeneity of Li-Fraumeni Syndrome + +A second form of Li-Fraumeni syndrome (LFS2; previous studies) is caused by mutation in the CHEK2 gene (previous studies)." +MONDO_0018919,"Definition: Activating or gain-of-function GNAS1 mutations in patients with the McCune-Albright syndrome (MAS) are present in the mosaic state, resulting from a postzygotic somatic mutation appearing early in the course of development which yields a monoclonal population of mutated cells within variously affected tissues. The nonmosaic state for most activating mutations is presumably lethal to the embryo. The disorder is characterized clinically by the classic triad of polyostotic fibrous dysplasia (POFD), cafe-au-lait skin pigmentation, and peripheral precocious puberty. However, the disorder is clinically heterogeneous and can include various other endocrinologic anomalies such as thyrotoxicosis, pituitary gigantism, and Cushing syndrome (previous studies) (previous studies)." +MONDO_0030695,"Definition: Developmental and epileptic encephalopathy-100 (DEE100) is a severe neurologic disorder characterized by global developmental delay and onset of variable types of seizures in the first months or years of life. Most patients have refractory seizures and show developmental regression after seizure onset. Affected individuals have ataxic gait or inability to walk and severe to profoundly impaired intellectual development, often with absent speech. Additional more variable features may include axial hypotonia, hyperkinetic movements, dysmorphic facial features, and brain imaging abnormalities (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0030964,"Definition: Autosomal dominant intellectual developmental disorder-67 (MRD67) is characterized by global developmental delay with variably impaired intellectual development apparent from infancy or early childhood. Additional features may include behavioral abnormalities, such as autism spectrum disorder (ASD) and ADHD, as well as language and sleeping difficulties. Brain imaging is normal (previous studies)." +MONDO_0034022,"Definition: Bethlem myopathy-2 (BTHLM2) is characterized by congenital hypotonia and myopathy. Motor development is delayed, but muscle strength improves with age, and patients are able to achieve ambulation. Proximal joint contractures that improve over time, as well as joint hyperlaxity, are also present. Muscle biopsy shows mild variability in fiber diameter, without degeneration or regeneration (previous studies; previous studies). + +For a discussion of genetic heterogeneity of Bethlem myopathy, see BTHLM1 (previous studies)." +MONDO_0100111,"Definition: Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS) is characterized by global developmental delay and renal dysfunction manifest as proteinuria and nephrotic syndrome apparent from infancy or early childhood. Some patients present with renal disease, whereas others present with developmental delay and develop renal disease later in childhood. Renal biopsy shows focal segmental glomerulosclerosis (FSGS), but the course of the disease is variable: some patients have transient proteinuria and others require renal transplant. Neurodevelopmental features are also variable, with some patients having only mildly impaired intellectual development, and others having a severe developmental disorder associated with early-onset refractory seizures or epileptic encephalopathy. Additional features, including feeding difficulties, poor overall growth, and nonspecific dysmorphic facial features, are commonly observed (summary by previous studies and previous studies)." +Orphanet_171629,"Definition: Autosomal recessive spastic paraplegia-35 is a complicated form of SPG characterized by childhood onset of gait difficulties due to progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur (summary by previous studies). In addition, some patients with mutations in the FA2H gene have radiographic evidence of neurodegeneration with brain iron accumulation (NBIA), thus expanding the phenotype. previous studies referred to this phenotypic spectrum of disorders as fatty acid hydrolase-associated neurodegeneration (FAHN). + +In a detailed report of 19 patients with biallelic FA2H mutations, previous studies stated that the phenotype was diagnostically consistent with a complicated form of SPG. The authors concluded that FA2H mutations cause a narrow phenotype despite prior attempts to classify it into separately defined disease entities. + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0012866,"Definition: Autosomal recessive spastic paraplegia-35 is a complicated form of SPG characterized by childhood onset of gait difficulties due to progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur (summary by previous studies). In addition, some patients with mutations in the FA2H gene have radiographic evidence of neurodegeneration with brain iron accumulation (NBIA), thus expanding the phenotype. previous studies referred to this phenotypic spectrum of disorders as fatty acid hydrolase-associated neurodegeneration (FAHN). + +In a detailed report of 19 patients with biallelic FA2H mutations, previous studies stated that the phenotype was diagnostically consistent with a complicated form of SPG. The authors concluded that FA2H mutations cause a narrow phenotype despite prior attempts to classify it into separately defined disease entities. + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +Orphanet_228363,"Definition: Neuronal ceroid lipofuscinosis-6A (CLN6A) is an autosomal recessive neurodegenerative disorder with a variable age at onset in the first years of life after normal early development. Affected individuals have progressive decline of neurologic function, including visual deterioration in most, cognitive impairment, loss of motor function, and seizures. As with all CLNs, CLN6A is characterized pathologically by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN6A comprises mixed combinations of 'curvilinear' and 'fingerprint' profiles (summary by previous studies; previous studies). + +For a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0011144,"Definition: Neuronal ceroid lipofuscinosis-6A (CLN6A) is an autosomal recessive neurodegenerative disorder with a variable age at onset in the first years of life after normal early development. Affected individuals have progressive decline of neurologic function, including visual deterioration in most, cognitive impairment, loss of motor function, and seizures. As with all CLNs, CLN6A is characterized pathologically by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN6A comprises mixed combinations of 'curvilinear' and 'fingerprint' profiles (summary by previous studies; previous studies). + +For a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_352447,"Definition: Mitochondrial DNA depletion syndrome-11 is an autosomal recessive mitochondrial disorder characterized by onset in childhood or adulthood of progressive external ophthalmoplegia (PEO), muscle weakness and atrophy, exercise intolerance, and respiratory insufficiency due to muscle weakness. More variable features include spinal deformity, emaciation, and cardiac abnormalities. Skeletal muscle biopsies show deletion and depletion of mitochondrial DNA (mtDNA) with variable defects in respiratory chain enzyme activities (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0014039,"Definition: Mitochondrial DNA depletion syndrome-11 is an autosomal recessive mitochondrial disorder characterized by onset in childhood or adulthood of progressive external ophthalmoplegia (PEO), muscle weakness and atrophy, exercise intolerance, and respiratory insufficiency due to muscle weakness. More variable features include spinal deformity, emaciation, and cardiac abnormalities. Skeletal muscle biopsies show deletion and depletion of mitochondrial DNA (mtDNA) with variable defects in respiratory chain enzyme activities (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0007381,"Definition: Epithelial recurrent erosion dystrophy (ERED) is characterized by frequent painful recurrent corneal erosions, with onset in the first decade of life and subsequent gradual decrease in frequency, with cessation in the third or fourth decade. Small gray anterior stromal flecks associated with larger focal gray-white disc-shaped, circular, or wreath-like lesions with central clarity, in the Bowman layer and immediately subjacent anterior stroma, varying from 0.2 to 1.5 mm in diameter, appear to be clinically diagnostic of ERED (previous studies)." +MONDO_0007540,"Definition: Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50. Less commonly associated tumors include foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas. Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone (summary by previous studies). + +Familial isolated hyperparathyroidism (see previous studies) occasionally results from the incomplete expression of MEN1 (summary by previous studies). + + Genetic Heterogeneity of Multiple Endocrine Neoplasia + +Other forms of multiple endocrine neoplasia include MEN2A (previous studies) and MEN2B (previous studies), both of which are caused by mutation in the RET gene (previous studies), and MEN4 (previous studies), which is caused by mutation in the CDKN1B gene (previous studies)." +MONDO_0008322,"Definition: Pseudoachondroplasia is an autosomal dominant osteochondrodysplasia characterized by disproportionate short stature, deformity of the lower limbs, brachydactyly, loose joints, and ligamentous laxity. Vertebral anomalies, present in childhood, usually resolve with age, but osteoarthritis is progressive and severe. PSACH and EDM1 comprise a clinical spectrum with phenotypic overlap between mild forms of PSACH and EDM1 (summary by previous studies)." +MONDO_0008610,Definition: Tritanopia is an autosomal dominant disorder of human vision characterized by a selective deficiency of blue spectral sensitivity (previous studies). +Orphanet_88629,Definition: Tritanopia is an autosomal dominant disorder of human vision characterized by a selective deficiency of blue spectral sensitivity (previous studies). +MONDO_0009213,"Definition: Fanconi anemia is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0009319,"Definition: Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, severity, and cognitive involvement are variable (review by previous studies). + +Panthothenate kinase-associated neurodegeneration has been classified clinically as 'classic,' 'atypical,' or 'intermediate.' In the classic form, patients present within the first decade of life with rapidly progressing disease and loss of ambulation approximately 15 years later. In the atypical form, patients have onset in the second decade with slow progression and maintain independent ambulation after 15 years. In the intermediate form, patients have early onset and slow progression or later onset and rapid progression. Patients with early onset tend to develop pigmentary retinopathy, whereas those with later onset tend to have speech disorders and psychiatric features. All patients have the 'eye of the tiger' sign on brain MRI (previous studies; previous studies). + +previous studies noted that the 'eye of the tiger' sign is not pathognomonic for PANK2 mutations. They reported 2 unrelated adult patients with cognitive dysfunction who had the characteristic sign on MRI but did not have mutations in the PANK2 gene. + +previous studies provided a detailed review of the different forms of neurodegeneration with brain iron accumulation. + +In addition, some patients with Kufor-Rakeb syndrome (previous studies), also known as Parkinson disease-9 (PARK9), have iron deposition in the basal ganglia. + + Genetic Heterogeneity of Neurodegeneration with Brain Iron Accumulation + +Neurodegeneration with brain iron accumulation is an umbrella term that encompasses a group of genetically heterogeneous disorders. See also NBIA2A (previous studies) and NBIA2B (previous studies), both caused by mutation in the PLA2G6 gene (previous studies); NBIA3 (previous studies), caused by mutation in the FTL gene (previous studies); NBIA4 (previous studies), caused by mutation in the C19ORF12 gene (previous studies); NBIA5 (previous studies), caused by mutation in the WDR45 gene (previous studies); NBIA6 (previous studies), caused by mutation in the COASY gene (previous studies); NBIA7 (previous studies), caused by mutation in the REPS1 gene (previous studies); and NBIA8 (previous studies), caused by mutation in the CRAT gene (previous studies). + +See review of previous studies on syndromes of neurodegeneration with brain iron accumulation, including Kufor-Rakeb disease (previous studies) and aceruloplasminemia (previous studies)." +MONDO_0010010,"Definition: Schinzel-Giedion syndrome is a highly recognizable syndrome characterized by severe mental retardation, distinctive facial features, and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, and cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia (summary by previous studies)." +MONDO_0010187,"Definition: Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (previous studies) and protein S (previous studies). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX. + + Genetic Heterogeneity of Combined Deficiency of Vitamin K-Dependent Clotting Factors + +Combined deficiency of vitamin K-dependent clotting factors-2 (VKFCD2; previous studies) is caused by mutation in the gene encoding vitamin K epoxide reductase (VKORC1; previous studies) on chromosome 16p11." +Orphanet_98434,"Definition: Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (previous studies) and protein S (previous studies). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX. + + Genetic Heterogeneity of Combined Deficiency of Vitamin K-Dependent Clotting Factors + +Combined deficiency of vitamin K-dependent clotting factors-2 (VKFCD2; previous studies) is caused by mutation in the gene encoding vitamin K epoxide reductase (VKORC1; previous studies) on chromosome 16p11." +MONDO_0012064,"Definition: Burn-McKeown syndrome (BMKS) is a rare disorder in which individuals with normal intellectual development exhibit the characteristic combination of choanal atresia, sensorineural deafness, cardiac defects, and typical craniofacial dysmorphism consisting of narrow palpebral fissures, coloboma of the lower eyelids, prominent nose with high nasal bridge, short philtrum, cleft lip and/or palate, and large and protruding ears (summary by previous studies)." +Orphanet_1200,"Definition: Burn-McKeown syndrome (BMKS) is a rare disorder in which individuals with normal intellectual development exhibit the characteristic combination of choanal atresia, sensorineural deafness, cardiac defects, and typical craniofacial dysmorphism consisting of narrow palpebral fissures, coloboma of the lower eyelids, prominent nose with high nasal bridge, short philtrum, cleft lip and/or palate, and large and protruding ears (summary by previous studies)." +MONDO_0012531,"Definition: For a general discussion of xeroderma pigmentosum, see XPA (previous studies), and of Cockayne syndrome, see CSA (previous studies). + +previous studies provided a review of the causes of xeroderma pigmentosum." +Orphanet_276252,"Definition: For a general discussion of xeroderma pigmentosum, see XPA (previous studies), and of Cockayne syndrome, see CSA (previous studies). + +previous studies provided a review of the causes of xeroderma pigmentosum." +MONDO_0013171,Definition: Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment (review by previous studies). +MONDO_0013361,"Definition: Prothrombin deficiency is an extremely rare autosomal recessive bleeding disorder characterized by low levels of circulating prothrombin; it affects about 1 in 2,000,000 individuals. There are 2 main types: type I deficiency, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia. Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein. Bleeding symptoms are more variable, depending on the amount of residual functional activity. Variant prothrombin gene alleles can result in 'hypoprothrombinemia' or 'dysprothrombinemia,' and individuals who are compound heterozygous for these 2 types of alleles have variable manifestations. Heterozygous mutation carriers, who have plasma levels between 40 and 60% of normal, are usually asymptomatic, but can show bleeding after tooth extraction or surgical procedures (review by previous studies)." +Orphanet_325,"Definition: Prothrombin deficiency is an extremely rare autosomal recessive bleeding disorder characterized by low levels of circulating prothrombin; it affects about 1 in 2,000,000 individuals. There are 2 main types: type I deficiency, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia. Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein. Bleeding symptoms are more variable, depending on the amount of residual functional activity. Variant prothrombin gene alleles can result in 'hypoprothrombinemia' or 'dysprothrombinemia,' and individuals who are compound heterozygous for these 2 types of alleles have variable manifestations. Heterozygous mutation carriers, who have plasma levels between 40 and 60% of normal, are usually asymptomatic, but can show bleeding after tooth extraction or surgical procedures (review by previous studies)." +MONDO_0013722,"Definition: Hypomyelinating leukodystrophy-8 (HLD8) is an autosomal recessive neurologic disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism (summary by previous studies). + +See also HLD7 (previous studies), which has similar features and is caused by mutation in the POLR3A gene (previous studies) on chromosome 10q22. The POLR3A and POLR3B genes encode the 2 largest subunits of RNA polymerase III. + +For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see previous studies." +MONDO_0014530,"Definition: Autosomal recessive spinocerebellar ataxia-18 is a neurologic disorder characterized by delayed psychomotor development, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and intellectual disability. Brain imaging shows progressive cerebellar atrophy (summary by previous studies)." +Orphanet_363432,"Definition: Autosomal recessive spinocerebellar ataxia-18 is a neurologic disorder characterized by delayed psychomotor development, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and intellectual disability. Brain imaging shows progressive cerebellar atrophy (summary by previous studies)." +MONDO_0033364,"Definition: Developmental and epileptic encephalopathy-55 (DEE55) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first weeks or months of life. Affected individuals have an extremely poor outcome, with profoundly impaired intellectual development, absent speech, spastic quadriplegia, and dyskinetic movements. Most have cortical visual impairment and require a feeding tube. Brain imaging shows nonspecific abnormalities, including cerebral atrophy, thin corpus callosum, and abnormal signals in the white matter. Death in childhood may occur. Biochemically, the disorder is associated with impaired synthesis of GPI-anchored proteins (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies. + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +Orphanet_166081,"Definition: Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. It results from a defect in platelet aggregation due to defects in the von Willebrand factor. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; previous studies). F8 is mutated in hemophilia A (previous studies) (review by previous studies). + +Whereas von Willebrand disease types 1 (previous studies) and 3 (previous studies) are characterized by quantitative defects in the VWF gene, von Willebrand disease type 2, which is divided in subtypes 2A, 2B, 2M, and 2N, is characterized by qualitative abnormalities of the VWF protein. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8. VWD2 accounts for 20 to 30% of cases of VWD (previous studies; previous studies; previous studies; previous studies). + +For a general discussion and a classification of the types of von Willebrand disease, see VWD type 1 (previous studies)." +MONDO_0013304,"Definition: Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. It results from a defect in platelet aggregation due to defects in the von Willebrand factor. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; previous studies). F8 is mutated in hemophilia A (previous studies) (review by previous studies). + +Whereas von Willebrand disease types 1 (previous studies) and 3 (previous studies) are characterized by quantitative defects in the VWF gene, von Willebrand disease type 2, which is divided in subtypes 2A, 2B, 2M, and 2N, is characterized by qualitative abnormalities of the VWF protein. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8. VWD2 accounts for 20 to 30% of cases of VWD (previous studies; previous studies; previous studies; previous studies). + +For a general discussion and a classification of the types of von Willebrand disease, see VWD type 1 (previous studies)." +Orphanet_2323,"Definition: HRDS is an autosomal recessive multisystem disorder characterized by intrauterine and postnatal growth retardation, infantile-onset hypoparathyroidism that can result in severe hypocalcemic seizures, dysmorphic facial features, and developmental delay (summary by previous studies and previous studies)." +MONDO_0009426,"Definition: HRDS is an autosomal recessive multisystem disorder characterized by intrauterine and postnatal growth retardation, infantile-onset hypoparathyroidism that can result in severe hypocalcemic seizures, dysmorphic facial features, and developmental delay (summary by previous studies and previous studies)." +EFO_0001060,"Definition: Celiac disease, also known as celiac sprue and gluten-sensitive enteropathy, is a multifactorial disorder of the small intestine that is influenced by both environmental and genetic factors. It is characterized by malabsorption resulting from inflammatory injury to the mucosa of the small intestine after the ingestion of wheat gluten or related rye and barley proteins (summary by previous studies). + +For additional information and a discussion of genetic heterogeneity of celiac disease, see previous studies." +MONDO_0007947,"Definition: A heritable disorder of fibrous connective tissue, Marfan syndrome (MFS) shows striking pleiotropism and clinical variability. The cardinal features occur in 3 systems--skeletal, ocular, and cardiovascular (previous studies; previous studies; previous studies). It shares overlapping features with congenital contractural arachnodactyly (previous studies), which is caused by mutation in the FBN2 gene (previous studies). + +previous studies gave a general review. They published Kaplan-Meier survival curves for a cohort of British Marfan syndrome patients demonstrating greater survivorship in females than in males; a similar result had been reported by previous studies and by previous studies. previous studies also proposed a grading scale for clinical comparison of the Marfan syndrome patients. The authors provided criteria for each grade and suggested uniform use of these scales may facilitate clinicomolecular correlations." +MONDO_0008593,"Definition: Trichomegaly (TCMGLY), or excessively long eyelashes, is a rare familial trait (previous studies)." +MONDO_0008708,"Definition: The acrocallosal syndrome is an autosomal recessive mental retardation syndrome with brain abnormalities such as corpus callosum agenesis and/or Dandy-Walker malformation as well as dysmorphic features, postaxial polydactyly of the hands, and preaxial polydactyly of the feet (previous studies). It is considered a ciliopathy (previous studies). + +Joubert syndrome-12 is a disorder with an overlapping phenotype characterized by the hallmark finding of the molar tooth sign (MTS) on brain MRI. For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see previous studies. + +Hydrolethalus-2 (HLS2; previous studies) is an allelic disorder with a more severe phenotype and death in utero." +MONDO_0009745,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN5 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_228360,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN5 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0011085,"Definition: Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive disorder of the peripheral nervous system characterized by early-onset distal muscle weakness and atrophy, foot deformities, and sensory loss affecting all modalities. Affected individuals develop deafness by the third decade of life (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive Charcot-Marie-Tooth disease, see CMT4A (previous studies)." +MONDO_0011888,"Definition: Immunodeficiency-67 (IMD67) is an autosomal recessive primary immunodeficiency characterized by recurrent severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae and Staphylococcus aureus; Pseudomonas and atypical Mycobacteria may also be observed. IMD67 is life-threatening in infancy and early childhood. The first invasive infection typically occurs before 2 years of age, with meningitis representing up to 41% of the bacterial infections. The mortality rate in early childhood is high, with most deaths occurring before 8 years of age. Affected individuals have an impaired inflammatory response to infection, including lack of fever and neutropenia, although erythrocyte sedimentation rate (ESR) and C-reactive protein may be elevated. General immunologic workup tends to be normal, with normal levels of B cells, T cells, and NK cells. However, more detailed studies indicate impaired cytokine response to lipopolysaccharide (LPS) and IL1B (previous studies) stimulation; response to TNFA (previous studies) is usually normal. Patients have good antibody responses to most vaccinations, with the notable exception of pneumococcal vaccination. Viral, fungal, and parasitic infections are not generally observed. Early detection is critical in early childhood because prophylactic treatment with IVIg or certain antibiotics is effective; the disorder tends to improve naturally around adolescence. At the molecular level, the disorder results from impaired function of selective Toll receptor (see TLR4, previous studies)/IL1R (see IL1R1, previous studies) signaling pathways that ultimately activate NFKB (previous studies) to produce cytokines (summary by previous studies; previous studies; previous studies). + +See also IMD68 (previous studies), caused by mutation in the MYD88 gene (previous studies), which shows a similar phenotype to IMD67. As the MYD88 and IRAK4 genes interact in the same intracellular signaling pathway, the clinical and cellular features are almost indistinguishable (summary by previous studies)." +Orphanet_70592,"Definition: Immunodeficiency-67 (IMD67) is an autosomal recessive primary immunodeficiency characterized by recurrent severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae and Staphylococcus aureus; Pseudomonas and atypical Mycobacteria may also be observed. IMD67 is life-threatening in infancy and early childhood. The first invasive infection typically occurs before 2 years of age, with meningitis representing up to 41% of the bacterial infections. The mortality rate in early childhood is high, with most deaths occurring before 8 years of age. Affected individuals have an impaired inflammatory response to infection, including lack of fever and neutropenia, although erythrocyte sedimentation rate (ESR) and C-reactive protein may be elevated. General immunologic workup tends to be normal, with normal levels of B cells, T cells, and NK cells. However, more detailed studies indicate impaired cytokine response to lipopolysaccharide (LPS) and IL1B (previous studies) stimulation; response to TNFA (previous studies) is usually normal. Patients have good antibody responses to most vaccinations, with the notable exception of pneumococcal vaccination. Viral, fungal, and parasitic infections are not generally observed. Early detection is critical in early childhood because prophylactic treatment with IVIg or certain antibiotics is effective; the disorder tends to improve naturally around adolescence. At the molecular level, the disorder results from impaired function of selective Toll receptor (see TLR4, previous studies)/IL1R (see IL1R1, previous studies) signaling pathways that ultimately activate NFKB (previous studies) to produce cytokines (summary by previous studies; previous studies; previous studies). + +See also IMD68 (previous studies), caused by mutation in the MYD88 gene (previous studies), which shows a similar phenotype to IMD67. As the MYD88 and IRAK4 genes interact in the same intracellular signaling pathway, the clinical and cellular features are almost indistinguishable (summary by previous studies)." +MONDO_0012833,"Definition: Crouzon syndrome with acanthosis nigricans is considered to be a distinct disorder from classic Crouzon syndrome (previous studies), which is caused by mutation in the FGFR2 gene (previous studies). previous studies argued that this condition is separate from Crouzon syndrome for 2 main reasons: it is caused by a highly specific mutation of the FGFR3 gene, whereas multiple different FGFR2 mutations result in Crouzon syndrome, and the phenotypes are different." +Orphanet_93262,"Definition: Crouzon syndrome with acanthosis nigricans is considered to be a distinct disorder from classic Crouzon syndrome (previous studies), which is caused by mutation in the FGFR2 gene (previous studies). previous studies argued that this condition is separate from Crouzon syndrome for 2 main reasons: it is caused by a highly specific mutation of the FGFR3 gene, whereas multiple different FGFR2 mutations result in Crouzon syndrome, and the phenotypes are different." +MONDO_0012876,Definition: Heparin cofactor II (HCF2; previous studies) rapidly inhibits thrombin in plasma in the presence of dermatan sulfate or heparin. Congenital HCF2 deficiency is associated with thromboembolism and is classified into type I (quantitative) or type II (qualitative) deficiency (previous studies). +MONDO_0014736,"Definition: Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant axonal peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood. Rare occurrence of global developmental delay with impaired intellectual development or learning difficulties has been observed. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN), which highlights the clinical spectrum associated with MORC2 mutations and may render the classification of patients into one or the other disorder challenging (summary by previous studies, previous studies, previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0021019,"Definition: Ocular albinism type I (OA1) is the most common form of ocular albinism. Clinical presentation of OA1 in Caucasians is characterized by nystagmus, impaired visual acuity, iris hypopigmentation with translucency, albinotic fundus, macular hypoplasia, and normally pigmented skin and hair. Carrier females usually have punctate iris translucency and a mottled pattern of fundus pigmentation. In contrast to Caucasian patients, black or Japanese patients with OA1 often have brown irides with little or no translucency and varying degrees of fundus hypopigmentation, the so-called 'nonalbinotic fundus' (summary by previous studies)." +MONDO_0030934,"Definition: Autosomal dominant intellectual developmental disorder-64 (MRD64) is characterized by mildly to severely impaired intellectual development (ID) with speech delays. Most patients also have autism spectrum disorder (ASD). Additional features are highly variable but may include motor delay, attention deficit-hyperactivity disorder (ADHD), and nonspecific dysmorphic features (summary by previous studies)." +MONDO_0030999,"Definition: Neurodevelopmental disorder with cerebral atrophy and facial dysmorphism (NEDCAFD) is an autosomal recessive disorder characterized by global developmental delay apparent from birth. Affected individuals have hypotonia with inability to walk and severely impaired intellectual development with absent language. Most patients have variable dysmorphic facial features including prominent eyes, protruding and low-set ears, and thin upper lip. Brain imaging shows cerebral atrophy, corpus callosum hypoplasia, and a simplified gyral pattern (summary by previous studies)." +MONDO_0036189,"Definition: Oculogastrointestinal neurodevelopmental syndrome (OGIN) is characterized by microphthalmia and/or coloboma in association with other congenital anomalies, including imperforate anus, horseshoe kidney, and structural cardiac defects. Hearing loss and severe developmental delay are also observed in most patients (previous studies; previous studies)." +MONDO_0044646,"Definition: PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity. Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. The disorder shows progressive features, including microcephaly, consistent with a neurodegenerative process (summary by previous studies; previous studies)." +Orphanet_140436,"Definition: Primary intraosseous vascular malformation (VMPI), previously called intraosseous hemangioma, is a rare malformation that usually involves the vertebral column and the skull. The most commonly affected bones in the skull are the mandible and the maxilla, and life-threatening bleeding after a simple tooth extraction is frequent (previous studies)." +MONDO_0011744,"Definition: Primary intraosseous vascular malformation (VMPI), previously called intraosseous hemangioma, is a rare malformation that usually involves the vertebral column and the skull. The most commonly affected bones in the skull are the mandible and the maxilla, and life-threatening bleeding after a simple tooth extraction is frequent (previous studies)." +Orphanet_289465,"Definition: Adermatoglyphia (ADERM) is characterized by the lack of epidermal ridges on the palms and soles, which results in the absence of fingerprints, and is associated with a reduced number of sweat gland openings and reduced sweating of palms and soles (summary by previous studies). + +Also see Naegeli-Franceschetti-Jadassohn syndrome (NFJS; previous studies) and dermatopathia pigmentosa reticularis (DPR; previous studies), 2 closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics and are caused by heterozygous nonsense or frameshift mutations in the KRT14 gene (previous studies)." +MONDO_0007619,"Definition: Adermatoglyphia (ADERM) is characterized by the lack of epidermal ridges on the palms and soles, which results in the absence of fingerprints, and is associated with a reduced number of sweat gland openings and reduced sweating of palms and soles (summary by previous studies). + +Also see Naegeli-Franceschetti-Jadassohn syndrome (NFJS; previous studies) and dermatopathia pigmentosa reticularis (DPR; previous studies), 2 closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics and are caused by heterozygous nonsense or frameshift mutations in the KRT14 gene (previous studies)." +Orphanet_370943,"Definition: Arthrogryposis, impaired intellectual development, and seizures (AMRS) is an autosomal recessive disorder characterized by skeletal abnormalities, including arthrogryposis, short limbs, and vertebral malformations, impaired intellectual development, and seizures consistent with early-onset epileptic encephalopathy in some patients. Other features may include cleft palate, micrognathia, posterior embryotoxon, talipes valgus, rocker-bottom feet, and dysmorphic facies (previous studies; previous studies)." +MONDO_0014248,"Definition: Arthrogryposis, impaired intellectual development, and seizures (AMRS) is an autosomal recessive disorder characterized by skeletal abnormalities, including arthrogryposis, short limbs, and vertebral malformations, impaired intellectual development, and seizures consistent with early-onset epileptic encephalopathy in some patients. Other features may include cleft palate, micrognathia, posterior embryotoxon, talipes valgus, rocker-bottom feet, and dysmorphic facies (previous studies; previous studies)." +EFO_0010664,"Definition: Individuals with PFBMFT5 have an age-dependent, rapidly progressive phenotype of pulmonary fibrosis and/or bone marrow failure with short telomeres and low levels of TERC (previous studies), a specialized noncoding RNA that provides the template for telomere repeat addition (previous studies)." +MONDO_0009067,"Definition: Cystinuria is an autosomal disorder characterized by impaired epithelial cell transport of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the proximal renal tubule and gastrointestinal tract. The impaired renal reabsorption of cystine and its low solubility causes the formation of calculi in the urinary tract, resulting in obstructive uropathy, pyelonephritis, and, rarely, renal failure (summary by previous studies)." +MONDO_0009070,"Definition: D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by previous studies)." +MONDO_0009699,"Definition: The action myoclonus-renal failure syndrome is an autosomal recessive progressive myoclonic epilepsy associated with renal failure. Cognitive function is preserved (previous studies). Some patients do not develop renal failure (previous studies). + +For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (previous studies)." +Orphanet_163696,"Definition: The action myoclonus-renal failure syndrome is an autosomal recessive progressive myoclonic epilepsy associated with renal failure. Cognitive function is preserved (previous studies). Some patients do not develop renal failure (previous studies). + +For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (previous studies)." +MONDO_0010196,"Definition: Werner syndrome (WRN) is a rare autosomal recessive segmental progeroid syndrome. Patients exhibit not only an appearance of accelerated aging (premature graying, thinning of hair, skin atrophy and atrophy of subcutaneous fat), but also several disorders commonly associated with aging, including bilateral cataracts, diabetes mellitus, osteoporosis, premature arteriosclerosis, and a variety of benign and malignant neoplasms (summary by previous studies)." +MONDO_0011408,"Definition: Spastic paraplegia-10 (SPG10) is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or young adulthood. Some patients show distal sensory impairment, which can be part of the 'pure' phenotype. However, some patients also show an axonal sensorimotor peripheral neuropathy with distal sensory impairment and distal muscle atrophy reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A, previous studies). Rarely, patients with KIF5A mutations may have additional neurologic features, including parkinsonism or cognitive decline, consistent with a 'complicated' phenotype. Spastic paraplegia and peripheral neuropathy in isolation may represent extreme ends of the phenotypic spectrum of KIF5A mutations (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +Orphanet_100991,"Definition: Spastic paraplegia-10 (SPG10) is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or young adulthood. Some patients show distal sensory impairment, which can be part of the 'pure' phenotype. However, some patients also show an axonal sensorimotor peripheral neuropathy with distal sensory impairment and distal muscle atrophy reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A, previous studies). Rarely, patients with KIF5A mutations may have additional neurologic features, including parkinsonism or cognitive decline, consistent with a 'complicated' phenotype. Spastic paraplegia and peripheral neuropathy in isolation may represent extreme ends of the phenotypic spectrum of KIF5A mutations (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +MONDO_0013144,"Definition: Deficiency of antithrombin III is a major risk factor for venous thromboembolic disease. Two categories of AT-III deficiency have been defined on the basis of AT-III antigen levels in the plasma of affected individuals. The majority of AT-III deficiency families belong in the type I (classic) deficiency group and have a quantitatively abnormal phenotype in which antigen and heparin cofactor levels are both reduced to about 50% of normal. The second category of AT-III deficiency has been termed type II (functional) deficiency. Affected individuals from these kindreds produce dysfunctional AT-III molecules; they have reduced heparin cofactor activity levels (about 50% of normal) but levels of AT-III antigen are often normal or nearly normal (summary by previous studies). + +The 2 categories of antithrombmin III deficiency have been classified further. Type I (low functional and immunologic antithrombin) has been subdivided into subtype Ia (reduced levels of normal antithrombin), and type Ib (reduced levels of antithrombin and the presence of low levels of a variant). Type II (low functional but normal immunologic antithrombin) has been subdivided into subtype IIa (functional abnormalities affecting both the reactive site and the heparin-binding site of AT3); subtype IIb (functional abnormalities limited to the reactive site); and subtype IIc (functional abnormalities limited to the heparin-binding site) (summary by previous studies)." +Orphanet_100044,"Definition: Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. + + Classification + +CMT neuropathy is subdivided into CMT1 (see previous studies) and CMT2 (see previous studies) types on the basis of electrophysiologic and neuropathologic criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Families of this type were reported by previous studies and previous studies. previous studies proposed that this form be designated 'intermediate' CMT. + +previous studies stated that some CMT families may have an even broader range of NCV than 25 to 45 m/s, with the lowest levels around 25 and the highest levels within the normal range (50+ m/s). They also suggested that the term 'intermediate' should not be used to describe a single NCV value, but rather the CMT subtype at the level of the family (e.g., in families with a range or combinations of NCV values). + +previous studies provided a detailed review of the different forms of intermediate CMT, noting that diagnoses may be controversial because of variable classification issues. The authors presented an algorithm for the interpretation of electrophysiologic studies in CMT, and suggested that nerve conduction studies should be conducted on the upper arm (axilla to elbow). They noted that distal axonal degeneration can result in secondary myelination defects, which may cause significantly decreased motor NCV and CMAP values that may be misinterpreted. + + Genetic Heterogeneity of Autosomal Dominant Intermediate CMT + +In addition to CMTDIB, which is caused by mutation in the DNM2 gene, other forms of dominant intermediate CMT include CMTDIA (previous studies), mapped to chromosome 10q24-q25; CMTDIC (previous studies), caused by mutation in the YARS gene (previous studies) on chromosome 1p35; CMTDID (previous studies), caused by mutation in the MPZ gene (previous studies) on chromosome 1q22; CMTDIE with focal segmental glomerulosclerosis (CMTDIE; previous studies), caused by mutation in the INF2 gene (previous studies) on chromosome 14q32; CMTDIF (previous studies), caused by mutation in the GNB4 gene (previous studies) on chromosome 3q26; and CMTDIG (previous studies), caused by mutation in the NEFL gene (previous studies) on chromosome 8p21." +MONDO_0011674,"Definition: Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. + + Classification + +CMT neuropathy is subdivided into CMT1 (see previous studies) and CMT2 (see previous studies) types on the basis of electrophysiologic and neuropathologic criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Families of this type were reported by previous studies and previous studies. previous studies proposed that this form be designated 'intermediate' CMT. + +previous studies stated that some CMT families may have an even broader range of NCV than 25 to 45 m/s, with the lowest levels around 25 and the highest levels within the normal range (50+ m/s). They also suggested that the term 'intermediate' should not be used to describe a single NCV value, but rather the CMT subtype at the level of the family (e.g., in families with a range or combinations of NCV values). + +previous studies provided a detailed review of the different forms of intermediate CMT, noting that diagnoses may be controversial because of variable classification issues. The authors presented an algorithm for the interpretation of electrophysiologic studies in CMT, and suggested that nerve conduction studies should be conducted on the upper arm (axilla to elbow). They noted that distal axonal degeneration can result in secondary myelination defects, which may cause significantly decreased motor NCV and CMAP values that may be misinterpreted. + + Genetic Heterogeneity of Autosomal Dominant Intermediate CMT + +In addition to CMTDIB, which is caused by mutation in the DNM2 gene, other forms of dominant intermediate CMT include CMTDIA (previous studies), mapped to chromosome 10q24-q25; CMTDIC (previous studies), caused by mutation in the YARS gene (previous studies) on chromosome 1p35; CMTDID (previous studies), caused by mutation in the MPZ gene (previous studies) on chromosome 1q22; CMTDIE with focal segmental glomerulosclerosis (CMTDIE; previous studies), caused by mutation in the INF2 gene (previous studies) on chromosome 14q32; CMTDIF (previous studies), caused by mutation in the GNB4 gene (previous studies) on chromosome 3q26; and CMTDIG (previous studies), caused by mutation in the NEFL gene (previous studies) on chromosome 8p21." +Orphanet_168572,"Definition: Congenital myopathy-13 (CMYP13), also known as Bailey-Bloch congenital myopathy and Native American myopathy (NAM), is an autosomal recessive disorder characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, myopathic facies, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia provoked by anesthesia. It was first reported in the Lumbee Indian tribe in North Carolina (summary by previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0009722,"Definition: Congenital myopathy-13 (CMYP13), also known as Bailey-Bloch congenital myopathy and Native American myopathy (NAM), is an autosomal recessive disorder characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, myopathic facies, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia provoked by anesthesia. It was first reported in the Lumbee Indian tribe in North Carolina (summary by previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +Orphanet_228346,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +The hallmark of CLN3 is the ultrastructural pattern of lipopigment with a 'fingerprint' profile, which can have 3 different appearances: pure within a lysosomal residual body; in conjunction with curvilinear or rectilinear profiles; and as a small component within large membrane-bound lysosomal vacuoles. The combination of fingerprint profiles within lysosomal vacuoles is a regular feature of blood lymphocytes from patients with CLN3 (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +MONDO_0008767,"Definition: The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure (previous studies). + +The hallmark of CLN3 is the ultrastructural pattern of lipopigment with a 'fingerprint' profile, which can have 3 different appearances: pure within a lysosomal residual body; in conjunction with curvilinear or rectilinear profiles; and as a small component within large membrane-bound lysosomal vacuoles. The combination of fingerprint profiles within lysosomal vacuoles is a regular feature of blood lymphocytes from patients with CLN3 (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (previous studies)." +Orphanet_71202,"Definition: Thrombocytopenia-6 is an autosomal dominant hematologic disorder characterized by increased bleeding episodes due to reduced platelet count and abnormal platelet morphology resulting from defective megakaryopoiesis. Patients may also have bone abnormalities, including osteoporosis or tooth loss, as well as an increased risk for myelofibrosis (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see previous studies." +EFO_0000497,"Definition: Hereditary desmoid disease usually presents as an extraintestinal manifestation of familial adenomatous polyposis (FAP; previous studies), also known as Gardner syndrome, which is an autosomal dominant disorder caused by germline mutation in the APC gene. The desmoid tumors are usually intraabdominal and, although benign, can be locally aggressive and result in significant morbidity. Desmoid tumors can also arise sporadically (previous studies)." +MONDO_0008788,"Definition: previous studies referred to this phenotype as iron-refractory iron deficiency anemia (IRIDA) and reviewed the key features: a congenital hypochromic, microcytic anemia; a very low mean corpuscular erythrocyte volume; a low transferrin saturation; abnormal iron absorption characterized by no hematologic improvement following treatment with oral iron; and abnormal iron utilization characterized by a sluggish, incomplete response to parenteral iron. The authors noted that although urinary levels of hepcidin (previous studies) are typically undetectable in individuals with iron deficiency, in 5 individuals with IRIDA urinary hepcidin/creatinine ratios were within or above the normal range." +MONDO_0009965,"Definition: Perlman syndrome is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; previous studies). Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor, with a 64% incidence in infants surviving beyond the neonatal period. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (less than 2 years and 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%). Histologic examination of the kidneys in children with Perlman syndrome shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor (summary by previous studies)." +MONDO_0010571,"Definition: Otopalatodigital syndrome-2 is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. The disorders, which include frontometaphyseal dysplasia (FMD1; previous studies), otopalatodigital syndrome-1 (OPD1; previous studies), and Melnick-Needles syndrome (MNS; previous studies), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD is characterized by a generalized skeletal dysplasia, deafness and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by previous studies). previous studies suggested that these disorders constitute a single entity, which they termed 'frontootopalatodigital osteodysplasia.'" +MONDO_0010808,"Definition: Fatal familial insomnia is a prion disorder showing autosomal dominant inheritance. It is clinically characterized by insomnia with or without a diurnal dreaming state, hallucinations, delirium, and dysautonomia preceding motor and cognitive deterioration. FFI is specifically associated with the asp178-to-asn mutation of the PRNP gene (D178N; previous studies) when the amino acid at position 129 is methionine (M129V; previous studies). The D178N mutation and the val129 allele results in Creutzfeldt-Jacob disease (CJD; previous studies) (see previous studies) (previous studies). CJD typically presents with dementia, ataxia, myoclonus, and other abnormal movements; however, there is considerable clinical and pathologic overlap between FFI and CJD, and some individuals with D178N and met129 may present with a phenotype suggestive of CJD. Thus, FFI and CJD may be viewed as extremes of a phenotypic spectrum (summary by previous studies)." +MONDO_0012411,Definition: Giant axonal neuropathy-2 is an autosomal dominant peripheral axonal neuropathy characterized by onset of distal sensory impairment and lower extremity muscle weakness and atrophy after the second decade. Foot deformities may be present in childhood. More severely affected individuals may develop cardiomyopathy. Sural nerve biopsy shows giant axonal swelling with neurofilament accumulation (summary by previous studies). +MONDO_0013061,"Definition: Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (previous studies)." +MONDO_0013656,"Definition: NESCAV syndrome (NESCAVS) is a neurodegenerative disorder characterized by onset of features in infancy or early childhood. Affected individuals show global developmental delay with delayed walking or difficulty walking due to progressive spasticity mainly affecting the lower limbs and often leading to loss of independent ambulation. There is variably impaired intellectual development, speech delay, and learning disabilities and/or behavioral abnormalities. Additional features may include cortical visual impairment, often associated with optic atrophy, axonal peripheral neuropathy, seizures, dysautonomia, ataxia, and dystonia. Brain imaging often shows progressive cerebellar atrophy and thin corpus callosum. Some patients may show developmental regression, particularly of motor skills. The phenotype and presentation are highly variable (summary by previous studies)." +MONDO_0014035,"Definition: Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is characterized by global developmental delay, impaired intellectual development, axial hypotonia, and dysmorphic craniofacial features with microcephaly. Many patients have visual abnormalities, ranging from strabismus to optic nerve atrophy and retinal abnormalities. Affected individuals also develop spasticity, particularly of the lower limbs, and may have behavioral abnormalities (summary by previous studies and previous studies)." +MONDO_0014180,"Definition: EBS3 is a mild autosomal recessive dermatologic disorder characterized by trauma-induced blistering mainly occurring on the feet and ankles. Ultrastructural analysis of skin biopsy shows abnormal hemidesmosomes with poorly formed inner plaques (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0014813,"Definition: Hypomyelinating leukodystrophy-13 is an autosomal recessive neurodegenerative disorder characterized by infantile onset of delayed psychomotor development, axial hypotonia, and spasticity associated with delayed myelination and periventricular white matter abnormalities on brain imaging. More variable neurologic deficits, such as visual impairment, may also occur. Some patients may experience cardiac failure during acute illness (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see previous studies." +MONDO_0030027,"Definition: Hereditary essential tremor-6 (ETM6) is an autosomal dominant neurologic disorder characterized by adult-onset kinetic and/or postural tremor usually affecting the upper limbs. Some patients may have involvement of the head, trunk, lower limbs, and/or voice. Additional neurologic features, such as cognitive impairment or pyramidal signs, are usually not observed. Brain imaging does not show cerebellar atrophy or leukodystrophy. Skin biopsy shows intranuclear eosinophilic inclusions in fibroblasts and sweat gland cells, which may be used for diagnosis. There is evidence of genetic anticipation, with progressive earlier age at onset in younger generations. In rare cases, the phenotype may convert to NIID over time (summary by previous studies; previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of hereditary essential tremor, see ETM1 (previous studies)." +Orphanet_2612,"Definition: Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous nevus syndrome, is characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects (summary by previous studies and previous studies). The linear sebaceous nevi follow the lines of Blaschko (previous studies; previous studies). All cases are sporadic. The syndrome is believed to be caused by an autosomal dominant lethal mutation that survives by somatic mosaicism (previous studies)." +MONDO_0008097,"Definition: Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous nevus syndrome, is characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects (summary by previous studies and previous studies). The linear sebaceous nevi follow the lines of Blaschko (previous studies; previous studies). All cases are sporadic. The syndrome is believed to be caused by an autosomal dominant lethal mutation that survives by somatic mosaicism (previous studies)." +Orphanet_411602,"Definition: Parkinson disease-17 is an autosomal dominant, adult-onset form of the disorder. It is phenotypically similar to idiopathic Parkinson disease (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see previous studies." +EFO_0004270,"Definition: Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (previous studies). + +For additional information and a discussion of genetic heterogeneity of restless legs syndrome, see RLS1 (previous studies)." +EFO_0005922,"Definition: Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), is one of the most common cancers worldwide. Both environmental and genetic risk factors play a role in the pathogenesis of the disorder. In Europe and North America, heavy smoking, alcohol consumption, and increased body mass index (BMI) are the main environmental risk factors. In contrast, the particularly high incidence of ESCC in some areas of China, central Asia, and southern Africa is associated with nutritional deficiencies, high intake of nitrosamine-rich or pickled vegetables, and low socioeconomic status; smoking, alcohol consumption, and BMI play a lesser role in these populations. There is a tendency for familial aggregation of ESCC in high-risk geographic areas, suggesting a genetic component to increased susceptibility. Gastric cardia adenocarcinoma is another common type of cancer in China that shows similarities to ESCC in terms of geographic distribution and environmental risk factors (summary by previous studies and previous studies). + + Genetic Heterogeneity of Susceptibility to Esophageal Cancer + +See a variant in the ADH1B gene (previous studies) for discussion of a possible genetic association with protection against squamous cell aerodigestive tract cancer, including esophageal cancer, in alcohol drinkers. See a variant in the ALDH2 gene (previous studies) for discussion of a possible genetic association with increased risk for esophageal cancer in alcohol drinkers due to interaction between variants in the ADH1B and ALDH2 genes. + +See the S100A14 gene (previous studies) on chromosome 1q21 for a discussion of a possible association between variation in that gene and susceptibility to esophageal squamous cell carcinoma among smokers. + + Genetic Heterogeneity of Somatic Mutations in Esophageal Cancer + +Somatic mutations in several different genes have been found in esophageal cancer tissue. These genes include TP53 (previous studies), CDKN2A (previous studies), DEC1 (previous studies), DCC (previous studies), DLEC1 (previous studies), TGFBR2 (previous studies), LZTS1 (previous studies), RNF6 (previous studies), WWOX (previous studies), APC (previous studies), and RUNX3 (previous studies)." +MONDO_0007576,"Definition: Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), is one of the most common cancers worldwide. Both environmental and genetic risk factors play a role in the pathogenesis of the disorder. In Europe and North America, heavy smoking, alcohol consumption, and increased body mass index (BMI) are the main environmental risk factors. In contrast, the particularly high incidence of ESCC in some areas of China, central Asia, and southern Africa is associated with nutritional deficiencies, high intake of nitrosamine-rich or pickled vegetables, and low socioeconomic status; smoking, alcohol consumption, and BMI play a lesser role in these populations. There is a tendency for familial aggregation of ESCC in high-risk geographic areas, suggesting a genetic component to increased susceptibility. Gastric cardia adenocarcinoma is another common type of cancer in China that shows similarities to ESCC in terms of geographic distribution and environmental risk factors (summary by previous studies and previous studies). + + Genetic Heterogeneity of Susceptibility to Esophageal Cancer + +See a variant in the ADH1B gene (previous studies) for discussion of a possible genetic association with protection against squamous cell aerodigestive tract cancer, including esophageal cancer, in alcohol drinkers. See a variant in the ALDH2 gene (previous studies) for discussion of a possible genetic association with increased risk for esophageal cancer in alcohol drinkers due to interaction between variants in the ADH1B and ALDH2 genes. + +See the S100A14 gene (previous studies) on chromosome 1q21 for a discussion of a possible association between variation in that gene and susceptibility to esophageal squamous cell carcinoma among smokers. + + Genetic Heterogeneity of Somatic Mutations in Esophageal Cancer + +Somatic mutations in several different genes have been found in esophageal cancer tissue. These genes include TP53 (previous studies), CDKN2A (previous studies), DEC1 (previous studies), DCC (previous studies), DLEC1 (previous studies), TGFBR2 (previous studies), LZTS1 (previous studies), RNF6 (previous studies), WWOX (previous studies), APC (previous studies), and RUNX3 (previous studies)." +MONDO_0007037,"Definition: Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand (summary by previous studies)." +MONDO_0008332,"Definition: Platelet-type von Willebrand disease, also known as pseudo-von Willebrand disease, is an autosomal dominant bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor by the platelet glycoprotein Ib (GP Ib) receptor complex. Hemostatic function is impaired due to the removal of VWF multimers from the circulation (previous studies). + +previous studies gave a comprehensive review of the disorder." +MONDO_0009661,"Definition: Mucopolysaccharidosis type VI (MPS6) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal (previous studies)." +MONDO_0009903,"Definition: Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (summary by previous studies)." +MONDO_0011664,"Definition: Immunodeficiency-41 is an autosomal recessive complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (summary by previous studies)." +MONDO_0011934,"Definition: Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive, but rarely metastasizing tumor of the deep dermis and subcutaneous tissue. It typically presents during early or middle adult life and is most frequently located on the trunk and proximal extremities (previous studies)." +MONDO_0012988,"Definition: Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; previous studies) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by previous studies). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' + +For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see previous studies." +MONDO_0018163,"Definition: Autosomal recessive cutis laxa type II represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted palpebral fissures, reversed-V eyebrows, and dental caries are characteristic. Patients with ARCL2 can be divided into 2 major groups: ARCL2A, comprising those with a combined N- and O-linked glycosylation defect (CDG type II), and ARCL2B, those without a metabolic disorder (summary by previous studies). previous studies concluded that ARCL2A should be considered more of a multisystem disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome rather than purely a dermatologic disorder. + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (previous studies). + + Genetic Heterogeneity of Cutis Laxa Type II + +ARCL2A is caused by mutation in the ATP6V0A2 gene. ARCL2B (previous studies) is caused by mutation in the PYCR1 gene (previous studies). ARCL2C (previous studies) is caused by mutation in the ATP6V1E1 gene (previous studies). ARCL2D (previous studies) is caused by mutation in the ATP6V1A gene (previous studies). ARCL2E (previous studies) is caused by mutation in the LTBP1 gene (previous studies)." +Orphanet_13,"Definition: Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; previous studies), tyrosine hydroxylase (TH; previous studies) and tryptophan hydroxylase (TPH1; previous studies), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (previous studies). + +HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (previous studies). Other forms of BH4-deficient HPA include HPABH4B (previous studies), caused by mutation in the GCH1 gene (previous studies), HPABH4C (previous studies), caused by mutation in the QDPR gene (previous studies), and HPABH4D (previous studies), caused by mutation in the PCBD1 gene (previous studies). previous studies noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; previous studies), caused by mutation in the PAH gene. + +Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (previous studies), caused by mutation in the SPR gene (previous studies), and autosomal dominant dopa-responsive dystonia (DYT5; previous studies), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed." +MONDO_0009863,"Definition: Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; previous studies), tyrosine hydroxylase (TH; previous studies) and tryptophan hydroxylase (TPH1; previous studies), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (previous studies). + +HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (previous studies). Other forms of BH4-deficient HPA include HPABH4B (previous studies), caused by mutation in the GCH1 gene (previous studies), HPABH4C (previous studies), caused by mutation in the QDPR gene (previous studies), and HPABH4D (previous studies), caused by mutation in the PCBD1 gene (previous studies). previous studies noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; previous studies), caused by mutation in the PAH gene. + +Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (previous studies), caused by mutation in the SPR gene (previous studies), and autosomal dominant dopa-responsive dystonia (DYT5; previous studies), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed." +Orphanet_2822,"Definition: Hereditary spastic paraplegia (SPG or HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. SPG11 is a form of complicated SPG, in that it has neurologic features in addition to spasticity. + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +MONDO_0011445,"Definition: Hereditary spastic paraplegia (SPG or HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. SPG11 is a form of complicated SPG, in that it has neurologic features in addition to spasticity. + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +Orphanet_98993,"Definition: Mutations in the CHMP4B gene have been found to cause multiple types of cataract, which have been described as posterior polar, progressive posterior subcapsular, nuclear, and anterior subcapsular. + +The preferred title/symbol of this entry was formerly 'Cataract, Posterior Polar, 3; CTPP3.'" +EFO_0000712,"Definition: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in the United States. previous studies noted that about 20% of strokes are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes, resulting from vascular occlusion, account for the majority of strokes. + +previous studies reviewed genetic polymorphisms that have been implicated in the development of stroke. Candidate genes include those involved in hemostasis (see, e.g., F5; previous studies), the renin-angiotensin-aldosterone system (see, e.g., ACE; previous studies), homocysteine (see, e.g., MTHFR; previous studies), and lipoprotein metabolism (see, e.g., APOE; previous studies). + +See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; previous studies)." +MONDO_0007437,"Definition: Dentin dysplasia type II (DTDP2) is a defect of dentin formation in which the clinical appearance of the secondary teeth is normal, but the primary teeth may appear opalescent, similar to teeth affected by dentinogenesis imperfecta. The roots of the teeth are of normal shape and morphologic character. The pulp chambers and root canals of the anterior teeth and the premolars are shaped like thistle tubes because of the radicular extension of the pulp chamber. Most teeth show accumulations of pulp stones in these unusually shaped pulp chambers (summary by previous studies). + +Also see dentin dysplasia type I (DTDP1; previous studies)." +MONDO_0007639,Definition: This form of fleck retina disease (see previous studies) is characterized by discrete uniform white dots over the entire fundus with greatest density in the midperiphery and no macular involvement. Night blindness occurs. Both autosomal dominant and autosomal recessive inheritance had been suggested (previous studies; previous studies). +MONDO_0007808,"Definition: The Curth-Macklin type of ichthyosis hystrix (IHCM) is clinically characterized by severe fissuring and mutilating palmoplantar keratoderma. Affected individuals also exhibit extensive dark spiky or verrucous hyperkeratotic plaques over the large joints and trunk, which in some patients may cover almost the entire body. Structural and ultrastructural hallmarks include compact orthokeratotic hyperkeratosis, hypergranulosis with perinuclear edema, binucleated cells, and formation of perinuclear filamentous shells composed of feathery entangled keratin intermediate filaments (summary by previous studies and previous studies). + +The Lambert type of ichthyosis hystrix (IHL; previous studies), in which palms and soles are spared, is caused by mutation in the KRT10 (previous studies) gene." +MONDO_0009593,"Definition: Sedaghatian-type spondylometaphyseal dysplasia (SMDS) is a rare lethal disorder characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, delayed epiphyseal ossification, irregular iliac crests, and pulmonary hemorrhage. Affected infants present with severe hypotonia and cardiorespiratory problems; most die within days of birth due to respiratory failure. Cardiac abnormalities include conduction defects, complete heart block, and structural anomalies. Half of infants with SMDS are reported to have central nervous system malformations consistent with abnormal neuronal migration, including agenesis of the corpus callosum, pronounced frontotemporal pachygyria, simplified gyral pattern, partial lissencephaly, and severe cerebellar hypoplasia (summary by previous studies)." +MONDO_0013458,"Definition: HUPRA syndrome is a severe autosomal recessive multisystem disorder characterized by onset in infancy of progressive renal failure leading to electrolyte imbalances, metabolic alkalosis, pulmonary hypertension, hypotonia, and delayed development. Affected individuals are born prematurely (summary by previous studies)." +MONDO_0013989,"Definition: Developmental and epileptic encephalopathy-14 (DEE14) is a severe neurologic disorder characterized by onset in the first 6 months of life of refractory focal seizures and arrest of psychomotor development. Ictal EEG shows discharges that arise randomly from various areas of both hemispheres and migrate from one brain region to another. The disorder presents as 'malignant migrating partial seizures of infancy' (MMPSI), a clinical designation (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0014276,"Definition: Immunodeficiency-17 (IMD17) is an autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, particularly of cytotoxic CD8 (see previous studies)-positive cells, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. B cells, natural killer (NK) cells, and immunoglobulins are usually normal. Although thymic output of functional naive T cells early in life is decreased, polyclonal expansion of functional memory T cells is substantial. The phenotype in some patients is reminiscent of severe combined immunodeficiency (SCID) (summary by previous studies and previous studies)." +MONDO_0054743,"Definition: PCLD3 is an autosomal dominant disorder characterized by the development of multiple liver cysts that usually becomes apparent in adulthood. Liver cysts range in size and number, and the clinical severity is variable. Most patients also have a few renal cysts, but they do not result in significant renal disease or renal failure (summary by previous studies). + +For a discussion of genetic heterogeneity of polycystic liver disease, see PCLD1 (previous studies)." +Orphanet_53689,"Definition: Congenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles the renal disorder Bartter syndrome (see previous studies), except that chloride diarrhea is not associated with calcium level abnormalities (summary by previous studies). + + Genetic Heterogeneity of Diarrhea + +Other forms of diarrhea include DIAR2 (previous studies), caused by mutation in the MYO5B gene (previous studies) on 18q21; DIAR3 (previous studies), caused by mutation in the SPINT2 gene (previous studies) on 19q13; DIAR4 (previous studies), caused by mutation in the NEUROG3 gene (previous studies) on 10q21; DIAR5 (previous studies), caused by mutation in the EPCAM gene (previous studies) on 2p21; DIAR6 (previous studies), caused by mutation in the GUCY2C gene (previous studies) on 12p12; DIAR7 (previous studies) caused by mutation in the DGAT1 gene (previous studies) on 8q24; DIAR8 (previous studies), caused by mutation in the SLC9A3 gene (previous studies) on 5p15; DIAR9 (previous studies), caused by mutation in the WNT2B gene (previous studies) on 1p13; DIAR10 (previous studies), caused by mutation in the PLVAP gene (previous studies) on 19p13; DIAR11 (previous studies), caused by deletion of the intestine critical region (ICR) on chromosome 16p13, resulting in loss of expression of the flanking gene PERCC1 (previous studies); DIAR12 (previous studies), caused by mutation in the STX3 gene (previous studies) on 11q12; and DIAR13 (previous studies), caused by mutation in the ACSL5 gene (previous studies) on chromosome 10q25." +MONDO_0008964,"Definition: Congenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles the renal disorder Bartter syndrome (see previous studies), except that chloride diarrhea is not associated with calcium level abnormalities (summary by previous studies). + + Genetic Heterogeneity of Diarrhea + +Other forms of diarrhea include DIAR2 (previous studies), caused by mutation in the MYO5B gene (previous studies) on 18q21; DIAR3 (previous studies), caused by mutation in the SPINT2 gene (previous studies) on 19q13; DIAR4 (previous studies), caused by mutation in the NEUROG3 gene (previous studies) on 10q21; DIAR5 (previous studies), caused by mutation in the EPCAM gene (previous studies) on 2p21; DIAR6 (previous studies), caused by mutation in the GUCY2C gene (previous studies) on 12p12; DIAR7 (previous studies) caused by mutation in the DGAT1 gene (previous studies) on 8q24; DIAR8 (previous studies), caused by mutation in the SLC9A3 gene (previous studies) on 5p15; DIAR9 (previous studies), caused by mutation in the WNT2B gene (previous studies) on 1p13; DIAR10 (previous studies), caused by mutation in the PLVAP gene (previous studies) on 19p13; DIAR11 (previous studies), caused by deletion of the intestine critical region (ICR) on chromosome 16p13, resulting in loss of expression of the flanking gene PERCC1 (previous studies); DIAR12 (previous studies), caused by mutation in the STX3 gene (previous studies) on 11q12; and DIAR13 (previous studies), caused by mutation in the ACSL5 gene (previous studies) on chromosome 10q25." +Orphanet_98806,"Definition: Dystonia-6 is an autosomal dominant movement disorder characterized by early involvement of craniofacial muscles with secondary generalization often involving the arms, and laryngeal dystonia that causes speech difficulties (review by previous studies). + +previous studies provided a review of dystonia-6 and the THAP1 gene." +MONDO_0011264,"Definition: Dystonia-6 is an autosomal dominant movement disorder characterized by early involvement of craniofacial muscles with secondary generalization often involving the arms, and laryngeal dystonia that causes speech difficulties (review by previous studies). + +previous studies provided a review of dystonia-6 and the THAP1 gene." +Orphanet_98974,"Definition: Fuchs endothelial corneal dystrophy (FECD) is the most common genetic disorder of the corneal endothelium. Late-onset FECD is marked by thickening of Descemets membrane and excrescences, called guttae, that typically appear in the fourth or fifth decade. Disease progression results in decreased visual acuity as a result of increasing corneal edema, and end-stage disease is marked by painful epithelial bullae (summary by previous studies). Patients with keratoconus have been observed (previous studies). + +For a discussion of genetic heterogeneity of Fuchs endothelial corneal dystrophy, see FECD1 (previous studies)." +EFO_0000275,"Definition: Brugada Syndrome 7 + +Brugada syndrome is characterized by an ST segment elevation in the right precordial electrocardiogram leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests during adulthood, with a mean age of sudden death of 41 +/- 15 years, but also occurs in infants and children (summary by previous studies). + +For a discussion of genetic heterogeneity of Brugada syndrome, see BRGDA1 (previous studies). + + Atrial Fibrillation 16 + +Atrial fibrillation (AF) is the most common cardiac arrhythmia in the clinical setting, with a prevalence of 1% in the general population; prevalence increases with age and reaches more than 8% in the ninth decade of life. AF accounts for more than 15% of strokes, and is associated with worsening heart failure and increased mortality. More than 30% of cases of AF are considered to be 'lone AF,' unassociated with coronary artery disease, hypertension, valvular heart disease, hyperthyroidism, heart failure, or structural heart disease (summary by previous studies). + +For a discussion of genetic heterogeneity of atrial fibrillation, see ATFB1 (previous studies)." +EFO_0010259,"Definition: IDDMSSD is a neurodevelopmental disorder characterized by impaired intellectual development, poor speech, postnatal macrocephaly, and seizures (previous studies)." +MONDO_0007918,"Definition: Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR) is an autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes (summary by previous studies). previous studies found that MCLMR includes a broader spectrum of ocular disease, including retinal detachment with avascularity of the peripheral retina, and noted phenotypic overlap with familial exudative vitreoretinopathy (FEVR; see EVR1, previous studies). + +previous studies observed intrafamilial and intraindividual variability in retinal phenotype, and noted that syndromic manifestations in some patients are too subtle to be detected during a routine ophthalmologic evaluation. Variable expressivity and reduced penetrance have also been observed in some families (previous studies; previous studies). + +Autosomal recessive forms of microcephaly with chorioretinopathy have been reported (see previous studies). + +See also Mirhosseini-Holmes-Walton syndrome (autosomal recessive microcephaly with pigmentary retinopathy and impaired intellectual development; previous studies), which has been mapped to chromosome 8q21.3-q22.1." +MONDO_0008763,"Definition: Alstrom syndrome is an autosomal recessive disorder characterized by progressive cone-rod dystrophy leading to blindness, sensorineural hearing loss, childhood obesity associated with hyperinsulinemia, and type 2 diabetes mellitus. Dilated cardiomyopathy occurs in approximately 70% of patients during infancy or adolescence. Renal failure, pulmonary, hepatic, and urologic dysfunction are often observed, and systemic fibrosis develops with age (summary by previous studies; previous studies)." +MONDO_0009394,"Definition: Paget disease of bone-5 is an autosomal recessive, juvenile-onset form of Paget disease, a disorder of the skeleton resulting from abnormal bone resorption and formation. Clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. There is phenotypic variability, with some patients presenting in infancy, while others present later in childhood (summary by previous studies). + +For discussion of genetic heterogeneity of Paget disease of bone, see previous studies." +MONDO_0014303,"Definition: Spastic paraplegia-64 (SPG64) is a neurologic disorder characterized by childhood onset of progressive spastic paraplegia with impaired intellectual development, gait impairment, dysarthria, and white matter abnormalities on brain imaging. Some individuals show neurocognitive regression (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +Orphanet_401810,"Definition: Spastic paraplegia-64 (SPG64) is a neurologic disorder characterized by childhood onset of progressive spastic paraplegia with impaired intellectual development, gait impairment, dysarthria, and white matter abnormalities on brain imaging. Some individuals show neurocognitive regression (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +MONDO_0014379,"Definition: Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental disorder characterized by impaired intellectual development/motor delay, autism spectrum disorder, facial dysmorphisms, hypotonia, congenital heart disease, visual difficulties, and gastrointestinal issues (summary by previous studies)." +Orphanet_404448,"Definition: Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental disorder characterized by impaired intellectual development/motor delay, autism spectrum disorder, facial dysmorphisms, hypotonia, congenital heart disease, visual difficulties, and gastrointestinal issues (summary by previous studies)." +MONDO_0014853,Definition: Autosomal dominant deafness-70 is a form of nonsyndromic sensorineural hearing loss. Hearing impairment shows postlingual onset and is slowly progressive (previous studies). +MONDO_0030931,"Definition: Proteasome-associated autoinflammatory syndrome-4 (PRAAS4) is an autosomal recessive immunologic disorder characterized by onset of panniculitis and erythematous skin lesions in early infancy. Additional features include hepatosplenomegaly, lymphadenopathy, fever, generalized lipodystrophy, myositis, and joint contractures, as well as delayed motor and speech development. Autoimmune features, such as hemolytic anemia, may also occur. Laboratory studies show elevation of acute phase reactants and abnormal activation of the type I interferon response. Treatment with the JAK (see previous studies) inhibitor ruxolitinib may result in clinical improvement (summary by previous studies). + +For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (previous studies)." +MONDO_0030966,"Definition: Neurofacioskeletal syndrome with or without renal agenesis (NFSRA) is characterized by developmental delay and/or intellectual disability; corpus callosum hypoplasia or agenesis; facial dysmorphism, including upslanting palpebral fissures, broad nasal tip, and wide mouth; and skeletal abnormalities, including short stature, scoliosis, and flexion contractures, with broad fingertips and/or toes. Renal agenesis, unilateral or bilateral, has also been observed in some patients (previous studies)." +EFO_0700020,"Definition: Birt-Hogg-Dube syndrome is an autosomal dominant genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax (previous studies). + +BHD is similar to, but histologically and genetically distinct from, familial multiple discoid fibromas (FMDF; previous studies)." +Orphanet_122,"Definition: Birt-Hogg-Dube syndrome is an autosomal dominant genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax (previous studies). + +BHD is similar to, but histologically and genetically distinct from, familial multiple discoid fibromas (FMDF; previous studies)." +MONDO_0007350,"Definition: Coloboma is an ocular birth defect resulting from abnormal development of the eye during embryogenesis. It is defined as a congenital defect in any ocular tissue, typically presenting as absent tissue or a gap, at a site consistent with aberrant closure of the optic fissure. Failure of fusion can lead to coloboma of one or multiple regions of the inferior portion of the eye affecting any part of the globe traversed by the fissure, from the iris to the optic nerve, including the ciliary body, retina, and choroid. Coloboma is also frequently associated with small (microphthalmic) or absent (anophthalmic) eyes as part of an interrelated spectrum of developmental eye anomalies, and can affect either one or both eyes (summary by previous studies). + + Genetic Heterogeneity of Ocular Coloboma + +A recessive form of ocular coloboma (previous studies) is caused by mutation in the SALL2 gene (previous studies) on chromosome 14q11." +MONDO_0009380,"Definition: Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, an increase in the urinary excretion of coproporphyrin isomer I, deposition of melanin-like pigment in hepatocytes, and prolonged retention of sulfobromophthalein, but otherwise normal liver function (summary by previous studies)." +MONDO_0009610,"Definition: 3-Methylglutaconic aciduria type I (MGCA1) is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: one with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by previous studies). + + Genetic Heterogeneity and Classification of Methylglutaconic Aciduria + +Methylglutaconic aciduria is a clinically and genetically heterogeneous disorder. Type II MGCA (MGCA2), also known as Barth syndrome (BTHS; previous studies), is caused by mutation in the tafazzin gene (TAZ; previous studies) on chromosome Xq28. It is characterized by mitochondrial cardiomyopathy, short stature, skeletal myopathy, and recurrent infections; cognitive development is normal. Type III MGCA (MGCA3; previous studies), caused by mutation in the OPA3 gene (previous studies) on chromosome 19q13, involves optic atrophy, movement disorder, and spastic paraplegia. In types II and III, the elevations of 3-methylglutaconate and 3-methylglutarate in urine are modest. Type IV MGCA (MGCA4; previous studies) represents an unclassified group of patients who have severe psychomotor retardation and cerebellar dysgenesis. Type V MGCA (MGCA5; previous studies), caused by mutation in the DNAJC19 gene (previous studies) on chromosome 3q26, is characterized by early-onset dilated cardiomyopathy with conduction defects, nonprogressive cerebellar ataxia, testicular dysgenesis, and growth failure in addition to 3-methylglutaconic aciduria (previous studies; previous studies). Type VI MGCA (MGCA6; previous studies), caused by mutation in the SERAC1 gene (previous studies) on chromosome 6q25, includes deafness, encephalopathy, and a Leigh-like syndrome. Type VII MGCA (MGCA7B, previous studies and MGCA7A, previous studies), caused by mutation in the CLPB gene (previous studies) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MGCA (MGCA8; previous studies) is caused by mutation in the HTRA2 gene (previous studies) on chromosome 2p13. Type IX MGCA (MGCA9; previous studies) is caused by mutation in the TIMM50 gene (previous studies) on chromosome 19q13. + +previous studies noted that type I MGCA is very rare, with only 13 patients reported in the literature as of 2003. + +previous studies proposed a pathomechanism-based classification for 'inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.'" +MONDO_0010725,"Definition: X-linked retinoschisis (XLRS) is a retinal dystrophy that leads to schisis (splitting) of the neural retina leading to reduced visual acuity in affected men. The condition accounts for almost all congenital retinoschisis, with occasional reports of autosomal dominant retinoschisis (see previous studies) making up the remainder. The split in the retina occurs predominantly within the inner retinal layers and is very different from retinal detachment, which is a split between the neural retina and the retinal pigment epithelium. In general, carrier females remain asymptomatic (summary by previous studies)." +MONDO_0010799,"Definition: The mechanism of ototoxicity of aminoglycosides is thought to be interference with the production of ATP in the mitochondria of hair cells in the cochlea (previous studies). The aminoglycosides include kanamycin, gentamicin, tobramycin, and neomycin in addition to streptomycin." +Orphanet_168609,"Definition: The mechanism of ototoxicity of aminoglycosides is thought to be interference with the production of ATP in the mitochondria of hair cells in the cochlea (previous studies). The aminoglycosides include kanamycin, gentamicin, tobramycin, and neomycin in addition to streptomycin." +MONDO_0013157,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0014080,"Definition: Osteosclerotic metaphyseal dysplasia (OSMD) is a rare condition characterized by distinctive radiographic changes, including osteosclerosis localized predominantly to the metaphyses of the long bones. The shafts of the long bones are osteopenic. Laboratory abnormalities include elevated alkaline phosphatase levels in some, but not all, patients. Elevated urinary pyridinoline and deoxypyridinoline levels, markers of osteoclastic activity, have also been reported (previous studies; previous studies; previous studies). + +Patients with OSMD have been described who also show hypotonia, developmental delay, seizures, and later-onset spastic paraplegia; however, OSMD resulting from mutation in the LRRK1 gene does not appear to include these neurologic features (previous studies; previous studies; previous studies). + + Reviews + +previous studies reviewed published reports of LRRK1-associated OSMD, and noted that patients typically present with recurrent pathologic fractures and osteosclerosis at multiple skeletal sites, predominantly at the metaphyses and vertebral bodies. Variable degrees of osteosclerosis of ribs and skull and of Erlenmeyer flask deformity of the femurs have been observed." +MONDO_0030986,Definition: ABOLM is characterized by suprabasal acantholytic blisters limited to the oral and laryngeal mucosa (previous studies). +MONDO_0859204,"Definition: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD) is an autosomal recessive syndrome characterized by hypotonia in utero resulting in fetal akinesia with generalized joint contractures and arthrogryposis at birth. Affected newborns have severe respiratory insufficiency at birth requiring ventilation and significant dysmorphic facial features; seizures may also occur. Brain imaging shows variable malformations of cortical development, most commonly polymicrogyria or other gyral anomalies. Death in infancy usually occurs (summary by previous studies)." +Orphanet_99027,"Definition: Autosomal dominant adult-onset demyelinating leukodystrophy is a slowly progressive and fatal disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. ADLD differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis (summary by previous studies). Characteristic MRI findings include T2-weighted hyperintense changes in the upper corticospinal tract and cerebellar peduncles, with later development of confluent white matter changes in the frontoparietal area with relative sparing of the periventricular white matter (summary by previous studies)." +MONDO_0008215,"Definition: Autosomal dominant adult-onset demyelinating leukodystrophy is a slowly progressive and fatal disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. ADLD differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis (summary by previous studies). Characteristic MRI findings include T2-weighted hyperintense changes in the upper corticospinal tract and cerebellar peduncles, with later development of confluent white matter changes in the frontoparietal area with relative sparing of the periventricular white matter (summary by previous studies)." +EFO_0006343,"Definition: Aggressive periodontitis, which may be generalized or localized, is characterized by severe and protracted gingival infections, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting (previous studies). The term 'aggressive periodontitis' replaced the terms 'early-onset,' 'prepubertal,' or 'juvenile periodontitis' at a 1999 International workshop for a classification of periodontal disease and conditions, where it was decided that the classification terminology should not be age dependent or require knowledge of rates of progression (previous studies). + + Genetic Heterogeneity of Aggressive Periodontitis + +Aggressive periodontitis-2 (previous studies) has been mapped to chromosome 1q25." +EFO_0009044,"Definition: Fanconi anemia is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +previous studies noted that the FANCA, -C, -E, -F, -G, and -L proteins are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 protein during S phase of the growth cycle and after exposure to DNA crosslinking agents. The FA/BRCA pathway is involved in the repair of DNA damage. + +Some cases of Fanconi anemia have presented with a VACTERL (previous studies) or VACTERL-H (previous studies, previous studies) phenotype. In a group of 27 patients with Fanconi anemia group D1 (previous studies) due to biallelic mutations in the BRCA2 gene (previous studies), previous studies found that 5 patients had 3 or more VATER association anomalies and 1 was diagnosed with VACTERL-H. A VATER phenotype has also been reported in Fanconi anemia of complementation groups A, C (previous studies), E (previous studies), F (previous studies), and G (previous studies); VACTERL-H has also been described in patients with FANCB (previous studies) mutations (previous studies). previous studies added patients with FANCI (previous studies) to this list and stated that patients with FANCD2 (previous studies) and FANCL (previous studies) had also been reported to have features of VACTERL association. + + Genetic Heterogeneity of Fanconi Anemia + +Other Fanconi anemia complementation groups include FANCB (previous studies), caused by mutation in the FANCB (previous studies) on chromosome Xp22; FANCC (previous studies), caused by mutation in the FANCC (previous studies) on chromosome 9q22; FANCD1 (previous studies), caused by mutation in the BRCA2 (previous studies) on chromosome 13q12; FANCD2 (previous studies), caused by mutation in the FANCD2 gene (previous studies) on chromosome 3p25; FANCE (previous studies), caused by mutation in the FANCE gene (previous studies) on chromosome 6p21; FANCF (previous studies), caused by mutation in the FANCF gene (previous studies) on chromosome 11p15; FANCG (previous studies), caused by mutation in the XRCC9 gene (FANCG; previous studies) on chromosome 9p13; FANCI (previous studies), caused by mutation in the FANCI gene (previous studies) on chromosome 15q26; FANCJ (previous studies), caused by mutation in the BRIP1 gene (previous studies) on chromosome 17q22; FANCL (previous studies), caused by mutation in the PHF9 gene (FANCL; previous studies) on chromosome 2p16; FANCN (previous studies), caused by mutation in the PALB2 gene (previous studies) on chromosome 16p12; FANCO (previous studies), caused by mutation in the RAD51C (previous studies) on chromosome 17q22; FANCP (previous studies), caused by mutation in the SLX4 gene (previous studies) on chromosome 16p13; FANCQ (previous studies), caused by mutation in the ERCC4 gene (previous studies) on chromosome 16p13; FANCR (previous studies), caused by mutation in the RAD51 gene (previous studies) on chromosome 15q15; FANCS (previous studies), caused by mutation in the BRCA1 gene (previous studies) on chromosome 17q21; FANCT (previous studies), caused by mutation in the UBE2T gene (previous studies) on chromosome 1q31; FANCU (previous studies), caused by mutation in the XRCC2 gene (previous studies) on chromosome 7q36; FANCV (previous studies), caused by mutation in the MAD2L2 gene (previous studies) on chromosome 1p36; and FANCW (previous studies), caused by mutation in the RFWD3 gene (previous studies) on chromosome 16q23. + +The previously designated FANCH complementation group (previous studies) was found by previous studies to be the same as FANCA. + +A patient originally reported to have Fanconi anemia of complementation group M (FANCM) due to mutation in the FAAP250 gene (previous studies) by previous studies was subsequently found by previous studies to have FANCA." +MONDO_0009624,"Definition: Microcephaly and chorioretinopathy is an autosomal recessive developmental disorder characterized by delayed psychomotor development and visual impairment, often accompanied by short stature (summary by previous studies). + + Genetic Heterogeneity of Microcephaly and Chorioretinopathy + +See also MCCRP2 (previous studies), caused by mutation in the PLK4 gene (previous studies) on chromosome 4q27, and MCCRP3 (previous studies), caused by mutation in the TUBGCP4 gene (previous studies) on chromosome 15q15. + +An autosomal dominant form of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is caused by heterozygous mutation in the KIF11 gene (previous studies) on chromosome 10q23. + +See also Mirhosseini-Holmes-Walton syndrome (autosomal recessive pigmentary retinopathy and mental retardation; previous studies), which has been mapped to chromosome 8q21.3-q22.1." +MONDO_0010317,Definition: Intellectual developmental disorder-29 (XLID29) is a nonspecific form of XLID. It is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; previous studies) to Proud syndrome (previous studies) to infantile spasms without brain malformations (DEE1; previous studies) to Partington syndrome (previous studies) (previous studies; previous studies). +MONDO_0010498,"Definition: Male EBP disorder with neurologic defects (MEND) is an X-linked recessive disorder representing a continuous phenotypic spectrum with variable manifestations associated with a defect in sterol biosynthesis. Features include intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. Not all patients show all features, and the severity is highly variable. Molecular studies indicate that affected males are hemizygous for a nonmosaic hypomorphic EBP allele. Carrier females are generally clinically asymptomatic, but may show biochemical abnormalities (summary by previous studies and previous studies)." +MONDO_0010650,"Definition: Melnick-Needles syndrome is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. These disorders, including frontometaphyseal dysplasia (FMD; previous studies), otopalatodigital syndrome-1 (OPD1; previous studies), and otopalatodigital syndrome-2 (OPD2; previous studies), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD is characterized by a generalized skeletal dysplasia, deafness and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by previous studies). previous studies suggested that these disorders constitute a single entity, which they called 'fronto-otopalatodigital osteodysplasia.'" +Orphanet_2484,"Definition: Melnick-Needles syndrome is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. These disorders, including frontometaphyseal dysplasia (FMD; previous studies), otopalatodigital syndrome-1 (OPD1; previous studies), and otopalatodigital syndrome-2 (OPD2; previous studies), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD is characterized by a generalized skeletal dysplasia, deafness and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by previous studies). previous studies suggested that these disorders constitute a single entity, which they called 'fronto-otopalatodigital osteodysplasia.'" +MONDO_0011178,"Definition: Benign familial infantile convulsions (BFIC; see previous studies) is an autosomal dominant disorder characterized by afebrile seizures occurring between 3 and 12 months of age. Paroxysmal choreoathetosis is a disorder of involuntary movements characterized by attacks that occur spontaneously or are induced by a variety of stimuli. + +The ICCA syndrome shares overlapping clinical features with benign familial infantile seizures-2 (BFIS2; previous studies) and episodic kinesigenic dyskinesia-1 (EKD1; previous studies), which are allelic disorders. + +See also rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (previous studies), which maps to 16p." +MONDO_0013400,"Definition: P450scc deficiency is a rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female external genitalia, sometimes with clitoromegaly. The phenotypic spectrum ranges from prematurity, complete underandrogenization, and severe early-onset adrenal failure to term birth with clitoromegaly and later-onset adrenal failure (summary by previous studies). + +Although hormonal and phenotypic features can resemble those of congenital lipoid adrenal hyperplasia (lipoid CAH; previous studies), no patient with P450scc deficiency has been described with the massive adrenal enlargement typical of lipoid CAH (summary by previous studies)." +Orphanet_168558,"Definition: P450scc deficiency is a rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female external genitalia, sometimes with clitoromegaly. The phenotypic spectrum ranges from prematurity, complete underandrogenization, and severe early-onset adrenal failure to term birth with clitoromegaly and later-onset adrenal failure (summary by previous studies). + +Although hormonal and phenotypic features can resemble those of congenital lipoid adrenal hyperplasia (lipoid CAH; previous studies), no patient with P450scc deficiency has been described with the massive adrenal enlargement typical of lipoid CAH (summary by previous studies)." +MONDO_0014389,"Definition: Polyglucosan body myopathy-1 (PGBM1) is an autosomal recessive disorder characterized by onset in childhood of progressive proximal muscle weakness, resulting in difficulties in ambulation. Most patients also develop progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. A small subset of patients present with severe immunodeficiency and a hyperinflammatory state in very early childhood (summary by previous studies and previous studies). + + Genetic Heterogeneity of Polyglucosan Body Myopathy + +See also PGBM2 (previous studies), caused by mutation in the GYG1 gene (previous studies) on chromosome 3q24." +MONDO_0032607,"Definition: Vertebral anomalies and variable endocrine and T-cell dysfunction is a syndrome characterized by an overlapping spectrum of features. Skeletal malformations primarily involve the vertebrae, and endocrine abnormalities involving parathyroid hormone (PTH; previous studies), growth hormone (GH1; previous studies), and the thyroid gland have been reported. T-cell abnormalities have been observed, with some patients showing thymus gland aplasia or hypoplasia. Patients have mild craniofacial dysmorphism, and some show developmental delay or behavioral problems. Cardiac defects may be present (previous studies)." +MONDO_0033645,"Definition: Mitochondrial complex IV deficiency nuclear type 11 (MC4DN11) is an autosomal recessive metabolic disorder characterized by a childhood-onset sensory neuronopathy and additional features which may include hypotonia, cerebellar ataxia, tremor, dystonia, choreoathetosis, and/or dysarthria. Patients may have variable motor delay, speech delay, or impaired intellectual development (summary by previous studies; previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0049221,"Definition: X-linked myopia-26 is characterized by female-limited early-onset high myopia. The fundus of affected individuals shows a tigroid appearance, and there is a temporal crescent of the optic nerve head (previous studies). + +For a discussion of genetic heterogeneity of myopia, see previous studies." +Orphanet_98619,"Definition: X-linked myopia-26 is characterized by female-limited early-onset high myopia. The fundus of affected individuals shows a tigroid appearance, and there is a temporal crescent of the optic nerve head (previous studies). + +For a discussion of genetic heterogeneity of myopia, see previous studies." +MONDO_0060702,"Definition: Spondyloepimetaphyseal dysplasia of the Di Rocco type (SEMDDR) is characterized by short stature, joint pain, and genu varum, as well as SEMD involving primarily the hips but also affecting the wrists, hands, knees, and ankles. Patients also exhibit variable degrees of metaphyseal and spine involvement (previous studies)." +Orphanet_289573,"Definition: Multiple mitochondrial dysfunctions syndrome-5 (MMDS5) is an autosomal recessive disorder characterized mainly by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Death usually occurs in early childhood (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (previous studies)." +Orphanet_88642,"Definition: Congenital indifference to pain is a rare autosomal recessive disorder characterized by the complete absence of pain perception typically associated with noxious stimuli. Affected individuals are aware of a stimulus, but have lost the ability to perceive pain. Most patients are hyposmic or anosmic. Other sensory modalities are unaffected, and there is an absence of overt autonomic symptoms. Sural nerve biopsy and nerve conduction velocity studies are normal (summary by previous studies; and previous studies). + +Hereditary sensory and autonomic neuropathy type IID (HSAN2D) is an autosomal recessive disorder characterized by congenital or childhood-onset distal loss of pain and temperature sensation as well as autonomic dysfunction accompanied by hyposmia, hearing loss, hypogeusia, and sometimes bone dysplasia. The phenotype is highly variable, even within families. Two Japanese families have been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of HSAN, see HSAN1 (previous studies)." +MONDO_0009459,"Definition: Congenital indifference to pain is a rare autosomal recessive disorder characterized by the complete absence of pain perception typically associated with noxious stimuli. Affected individuals are aware of a stimulus, but have lost the ability to perceive pain. Most patients are hyposmic or anosmic. Other sensory modalities are unaffected, and there is an absence of overt autonomic symptoms. Sural nerve biopsy and nerve conduction velocity studies are normal (summary by previous studies; and previous studies). + +Hereditary sensory and autonomic neuropathy type IID (HSAN2D) is an autosomal recessive disorder characterized by congenital or childhood-onset distal loss of pain and temperature sensation as well as autonomic dysfunction accompanied by hyposmia, hearing loss, hypogeusia, and sometimes bone dysplasia. The phenotype is highly variable, even within families. Two Japanese families have been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of HSAN, see HSAN1 (previous studies)." +EFO_0020858,"Definition: Autosomal recessive spastic paraplegia-84 (SPG84) is characterized by onset of slowly progressive walking difficulties due to lower limb weakness, stiffness, and spasticity in the first 2 decades of life. Additional features may include nystagmus, urinary urgency, joint contractures, and possible learning disabilities (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0007585,"Definition: Multiple hereditary exostoses (EXT) is an autosomal dominant disorder characterized by multiple projections of bone capped by cartilage, most numerous in the metaphyses of long bones, but also occurring on the diaphyses of long bones. Flat bones, vertebrae, and the ribs may also be affected, but the skull is usually not involved. Deformity of the legs, forearms (resembling Madelung deformity), and hands is frequent (previous studies). + +Two conditions in which multiple exostoses occur are metachondromatosis (previous studies) and the Langer-Giedion syndrome (LGS; previous studies); the latter condition is also known as trichorhinophalangeal syndrome type II. Furthermore, exostosis-like lesions occur with fibrodysplasia ossificans progressiva (FOP; previous studies), occipital horn syndrome (previous studies), and the adult stage of hereditary hypophosphatemia (see previous studies); these exostoses are located at sites of tendon and muscle attachment. A relatively rare variant of the supracondylar process, on the anteromedial surface of the distal humerus, can be confused with an exostosis; the variant is said to be present in about 1% of persons of European descent (previous studies). + + Genetic Heterogeneity of Multiple Exostoses + +Multiple exostoses type II (EXT2; previous studies) is caused by mutation in the EXT2 gene (previous studies) on chromosome 11p11. Multiple exostoses type III (EXT3; previous studies) has been mapped to a locus on chromosome 19." +MONDO_0009868,"Definition: Glycogen storage disease IXb (GSD9B), in which phosphorylase kinase is deficient in both liver and muscle, is characterized by predominantly mild symptoms including hepatomegaly, hypoglycaemia only after prolonged fasting, and in some cases muscle hypotonia (summary by previous studies). + +For a discussion of genetic heterogeneity of GSD IX, see GSD9A (previous studies)." +MONDO_0009959,"Definition: The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see previous studies. + +Individuals with mutations in the PEX12 gene have cells of complementation group 3 (CG3). For information on the history of PBD complementation groups, see previous studies." +MONDO_0010392,"Definition: Phosphoglycerate kinase-1 deficiency is an X-linked recessive condition with a highly variable clinical phenotype that includes hemolytic anemia, myopathy, and neurologic involvement. Patients can express 1, 2, or all 3 of these manifestations (previous studies)." +MONDO_0010743,"Definition: Hereditary nonsyndromic thrombocytopenia is characterized by decreased numbers of platelets and bleeding tendency (summary by previous studies). + + Genetic Heterogeneity of Hereditary Thrombocytopenia + +Autosomal dominant forms of thrombocytopenia include THC2 (previous studies), caused by mutation in the ANKRD26 (previous studies) gene on chromosome 10; THC4 (previous studies), caused by mutation in the CYCS gene (previous studies) on chromosome 7; THC5 (previous studies), caused by mutation in the ETV6 gene (previous studies) on chromosome 12p13; THC6 (previous studies), caused by mutation in the SRC gene (previous studies) on chromosome 20q12; and THC7 (previous studies), caused by mutation in the IKZF5 gene (previous studies) on chromosome 10q26. + +An autosomal recessive form (THC3; previous studies) is caused by mutation in the FYB gene (previous studies) on chromosome 5p13." +Orphanet_852,"Definition: Hereditary nonsyndromic thrombocytopenia is characterized by decreased numbers of platelets and bleeding tendency (summary by previous studies). + + Genetic Heterogeneity of Hereditary Thrombocytopenia + +Autosomal dominant forms of thrombocytopenia include THC2 (previous studies), caused by mutation in the ANKRD26 (previous studies) gene on chromosome 10; THC4 (previous studies), caused by mutation in the CYCS gene (previous studies) on chromosome 7; THC5 (previous studies), caused by mutation in the ETV6 gene (previous studies) on chromosome 12p13; THC6 (previous studies), caused by mutation in the SRC gene (previous studies) on chromosome 20q12; and THC7 (previous studies), caused by mutation in the IKZF5 gene (previous studies) on chromosome 10q26. + +An autosomal recessive form (THC3; previous studies) is caused by mutation in the FYB gene (previous studies) on chromosome 5p13." +MONDO_0011338,"Definition: Omenn syndrome is an autosomal recessive disorder characterized by severe combined immunodeficiency (SCID) associated with erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire (summary by previous studies). + +Another distinct form of familial histiocytic reticulocytosis (previous studies) is caused by mutation in the perforin-1 gene (PRF1; previous studies) on chromosome 10q22." +MONDO_0011534,"Definition: HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (previous studies)." +MONDO_0013547,"Definition: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 (MC5DN3) is an autosomal recessive disorder with variable manifestations. Affected individuals present soon after birth or in early infancy with hypotonia, respiratory distress, and poor sucking. They have global developmental delay with mildly impaired intellectual disability. Additional features may include dystonia, ataxia, peripheral neuropathy, and seizures. Congenital cataracts, hearing impairment, and mild left cardiac ventricular hypertrophy have been reported in 1 patient each. Laboratory studies show increased lactate; some patients have hyperammonemia, 3-methylglutaconic aciduria, and hyperCKemia (previous studies; previous studies). + +For a general phenotypic description of the nuclear type of mitochondrial complex V deficiency and a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see previous studies." +Orphanet_254913,"Definition: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 (MC5DN3) is an autosomal recessive disorder with variable manifestations. Affected individuals present soon after birth or in early infancy with hypotonia, respiratory distress, and poor sucking. They have global developmental delay with mildly impaired intellectual disability. Additional features may include dystonia, ataxia, peripheral neuropathy, and seizures. Congenital cataracts, hearing impairment, and mild left cardiac ventricular hypertrophy have been reported in 1 patient each. Laboratory studies show increased lactate; some patients have hyperammonemia, 3-methylglutaconic aciduria, and hyperCKemia (previous studies; previous studies). + +For a general phenotypic description of the nuclear type of mitochondrial complex V deficiency and a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see previous studies." +MONDO_0014306,"Definition: Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits (summary by previous studies and previous studies). Some patients present with clinical immunodeficiency (previous studies). + +previous studies reviewed the basic biology of ADA2 and the various clinical manifestations of ADA2 deficiency, which include vasculitis affecting small- and medium-sized vessels causing early-onset stroke with subsequent neurologic signs, skin ulcerations resembling polyarteritis nodosa, peripheral neuropathy, immunodeficiency, autoimmune features, and hematologic abnormalities, including anemia and leukopenia. The clinical features are highly pleiotropic, and patients can present with only some of these main features. The hematologic manifestations of the disorder may sometimes resemble Diamond-Blackfan anemia (see, e.g., DBA1, previous studies)." +EFO_0006803,"Definition: Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits (summary by previous studies and previous studies). Some patients present with clinical immunodeficiency (previous studies). + +previous studies reviewed the basic biology of ADA2 and the various clinical manifestations of ADA2 deficiency, which include vasculitis affecting small- and medium-sized vessels causing early-onset stroke with subsequent neurologic signs, skin ulcerations resembling polyarteritis nodosa, peripheral neuropathy, immunodeficiency, autoimmune features, and hematologic abnormalities, including anemia and leukopenia. The clinical features are highly pleiotropic, and patients can present with only some of these main features. The hematologic manifestations of the disorder may sometimes resemble Diamond-Blackfan anemia (see, e.g., DBA1, previous studies)." +EFO_0009295,"Definition: Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS) is an autosomal recessive multisystem disorder with onset in childhood. The phenotype is highly variable, but most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes affecting the small vessels of the brain resulting in neurologic dysfunction. Other features may include recurrent fever, elevated acute-phase proteins, myalgias, lesions resembling polyarteritis nodosa, and/or livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients may have renal and/or gastrointestinal involvement, hypertension, aneurysms, or ischemic necrosis of the digits (summary by previous studies and previous studies). Some patients present with clinical immunodeficiency (previous studies). + +previous studies reviewed the basic biology of ADA2 and the various clinical manifestations of ADA2 deficiency, which include vasculitis affecting small- and medium-sized vessels causing early-onset stroke with subsequent neurologic signs, skin ulcerations resembling polyarteritis nodosa, peripheral neuropathy, immunodeficiency, autoimmune features, and hematologic abnormalities, including anemia and leukopenia. The clinical features are highly pleiotropic, and patients can present with only some of these main features. The hematologic manifestations of the disorder may sometimes resemble Diamond-Blackfan anemia (see, e.g., DBA1, previous studies)." +MONDO_0014611,"Definition: MMDS4 is an autosomal recessive neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased CSF glycine and decreased activity of mitochondrial complex II; there may be additional biochemical evidence of mitochondrial dysfunction (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (previous studies)." +MONDO_0014800,"Definition: Scapulohumeroperoneal myopathy is an autosomal dominant muscle disorder characterized by slowly progressive muscle weakness and atrophy affecting both proximal and distal muscles of the upper and lower limbs. Onset is usually in the first decade and can be as early as infancy, although some patients do not notice symptoms until young adulthood. There is marked variability in severity (summary by previous studies)." +MONDO_0032703,"Definition: Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS)is characterized by disproportionate short stature, defective tooth enamel formation, and skeletal dysplasia with severe scoliosis in some patients. Variable features include facial dysmorphism, moderate hearing impairment, and mildly impaired intellectual development (previous studies)." +MONDO_0032894,"Definition: Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA) is an autosomal recessive disorder characterized by severely impaired global development apparent soon after birth. Affected individuals develop seizures in the first year of life and achieve almost no psychomotor progress, resulting in feeding difficulties and an inability to walk or speak. Other features include hypotonia, peripheral spasticity with contractures, cortical visual impairment, and dysmorphic features, including microcephaly. Death in childhood may occur (summary by previous studies). + +previous studies noted that the molecular mechanism of this disorder can be classified into a group of similar phenotypes resulting from mutations in genes associated with transport protein particles, sometimes referred to as 'TRAPPopathies' (review by previous studies)." +MONDO_0042979,"Definition: There are 2 dominantly inherited, clinically similar types of episodic flaccid generalized weakness, HOKPP and HYPP, that are distinguished by the changes in serum potassium levels during paralytic attacks. In contrast to HYPP, myotonia is usually not present in HOKPP (previous studies). Hypokalemic periodic paralysis may also occur as a rare complication of thyrotoxicosis (see TTPP1, previous studies), a disorder with a high frequency in individuals of Asian descent (previous studies)." +MONDO_0054785,"Definition: Multiple mitochondrial dysfunctions syndrome-6 is an autosomal recessive severe neurodegenerative disorder with onset in early childhood. Affected individuals may have initial normal development, but show neurologic regression in the first year of life. They have hypotonia, inability to walk, poor speech, intellectual disability, and motor abnormalities, such as ataxia, dystonia, and spasticity. Some patients may die in childhood. Laboratory evidence indicates that the disorder results from mitochondrial dysfunction (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (previous studies)." +Orphanet_661,"Definition: Idiopathic congenital central hypoventilation syndrome (CCHS), also known as 'Ondine's curse' (previous studies), is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. Affected individuals typically present in the first hours of life with cyanosis and increased carbon dioxide during sleep. Patients breathe normally while awake, but hypoventilate with normal respiratory rates and shallow breathing during sleep; more severely affected patients hypoventilate both awake and asleep. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia (reviewed by previous studies). + +Congenital central hypoventilation syndrome has been associated with several disorders classified as neurocristopathies, that is, aberrant phenotypes arising from a defect of migration or differentiation of neural crest cells. These include neuroblastoma (previous studies), ganglioneuroma (previous studies), and most frequently Hirschsprung disease (HSCR) which appears in 16% of CCHS patients. The association of CCHS and HSCR is referred to as Haddad syndrome. + + Genetic Heterogeneity of CCHS + +See also CCHS2 (previous studies), caused by mutation in the MYOH1 gene (previous studies) on chromosome 12q24, and CCHS3 (previous studies), caused by mutation in the LBX1 gene (previous studies) on chromosome 10q24. + +Congenital central hypoventilation can be a feature of other developmental disorders, such as those caused by mutation in the MECP2 gene (previous studies)." +MONDO_0800026,"Definition: Idiopathic congenital central hypoventilation syndrome (CCHS), also known as 'Ondine's curse' (previous studies), is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. Affected individuals typically present in the first hours of life with cyanosis and increased carbon dioxide during sleep. Patients breathe normally while awake, but hypoventilate with normal respiratory rates and shallow breathing during sleep; more severely affected patients hypoventilate both awake and asleep. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia (reviewed by previous studies). + +Congenital central hypoventilation syndrome has been associated with several disorders classified as neurocristopathies, that is, aberrant phenotypes arising from a defect of migration or differentiation of neural crest cells. These include neuroblastoma (previous studies), ganglioneuroma (previous studies), and most frequently Hirschsprung disease (HSCR) which appears in 16% of CCHS patients. The association of CCHS and HSCR is referred to as Haddad syndrome. + + Genetic Heterogeneity of CCHS + +See also CCHS2 (previous studies), caused by mutation in the MYOH1 gene (previous studies) on chromosome 12q24, and CCHS3 (previous studies), caused by mutation in the LBX1 gene (previous studies) on chromosome 10q24. + +Congenital central hypoventilation can be a feature of other developmental disorders, such as those caused by mutation in the MECP2 gene (previous studies)." +EFO_0005252,"Definition: Orthostatic hypotension-2 is an autosomal recessive disorder characterized by severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood. Some patients may also have renal dysfunction and reduced life expectancy. The disorder results from a defect in the biosynthesis of norepinephrine from dopamine due to a cofactor deficiency. + +For a discussion of genetic heterogeneity of ORTHYP, see ORTHYP1 (previous studies)." +MONDO_0008153,"Definition: Progressive osseous heteroplasia is a rare autosomal dominant disorder characterized by dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia (previous studies). + +The molecular defect causing POH is the same as that causing PPHP: an inactivating GNAS mutation caused only by paternal inheritance of the mutant allele. However, patients with PPHP have a constellation of physical findings referred to as Albright hereditary osteodystrophy (AHO; see previous studies) that is often not seen in patients with POH. previous studies suggested that POH may be an extreme end of the spectrum of the AHO features seen in PPHP." +MONDO_0008670,"Definition: Waardenburg syndrome type 1 (WS1) is an autosomal dominant auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and 'dystopia canthorum,' the lateral displacement of the ocular inner canthi (reviews by previous studies, previous studies, and previous studies). + + Clinical Variability of Waardenburg Syndrome Types 1-4 + +Waardenburg syndrome is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia irides and brilliant blue eyes; and congenital sensorineural hearing loss. Waardenburg syndrome has been classified into 4 main phenotypes. WS type 1 is distinguished by the presence of dystopia canthorum. WS type 2 (WS2; see previous studies) is distinguished from type 1 by the absence of dystopia canthorum. WS type 3 (WS3; previous studies) has dystopia canthorum and upper limb abnormalities. WS type 4 (WS4; see previous studies), also known as Waardenburg-Shah syndrome, has the additional feature of Hirschsprung disease (reviews by previous studies and previous studies). + + Genetic Heterogeneity of All Types of Waardenburg Syndrome + +Waardenburg syndrome is genetically heterogeneous. WS1 and WS3 are both caused by mutation in the PAX3 gene. See WS2A (previous studies) for a discussion of genetic heterogeneity of WS type 2, and WS4A (previous studies) for a discussion of genetic heterogeneity of WS type 4." +MONDO_0008771,"Definition: Amelogenesis imperfecta type IG, also known as enamel-renal syndrome, is characterized by hypoplastic enamel on primary and secondary dentition, pulp stones, delayed or failed eruption of secondary dentition, gingival overgrowth, and nephrocalcinosis. Blood chemistry analyses are typically normal, and nephrocalcinosis, which is found on renal ultrasound, may not appear until later in life (summary by previous studies)." +MONDO_0009009,"Definition: Congenital plasminogen deficiency is a rare autosomal recessive disorder characterized clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous ('wood-like') conjunctivitis, a redness and subsequent formation of pseudomembranes mostly on the palpebral surfaces of the eye that progress to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after local excision. Pseudomembranous lesions of other mucous membranes often occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus. A slightly increased female:male ratio has been observed (1.4:1 to 2:1) (previous studies; previous studies). + +Type I plasminogen deficiency is characterized by decreased serum plasminogen activity, decreased plasminogen antigen levels, and clinical symptoms, whereas type II plasminogen deficiency, also known as 'dysplasminogenemia,' is characterized by decreased plasminogen activity with normal or slightly reduced antigen levels. Patients with type II deficiency are usually asymptomatic. Ligneous conjunctivitis and pseudomembranous formation has only been associated with type I plasminogen deficiency. Presumably, normal amounts of plasminogen antigen with decreased activity, as seen in type II, is sufficient for normal wound healing (previous studies)." +MONDO_0010879,"Definition: CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by previous studies)." +MONDO_0012130,"Definition: Alpha-B crystallin-related myofibrillar myopathy is an autosomal dominant muscular disorder characterized by adult onset of progressive muscle weakness affecting both the proximal and distal muscles and associated with respiratory insufficiency, cardiomyopathy, and cataracts. There is phenotypic variability both within and between families (previous studies; previous studies). + +A homozygous founder mutation in the CRYAB gene has been identified in Canadian aboriginal infants of Cree origin who have a severe fatal infantile hypertonic form of myofibrillar myopathy; see previous studies. + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (previous studies)." +MONDO_0013960,"Definition: Patients with sinoatrial node dysfunction and deafness have congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia (previous studies). + +See Jervell and Lange-Nielsen syndrome (previous studies) for discussion of another deafness syndrome with impaired cardiac conduction." +MONDO_0014733,"Definition: Charcot-Marie-Tooth disease type 4K is an autosomal recessive demyelinating peripheral neuropathy characterized by onset in the first decade of distal muscle weakness and atrophy associated with impaired distal sensation. Both upper and lower limbs are affected. Affected individuals may also have nystagmus and late-onset cerebellar ataxia. Laboratory studies show increased serum lactate and isolated mitochondrial complex IV deficiency (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (previous studies)." +Orphanet_391351,"Definition: Charcot-Marie-Tooth disease type 4K is an autosomal recessive demyelinating peripheral neuropathy characterized by onset in the first decade of distal muscle weakness and atrophy associated with impaired distal sensation. Both upper and lower limbs are affected. Affected individuals may also have nystagmus and late-onset cerebellar ataxia. Laboratory studies show increased serum lactate and isolated mitochondrial complex IV deficiency (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (previous studies)." +MONDO_0014885,"Definition: Hermansky-Pudlak syndrome-10 (HPS10) is an autosomal recessive multisystem disorder characterized by infantile onset of immunodeficiency, oculocutaneous albinism, and severe neurologic impairment, including severely delayed global development and intractable seizures (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (previous studies)." +MONDO_0030748,"Definition: Intermediate junctional epidermolysis bullosa 3A (JEB3A) is an autosomal recessive blistering disease of skin and mucous membranes. Blistering is less severe than in severe JEB (see previous studies). The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Nail and dental abnormalities occur. Blistering does not affect the life span of affected individuals (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +MONDO_0030996,"Definition: Platelet-type bleeding disorder-24 (BDPLT24) is an autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of Glanzmann thrombasthenia-like with macrothrombocytopenia, see previous studies." +MONDO_0859190,"Definition: Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC) is an autosomal dominant disorder characterized by dysmorphic craniofacial features associated with mild developmental delay, mildly impaired intellectual development or learning difficulties, speech delay, and behavioral abnormalities. About half of patients have congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital cardiac defects, including septal defects (previous studies)." +MONDO_0859228,"Definition: Combined oxidative phosphorylation deficiency-55 (COXPD55) is characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia phenotype has been described in 1 patient (summary by previous studies)." +MONDO_0859317,"Definition: Autosomal recessive pseudohypoaldosteronism type IB2 (PHA1B2) is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Laboratory evaluation shows hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. Respiratory tract infections are common in affected children and may be mistaken for cystic fibrosis (CF; previous studies). Aggressive salt replacement and control of hyperkalemia results in survival, and the disorder appears to become less severe with age (review by previous studies)." +Orphanet_2556,"Definition: The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder characterized by unilateral or bilateral microphthalmia and linear skin defects--which are limited to the face and neck, consisting of areas of aplastic skin that heal with age to form hyperpigmented areas--in affected females and in utero lethality for males (previous studies). + + Genetic Heterogeneity of Linear Skin Defects with Multiple Congenital Anomalies + +Also see LSDMCA2 (previous studies), caused by mutation in the COX7B gene (previous studies) on Xq21, and LSDMCA3 (previous studies), caused by mutation in the NDUFB11 gene (previous studies) on Xp11.3." +EFO_0010166,"Definition: Warburg-Cinotti syndrome (WRCN) is characterized by progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acroosteolysis (previous studies)." +EFO_0010252,"Definition: Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-1 (RSTS1; previous studies), patients with MKHK1 do not resemble the striking phenotype of RSTS1. + + Genetic Heterogeneity of Menke-Hennekam Syndrome + +Menke-Hennekam syndrome-2 (MKHK2; previous studies) is caused by heterozygous mutation in exons 30 or 31 of the EP300 gene (previous studies). Mutation elsewhere in that gene results in RSTS2 (previous studies)." +MONDO_0009499,"Definition: Krabbe disease (KRB) is an autosomal recessive lysosomal disorder affecting the white matter of the central and peripheral nervous systems. Most patients present within the first 6 months of life with 'infantile' or 'classic' disease manifest as extreme irritability, spasticity, and developmental delay (previous studies). There is severe motor and mental deterioration, leading to decerebration and death by age 2 years. Approximately 10 to 15% of patients have a later onset, commonly differentiated as late-infantile (6 months to 3 years), juvenile (3 to 8 years), and even adult-onset forms. The later-onset forms have less disease severity and slower progression. These later-onset patients can be clinically normal until weakness, vision loss and intellectual regression become evident; those with adult onset may have spastic paraparesis as the only symptom. Disease severity is variable, even within families (summary by previous studies)." +MONDO_0010371,"Definition: Aland Island eye disease (AIED) is an X-linked recessive retinal disease characterized by fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect (previous studies), progressive myopia, and defective dark adaptation. Although AIED has been referred to as a form of albinism, there is no misrouting of the optic nerves, which excludes it from the formal diagnosis of classic albinism (previous studies)." +Orphanet_178333,"Definition: Aland Island eye disease (AIED) is an X-linked recessive retinal disease characterized by fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect (previous studies), progressive myopia, and defective dark adaptation. Although AIED has been referred to as a form of albinism, there is no misrouting of the optic nerves, which excludes it from the formal diagnosis of classic albinism (previous studies)." +MONDO_0011101,"Definition: Peroxisome biogenesis disorder-1B (PBD1B) is characterized by the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). Initial presentation and natural history varies, with many children presenting as newborns, whereas others do not come to attention until later. Most affected children have hypotonia, but unlike Zellweger syndrome (see PBD1A, previous studies) there is a degree of psychomotor development, and some patients achieve head control, sit unsupported, and may even walk independently. Many can communicate, and although language is rare, there have been children who have near normal language for age. Craniofacial anomalies are similar to but less pronounced than in Zellweger syndrome. In some individuals a leukodystrophy develops, with degeneration of myelin, loss of previously acquired skills, and development of spasticity; this may stabilize, or progress and be fatal. In PBD1B, the most common manifestations that are less apparent in ZS are sensorineural hearing loss and retinitis pigmentosa (summary by previous studies). While Zellweger syndrome usually results in death in the first year of life, children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by previous studies). + +Individuals with mutations in the PEX1 gene have cells of complementation group 1 (CG1, equivalent to CGE). For information on the history of PBD complementation groups, see previous studies. + + Genetic Heterogeneity of Peroxisome Biogenesis Disorder NALD/IRD + +The phenotypic spectrum of NALD/IRD peroxisome biogenesis disorders can be caused by mutation in members of the peroxin (PEX) gene family. The PEX genes encode proteins essential for the assembly of functional peroxisomes (summary by previous studies). PBD1B is caused by mutation in the PEX1 gene on chromosome 7q21; PBD2B (previous studies) is caused by mutation in the PEX5 gene (previous studies) on chromosome 12p13.3; PBD3B (previous studies) is caused by mutation in the PEX12 gene (previous studies) on chromosome 17; PBD4B (previous studies) is caused by mutation in the PEX6 gene (previous studies) on chromosome 6p21.1; PBD5B (previous studies) is caused by mutation in the PEX2 gene (previous studies) on chromosome 8q21.1; PBD6B (previous studies) is caused by mutation in the PEX10 gene (previous studies) on chromosome 1p36.32; PBD7B (previous studies)is caused by mutation in the PEX26 gene (previous studies) on chromosome 22q11.21; PBD8B (previous studies) is caused by mutation in the PEX16 gene (previous studies) on chromosome 11p11; PBD10B (previous studies) is caused by mutation in the PEX3 gene (previous studies) on chromosome 6q24; and PBD11B (previous studies) is caused by mutation in the PEX13 gene (previous studies) on chromosome 2p15. + +See PBD1A (previous studies) for a phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, which is also caused by mutation in peroxin genes. The rhizomelic chondrodysplasia subtype of PBD (RCDP1, PBD9; previous studies), and a mild PBD without rhizomelia (PBD9B; previous studies), are caused by mutation in the PEX7 gene (previous studies) on chromosome 6q23." +MONDO_0011719,"Definition: Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (previous studies). + +GISTs are also seen as a feature in several syndromes, e.g., neurofibromatosis-1 (NF1; previous studies) and GIST-plus syndrome (previous studies)." +MONDO_0012213,"Definition: SPG26 is an autosomal recessive form of complicated spastic paraplegia characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients have upper limb involvement. Additional features include intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder is slowly progressive (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +Orphanet_101006,"Definition: SPG26 is an autosomal recessive form of complicated spastic paraplegia characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients have upper limb involvement. Additional features include intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder is slowly progressive (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +MONDO_0013127,"Definition: Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by previous studies and previous studies). + +There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, previous studies). + +For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (previous studies)." +MONDO_0013392,"Definition: Autosomal recessive spinocerebellar ataxia-10 is an autosomal recessive neurodegenerative disorder with onset in the teenage or young adult years of gait and limb ataxia, dysarthria, and nystagmus associated with marked cerebellar atrophy on brain imaging (summary by previous studies). Some patients have low levels of coenzyme Q10 (CoQ10) in muscle and may show some clinical improvement with CoQ10 treatment (previous studies)." +MONDO_0030062,"Definition: Arrhythmogenic right ventricular cardiomyopathy/dysplasia-14 (ARVD14) is characterized by palpitations, chest pain, and presyncope. Electrocardiography shows epsilon waves, T-wave inversion across anterior leads, premature ventricular contractions, ventricular tachycardia, and left bundle branch block. Dilation of the right ventricle with hypokinesia and aneurysmal changes are seen on echocardiography. Cardiac MRI may show fibrofatty infiltration, which has been confirmed by endocardial biopsy in some patients. Sudden death may occur (previous studies). + +For a discussion of genetic heterogeneity of ARVD, see ARVD1 (previous studies)." +MONDO_0033363,"Definition: Developmental and epileptic encephalopathy-54 (DEE54) is a severe neurodevelopmental disorder characterized by delayed psychomotor development, early-onset refractory seizures that are often initially febrile but later afebrile, and severe intellectual disability (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0859221,"Definition: Yoon-Bellen neurodevelopmental syndrome (YOBELN) is an autosomal recessive disorder characterized mainly by global developmental delay with variably impaired intellectual development. The manifestations and severity of the phenotype are highly variable. Additional neurologic features may include hypotonia, spasticity, ataxia, hearing loss, visual problems, seizures, and nonspecific anomalies on brain imaging (summary by previous studies)." +Orphanet_1145,"Definition: X-linked spinal muscular atrophy-2 (SMAX2) is characterized by neonatal onset of severe hypotonia, areflexia, and multiple congenital contractures, known as arthrogryposis, associated with loss of anterior horn cells and infantile death (summary by previous studies). + +Historically, previous studies distinguished at least 3 clinical varieties of X-linked arthrogryposis. (1) One family had a severe lethal form with severe contractures, scoliosis, chest deformities, hypotonia, micrognathia, and death from respiratory insufficiency by age 3 months. Apparently progressive loss of anterior horn cells was the cause. (2) Two families had moderately severe AMC associated with ptosis, microphallus, cryptorchidism, inguinal hernias, and normal intelligence. Nonprogressive intrauterine myopathy appeared to be the 'cause'. (3) In 2 families and a sporadic case, the disorder took the form of a resolving AMC, with mild to moderate contractures improving dramatically with time, normal intelligence, and no other anomalies; tight connective tissues on misplaced tendons was postulated." +MONDO_0010532,"Definition: X-linked spinal muscular atrophy-2 (SMAX2) is characterized by neonatal onset of severe hypotonia, areflexia, and multiple congenital contractures, known as arthrogryposis, associated with loss of anterior horn cells and infantile death (summary by previous studies). + +Historically, previous studies distinguished at least 3 clinical varieties of X-linked arthrogryposis. (1) One family had a severe lethal form with severe contractures, scoliosis, chest deformities, hypotonia, micrognathia, and death from respiratory insufficiency by age 3 months. Apparently progressive loss of anterior horn cells was the cause. (2) Two families had moderately severe AMC associated with ptosis, microphallus, cryptorchidism, inguinal hernias, and normal intelligence. Nonprogressive intrauterine myopathy appeared to be the 'cause'. (3) In 2 families and a sporadic case, the disorder took the form of a resolving AMC, with mild to moderate contractures improving dramatically with time, normal intelligence, and no other anomalies; tight connective tissues on misplaced tendons was postulated." +Orphanet_398069,"Definition: SHFYNG syndrome is an autosomal dominant multisystem disorder characterized by delayed psychomotor development, impaired intellectual development, hypotonia, and behavioral abnormalities. Additional features include contractures, feeding difficulties, and variable dysmorphic facial features. The severity of the disorder is highly variable: some patients may die in utero with fetal akinesia, whereas others can live with moderate disability. Some patients may have central endocrine abnormalities, such as growth hormone deficiency or hypothyroidism. Individuals are affected only if the mutation occurs on the paternal allele, since MAGEL2 is a maternally imprinted gene. Some of the features overlap with those observed in Prader-Will syndrome (PWS; previous studies) (summary by previous studies; previous studies)." +MONDO_0008210,"Definition: Patterned dystrophies of the retinal pigment epithelium (RPE) refer to a heterogeneous group of macular disorders, characterized by an abnormal accumulation of lipofuscin in the RPE. The lipofuscin is most apparent in the macular area, and its distribution can show various sizes and shapes. High inter- and intrafamilial variability has been described, and retinitis pigmentosa (RP; see previous studies)-like changes have sometimes been observed in association with patterned dystrophies (summary by previous studies). + +Three main varieties of patterned dystrophy of the RPE have been described: reticular ('fishnet-like') dystrophy (see previous studies and previous studies), macroreticular ('spider-shaped') dystrophy, and butterfly-shaped pigment dystrophy of the fovea. + + Genetic Heterogeneity of Patterned Macular Dystrophy + +Also see MDPT2 (previous studies), caused by mutation in the CTNNA1 gene (previous studies) on chromosome 5q31; and MDPT3 (previous studies), caused by mutation in the MAPKAPK3 gene (previous studies) on chromosome 3p21." +Orphanet_99001,"Definition: Patterned dystrophies of the retinal pigment epithelium (RPE) refer to a heterogeneous group of macular disorders, characterized by an abnormal accumulation of lipofuscin in the RPE. The lipofuscin is most apparent in the macular area, and its distribution can show various sizes and shapes. High inter- and intrafamilial variability has been described, and retinitis pigmentosa (RP; see previous studies)-like changes have sometimes been observed in association with patterned dystrophies (summary by previous studies). + +Three main varieties of patterned dystrophy of the RPE have been described: reticular ('fishnet-like') dystrophy (see previous studies and previous studies), macroreticular ('spider-shaped') dystrophy, and butterfly-shaped pigment dystrophy of the fovea. + + Genetic Heterogeneity of Patterned Macular Dystrophy + +Also see MDPT2 (previous studies), caused by mutation in the CTNNA1 gene (previous studies) on chromosome 5q31; and MDPT3 (previous studies), caused by mutation in the MAPKAPK3 gene (previous studies) on chromosome 3p21." +MONDO_0009063,"Definition: Ventriculomegaly with cystic kidney disease is a severe autosomal recessive developmental disorder characterized by onset in utero of dilated cerebral ventricles and microscopic renal tubular cysts. The pregnancies of affected individuals are associated with increased alpha-fetoprotein (AFP). Most affected pregnancies have been terminated (summary by previous studies). + +See also previous studies for a disorder characterized by ventriculomegaly and defects of the radius and kidney." +MONDO_0009115,Definition: Congenital lactase deficiency is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. +MONDO_0010161,"Definition: Hereditary tyrosinemia type I is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The disorder is characterized by progressive liver disease and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. Onset varies from infancy to adolescence. In the most acute form patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinemia. Untreated, patients die from cirrhosis or hepatocellular carcinoma at a young age (summary by previous studies). + + Genetic Heterogeneity of Hereditary Tyrosinemia + +Tyrosinemia type II (TYRSN2; previous studies), also known as Richner-Hanhart syndrome, is caused by mutation in the TAT gene (previous studies) on chromosome 16q22. Tyrosinemia type III (TYRNS3; previous studies) is caused by mutation in the HPD gene (previous studies) on chromosome 12q24." +Orphanet_882,"Definition: Hereditary tyrosinemia type I is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The disorder is characterized by progressive liver disease and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. Onset varies from infancy to adolescence. In the most acute form patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinemia. Untreated, patients die from cirrhosis or hepatocellular carcinoma at a young age (summary by previous studies). + + Genetic Heterogeneity of Hereditary Tyrosinemia + +Tyrosinemia type II (TYRSN2; previous studies), also known as Richner-Hanhart syndrome, is caused by mutation in the TAT gene (previous studies) on chromosome 16q22. Tyrosinemia type III (TYRNS3; previous studies) is caused by mutation in the HPD gene (previous studies) on chromosome 12q24." +MONDO_0010284,"Definition: MRXSA is an X-linked recessive neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, usually accompanied by walking difficulties and poor or absent speech. Affected individuals have dysmorphic features, including large head circumference, downslanting palpebral fissures, bulbous nose, high-arched palate, short stature, and small hands and feet. Ocular anomalies, including strabismus, exotropia, myopia, and keratoconus, are common. Some patients may develop seizures. Additional variable features, such as mild congenital heart defects, joint stiffness, renal anomalies, and hemangiomas, may also be present (summary by previous studies)." +MONDO_0013081,"Definition: Lymphoproliferative syndrome-1 is an autosomal recessive primary immunodeficiency characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinemia. Autoimmune disorders, such as autoimmune hemolytic anemia or renal disease, may also occur. Patients show a high EBV viral load and decreased invariant natural killer T cells. It is unknown whether patients with ITK mutations are intrinsically susceptible to development of lymphoma or dysgammaglobulinemia in the absence of EBV infection (summary by previous studies; previous studies). + +For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (previous studies)." +MONDO_0013523,"Definition: Nestor-Guillermo progeria syndrome (NGPS) is an autosomal recessive disorder characterized by lipoatrophy, osteoporosis, and very severe osteolysis. Patients have no cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia, but suffer profound skeletal abnormalities that affect their quality of life. Onset is after 2 years of age, and lifespan is relatively long (summary by previous studies)." +MONDO_0013536,"Definition: Heme oxygenase-1 deficiency (HMOX1D) is a rare autosomal recessive disorder with a complex clinical presentation including direct antibody negative hemolytic anemia, low bilirubin, and hyperinflammation (summary by previous studies). Other features may include asplenia and nephritis (previous studies)." +MONDO_0018820,"Definition: Recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) is an autosomal recessive disorder characterized by episodic metabolic degeneration affecting skeletal muscle, cardiac muscle, and the nervous system. Affected individuals usually present in childhood with acute encephalomyopathic features, including rhabdomyolysis, hypotonia, and neurologic regression, although most patients have delayed psychomotor development before the acute onset. The overall disease course is characterized by progressive neurodegeneration with epilepsy, cognitive impairment, pyramidal and cerebellar signs, and loss of expressive language. Cardiac involvement with severe arrhythmias is a consistent and potentially life-threatening manifestation (summary by previous studies and previous studies)." +MONDO_0033542,"Definition: Immunodeficiency-70 (IMD70) is an autosomal dominant immunologic disorder characterized by severe cutaneous warts on the hands, feet, and face, suggesting increased susceptibility to human papillomavirus (HPV) infection. Affected individuals may also have recurrent bacterial infections, such as sinusitis, as well as feature of autoinflammation, such as colitis, celiac disease, and retinal vasculitis. Laboratory studies show decreased CD4+ T cells and decreased CD19+ B cells; hypogammaglobulinemia has also been observed (summary by previous studies)." +Orphanet_168612,Definition: Alpha-fetoprotein deficiency appears to be a benign genetic trait (previous studies; previous studies). +EFO_0000621,"Definition: Neuroblastoma is the most common childhood cancer diagnosed before the age of 1 year, and accounts for 10 to 15% of all cancer deaths in children. Some patients inherit a genetic predisposition to neuroblastoma due to germline mutations, whereas others develop sporadic disease that may result from either germline or somatic mutations. Neuroblastoma tumors are derived from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system (previous studies; previous studies). Histopathologically, neuroblastoma can range in type from the most aggressive form, neuroblastoma, composed entirely of immature neural precursor cells, to ganglioneuroma, composed entirely of mature neural tissue. The most important prognostic factor for patients with neuroblastoma is the extent of the tumor at the time of diagnosis (previous studies). + +Neuroblastoma can also be part of cancer-prone syndromes, such as paragangliomas (see, e.g., PGL4; previous studies). + + Genetic Heterogeneity of Susceptibility to Neuroblastoma + +Susceptibility to neuroblastoma is genetically heterogeneous and is conferred by mutation in the PHOX2B gene (previous studies) on chromosome 4p12 (NBLST2; previous studies) and by mutation in the ALK gene (previous studies) on chromosome 2p23 (NBLST3; previous studies). + +Loci implicated in the development of neuroblastoma include 6p (NBLST4; previous studies), 2q35 (NBLST5; previous studies), and 1q21 (NBLST6; previous studies)." +MONDO_0007201,"Definition: BPES syndrome includes a characteristic eyelid dysplasia, namely, small palpebral fissures (blepharophimosis), drooping eyelids (ptosis), and a tiny skin fold running inward and upward from the lower lid (epicanthus inversus). In type I BPES, the eyelid abnormalities are coinherited with ovarian failure; type II BPES consists of the eyelid defects only (summary by previous studies)." +MONDO_0008737,"Definition: Inherited disorders of fibrinogen affect either the quantity (afibrinogenemia and hypofibrinogenemia; previous studies) or the quality (dysfibrinogenemia; previous studies) of the circulating fibrinogen or both (hypodysfibrinogenemia; see previous studies). Afibrinogenemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial hemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. Menstruating women may experience menometrorrhagia. First-trimester abortion is common. Both arterial and venous thromboembolic complications have been reported (summary by previous studies). + +Hypofibrinogenemia is characterized by reduced amounts of immunoreactive fibrinogen. Patients are often heterozygous carriers of afibrinogenemia mutations and are usually asymptomatic. However, they may bleed when exposed to trauma or if they have a second associated hemostatic abnormality. Women may experience miscarriages. Liver disease occurs in rare cases (summary by previous studies)." +Orphanet_98880,"Definition: Inherited disorders of fibrinogen affect either the quantity (afibrinogenemia and hypofibrinogenemia; previous studies) or the quality (dysfibrinogenemia; previous studies) of the circulating fibrinogen or both (hypodysfibrinogenemia; see previous studies). Afibrinogenemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial hemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. Menstruating women may experience menometrorrhagia. First-trimester abortion is common. Both arterial and venous thromboembolic complications have been reported (summary by previous studies). + +Hypofibrinogenemia is characterized by reduced amounts of immunoreactive fibrinogen. Patients are often heterozygous carriers of afibrinogenemia mutations and are usually asymptomatic. However, they may bleed when exposed to trauma or if they have a second associated hemostatic abnormality. Women may experience miscarriages. Liver disease occurs in rare cases (summary by previous studies)." +MONDO_0008869,"Definition: Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance (previous studies). + + Genetic Heterogeneity of Seckel Syndrome + +Other forms of Seckel syndrome include SCKL2 (previous studies), caused by mutation in the RBBP8 gene (previous studies) on chromosome 18q11; SCKL4 (previous studies), caused by mutation in the CENPJ gene (previous studies) on chromosome 13q12; SCKL5 (previous studies), caused by mutation in the CEP152 gene (previous studies) on chromosome 15q21; SCKL6 (previous studies), caused by mutation in the CEP63 gene (previous studies) on chromosome 3q22; SCKL7 (previous studies), caused by mutation in the NIN gene (previous studies) on chromosome 14q22; SCKL8 (previous studies), caused by mutation in the DNA2 gene (previous studies) on chromosome 10q21; SCKL9 (previous studies), caused by mutation in the TRAIP gene (previous studies) on chromosome 3p21; and SCKL10 (previous studies), caused by mutation in the NSMCE2 gene (previous studies) on chromosome 8q24. + +The report of a Seckel syndrome locus on chromosome 14q, designated SCKL3, by previous studies was found to be in error; see History section." +MONDO_0010222,"Definition: Opitz GBBB syndrome (GBBB) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay, and cardiac defects (previous studies)." +MONDO_0011997,"Definition: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. HPS2 differs from the other forms of HPS in that it includes immunodeficiency, and patients with HPS2 have an increased susceptibility to infections due to congenital neutropenia (previous studies)." +Orphanet_183678,"Definition: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. HPS2 differs from the other forms of HPS in that it includes immunodeficiency, and patients with HPS2 have an increased susceptibility to infections due to congenital neutropenia (previous studies)." +MONDO_0013986,"Definition: COXPD14 is a severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes. Neuropathologic studies in 1 patient showed laminar cortical necrosis, characteristic of Alpers syndrome (previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0014637,"Definition: Immunodeficiency-40 is an autosomal recessive primary form of combined immunodeficiency mainly affecting T-cell number and function, with other more variable defects in B-cell and NK-cell function. Patients have onset of severe invasive bacterial and viral infections in early childhood and may die without bone marrow transplantation (summary by previous studies)." +MONDO_0015023,"Definition: Congenital myopathy-24 (CMYP24) is an autosomal recessive congenital myopathy characterized by onset of slowly progressive muscle weakness in the first decade. Affected individuals present with gait difficulties due to proximal muscle weakness and atrophy mainly affecting the lower limbs and neck. Muscle biopsy shows nemaline bodies. Some patients may have mild cardiac or respiratory involvement, but they do not have respiratory failure (summary by previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see previous studies. + +For a discussion of genetic heterogeneity of nemaline myopathy, see previous studies." +MONDO_0030134,"Definition: Oculopharyngodistal myopathy-2 (OPDM2) is an autosomal dominant muscle disorder characterized by onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. The disorder is slowly progressive, and patients develop facial weakness, bulbar weakness, and difficulty walking or climbing stairs. Some patients may have upper limb involvement and subclinical respiratory insufficiency. Laboratory studies show increased serum creatine kinase; skeletal muscle biopsy shows myopathic changes with abnormal cytoplasmic and intranuclear inclusions (summary by previous studies). + +For a discussion of genetic heterogeneity of OPDM, see OPDM1 (previous studies)." +MONDO_0030768,"Definition: Intermediate junctional epidermolysis bullosa 5A (JEB5A) is an autosomal recessive blistering disease of skin and mucous membranes. Blistering is less severe than in severe JEB (see previous studies). The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Nails may be dystrophic and dental enamel defects are present. Blistering does not affect the life span of affected individuals (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +MONDO_0030867,"Definition: Thrombocytopenia-7 (THC7) is an autosomal dominant disorder characterized by reduced peripheral platelet count. The expression and severity of the disorder is highly variable: some patients have no bleeding symptoms, whereas other have recurrent petechiae, epistaxis, or more severe bleeding episodes. A common finding is decreased alpha-granules in the platelets. There are variable findings on light and electron microscopic analysis: some patients have normal platelet morphology, whereas others show abnormal platelet morphology with cytoskeletal defects. Flow cytometric studies may show reduced expression of platelet membrane glycoproteins and activation markers (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see previous studies." +MONDO_0100058,"Definition: Hypervalinemia and hyperleucine-isoleucinemia (HVLI) is a branched-chain amino acid metabolic disorder characterized by highly elevated plasma valine and leucine concentrations. The patient presented in adulthood with headache and mild memory impairment, and had abnormal symmetric white matter signals on brain MRI (previous studies)." +EFO_0010655,"Definition: Congenital megabladder (MGBL) is characterized by a massively dilated bladder with disrupted smooth muscle in the bladder wall. MGBL is a sex-limited trait with 95% male predominance, likely the result of differences in urethra and bladder development and length differences in urethra between males and females (previous studies)." +MONDO_0007072,"Definition: ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome is characterized by ectrodactyly, syndactyly, fingernail and toenail dysplasia, hypoplasia of the breast and nipple, excessive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, and/or early loss of permanent teeth (summary by previous studies)." +MONDO_0008267,"Definition: Orofaciodigital syndrome V (OFD5) is an autosomal recessive disorder characterized by cleft palate/uvula, lobulated tongue, frontal bossing, hypertelorism, postaxial polydactyly, and impaired intellectual development (summary by previous studies)." +Orphanet_2919,"Definition: Orofaciodigital syndrome V (OFD5) is an autosomal recessive disorder characterized by cleft palate/uvula, lobulated tongue, frontal bossing, hypertelorism, postaxial polydactyly, and impaired intellectual development (summary by previous studies)." +MONDO_0009821,"Definition: Raine syndrome (RNS) is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by previous studies). Some patients survive infancy (previous studies; previous studies)." +MONDO_0010397,"Definition: The MECP2 gene is mutated in Rett syndrome (RTT; previous studies), a severe neurodevelopmental disorder that almost always occurs in females. Although it was first thought that MECP2 mutations causing Rett syndrome were lethal in males, later reports identified a severe neonatal encephalopathy in surviving male sibs of patients with Rett syndrome. Since then, additional reports have confirmed a severe phenotype in males with RTT-associated MECP2 mutations (previous studies; previous studies). + +Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes: see also nonspecific X-linked mental retardation, X-linked mental retardation with spasticity (previous studies), and X-linked mental retardation due to increased dosage of the MECP2 gene (previous studies)." +MONDO_0012345,"Definition: Peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis. In an acral form of the disorder (PSS2), the dorsa of the hands and feet are predominantly affected, and ultrastructural analysis shows separation at the junction between the granular cells and the stratum corneum in the outer epidermis (summary by previous studies). + +For a discussion of genetic heterogeneity of peeling skin syndrome, see PSS1 (previous studies)." +MONDO_0012481,"Definition: Mevalonic aciduria (MEVA), the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; previous studies). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (previous studies). + +Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; previous studies), which is also caused by mutation in the MVK gene (summary by previous studies)." +MONDO_0012622,"Definition: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (previous studies). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline." +Orphanet_137898,"Definition: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (previous studies). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline." +MONDO_0013189,"Definition: Trichotillomania (TTM) is a neuropsychiatric disorder characterized by chronic, repetitive, or compulsive hair pulling resulting in noticeable hair loss. The activity causes distress to the individual and often interferes with functioning. Affected individuals may develop physical complications and often have overlapping psychologic disorders, such as Tourette syndrome (GTS; previous studies) or obsessive-compulsive disorder (OCD; previous studies) (review by previous studies)." +MONDO_0014347,"Definition: Short stature with microcephaly and distinctive facies is characterized by pre- or postnatal growth retardation, frontal bossing, high forehead, sparse hair and eyebrows, and telecanthus. Patients also show skin dyspigmentation, with hyper- and/or hypopigmented areas (previous studies)." +MONDO_0025351,"Definition: X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade. Pathogenetically, the disorder results from disrupted gene expression and signaling during embryogenesis, thus affecting multiple systems (summary by previous studies and previous studies). previous studies referred to the disorder as LINKED syndrome (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects)." +MONDO_0030531,"Definition: Spermatogenic failure-65 (SPGF65) is characterized by male infertility due to asthenoteratozoospermia. Progressive sperm motility is severely reduced or absent, and patients exhibit multiple morphologic abnormalities of the flagella (MMAF), including coiled, irregular-caliber, short, and absent flagella. Abnormalities of the flagellar midpiece are also present (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of SPGF, see SPGF1 (previous studies)." +MONDO_0030947,"Definition: Childhood-onset neurodegeneration with hypotonia, respiratory insufficiency, and brain imaging abnormalities (CONRIBA) is characterized by severe global developmental delay apparent in infancy or early childhood. Affected individuals have hypotonia with impaired motor development, respiratory insufficiency, and feeding difficulties requiring intervention. Intellectual and speech development is also delayed, and most have visual defects, including cortical visual blindness, nystagmus, and esotropia. The disorder is progressive, as manifest by developmental regression consistent with neurodegeneration. Although overt seizures are not observed, some patients may have episodic hypertonia or apnea, and EEG may show nonspecific abnormalities. Brain imaging shows unique diffusion restriction signal abnormalities affecting the brainstem, cerebellum, and corticospinal tracts. Early death may occur (summary by previous studies)." +MONDO_0032787,"Definition: Holoprosencephaly-12 with or without pancreatic agenesis (HPE12) is a developmental disorder characterized by abnormal separation of the embryonic forebrain (HPE) resulting in dysmorphic facial features and often, but not always, impaired neurologic development. Most patients with this form of HPE also have congenital absence of the pancreas, resulting in early-onset type 1 diabetes mellitus and requiring pancreatic enzyme replacement. Other features may include hearing loss and absence of the gallbladder (summary by previous studies and previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (previous studies)." +MONDO_0033622,"Definition: Spermatogenic failure-44 (SPGF44) is characterized by male infertility due to headless sperm in the ejaculate (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0859234,"Definition: Autosomal recessive agammaglobulinemia-8B (AGM8B) is characterized by onset of recurrent infections in early childhood. Laboratory studies of affected individuals show decreased circulating immunoglobulins and decreased peripheral B cells. More variable features may include dysmorphic facies and subtle abnormalities of other immune cells, such as T cells. One patient who developed childhood B-cell acute lymphocytic leukemia (B-ALL) has been described (summary by previous studies)." +Orphanet_1344,"Definition: Atrial standstill (AS) is a rare condition characterized by the absence of electrical and mechanical activity in the atria. On surface ECG, AS is distinguished by bradycardia, junctional (usually narrow complex) escape rhythm, and absence of the P wave. Nearly 50% of patients with AS experience syncope. AS can be persistent or transient, and diffuse or partial (summary by previous studies)." +Orphanet_240,"Definition: Leri-Weill dyschondrosteosis (LWD) is a dominantly inherited skeletal dysplasia characterized by short stature, mesomelia, and Madelung wrist deformity. Although the disorder occurs in both sexes, it is usually more severe in females, perhaps due to sex difference in estrogen levels. However, pubertal development and fertility are generally normal in both sexes with the disorder (summary by previous studies). The Madelung wrist deformity includes deformity of the distal radius and ulna and proximal carpal bones (previous studies). + +See also Langer mesomelic dysplasia (LMD; previous studies), a more severe phenotype that results from homozygous defect in the SHOX or SHOXY genes." +MONDO_0007481,"Definition: Leri-Weill dyschondrosteosis (LWD) is a dominantly inherited skeletal dysplasia characterized by short stature, mesomelia, and Madelung wrist deformity. Although the disorder occurs in both sexes, it is usually more severe in females, perhaps due to sex difference in estrogen levels. However, pubertal development and fertility are generally normal in both sexes with the disorder (summary by previous studies). The Madelung wrist deformity includes deformity of the distal radius and ulna and proximal carpal bones (previous studies). + +See also Langer mesomelic dysplasia (LMD; previous studies), a more severe phenotype that results from homozygous defect in the SHOX or SHOXY genes." +Orphanet_320406,"Definition: Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive spastic paraplegia resulting in loss of independent ambulation in the teenage years. Additional features include optic atrophy, later onset of sensorimotor peripheral neuropathy, and progressive joint contractures; cognition remains intact (summary by previous studies)." +MONDO_0012297,"Definition: Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive spastic paraplegia resulting in loss of independent ambulation in the teenage years. Additional features include optic atrophy, later onset of sensorimotor peripheral neuropathy, and progressive joint contractures; cognition remains intact (summary by previous studies)." +EFO_0009045,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +Clinical features of FANCF include microcephaly, small or absent thumbs, short stature, microphthalmia, microtia, hearing loss, pigmentary anomalies (cafe-au-lait spots or hyperpigmentation), small or pelvic kidneys, and cardiac anomalies (previous studies; previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0007182,"Definition: Machado-Joseph disease, named for affected families of Azorean extraction, is an autosomal dominant progressive neurologic disorder characterized principally by ataxia, spasticity, and ocular movement abnormalities. Although independently described as a seemingly separate disorder, spinocerebellar ataxia-3 is now known to be the same as Machado-Joseph disease. + +Three classic clinical subtypes of MJD are recognized: type 1 with early onset and marked pyramidal and dystonic signs; type 2, or pure, with predominant cerebellar ataxia; and type 3 with later-onset and peripheral neuropathy (previous studies)." +Orphanet_98757,"Definition: Machado-Joseph disease, named for affected families of Azorean extraction, is an autosomal dominant progressive neurologic disorder characterized principally by ataxia, spasticity, and ocular movement abnormalities. Although independently described as a seemingly separate disorder, spinocerebellar ataxia-3 is now known to be the same as Machado-Joseph disease. + +Three classic clinical subtypes of MJD are recognized: type 1 with early onset and marked pyramidal and dystonic signs; type 2, or pure, with predominant cerebellar ataxia; and type 3 with later-onset and peripheral neuropathy (previous studies)." +MONDO_0007537,"Definition: Lateral meningocele syndrome is a rare disorder characterized by distinctive facial features, hyperextensibility, hypotonia, and characteristic lateral meningoceles, which can result in neurologic complications such as bladder dysfunction and neuropathy. Dysmorphic features include dolichocephaly, hypertelorism, ptosis, microretrognathia, high-arched palate, long, flat philtrum, and low-set ears. Multiple additional variable features may also be observed, including cryptorchidism, vertebral anomalies, and connective tissue abnormalities. Early motor development is delayed, but cognition is usually normal (summary by previous studies)." +MONDO_0008082,"Definition: Multiple endocrine neoplasia type IIB (MEN2B) is an autosomal dominant hamartoneoplastic syndrome characterized by aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and thickened corneal nerves. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus. Other more variable features include skeletal anomalies and gastrointestinal problems (review by previous studies). + +For a discussion of genetic heterogeneity of multiple endocrine neoplasia (MEN), see MEN1 (previous studies)." +MONDO_0011291,"Definition: Congenital disorders of glycosylation, previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are caused by defects in mannose addition during N-linked oligosaccharide assembly. CDGs can be divided into 2 types, depending on whether they impair lipid-linked oligosaccharide (LLO) assembly and transfer (CDG I), or affect trimming of the protein-bound oligosaccharide or the addition of sugars to it (CDG II) (previous studies). + +CDG Ic is characterized by psychomotor retardation with delayed walking and speech, hypotonia, seizures, and sometimes protein-losing enteropathy. It is the second largest subtype of CDG (summary by previous studies). + +For a discussion of the classification of CDGs, see CDG1A (previous studies). + +previous studies reviewed CDG Ib (previous studies) and CDG Ic." +MONDO_0011468,"Definition: HMSNO is an autosomal dominant neurodegenerative disorder characterized by young adult onset of proximal or distal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. The disorder is slowly progressive and clinically resembles amyotrophic lateral sclerosis (ALS; see previous studies) (summary by previous studies)." +MONDO_0012251,"Definition: MEDNIK syndrome is a severe multisystem disorder characterized by impaired intellectual development, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (summary by previous studies). + +Patients with MEDNIK exhibit distinct dysmorphic features, including high forehead, upslanting palpebral fissures, depressed nasal bridge, and low-set ears, as well as growth retardation and moderate to severe mental retardation, with brain atrophy on imaging. Other features include sensorineural deafness, enteropathy with congenital diarrhea, abnormalities of copper metabolism associated with liver disease, and ichthyosis, hyperkeratosis, and erythroderma. Peripheral neuropathy has also been observed in adult patients (previous studies). + +MEDNIK syndrome shows phenotypic similarities to CEDNIK syndrome (previous studies)." +MONDO_0012791,"Definition: Mitochondrial DNA depletion syndrome-5 is an autosomal recessive disorder characterized by infantile onset of hypotonia, progressive neurologic deterioration, a hyperkinetic-dystonic movement disorder, external ophthalmoplegia, deafness, and variable renal tubular dysfunction. Laboratory studies often show mild methylmalonic aciduria (previous studies). + +For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0013187,"Definition: Factor XIII deficiency is an autosomal recessive hematologic disorder characterized by increased bleeding and poor wound healing. Most cases of congenital factor XIII deficiency result from mutation in the A subunit (previous studies). + +previous studies proposed a classification of factor XIII deficiency: XIIIA deficiency (formerly 'type II' F13 deficiency) and XIIIB deficiency (formerly 'type I' F13 deficiency), as well as a possible combined deficiency of the 2." +MONDO_0014969,Definition: SHPK deficiency is an autosomal recessive inborn error of metabolism characterized by increased urinary erythritol and sedoheptulose. Additional phenotypic consequences of this deficiency are unclear (summary by previous studies). +MONDO_0032805,"Definition: Hypopigmentation, organomegaly, and delayed myelination and development (HOD) is characterized by hypopigmented skin and hair with normally pigmented irides; organomegaly including enlargement of liver, kidney, and spleen; and delayed myelination on brain MRI accompanied by developmental delay in both gross and fine motor skills. Biopsy findings from skin and other organs are consistent with a lysosomal storage disorder (previous studies)." +Orphanet_75496,"Definition: The features of Ehlers-Danlos syndrome spondylodysplastic type 2 (EDSSPD2) include an aged appearance, developmental delay, short stature, craniofacial disproportion, generalized osteopenia, defective wound healing, hypermobile joints, hypotonic muscles, and loose but elastic skin (previous studies). + +For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see previous studies." +Orphanet_79402,"Definition: Intermediate junctional epidermolysis bullosa 1A (JEB1A) is an autosomal recessive blistering disease of skin and mucous membranes. Generalized trauma-induced blistering occurs from birth. Blistering is less severe than in severe JEB (see previous studies), usually without the tendency for developing chronic granulation tissue. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Nail dystrophy or loss and dental enamel defects are present. Scarring or nonscarring alopecia and diffuse hair loss may occur (summary by previous studies). Blistering does not affect the life span of affected individuals (previous studies; previous studies). + + Genetic Heterogeneity of Junctional Epidermolysis Bullosa + +Another form of JEB that is caused by mutation in the LAMB3 gene is severe JEB1B (previous studies). + +Forms of JEB caused by mutation in the LAMA3 gene (previous studies) are intermediate JEB2A (previous studies), severe JEB2B (previous studies), and laryngoonychocutaneous JEB2C (previous studies). + +Forms of JEB caused by mutation in the LAMC2 gene (previous studies) are intermediate JEB3A (previous studies) and severe JEB3B (previous studies). + +Intermediate JEB4 (previous studies) is caused by mutation in the COL17A1 gene (previous studies). + +Forms of JEB caused by mutation in the ITGB4 gene (previous studies) are intermediate JEB5A (previous studies) and JEB with pyloric atresia (JEB5B; previous studies). + +Another form of JEB that includes pyloric atresia (JEB6; previous studies) is caused by mutation in the ITGA6 gene (previous studies). + +JEB with interstitial lung disease and nephrotic syndrome (JEB7; previous studies), also known as interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB), is caused by mutation in the ITGA3 gene (previous studies). + + Reviews + +previous studies reviewed the pathophysiology and phenotypic and genetic heterogeneity of epidermolysis bullosa." +MONDO_0009180,"Definition: Intermediate junctional epidermolysis bullosa 1A (JEB1A) is an autosomal recessive blistering disease of skin and mucous membranes. Generalized trauma-induced blistering occurs from birth. Blistering is less severe than in severe JEB (see previous studies), usually without the tendency for developing chronic granulation tissue. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Nail dystrophy or loss and dental enamel defects are present. Scarring or nonscarring alopecia and diffuse hair loss may occur (summary by previous studies). Blistering does not affect the life span of affected individuals (previous studies; previous studies). + + Genetic Heterogeneity of Junctional Epidermolysis Bullosa + +Another form of JEB that is caused by mutation in the LAMB3 gene is severe JEB1B (previous studies). + +Forms of JEB caused by mutation in the LAMA3 gene (previous studies) are intermediate JEB2A (previous studies), severe JEB2B (previous studies), and laryngoonychocutaneous JEB2C (previous studies). + +Forms of JEB caused by mutation in the LAMC2 gene (previous studies) are intermediate JEB3A (previous studies) and severe JEB3B (previous studies). + +Intermediate JEB4 (previous studies) is caused by mutation in the COL17A1 gene (previous studies). + +Forms of JEB caused by mutation in the ITGB4 gene (previous studies) are intermediate JEB5A (previous studies) and JEB with pyloric atresia (JEB5B; previous studies). + +Another form of JEB that includes pyloric atresia (JEB6; previous studies) is caused by mutation in the ITGA6 gene (previous studies). + +JEB with interstitial lung disease and nephrotic syndrome (JEB7; previous studies), also known as interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB), is caused by mutation in the ITGA3 gene (previous studies). + + Reviews + +previous studies reviewed the pathophysiology and phenotypic and genetic heterogeneity of epidermolysis bullosa." +Orphanet_927,"Definition: N-acetylglutamate synthase deficiency is an autosomal recessive disorder of the urea cycle. The clinical and biochemical features of the disorder are indistinguishable from carbamoyl phosphate synthase I deficiency (previous studies), since the CPS1 enzyme (previous studies) has an absolute requirement for NAGS (previous studies)." +MONDO_0009377,"Definition: N-acetylglutamate synthase deficiency is an autosomal recessive disorder of the urea cycle. The clinical and biochemical features of the disorder are indistinguishable from carbamoyl phosphate synthase I deficiency (previous studies), since the CPS1 enzyme (previous studies) has an absolute requirement for NAGS (previous studies)." +EFO_1000453,"Definition: Paragangliomas-6 (PGL6) is an adult-onset tumor predisposition syndrome in which affected individuals develop neuroendocrine neoplasms, known as paragangliomas. Many tumors arise in the abdomen, although some may arise in other regions, including the head and neck. Some of the tumors may secrete biologically active normetanephrines, resulting in secondary hypertension. Tumors may be benign or malignant, and some may metastasize (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of familial paragangliomas, see PGL1 (previous studies)." +MONDO_0007451,"Definition: Nephrogenic diabetes insipidus (NDI) is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopressin (AVP; previous studies). Approximately 90% of patients are males with the X-linked recessive form, type I (NDI1; previous studies), which is caused by mutation in the gene encoding the vasopressin V2 receptor (AVPR2; previous studies). The remaining 10% of patients have the autosomal form, type II (NDI2), caused by mutation in the AQP2 gene (previous studies). + +Neurogenic, or central, diabetes insipidus (CDI; previous studies) is caused by mutation in the gene encoding arginine vasopressin, located on 20p13." +MONDO_0007818,"Definition: Hyper-IgE recurrent infection syndrome is a primary immunodeficiency disorder characterized by chronic eczema, recurrent Staphylococcal infections, increased serum IgE, and eosinophilia. Other more variable immunologic abnormalities include defective granulocyte chemotaxis, abnormalities in T-lymphocyte subgroups, impaired antibody production, and decreased production of or response to certain cytokines. Importantly, the same immune system defects are not found in all patients. Some patients may have a distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures (previous studies; previous studies). + + Genetic Heterogeneity of Hyper-IgE Recurrent Infection Syndrome + +See also HIES2 (previous studies), caused by mutation in the DOCK8 gene (previous studies), HIES3 (previous studies), caused by mutation in the ZNF341 gene (previous studies), HIES4A (previous studies) and HIES4B (previous studies), both caused by mutation in the IL6ST gene (previous studies), and HIES5 (previous studies), caused by mutation in the IL6R gene (previous studies)." +Orphanet_2314,"Definition: Hyper-IgE recurrent infection syndrome is a primary immunodeficiency disorder characterized by chronic eczema, recurrent Staphylococcal infections, increased serum IgE, and eosinophilia. Other more variable immunologic abnormalities include defective granulocyte chemotaxis, abnormalities in T-lymphocyte subgroups, impaired antibody production, and decreased production of or response to certain cytokines. Importantly, the same immune system defects are not found in all patients. Some patients may have a distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures (previous studies; previous studies). + + Genetic Heterogeneity of Hyper-IgE Recurrent Infection Syndrome + +See also HIES2 (previous studies), caused by mutation in the DOCK8 gene (previous studies), HIES3 (previous studies), caused by mutation in the ZNF341 gene (previous studies), HIES4A (previous studies) and HIES4B (previous studies), both caused by mutation in the IL6ST gene (previous studies), and HIES5 (previous studies), caused by mutation in the IL6R gene (previous studies)." +MONDO_0008723,"Definition: Inborn errors of mitochondrial fatty acid beta-oxidation include medium-chain acyl-CoA dehydrogenase deficiency (ACADMD; previous studies), short-chain acyl-CoA dehydrogenase deficiency (ACADSD; previous studies), and very long-chain acyl-CoA dehydrogenase deficiency. + +VLCAD deficiency can be classified clinically into 3 forms: a severe early-onset form with high incidence of cardiomyopathy and high mortality; an intermediate form with childhood onset, usually with hypoketotic hypoglycemia and more favorable outcome; and an adult-onset, myopathic form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria after exercise or fasting (previous studies). + +Patients reported with long-chain acyl-CoA dehydrogenase (LCAD) deficiency before VLCAD deficiency was defined were later found to have VLCAD deficiency (previous studies; previous studies)." +MONDO_0008853,"Definition: Barber-Say syndrome is a rare congenital condition characterized by severe hypertrichosis, especially of the back, skin abnormalities such as hyperlaxity and redundancy, and facial dysmorphism, including macrostomia, eyelid deformities, ocular telecanthus, abnormal and low-set ears, bulbous nasal tip with hypoplastic alae nasi, and low frontal hairline (summary by previous studies)." +MONDO_0008887,"Definition: Bronchiectasis with or without elevated sweat chloride-1 (BESC1) is characterized by dilation of the airways arising from chronic bronchial inflammation accompanied by chronic cough, purulent sputum, and recurrent respiratory tract infections. Severity is variable, and some patients may be identified in adulthood and have normal respiratory function (previous studies, previous studies). + + Genetic Heterogeneity of Bronchiectasis with or without Elevated Sweat Chloride + +Bronchiectasis with or without elevated sweat chloride-2 (BESC2; previous studies) is caused by mutation in the gene encoding the alpha subunit of the epithelial sodium channel (SCNN1A; previous studies) on chromosome 12p13, and BESC3 (previous studies) is caused by mutation in the gene encoding the gamma subunit (SCNN1G; previous studies) on chromosome 16p12. + +Bronchiectasis and elevated sweat chloride associated with pancreatic exocrine dysfunction and infertility are also features of cystic fibrosis (CF; previous studies), which is caused by mutation in the CFTR gene (previous studies)." +MONDO_0009779,"Definition: Omodysplasia-1 (OMOD1) is a rare autosomal recessive skeletal dysplasia characterized by severe congenital micromelia with shortening and distal tapering of the humeri and femora to give a club-like appearance. Typical facial features include a prominent forehead, frontal bossing, short nose with a depressed broad bridge, short columella, anteverted nostrils, long philtrum, and small chin. Variable findings are cryptorchidism, hernias, congenital heart defects, and cognitive delay (previous studies; previous studies). + + Genetic Heterogeneity of Omodysplasia + +Also see omodysplasia-2 (OMOD2; previous studies), an autosomal dominant form of the disorder in which abnormalities are limited to the upper limbs. The facial changes and typical growth defect of the distal humerus with complex deformity of the elbows appear to be similar in both entities (previous studies)." +MONDO_0010092,"Definition: Filippi syndrome is characterized by short stature, microcephaly, syndactyly, intellectual disability, and facial dysmorphism consisting of bulging forehead, broad and prominent nasal bridge, and diminished alar flare. Common features include cryptorchidism, speech impairment, and clinodactyly of the fifth finger, Some patients exhibit visual disturbances, polydactyly, seizures, and/or ectodermal abnormalities, such as nail hypoplasia, long eyelashes, hirsutism, and microdontia (summary by previous studies)." +MONDO_0011638,"Definition: Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, cognitive involvement, and mode of inheritance is variable (review by previous studies)." +MONDO_0013049,"Definition: Limb-girdle muscular dystrophy-dystroglycanopathy type C15 (MDDGC15) is an autosomal recessive disorder characterized by progressive proximal muscle weakness, manifest initially as unsteady gait, but later including more distal muscles, and dilated cardiomyopathy. The age at onset varies widely from the first decade to adulthood; those with earlier onset may have delayed motor development. Laboratory studies show increased serum creatine kinase and muscle biopsy shows dystrophic features with decreased alpha-dystroglycan (DAG1; previous studies). Biochemical studies often show evidence of abnormal N-glycosylation of serum proteins, consistent with a congenital disorder of glycosylation (CDG) (summary by previous studies). + +For a discussion of genetic heterogeneity of muscular dystrophy- dystroglycanopathy type C, see MDDGC1 (previous studies). + +For a discussion of the classification of CDGs, see CDG1A (previous studies)." +MONDO_0030258,"Definition: Pontocerebellar hypoplasia type 14 (PCH14) is a severe autosomal recessive neurodevelopmental disorder characterized by congenital onset of progressive microcephaly and poor or absent psychomotor development with severely impaired intellectual development apparent from birth. Other features may include hypotonia, spastic quadriplegia, and early-onset seizures. Brain imaging shows pontocerebellar hypoplasia, agenesis or partial agenesis of the corpus callosum, and sometimes a simplified gyral pattern. Early death may occur (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (previous studies)." +MONDO_0859226,"Definition: Craniotubular dysplasia, Ikegawa type (CTDI) is characterized by childhood-onset short stature in association with macrocephaly, dolichocephaly, or prominent forehead. Radiography shows hyperostosis of the calvaria and skull base, with metadiaphyseal undermodeling of the long tubular bones and mild shortening and diaphyseal broadening of the short tubular bones. Affected individuals experience progressive vision loss in the first decade of life due to optic nerve compression, and deafness may develop in the second decade of life (previous studies)." +Orphanet_1520,"Definition: Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (previous studies; previous studies)." +MONDO_0010570,"Definition: Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (previous studies; previous studies)." +Orphanet_168598,"Definition: Methionine adenosyltransferase deficiency is an inborn error of metabolism resulting in isolated hypermethioninemia. Most patients have no clinical abnormalities, although some with the autosomal recessive form have have neurologic abnormalities (previous studies; previous studies)." +MONDO_0009607,"Definition: Methionine adenosyltransferase deficiency is an inborn error of metabolism resulting in isolated hypermethioninemia. Most patients have no clinical abnormalities, although some with the autosomal recessive form have have neurologic abnormalities (previous studies; previous studies)." +Orphanet_324588,"Definition: Autosomal dominant dyskinesia with orofacial involvement (DSKOD) is a complex neurologic disorder characterized by onset of involuntary choreiform, myoclonic, and dystonic movements involving the neck, limb, and facial muscles in the first decade of life. The manifestations and severity are variable; the disorder can also include episodic weakness and spasticity, resulting in difficulty walking and talking. It is generally nonprogressive, especially in adulthood, and dementia is not observed, although some individuals may have difficulties in school or behavioral abnormalities, such as social isolation (summary by previous studies; previous studies; previous studies; previous studies). + +previous studies provided a review of ADCY5-related dyskinesia, noting that the phenotypic features, manifestations, and severity are broad and variable. There are also variable molecular findings, including de novo mutations and mosaicism, the latter of which can influence expressivity." +MONDO_0800028,"Definition: Autosomal dominant dyskinesia with orofacial involvement (DSKOD) is a complex neurologic disorder characterized by onset of involuntary choreiform, myoclonic, and dystonic movements involving the neck, limb, and facial muscles in the first decade of life. The manifestations and severity are variable; the disorder can also include episodic weakness and spasticity, resulting in difficulty walking and talking. It is generally nonprogressive, especially in adulthood, and dementia is not observed, although some individuals may have difficulties in school or behavioral abnormalities, such as social isolation (summary by previous studies; previous studies; previous studies; previous studies). + +previous studies provided a review of ADCY5-related dyskinesia, noting that the phenotypic features, manifestations, and severity are broad and variable. There are also variable molecular findings, including de novo mutations and mosaicism, the latter of which can influence expressivity." +EFO_0010250,"Definition: Postaxial polydactyly type A9 (PAPA9) is characterized by one or more posterior or postaxial digits. There is intrafamilial and intraindividual variability (previous studies). + +For a discussion of genetic heterogeneity of postaxial polydactyly, see previous studies." +EFO_0010567,"Definition: Progressive spastic tetraplegia and axial hypotonia (STAHP) is an autosomal recessive neurologic disorder characterized by onset of severe and progressive motor dysfunction in the first year of life. Affected individuals have severe axial hypotonia combined with spastic tetraplegia, hyperekplexia, hypertonia, and myokymia, reflecting upper motor neuron involvement. Cognitive development may be affected, but only 2 unrelated patients have been reported (previous studies; previous studies)." +MONDO_0009234,"Definition: High molecular weight kininogen (HMWK) deficiency is an autosomal recessive coagulation defect. It is known by a variety of names, including Fitzgerald trait, Flaujeac trait, and Williams trait. Patients with HWMK deficiency do not have a hemorrhagic tendency, but they exhibit abnormal surface-mediated activation of fibrinolysis. Fitzgerald trait represents a 'true' deficiency of HMWK, whereas Flaujeac and Williams traits represent total kininogen deficiency, in which both HMWK and low molecular weight kininogen (LMWK) are deficient. HMWK and LMWK are both encoded by the KNG1 gene (previous studies) (previous studies; previous studies)." +MONDO_0009609,"Definition: Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase. Clinical features are somewhat variable, but include delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE (previous studies) and CblG (previous studies). Most patients present in early infancy, but some patients with CblG have shown later onset (previous studies). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by previous studies). + +CblE is caused by mutation in the MTRR gene (previous studies). + +previous studies commented on the clinical and biochemical heterogeneity in patients with cblE and cblG." +MONDO_0010041,"Definition: Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a complex neurodegenerative disorder usually characterized by early childhood onset of cerebellar ataxia, pyramidal tract signs, and peripheral neuropathy. Most patients become wheelchair-bound; cognitive function is usually not affected. Some patients may have atypical features, such as later onset or initial presentation of peripheral neuropathy (summary by previous studies)." +Orphanet_98,"Definition: Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a complex neurodegenerative disorder usually characterized by early childhood onset of cerebellar ataxia, pyramidal tract signs, and peripheral neuropathy. Most patients become wheelchair-bound; cognitive function is usually not affected. Some patients may have atypical features, such as later onset or initial presentation of peripheral neuropathy (summary by previous studies)." +MONDO_0010047,"Definition: Spastic paraplegia-5A (SPG5A) is an autosomal recessive neurologic disorder with a wide phenotypic spectrum. Some patients have pure spastic paraplegia affecting only gait, whereas others may have a complicated phenotype with additional manifestations, including optic atrophy or cerebellar ataxia (summary by previous studies). + +The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of previous studies and previous studies. Inheritance is most often autosomal dominant (see previous studies), but X-linked (see previous studies) and autosomal recessive forms also occur. + + Genetic Heterogeneity of Autosomal Recessive Spastic Paraplegia + +Autosomal recessive forms of SPG include SPG7 (previous studies), caused by mutation in the paraplegin gene (previous studies) on chromosome 16q24; SPG9B (previous studies), caused by mutation in the ALDH18A1 gene (previous studies) on 10q24; SPG11 (previous studies), caused by mutation in the spatacsin gene (previous studies) on 15q21; SPG15 (previous studies), caused by mutation in the ZFYVE26 gene (previous studies) on 14q24; SPG18 (previous studies), caused by mutation in the ERLIN2 gene (previous studies) on 8p11; SPG20 (previous studies), caused by mutation in the spartin gene (previous studies) on 13q12; SPG21 (previous studies), caused by mutation in the maspardin gene (previous studies) on 15q21; SPG26 (previous studies), caused by mutation in the B4GALNT1 gene (previous studies) on 12q13; SPG28 (previous studies), caused by mutation in the DDHD1 gene (previous studies) on 14q22; SPG30 (previous studies), caused by mutation in the KIF1A gene (previous studies) on 2q37; SPG35 (previous studies), caused by mutation in the FA2H gene (previous studies) on 16q23; SPG39 (previous studies), caused by mutation in the PNPLA6 gene (previous studies) on 19p13.3; SPG43 (previous studies), caused by mutation in the C19ORF12 gene (previous studies) on 19q12; SPG44 (previous studies), caused by mutation in the GJC2 gene (previous studies) on 1q42; SPG45 (previous studies), caused by mutation in the NT5C2 gene (previous studies) on 10q24; SPG46 (previous studies), caused by mutation in the GBA2 gene (previous studies) on 9p13; SPG48 (previous studies), caused by mutation in the KIAA0415 gene (previous studies) on 7p22.1; SPG54 (previous studies), caused by mutation in the DDHD2 gene (previous studies) on 8p11; SPG55 (previous studies), caused by mutation in the MTRFR gene on 12q24; SPG56 (previous studies), caused by mutation in the CYP2U1 gene (previous studies) on 4q25; SPG57 (previous studies), caused by mutation in the TFG gene (previous studies) on 3q12; SPG61 (previous studies), caused by mutation in the ARL6IP1 gene (previous studies) on 1p12; SPG62 (previous studies), caused by mutation in the ERLIN1 gene on 10q24; SPG63 (previous studies), caused by mutation in the AMPD2 gene (previous studies) on 1p13; SPG64 (previous studies), caused by mutation in the ENTPD1 gene (previous studies) on 10q24; SPG72 (previous studies), caused by mutation in the REEP2 gene (previous studies) on 5q31; SPG74 (previous studies), caused by mutation in the IBA57 gene (previous studies) on 1q42; SPG75 (previous studies), caused by mutation in the MAG gene (previous studies) on 19q13; SPG76 (previous studies), caused by mutation in the CAPN1 gene (previous studies) on 11q13; SPG77 (previous studies), caused by mutation in the FARS2 gene (previous studies) on 6p25; SPG78 (previous studies), caused by mutation in the ATP13A2 gene (previous studies) on 1p36; SPG79 (previous studies), caused by mutation in the UCHL1 gene (previous studies) on 4p13; SPG81 (previous studies), caused by mutation in the SELENOI gene (previous studies) on 2p23; SPG82 (previous studies), caused by mutation in the PCYT2 gene (previous studies) on 17q25; SPG83 (previous studies), caused by mutation in the HPDL gene (previous studies) on 1p34; SPG84 (previous studies), caused by mutation in the PI4KA gene (previous studies) on 22q11; SPG85 (previous studies), caused by mutation in the RNF170 gene (previous studies) on 8p11; SPG86 (previous studies), caused by mutation in the ABHD16A gene (previous studies) on 6p21; SPG87 (previous studies), caused by mutation in the TMEM63C gene (previous studies) on 14q24; SPG89 (previous studies), caused by mutation in the AMFR gene (previous studies) on 16q13; and SPG90B (previous studies), caused by mutation in the SPTSSA gene (previous studies) on 14q13. + +Additional autosomal recessive forms of SPG have been mapped to chromosomes 3q (SPG14; previous studies), 13q14 (SPG24; previous studies), 6q (SPG25; previous studies), and 10q22 (SPG27; previous studies). + +A disorder that was formerly designated SPG49 has been reclassified as hereditary sensory and autonomic neuropathy-9 with developmental delay (HSAN9; previous studies)." +Orphanet_100986,"Definition: Spastic paraplegia-5A (SPG5A) is an autosomal recessive neurologic disorder with a wide phenotypic spectrum. Some patients have pure spastic paraplegia affecting only gait, whereas others may have a complicated phenotype with additional manifestations, including optic atrophy or cerebellar ataxia (summary by previous studies). + +The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of previous studies and previous studies. Inheritance is most often autosomal dominant (see previous studies), but X-linked (see previous studies) and autosomal recessive forms also occur. + + Genetic Heterogeneity of Autosomal Recessive Spastic Paraplegia + +Autosomal recessive forms of SPG include SPG7 (previous studies), caused by mutation in the paraplegin gene (previous studies) on chromosome 16q24; SPG9B (previous studies), caused by mutation in the ALDH18A1 gene (previous studies) on 10q24; SPG11 (previous studies), caused by mutation in the spatacsin gene (previous studies) on 15q21; SPG15 (previous studies), caused by mutation in the ZFYVE26 gene (previous studies) on 14q24; SPG18 (previous studies), caused by mutation in the ERLIN2 gene (previous studies) on 8p11; SPG20 (previous studies), caused by mutation in the spartin gene (previous studies) on 13q12; SPG21 (previous studies), caused by mutation in the maspardin gene (previous studies) on 15q21; SPG26 (previous studies), caused by mutation in the B4GALNT1 gene (previous studies) on 12q13; SPG28 (previous studies), caused by mutation in the DDHD1 gene (previous studies) on 14q22; SPG30 (previous studies), caused by mutation in the KIF1A gene (previous studies) on 2q37; SPG35 (previous studies), caused by mutation in the FA2H gene (previous studies) on 16q23; SPG39 (previous studies), caused by mutation in the PNPLA6 gene (previous studies) on 19p13.3; SPG43 (previous studies), caused by mutation in the C19ORF12 gene (previous studies) on 19q12; SPG44 (previous studies), caused by mutation in the GJC2 gene (previous studies) on 1q42; SPG45 (previous studies), caused by mutation in the NT5C2 gene (previous studies) on 10q24; SPG46 (previous studies), caused by mutation in the GBA2 gene (previous studies) on 9p13; SPG48 (previous studies), caused by mutation in the KIAA0415 gene (previous studies) on 7p22.1; SPG54 (previous studies), caused by mutation in the DDHD2 gene (previous studies) on 8p11; SPG55 (previous studies), caused by mutation in the MTRFR gene on 12q24; SPG56 (previous studies), caused by mutation in the CYP2U1 gene (previous studies) on 4q25; SPG57 (previous studies), caused by mutation in the TFG gene (previous studies) on 3q12; SPG61 (previous studies), caused by mutation in the ARL6IP1 gene (previous studies) on 1p12; SPG62 (previous studies), caused by mutation in the ERLIN1 gene on 10q24; SPG63 (previous studies), caused by mutation in the AMPD2 gene (previous studies) on 1p13; SPG64 (previous studies), caused by mutation in the ENTPD1 gene (previous studies) on 10q24; SPG72 (previous studies), caused by mutation in the REEP2 gene (previous studies) on 5q31; SPG74 (previous studies), caused by mutation in the IBA57 gene (previous studies) on 1q42; SPG75 (previous studies), caused by mutation in the MAG gene (previous studies) on 19q13; SPG76 (previous studies), caused by mutation in the CAPN1 gene (previous studies) on 11q13; SPG77 (previous studies), caused by mutation in the FARS2 gene (previous studies) on 6p25; SPG78 (previous studies), caused by mutation in the ATP13A2 gene (previous studies) on 1p36; SPG79 (previous studies), caused by mutation in the UCHL1 gene (previous studies) on 4p13; SPG81 (previous studies), caused by mutation in the SELENOI gene (previous studies) on 2p23; SPG82 (previous studies), caused by mutation in the PCYT2 gene (previous studies) on 17q25; SPG83 (previous studies), caused by mutation in the HPDL gene (previous studies) on 1p34; SPG84 (previous studies), caused by mutation in the PI4KA gene (previous studies) on 22q11; SPG85 (previous studies), caused by mutation in the RNF170 gene (previous studies) on 8p11; SPG86 (previous studies), caused by mutation in the ABHD16A gene (previous studies) on 6p21; SPG87 (previous studies), caused by mutation in the TMEM63C gene (previous studies) on 14q24; SPG89 (previous studies), caused by mutation in the AMFR gene (previous studies) on 16q13; and SPG90B (previous studies), caused by mutation in the SPTSSA gene (previous studies) on 14q13. + +Additional autosomal recessive forms of SPG have been mapped to chromosomes 3q (SPG14; previous studies), 13q14 (SPG24; previous studies), 6q (SPG25; previous studies), and 10q22 (SPG27; previous studies). + +A disorder that was formerly designated SPG49 has been reclassified as hereditary sensory and autonomic neuropathy-9 with developmental delay (HSAN9; previous studies)." +MONDO_0010817,Definition: Autosomal dominant deafness-2A (DFNA2A) is a form of postlingual nonsyndromic progressive sensorineural hearing loss that begins with impairment at high frequencies and progresses to include mid to low frequencies (previous studies; previous studies). +MONDO_0012216,"Definition: Foveal hypoplasia is defined as the lack of foveal depression with continuity of all neurosensory retinal layers in the presumed foveal area. Foveal hypoplasia as an isolated entity is a rare phenomenon; it is usually described in association with other ocular disorders, such as aniridia (previous studies), microphthalmia (see previous studies), albinism (see previous studies), or achromatopsia (see previous studies). All reported cases of foveal hypoplasia have been accompanied by decreased visual acuity and nystagmus (summary by previous studies). + +For a discussion of genetic heterogeneity of foveal hypoplasia, see FVH1 (previous studies)." +Orphanet_397618,"Definition: Foveal hypoplasia is defined as the lack of foveal depression with continuity of all neurosensory retinal layers in the presumed foveal area. Foveal hypoplasia as an isolated entity is a rare phenomenon; it is usually described in association with other ocular disorders, such as aniridia (previous studies), microphthalmia (see previous studies), albinism (see previous studies), or achromatopsia (see previous studies). All reported cases of foveal hypoplasia have been accompanied by decreased visual acuity and nystagmus (summary by previous studies). + +For a discussion of genetic heterogeneity of foveal hypoplasia, see FVH1 (previous studies)." +MONDO_0013815,"Definition: Bent bone dysplasia syndrome-1 (BBDS1) is a perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones (previous studies). + + Genetic Heterogeneity of Bent Bone Dysplasia Syndrome + +BBDS2 (previous studies) is caused by mutation in the LAMA5 gene (previous studies) on chromosome 20q13." +MONDO_0014118,"Definition: Severe congenital neutropenia-5 is an autosomal recessive primary immunodeficiency disorder characterized primarily by neutropenia and neutrophil dysfunction, a lack of response to G-CSF, life-threatening infections, bone marrow fibrosis, and renal extramedullary hematopoiesis (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (previous studies)." +Orphanet_369852,"Definition: Severe congenital neutropenia-5 is an autosomal recessive primary immunodeficiency disorder characterized primarily by neutropenia and neutrophil dysfunction, a lack of response to G-CSF, life-threatening infections, bone marrow fibrosis, and renal extramedullary hematopoiesis (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (previous studies)." +MONDO_0014893,"Definition: Okur-Chung neurodevelopmental syndrome (OCNDS) is characterized by delayed psychomotor development, intellectual disability with poor speech, behavioral abnormalities, cortical malformations in some patients, and variable dysmorphic facial features. Additional features, including microcephaly, gastrointestinal problems, and low levels of immunoglobulins, may be observed in some patients (previous studies)." +MONDO_0030331,"Definition: Ritscher-Schinzel syndrome-4 (RTSC4) is characterized by a constellation of congenital anomalies, including dysmorphic craniofacial features and structural brain anomalies, such as Dandy-Walker malformation (previous studies), hindbrain malformations, or agenesis of the corpus callosum, associated with global developmental delay and impaired intellectual development. Congenital cardiac defects have been reported in 1 family (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of Ritscher-Schinzel syndrome, see RTSC1 (previous studies)." +MONDO_0060611,"Definition: Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is an inborn error of folate metabolism due to deficiency of methylenetetrahydrofolate dehydrogenase-1. Manifestations may include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, lymphopenia involving all subsets, and low T-cell receptor excision circles. Folinic acid supplementation is an effective treatment (summary by previous studies)." +Orphanet_1168,"Definition: Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia (previous studies). + + Genetic Heterogeneity of Ataxia-Oculomotor Apraxia + +See also AOA2 (previous studies), caused by mutation in the SETX gene (previous studies) on chromosome 9q34; AOA3 (previous studies), caused by mutation in the PIK3R5 gene (previous studies) on chromosome 17p; and AOA4 (previous studies), caused by mutation in the PNKP gene (previous studies) on chromosome 19q13." +MONDO_0008842,"Definition: Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia (previous studies). + + Genetic Heterogeneity of Ataxia-Oculomotor Apraxia + +See also AOA2 (previous studies), caused by mutation in the SETX gene (previous studies) on chromosome 9q34; AOA3 (previous studies), caused by mutation in the PIK3R5 gene (previous studies) on chromosome 17p; and AOA4 (previous studies), caused by mutation in the PNKP gene (previous studies) on chromosome 19q13." +Orphanet_306661,"Definition: Hyperphosphatemic familial tumoral calcinosis is a rare autosomal recessive metabolic disorder characterized by the progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone (previous studies). The biochemical hallmark of tumoral calcinosis is hyperphosphatemia caused by increased renal absorption of phosphate due to loss-of-function mutations in the FGF23 (previous studies) or GALNT3 gene. The term 'hyperostosis-hyperphosphatemia syndrome' is sometimes used when the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis. Although some have distinguished HHS from FTC by the presence of bone involvement and the absence of skin involvement (previous studies), previous studies concluded that the 2 entities represent a continuous spectrum of the same disease, best described as familial hyperphosphatemic tumoral calcinosis. + +HFTC is considered to be the clinical converse of autosomal dominant hypophosphatemic rickets (ADHR; previous studies), an allelic disorder caused by gain-of-function mutations in the FGF23 gene and associated with hypophosphatemia and decreased renal phosphate absorption (previous studies; previous studies). + + Genetic Heterogeneity of Hyperphosphatemic Familial Tumoral Calcinosis + +Also see HFTC2 (previous studies), caused by mutation in the FGF23 gene (previous studies) on chromosome 12p13, and HFTC3 (previous studies), caused by mutation in the KL gene (previous studies) on chromosome 13q13. Most cases are caused by mutation in the GALNT3 gene." +Orphanet_314679,"Definition: Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by previous studies). + + Genetic Heterogeneity of Van Maldergem Syndrome + +See also VMLDS2 (previous studies), caused by mutation in the FAT4 gene (previous studies) on chromosome 4q28." +Orphanet_667,"Definition: Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a characteristic facial appearance. Defective bone remodeling of the skull results in choanal stenosis with concomitant respiratory problems and feeding difficulties, which are the first clinical manifestation of disease. The expanding bone encroaches on neural foramina, leading to blindness, deafness, and facial palsy. Complete visual loss invariably occurs in all untreated patients, and hearing loss is estimated to affect 78% of patients with OPT. Tooth eruption defects and severe dental caries are common. Calcium feedback hemostasis is impaired, and children with OPT are at risk of developing hypocalcemia with attendant tetanic seizures and secondary hyperparathyroidism. The most severe complication of OPT, limiting survival, is bone marrow insufficiency. The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the liver and spleen (summary by previous studies). + + Genetic Heterogeneity of Autosomal Recessive Osteopetrosis + +Other forms of autosomal recessive infantile malignant osteopetrosis include OPTB4 (previous studies), which is caused by mutation in the CLCN7 gene (previous studies) on chromosome 16p13, and OPTB5 (previous studies), which is caused by mutation in the OSTM1 gene (previous studies) on chromosome 6q21. A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2; previous studies) is caused by mutation in the TNFSF11 gene (previous studies) on chromosome 13q14, an intermediate form (OPTB6; previous studies) is caused by mutation in the PLEKHM1 gene (previous studies) on chromosome 17q21, and a severe osteoclast-poor form associated with hypogammaglobulinemia (OPTB7; previous studies) is caused by mutation in the TNFRSF11A gene (previous studies) on chromosome 18q22. Another form of autosomal recessive osteopetrosis (OPTB8; previous studies) is caused by mutation in the SNX10 gene (previous studies) on chromosome 7p15. A form of autosomal recessive osteopetrosis associated with renal tubular acidosis (OPTB3; previous studies) is caused by mutation in the CA2 gene (previous studies) on chromosome 8q21. OPTB9 (previous studies) is caused by mutation in the SLC4A2 gene (previous studies) on chromosome 7q36. + +Autosomal dominant forms of osteopetrosis are more benign (see OPTA1, previous studies)." +MONDO_0009815,"Definition: Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a characteristic facial appearance. Defective bone remodeling of the skull results in choanal stenosis with concomitant respiratory problems and feeding difficulties, which are the first clinical manifestation of disease. The expanding bone encroaches on neural foramina, leading to blindness, deafness, and facial palsy. Complete visual loss invariably occurs in all untreated patients, and hearing loss is estimated to affect 78% of patients with OPT. Tooth eruption defects and severe dental caries are common. Calcium feedback hemostasis is impaired, and children with OPT are at risk of developing hypocalcemia with attendant tetanic seizures and secondary hyperparathyroidism. The most severe complication of OPT, limiting survival, is bone marrow insufficiency. The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the liver and spleen (summary by previous studies). + + Genetic Heterogeneity of Autosomal Recessive Osteopetrosis + +Other forms of autosomal recessive infantile malignant osteopetrosis include OPTB4 (previous studies), which is caused by mutation in the CLCN7 gene (previous studies) on chromosome 16p13, and OPTB5 (previous studies), which is caused by mutation in the OSTM1 gene (previous studies) on chromosome 6q21. A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2; previous studies) is caused by mutation in the TNFSF11 gene (previous studies) on chromosome 13q14, an intermediate form (OPTB6; previous studies) is caused by mutation in the PLEKHM1 gene (previous studies) on chromosome 17q21, and a severe osteoclast-poor form associated with hypogammaglobulinemia (OPTB7; previous studies) is caused by mutation in the TNFRSF11A gene (previous studies) on chromosome 18q22. Another form of autosomal recessive osteopetrosis (OPTB8; previous studies) is caused by mutation in the SNX10 gene (previous studies) on chromosome 7p15. A form of autosomal recessive osteopetrosis associated with renal tubular acidosis (OPTB3; previous studies) is caused by mutation in the CA2 gene (previous studies) on chromosome 8q21. OPTB9 (previous studies) is caused by mutation in the SLC4A2 gene (previous studies) on chromosome 7q36. + +Autosomal dominant forms of osteopetrosis are more benign (see OPTA1, previous studies)." +Orphanet_69076,Definition: Patients with familial renal glucosuria have decreased renal tubular resorption of glucose form the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from less than 1 to over 150 g/1.73 m(2) per day (previous studies). +MONDO_0009297,Definition: Patients with familial renal glucosuria have decreased renal tubular resorption of glucose form the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from less than 1 to over 150 g/1.73 m(2) per day (previous studies). +MONDO_0008652,"Definition: Congenital vertical talus (CVT), also known as 'rocker-bottom foot' deformity, is a dislocation of the talonavicular joint characterized by vertical orientation of the talus with a rigid dorsal dislocation of the navicular, equinus deformity of the calcaneus, abduction deformity of the forefoot, and contracture of the soft tissues of the hind- and mid-foot. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity with familial occurrence (summary by previous studies). The condition is transmitted in an autosomal dominant pattern of inheritance, and sometimes shows incomplete penetrance and variable expressivity. There may be a broad spectrum of deformities, including flatfoot, talipes equinovarus (TEV or clubfoot), cavus foot, metatarsus adductus, and even hypoplasia of the tibia (summary by previous studies)." +MONDO_0009359,"Definition: MARCH is an autosomal recessive lethal congenital disorder characterized by severe hydranencephaly with almost complete absence of the cerebral hemispheres, which are replaced by fluid, relative preservation of the posterior fossa structures, and renal dysplasia or agenesis. Affected fetuses either die in utero or shortly after birth, and show arthrogryposis and features consistent with anhydramnios. Histologic examination of residual brain tissue shows multinucleated neurons resulting from impaired cytokinesis (summary by previous studies)." +MONDO_0010699,"Definition: The phenotype of X-linked Charcot-Marie-Tooth disease-5 typically comprises the triad of optic atrophy, deafness, and polyneuropathy. However, patients without optic atrophy have been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of X-linked Charcot-Marie-Tooth disease, see CMTX1 (previous studies). + +See previous studies and previous studies for possible autosomal dominant and autosomal recessive forms of the disorder." +Orphanet_99014,"Definition: The phenotype of X-linked Charcot-Marie-Tooth disease-5 typically comprises the triad of optic atrophy, deafness, and polyneuropathy. However, patients without optic atrophy have been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of X-linked Charcot-Marie-Tooth disease, see CMTX1 (previous studies). + +See previous studies and previous studies for possible autosomal dominant and autosomal recessive forms of the disorder." +MONDO_0011054,"Definition: Posterior amelia with pelvic and pulmonary hypoplasia syndrome (PAPPAS) is characterized by absent lower limbs, severely hypoplastic or absent pelvic bones, and hypoplasia of the sacrum, as well as hypoplasia of the lungs with pulmonary segmentation defect. Ambiguous genitalia have also been observed (previous studies). + +Heterozygous mutation in the TBX4 gene causes ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (ICPPS; previous studies)." +MONDO_0011631,"Definition: Hemochromatosis type 4 (HFE4) is a dominantly inherited iron overload disorder with heterogeneous phenotypic manifestations that can be classified into 2 groups. One group is characterized by an early rise in ferritin (see previous studies) levels with low to normal transferrin (previous studies) saturation and iron accumulation predominantly in macrophages. The other group is similar to classical hemochromatosis, with high transferrin saturation and prominent parenchymal iron loading (summary by previous studies). + +For general background information and a discussion of genetic heterogeneity of hereditary hemochromatosis, see previous studies." +MONDO_0029134,"Definition: Immunodeficiency-58 is an autosomal recessive primary immunologic disorder characterized by early-onset skin lesions, including eczematous dermatitis, infectious abscesses, and warts, recurrent respiratory infections or allergies, and chronic persistent infections with candida, Molluscum contagiosum, mycobacteria, EBV, bacteria, and viruses. Some patients may have gastrointestinal involvement, including inflammatory bowel disease, EBV+ smooth muscle tumors, and esophagitis. Immunologic analysis shows defective T-cell function with decreased Treg cells and deficient CD3/CD28 costimulation responses in both CD4+ and CD8+ T cells. B-cell function may also be impaired (summary by previous studies and previous studies)." +MONDO_0029136,"Definition: Autosomal recessive limb-girdle muscular dystrophy-23 is characterized by slowly progressive proximal muscle weakness primarily affecting the lower limbs and resulting in gait difficulties. Age at onset generally ranges from childhood to mid-adulthood. Additional features include white matter abnormalities on brain imaging, increased serum creatine kinase, and dystrophic features, with partial LAMA2 deficiency on muscle biopsy. Some patients may have additional neurologic features, including executive deficits, seizures, and peripheral neuropathy. Patients remain ambulatory well into adulthood (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (previous studies)." +MONDO_0033368,"Definition: Developmental and epileptic encephalopathy-59 (DEE59) is characterized by severe global developmental delay apparent in infancy with onset of various types of seizures in the first months of life (range 3 to 11 months). The seizures are usually refractory and are often associated with hypsarrhythmia on EEG, although brain imaging is usually normal. More severely affected individuals may be unable to speak or walk, have poor interaction, and require a feeding tube (summary by the previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +Orphanet_2590,"Definition: Spinal muscular atrophy with progressive myoclonic epilepsy is an autosomal recessive neuromuscular disorder characterized by childhood onset of proximal muscle weakness and generalized muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder is progressive, and usually results in loss of ambulation and early death from respiratory insufficiency (summary by previous studies)." +MONDO_0008045,"Definition: Spinal muscular atrophy with progressive myoclonic epilepsy is an autosomal recessive neuromuscular disorder characterized by childhood onset of proximal muscle weakness and generalized muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder is progressive, and usually results in loss of ambulation and early death from respiratory insufficiency (summary by previous studies)." +EFO_0010262,"Definition: Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is an autosomal recessive disorder characterized by acute reversible neurologic deterioration in the context of a febrile illness. The disorder is associated with transient leukoencephalopathy on brain imaging concurrent with the acute episode, as well as persistently increased excretion of dicarboxylic acids, particularly alpha-ketoglutarate (summary by previous studies)." +MONDO_0008224,"Definition: The 2 dominantly inherited, clinically similar types of episodic flaccid generalized weakness, HOKPP and HYPP, are distinguished by the changes in serum potassium levels during paralytic attacks. An important clinical difference between the 2 entities is represented by the triggers of attacks of weakness, e.g., HYPP can be provoked by oral potassium administration, whereas this is a remedy for HOKPP. Concurrence of myotonia is found in HYPP but usually not in HOKPP patients (previous studies). + +previous studies provided a review of the clinical features, pathogenesis, and therapeutic options for HYPP." +MONDO_0010100,"Definition: Tay-Sachs disease is an autosomal recessive, progressive neurodegenerative disorder which, in the classic infantile form, is usually fatal by age 2 or 3 years." +MONDO_0010512,"Definition: MRXSB is an X-linked neurodevelopmental disorder characterized by delayed psychomotor development, impaired intellectual development with behavioral abnormalities, and dysmorphic facial features. Additional variable features include musculoskeletal abnormalities, seizures, acquired microcephaly, and feeding problems with poor overall growth (summary by previous studies)." +MONDO_0010585,"Definition: Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. + +Hypohidrotic, or anhidrotic, ectodermal dysplasia (HED/EDA) is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia), and inability to sweat (anhidrosis or hypohidrosis). Typical clinical manifestations also include dryness of the skin, eyes, airways, and mucous membranes presumably due to the defective development of several exocrine glands. Hypohidrotic ectodermal dysplasia can be associated with dysmorphic features (forehead bumps, rings under the eyes, everted nose, and prominent lips) and occasionally with absent nipples. Ectodermal dysplasia-1, due to mutation in the EDA gene, is the most frequent form of hypohidrotic ectodermal dysplasia (summary by previous studies)." +MONDO_0011907,"Definition: Acrocapitofemoral dysplasia (ACFD) is an autosomal recessive skeletal dysplasia characterized by postnatal-onset disproportionate short stature, relatively large head, narrow thorax, lumbar lordosis, short limbs, and brachydactyly with small broad nails (previous studies)." +MONDO_0012043,"Definition: Reis-Bucklers corneal dystrophy (CDRB) is an autosomal dominant disorder of the superficial corneal stroma that manifests as recurrent corneal erosions in early childhood. Affected individuals develop corneal opacities that result in significant visual impairment. Microscopically, CDRB may be differentiated from other forms of corneal dystrophy by confluent opacities in the Bowman layer and subepithelium, which are the product of extracellular bodies that stain red with Masson trichrome stain and appear as crystalloid rod-shaped bodies on transmission electron microscopy (summary by previous studies)." +Orphanet_98961,"Definition: Reis-Bucklers corneal dystrophy (CDRB) is an autosomal dominant disorder of the superficial corneal stroma that manifests as recurrent corneal erosions in early childhood. Affected individuals develop corneal opacities that result in significant visual impairment. Microscopically, CDRB may be differentiated from other forms of corneal dystrophy by confluent opacities in the Bowman layer and subepithelium, which are the product of extracellular bodies that stain red with Masson trichrome stain and appear as crystalloid rod-shaped bodies on transmission electron microscopy (summary by previous studies)." +MONDO_0012897,"Definition: Factor XI deficiency is an autosomal bleeding disorder characterized by reduced levels of factor XI in plasma (less than 15 IU/dL). Bleeding occurs mainly after trauma or surgery. On the basis of the concordance or discordance of F11 antigen and activity, the disorder is classified into the more frequent cross-reactive negative (CRM-) and the rarer CRM positive (CRM+) (summary by previous studies)." +MONDO_0014226,Definition: Idiopathic CD4 lymphopenia (ICL) is a rare and heterogeneous syndrome defined by a reproducible reduction in the CD4 T-lymphocyte count (less than 300 cells per microliter or less than 20% of total T cells) in the absence of HIV infection or other known causes of immunodeficiency. ICL predisposes to infections and malignancy (summary by previous studies). +MONDO_0030067,"Definition: Treacher Collins syndrome-4 (TCS4) is characterized by craniofacial dysmorphisms including downslanting palpebral fissures, malar and mandibular hypoplasia, and microtia. Most patients have conductive deafness with atretic external ear canals. Choanal atresia and cleft palate have also been observed (previous studies)." +MONDO_0044311,"Definition: BTDD is an autosomal dominant disorder characterized by brachycephaly, trichomegaly, and developmental delay. Although it is caused by dysfunction of the ribosome, patients do not have anemia (summary by previous studies)." +MONDO_0054732,"Definition: Spermatogenic failure-28 (SPGF28) is characterized by nonobstructive azoospermia, with a Sertoli cell-only phenotype observed in testicular tissue (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0800131,"Definition: Autosomal dominant hyper-IgE recurrent infection syndrome-4A (HIES4A) is an immunologic disorder characterized by recurrent mainly sinopulmonary infections associated with increased serum IgE. The phenotype is variable, even within families. Some patients have onset of symptoms in early childhood and develop complications, including bronchiectasis or hemoptysis, whereas others have later onset of less severe infections. Immunologic workup usually shows normal leukocyte levels, although some patients may demonstrate alterations in lymphocyte subsets, including T cells. Affected individuals also have variable skeletal abnormalities, including high-arched palate, hyperextensible joints, scoliosis, and bone fractures. The IL6ST mutations are loss-of-function, although the truncated mutant proteins are expressed and interfere with the wildtype protein in a dominant-negative manner by disrupting IL6 (previous studies) and IL11 (previous studies) signaling (summary by previous studies). + +For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see HIES1 (previous studies)." +Orphanet_79153,"Definition: Many types of nonsyndromic congenital nail disorders (NDNC) have been described. Twenty-nail dystrophy (TND), also known as trachyonychia (from the Greek for 'rough nails'), is an autosomal dominant nail dystrophy characterized by excessive longitudinal striations and numerous superficial pits on the nails, which have a distinctive rough sandpaper-like appearance. Occasionally some nails are spared. The slowly progressive condition is usually apparent at birth and may be self-limiting, with spontaneous resolution in some patients (summary by previous studies). TND is referred to here as nonsyndromic congenital nail disorder-1 (NDNC1). + + Genetic Heterogeneity of Nonsyndromic Congenital Nail Disorders + +Other nonsyndromic congenital nail disorders include koilonychia (NDNC2; previous studies); leukonychia (NDNC3; previous studies) caused by mutation in the PLCD1 gene (previous studies) on chromosome 3p22; anonychia/hyponychia (NDNC4; previous studies) caused by mutation in the RSPO4 gene (previous studies) on chromosome 20p13; partial onycholysis with scleronychia (NDNC5; previous studies); anonychia of thumbs with onychodystrophy of other nails (NDNC6; previous studies); onychodystrophy mapping to chromosome 17p13 (NDNC7; previous studies); toenail dystrophy (NDNC8; previous studies) caused by mutation in the COL7A1 gene (previous studies) on chromosome 3p21; onychodystrophy mapping to chromosome 17q25.1-q25.3 (NDNC9; previous studies)." +MONDO_0008060,"Definition: Many types of nonsyndromic congenital nail disorders (NDNC) have been described. Twenty-nail dystrophy (TND), also known as trachyonychia (from the Greek for 'rough nails'), is an autosomal dominant nail dystrophy characterized by excessive longitudinal striations and numerous superficial pits on the nails, which have a distinctive rough sandpaper-like appearance. Occasionally some nails are spared. The slowly progressive condition is usually apparent at birth and may be self-limiting, with spontaneous resolution in some patients (summary by previous studies). TND is referred to here as nonsyndromic congenital nail disorder-1 (NDNC1). + + Genetic Heterogeneity of Nonsyndromic Congenital Nail Disorders + +Other nonsyndromic congenital nail disorders include koilonychia (NDNC2; previous studies); leukonychia (NDNC3; previous studies) caused by mutation in the PLCD1 gene (previous studies) on chromosome 3p22; anonychia/hyponychia (NDNC4; previous studies) caused by mutation in the RSPO4 gene (previous studies) on chromosome 20p13; partial onycholysis with scleronychia (NDNC5; previous studies); anonychia of thumbs with onychodystrophy of other nails (NDNC6; previous studies); onychodystrophy mapping to chromosome 17p13 (NDNC7; previous studies); toenail dystrophy (NDNC8; previous studies) caused by mutation in the COL7A1 gene (previous studies) on chromosome 3p21; onychodystrophy mapping to chromosome 17q25.1-q25.3 (NDNC9; previous studies)." +EFO_0001356,"Definition: Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (previous studies). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. + +previous studies and previous studies provided extensive reviews of ALS. + +Some forms of ALS occur with frontotemporal dementia (FTD); see previous studies. previous studies provided a detailed review of the genes involved in different forms of ALS with FTD, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration. + +Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (previous studies) (previous studies; previous studies), in which the histology is different and dementia and parkinsonism complicate the clinical picture. + + Genetic Heterogeneity of Amyotrophic Lateral Sclerosis + +ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. + +ALS6 (previous studies) is caused by mutation in the FUS gene (previous studies) on chromosome 16p11; ALS8 (previous studies) is caused by mutation in the VAPB gene (previous studies) on chromosome 13; ALS9 (previous studies) is caused by mutation in the ANG gene (previous studies) on chromosome 14q11; ALS10 (previous studies) is caused by mutation in the TARDBP gene (previous studies) on 1p36; ALS11 (previous studies) is caused by mutation in the FIG4 gene (previous studies) on chromosome 6q21; ALS12 (previous studies) is caused by mutation in the OPTN gene (previous studies) on chromosome 10p13; ALS15 (previous studies) is caused by mutation in the UBQLN2 gene (previous studies) on chromosome Xp11; ALS18 (previous studies) is caused by mutation in the PFN1 gene (previous studies) on chromosome 17p13; ALS19 (previous studies) is caused by mutation in the ERBB4 gene (previous studies) on chromosome 2q34; ALS20 (previous studies) is caused by mutation in the HNRNPA1 gene (previous studies) on chromosome 12q13; ALS21 (previous studies) is caused by mutation in the MATR3 gene (previous studies) on chromosome 5q31; ALS22 (previous studies) is caused by mutation in the TUBA4A gene (previous studies) on chromosome 2q35; ALS23 (previous studies) is caused by mutation in the ANXA11 gene (previous studies) on chromosome 10q23; and ALS26 (previous studies) is caused by mutation in the TIA1 gene (previous studies) on chromosome 2p13. + +Loci associated with ALS have been found on chromosomes 18q21 (ALS3; previous studies) and 20p13 (ALS7; previous studies). + +Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (previous studies) contribute to susceptibility to ALS (ALS13; previous studies). Susceptibility to ALS24 (previous studies) is conferred by mutation in the NEK1 gene (previous studies) on chromosome 4q33, and susceptibility to ALS25 (previous studies) is conferred by mutation in the KIF5A gene (previous studies) on chromosome 12q13. Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; previous studies); deletions in the gene encoding peripherin (PRPH; previous studies); and mutations in the dynactin gene (DCTN1; previous studies). + +Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (previous studies), caused by mutation in the alsin (previous studies) gene on 2q33; ALS4 (previous studies), caused by mutation in the senataxin gene (SETX; previous studies) on 9q34; ALS5 (previous studies), caused by mutation in the SPG11 gene (previous studies) on 15q21; and ALS16 (previous studies), caused by mutation in the SIGMAR1 gene (previous studies) on 9p13." +EFO_0010738,"Definition: Retinal dystrophy and leukodystrophy (RDLKD) is a peroxisomal enzyme deficiency caused by impaired very long chain fatty acid (VLCFA) metabolism. Patients exhibit ataxia and spastic paraparesis as well as developmental delay, and may show facial dysmorphism (previous studies)." +MONDO_0008152,"Definition: Multicentric carpotarsal osteolysis syndrome is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bone usually occurs and other bones may also be involved. Chronic renal failure is a frequent component of the syndrome. Mental retardation and minor facial anomalies have been noted in some patients. Autosomal dominant inheritance has been documented in many families (previous studies). + +See also Torg-Winchester syndrome (previous studies), an autosomal recessive multicentric osteolysis syndrome." +MONDO_0008201,"Definition: Perry syndrome is an autosomal dominant neurodegenerative disorder classically characterized by adult-onset parkinsonism and depression, followed by weight loss and respiratory hypoventilation (previous studies). The phenotype has subsequently been expanded to include features that overlap with other neurodegenerative conditions, including frontotemporal dementia (see, e.g., previous studies) and progressive supranuclear palsy (PSP; previous studies). There is intrafamilial variation in the manifestations of the disorder (summary by previous studies; review by previous studies). + +Mutation in the DCTN1 gene can also cause distal motor neuronopathy type VIIB (HMN7B; previous studies) and confer increased susceptibility to amyotrophic lateral sclerosis (ALS; see previous studies)." +MONDO_0008251,"Definition: Pityriasis rubra pilaris is an uncommon skin disorder characterized by the appearance of keratotic follicular papules, well-demarcated salmon-colored erythematous plaques covered with fine powdery scales interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. Most cases are sporadic, although up to 6.5% of PRP-affected individuals report a positive family history. The rare familial cases show autosomal dominant inheritance with incomplete penetrance and variable expression: the disorder is usually present at birth or appears during the first years of life and is characterized by prominent follicular hyperkeratosis, diffuse palmoplantar keratoderma, and erythema, with only a modest response to treatment (summary by previous studies)." +MONDO_0009372,"Definition: Hydroxykynureninuria, also known as xanthurenicaciduria, is an autosomal recessive condition characterized by high urinary excretion of kynurenine (KYN), xanthurenic acid (XA) and 3-hydroxykynurenine (3-OHKYN), with no detectable anthranilic acid (AA) or 3-hydroxyanthranilic acid (3-OHAA) (previous studies)." +MONDO_0011758,"Definition: The mucopolysaccharidoses are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function. + +Deficiency of alpha-L-iduronidase can result in a wide range of phenotypic involvement with 3 major recognized clinical entities: Hurler (MPS IH), Scheie (MPS IS; previous studies), and Hurler-Scheie (MPS IH/S; previous studies) syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression (previous studies). + +MPS I is more frequent than MPS II (Hunter syndrome; previous studies), which has no corneal clouding and pursues a slower course." +MONDO_0012204,"Definition: 'Familial pseudohyperkalemia' (PSHK) is a term that was coined to describe conditions in which a patient presents with pseudohyperkalemia as a result of a temperature-based abnormality in the transport of potassium (K) and sodium (Na) across the red cell membrane, in association with essentially normal hematology. PSHK can be considered to be the clinically benign, nonhemolytic cousin of hereditary stomatocytic leaky-cell, congenital hemolytic anemias (see previous studies) (summary by previous studies). + +For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see previous studies." +MONDO_0013160,"Definition: MDDGB2 is an autosomal recessive congenital muscular dystrophy associated with impaired intellectual development and mild structural brain abnormalities (previous studies). It is part of a group of similar disorders, collectively known as 'dystroglycanopathies,' resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies) (previous studies). + +For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (previous studies)." +MONDO_0014168,"Definition: Immunodeficiency-8 with lymphoproliferation (IMD8) is an autosomal recessive primary immunodeficiency characterized by early-childhood onset of recurrent infections and lymphoproliferative disorders, often associated with EBV infection. Laboratory studies show defects in the numbers and function of certain lymphocyte subsets, particularly T cells (previous studies; previous studies)." +MONDO_0014553,"Definition: Tenorio syndrome is characterized by overgrowth, macrocephaly, and intellectual disability (ID). Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome (previous studies) (summary by previous studies)." +MONDO_0030038,"Definition: Primary closed-angle glaucoma (GLCC) is characterized by age-related variation in the degree of iridocorneal angle closure and its sequelae, with patients in the first 3 decades of life showing a normal eye exam, whereas older patients progressively show more evidence of angle closure and glaucomatous damage, including optic nerve head changes and visual field defects (previous studies)." +MONDO_0030487,Definition: Spondylometaphyseal dysplasia Pagnamenta type (SMDP) is characterized by short stature and mild platyspondyly with no disproportion between the limbs. Mild metaphyseal changes are present (previous studies). +MONDO_0030677,"Definition: Demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I) is a neurologic disorder characterized predominantly by delayed motor development in the first years of life associated with gait abnormalities, sensory ataxia, hyporeflexia, and distal sensory impairment due to a sensorimotor peripheral neuropathy that mainly affects the lower limbs. The disorder is progressive, and some may have upper limb involvement. A subset of patients has central nervous system involvement that manifests as global developmental delay with impaired intellectual development and speech difficulties. Other features may include spasticity, hyperreflexia, tremor, dysmetria, seizures, or cerebellar findings. Brain imaging may be normal or show nonspecific abnormalities, such as white matter signal changes and delayed myelination (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (previous studies)." +MONDO_0030957,"Definition: Developmental and epileptic encephalopathy-103 (DEE103) is characterized by onset of various types of seizures in the first year of life, most of which are refractory to treatment. Affected individuals show global developmental delay with impaired intellectual development ranging from mild to severe. Additional features may include hypotonia, ataxia, and behavioral abnormalities, including autism and hyperactivity (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0033662,"Definition: Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy (NEDMISB) is an autosomal recessive disorder characterized by severe global developmental delay, developmental regression with loss of milestones, severe microcephaly, and brain abnormalities, primarily cerebral atrophy and hypoplasia of the corpus callosum. Affected individuals develop seizures in the first year of life; eventually they are unable to sit, feed, or communicate, and may be unresponsive to stimuli. Other features include muscle weakness, spasticity with hyperreflexia, irritability, and contractures (previous studies)." +Orphanet_276249,"Definition: Xeroderma pigmentosum is a genetically heterogeneous autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Some patients develop neurologic symptoms or a more severe clinical phenotype known as de Sanctis-Cacchione syndrome (previous studies) (previous studies). + +See also XPB (previous studies), XPC (previous studies), XPD (previous studies), XPE (previous studies), XPF (previous studies), XPG (previous studies), and variant XP (XPV; previous studies)." +MONDO_0010210,"Definition: Xeroderma pigmentosum is a genetically heterogeneous autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Some patients develop neurologic symptoms or a more severe clinical phenotype known as de Sanctis-Cacchione syndrome (previous studies) (previous studies). + +See also XPB (previous studies), XPC (previous studies), XPD (previous studies), XPE (previous studies), XPF (previous studies), XPG (previous studies), and variant XP (XPV; previous studies)." +MONDO_0007352,"Definition: Papillorenal syndrome (PAPRS) is an autosomal dominant disorder characterized by both ocular and renal anomalies. Less common findings include high frequency hearing loss, central nervous system anomalies, soft skin, ligamentous laxity, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development (summary by previous studies; previous studies). The disorder shows wide inter- and intrafamilial variability. The renal features are part of a spectrum of malformations termed congenital anomalies of the kidney and urinary tract (CAKUT; see, e.g., previous studies), and some patients with PAX2 mutations may present with CAKUT without obvious ocular abnormalities. In these patients, ocular abnormalities may be subtle and difficult to detect without advanced screening methods or may be normal (summary by previous studies; previous studies). + +Eye anomalies associated with PAX2 mutations consist of a wide and sometimes excavated dysplastic optic disc with the emergence of the retinal vessels from the periphery of the disc, designated optic nerve 'coloboma' or 'morning glory' anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst, microphthalmia, and pigmentary macular dysplasia. The kidneys are small and abnormally formed (renal hypodysplasia), and have fewer than the normal number of glomeruli, which are enlarged (oligomeganephronia). These ocular and renal anomalies result in decreased visual acuity and retinal detachment, as well as hypertension, proteinuria, and renal insufficiency that frequently progresses to end-stage renal disease (summary by previous studies)." +MONDO_0009530,"Definition: Lipoid proteinosis of Urbach and Wiethe is a rare autosomal recessive disorder typified by generalized thickening of skin, mucosae, and certain viscera. Classic features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. The disorder is clinically heterogeneous, with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurologic abnormalities such as temporal lobe epilepsy. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane (summary by previous studies and previous studies)." +MONDO_0010545,"Definition: Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation (summary by previous studies)." +MONDO_0011818,"Definition: Focal cortical dysplasia type II (FCORD2), or focal cortical dysplasia of Taylor (FCDT), is a cerebral developmental malformation that results in a clinical phenotype of intractable epilepsy, usually requiring surgery. FCORD2 has been classified histologically into 2 subtypes: a type without balloon cells, known as type IIA, and a type with balloon cells, known as type IIB (previous studies). Affected individuals have refractory seizures, usually with onset in early childhood, and may have persistent intellectual disability. Most patients require neurosurgical resection of affected brain tissue to ameliorate seizure frequency and severity (summary by previous studies)." +MONDO_0012320,"Definition: Familial hemiplegic migraine-3 (FHM3) is a severe subtype of migraine with aura characterized by some degree of hemiparesis during the attacks (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of FHM, see FHM1 (previous studies)." +MONDO_0013343,"Definition: C1q deficiency (C1QD) is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; see previous studies) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (summary by previous studies and previous studies). + + Genetic Heterogeneity of C1q Deficiency + +See also C1q deficiency-2 (C1QD2; previous studies), caused by mutation in the C1QB gene (previous studies), and C1q deficiency-3 (C1QD3; previous studies), caused by mutation in the C1QC gene (previous studies)." +Orphanet_401869,"Definition: Multiple mitochondrial dysfunctions syndrome is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (summary by previous studies). + + Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome + +See also MMDS2 (previous studies), caused by mutation in the BOLA3 gene (previous studies) on chromosome 2p13; MMDS3 (previous studies), caused by mutation in the IBA57 gene (previous studies) on chromosome 1q42; MMDS4 (previous studies), caused by mutation in the ISCA2 gene (previous studies) on chromosome 14q24; MMDS5 (previous studies), caused by mutation in the ISCA1 gene (previous studies) on chromosome 9q21; MMDS6 (previous studies), caused by mutation in the PMPCB gene (previous studies) on chromosome 7q22; and MMDS7 (previous studies), caused by mutation in the GCSH gene (previous studies) on chromosome 16q23." +MONDO_0011582,"Definition: Multiple mitochondrial dysfunctions syndrome is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (summary by previous studies). + + Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome + +See also MMDS2 (previous studies), caused by mutation in the BOLA3 gene (previous studies) on chromosome 2p13; MMDS3 (previous studies), caused by mutation in the IBA57 gene (previous studies) on chromosome 1q42; MMDS4 (previous studies), caused by mutation in the ISCA2 gene (previous studies) on chromosome 14q24; MMDS5 (previous studies), caused by mutation in the ISCA1 gene (previous studies) on chromosome 9q21; MMDS6 (previous studies), caused by mutation in the PMPCB gene (previous studies) on chromosome 7q22; and MMDS7 (previous studies), caused by mutation in the GCSH gene (previous studies) on chromosome 16q23." +Orphanet_93952,"Definition: The Hedera type of X-linked syndromic intellectual developmental disorder (MRXSH) is characterized by global developmental delay apparent from infancy and progressive neurologic decline with abnormal movements, spasticity, and seizures. Brain imaging shows volume loss of cortical white and gray matter, thin corpus callosum, and myelination defects, consistent with a neurodegenerative process. Only males are affected (summary by previous studies)." +MONDO_0010319,"Definition: The Hedera type of X-linked syndromic intellectual developmental disorder (MRXSH) is characterized by global developmental delay apparent from infancy and progressive neurologic decline with abnormal movements, spasticity, and seizures. Brain imaging shows volume loss of cortical white and gray matter, thin corpus callosum, and myelination defects, consistent with a neurodegenerative process. Only males are affected (summary by previous studies)." +EFO_0000632,"Definition: Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, ependymomas, and subependymomas. Glial cells can show various degrees of differentiation even within the same tumor (summary by previous studies). + +Ependymomas are rare glial tumors of the brain and spinal cord (previous studies). + +Subependymomas are unusual tumors believed to arise from the bipotential subependymal cell, which normally differentiates into either ependymal cells or astrocytes. They were characterized as a distinct entity by previous studies. They tend to be slow-growing, noninvasive, and located in the ventricular system, septum pellucidum, cerebral aqueduct, or proximal spinal cord (summary by previous studies). + +Gliomas are known to occur in association with several other well-defined hereditary tumor syndromes such as mismatch repair cancer syndrome (see previous studies), melanoma-astrocytoma syndrome (previous studies), neurofibromatosis-1 (NF1; previous studies) and neurofibromatosis-2 (see SWNV, previous studies), and tuberous sclerosis (TSC1; previous studies). Familial clustering of gliomas may occur in the absence of these tumor syndromes, however. + + Genetic Heterogeneity of Susceptibility to Glioma + +Other glioma susceptibilities include GLM2 (previous studies), caused by variation in the PTEN gene (previous studies) on chromosome 10q23; GLM3 (previous studies), caused by variation in the BRCA2 gene (previous studies) on chromosome 13q13; GLM4 (previous studies), mapped to chromosome 15q23-q26.3; GLM5 (previous studies), mapped to chromosome 9p21; GLM6 (previous studies), mapped to chromosome 20q13; GLM7 (previous studies), mapped to chromosome 8q24; GLM8 (previous studies), mapped to chromosome 5p15; and GLM9, caused by variation in the POT1 gene (previous studies) on chromosome 7q31. + +Somatic mutation, disruption, or copy number variation of the following genes or loci may also contribute to the formation of glioma: ERBB (EGFR; previous studies), ERBB2 (previous studies), LGI1 (previous studies), GAS41 (previous studies), GLI (previous studies), DMBT1 (previous studies), IDH1 (previous studies), IDH2 (previous studies), BRAF (previous studies), PARK2 (previous studies), TP53 (previous studies), RB1 (previous studies), PIK3CA (previous studies), 10p15, 19q, and 17p13.3." +EFO_0010634,"Definition: Snijders Blok-Fisher syndrome (SNIBFIS) is a neurodevelopmental disorder characterized by global developmental delay, hypotonia, variable impaired intellectual development, and specifically impaired speech and language acquisition. Patients achieve independent ambulation and most have mildly to moderately impaired cognition with autistic features, although a few may develop seizures and have a more severe phenotype. Dysmorphic features include abnormal, cupped, or prominent ears and ocular anomalies. Mutations usually occur de novo, although 1 family with autosomal dominant inheritance has been reported (summary by previous studies)." +MONDO_0007790,"Definition: Dejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (summary by previous studies)." +Orphanet_64748,"Definition: Dejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (summary by previous studies)." +MONDO_0008026,"Definition: Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. SMALED shows autosomal dominant inheritance with muscle weakness predominantly affecting the proximal lower extremities (previous studies). + +The most common form of SMA (see, e.g., SMA1, previous studies) shows autosomal recessive inheritance and is due to mutation in the SMN1 gene (previous studies) on chromosome 5q. + + Genetic Heterogeneity of Lower Extremity-Predominant Spinal Muscular Atrophy + +See also SMALED2A (previous studies) and SMALED2B (previous studies), both of which are caused by mutation in the BICD2 gene (previous studies) on chromosome 9q22. SMALED2A and SMALED2B differ in age at onset and severity, with SMALED2B being more severe." +MONDO_0008961,"Definition: By convention, the designation CMT4 is applied to autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease, which is a peripheral neuropathy characterized by distal motor and sensory impairment resulting in gait difficulties and associated with foot deformities. Motor nerve conduction velocities are decreased, and sural nerve biopsies show loss of myelinated fibers. The age at onset and severity is variable (summary by previous studies). + + Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 4 + +Several different subtypes of autosomal recessive demyelinating CMT (CMT4) have been identified, each with particular ethnic, pathologic, or clinical characteristics: CMT4A; CMT4B, which includes CMT4B1 (previous studies), caused by mutation in the MTMR2 gene (previous studies), CMT4B2 (previous studies), caused by mutation in the SBF2 gene (previous studies), and CMT4B3 (previous studies), caused by mutation in the SBF1 gene (previous studies); CMT4C (previous studies), caused by mutation in the SH3TC2 gene (previous studies); CMT4D (previous studies), caused by mutation in the NDRG1 gene (previous studies); CMT4E (previous studies), caused by mutation in the EGR2 (previous studies) or MPZ (previous studies) genes; CMT4F (previous studies), caused by mutation in the PRX gene (previous studies); CMT4G, or Russe-type hereditary motor and sensory neuropathy, (previous studies), which maps to chromosome 10q23; CMT4H (previous studies), caused by mutation in the FGD4 gene (previous studies); CMT4J (previous studies), caused by mutation in the FIG4 gene (previous studies); and CMT4K (previous studies), caused by mutation in the SURF1 gene (previous studies)." +MONDO_0011694,"Definition: SCA15 is an autosomal dominant, adult-onset, very slowly progressive form of cerebellar ataxia. Most patients also have disabling action and postural tremor, and some have pyramidal tract affection, dorsal column involvement, and gaze palsy. Brain imaging shows cerebellar atrophy mainly affecting the vermis (summary by previous studies). + +Heterozygous mutation in the ITPR1 gene can also cause SCA29 (previous studies), which is distinguished by onset in infancy of delayed motor development followed by nonprogressive ataxia and mild cognitive impairment. + +Autosomal dominant 'pure' cerebellar ataxia, classified as ADCA type III by previous studies, is a genetically heterogeneous disorder (see, e.g., previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0013873,"Definition: IMAGE is a rare multisystem disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. Patients with this condition may present shortly after birth with severe adrenal insufficiency, which can be life-threatening if not recognized early and steroid replacement therapy commenced. Other reported features in this condition include hypercalciuria and/or hypocalcemia, craniosynostosis, cleft palate, and scoliosis (summary by previous studies). + +A recessive form of IMAGE with immunodeficiency (IMAGEI; previous studies) is caused by mutation in the POLE gene (previous studies) on chromosome 12q24." +MONDO_0030399,"Definition: Autosomal recessive visceral neuropathy-2 (VSCN2) is characterized by intestinal dysmotility due to aganglionosis or hypoganglionosis of the colon. Patients also exhibit peripheral axonal neuropathy, ptosis, and sensorineural hearing loss (previous studies). + +For a discussion of genetic heterogeneity of VSCN, see VSCN1 (previous studies)." +MONDO_0030676,"Definition: Childhood-onset parkinsonism-dystonia-3 (PKDYS3) is an autosomal recessive neurodegenerative disorder with onset in infancy or early childhood. Affected individuals present with progressive movement abnormalities, including parkinsonism with tremor, dystonia, myoclonus ataxia, and hyperkinetic movements such as ballismus. The parkinsonism features may be responsive to treatment with levodopa, although many patients develop levodopa-induced dyskinesia. Some patients may have mild cognitive impairment or psychiatric disturbances (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of PKDYS, see previous studies." +MONDO_0032641,"Definition: Congenital mirror movements-4 is an autosomal dominant condition characterized by involuntary movements on either side of the body that accompany and mirror intentional movements on the opposite side. Mirror movements usually involve the upper limb and hands, resulting in difficulty performing pure unimanual movements. The pathophysiology is probably related to developmental abnormalities of fiber decussation in the corticospinal tract (summary by previous studies). + +For a discussion of genetic heterogeneity of mirror movements, see MRMV1 (previous studies)." +MONDO_0032773,Definition: Uridine-cytidineuria (URCTU) is an inborn error of metabolism comprising increased excretion of the pyrimidine nucleosides. This condition has been identified incidentally and may be a benign metabolic phenotype (summary by previous studies). +MONDO_0033641,"Definition: Cleft palate, proliferative retinopathy, and developmental delay (CPPRDD) is characterized by motor and speech delay, with intellectual disability ranging from mild to severe. Brain imaging shows ventriculomegaly as well as other malformations (previous studies)." +Orphanet_101075,"Definition: Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1) and primary peripheral axonal (type 2) neuropathies. The demyelinating neuropathies classified as CMT type 1, also known as HMSN I, are characterized by severely reduced motor nerve conduction velocities (NCV) (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy (see CMT1B; previous studies). The axonal neuropathies classified as CMT type 2, also known as HMSN II, are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (see CMT2A1; previous studies). Distal hereditary motor neuropathy (dHMN) (see previous studies) is a spinal type of CMT characterized by exclusive motor involvement and sparing of sensory nerves (previous studies). There are X-linked, autosomal dominant (see previous studies), and autosomal recessive (see previous studies) forms of CMT. + +The form of Charcot-Marie-Tooth neuropathy that maps to chromosome Xq13 (CMTX1) is X-linked dominant or X-linked intermediate; heterozygous females are more mildly affected than are hemizygous males. + + Genetic Heterogeneity of X-linked Charcot-Marie-Tooth Disease + +previous studies presented data suggesting the existence of an X-linked recessive CMT disease on Xp22.2 (CMTX2; previous studies). CMTX3 is caused by a genomic rearrangement between chromosomes 8q24.3 and Xq27.1. Cowchock syndrome (previous studies), which maps to chromosome Xq26, is also referred to as CMTX4. CMTX5 (previous studies) is caused by mutation in the PRPS1 gene (previous studies) on chromosome Xq22. CMTX6 (previous studies) is caused by mutation in the PDK3 gene (previous studies) on Xp22." +MONDO_0010549,"Definition: Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1) and primary peripheral axonal (type 2) neuropathies. The demyelinating neuropathies classified as CMT type 1, also known as HMSN I, are characterized by severely reduced motor nerve conduction velocities (NCV) (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy (see CMT1B; previous studies). The axonal neuropathies classified as CMT type 2, also known as HMSN II, are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (see CMT2A1; previous studies). Distal hereditary motor neuropathy (dHMN) (see previous studies) is a spinal type of CMT characterized by exclusive motor involvement and sparing of sensory nerves (previous studies). There are X-linked, autosomal dominant (see previous studies), and autosomal recessive (see previous studies) forms of CMT. + +The form of Charcot-Marie-Tooth neuropathy that maps to chromosome Xq13 (CMTX1) is X-linked dominant or X-linked intermediate; heterozygous females are more mildly affected than are hemizygous males. + + Genetic Heterogeneity of X-linked Charcot-Marie-Tooth Disease + +previous studies presented data suggesting the existence of an X-linked recessive CMT disease on Xp22.2 (CMTX2; previous studies). CMTX3 is caused by a genomic rearrangement between chromosomes 8q24.3 and Xq27.1. Cowchock syndrome (previous studies), which maps to chromosome Xq26, is also referred to as CMTX4. CMTX5 (previous studies) is caused by mutation in the PRPS1 gene (previous studies) on chromosome Xq22. CMTX6 (previous studies) is caused by mutation in the PDK3 gene (previous studies) on Xp22." +Orphanet_284169,"Definition: DeSanto-Shinawi syndrome is a rare neurodevelopmental disorder characterized by global developmental delay apparent in infancy or early childhood and associated with characteristic dysmorphic facial features, such as broad forehead, depressed nasal bridge with bulbous nasal tip, and deep-set eyes. Most patients also have gastrointestinal and mild ocular abnormalities, as well as behavioral problems (summary by previous studies)." +MONDO_0014741,"Definition: DeSanto-Shinawi syndrome is a rare neurodevelopmental disorder characterized by global developmental delay apparent in infancy or early childhood and associated with characteristic dysmorphic facial features, such as broad forehead, depressed nasal bridge with bulbous nasal tip, and deep-set eyes. Most patients also have gastrointestinal and mild ocular abnormalities, as well as behavioral problems (summary by previous studies)." +MONDO_0007848,Definition: Keratitis is a rare ocular disorder presenting with congenital and progressive features predominantly involving the anterior segment of the eye. The major clinical symptoms are anterior stromal corneal opacification and vascularization of the peripheral cornea. Progression of the opacification and vascularization into the central cornea may occur with corresponding reduction in visual acuity. Other anterior segment features include variable radial defects of the iris stroma and foveal hypoplasia (summary by previous studies). +MONDO_0009341,"Definition: Mowat-Wilson syndrome (MOWS) is an autosomal dominant complex developmental disorder; individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels. Mowat-Wilson syndrome has many clinical features in common with Goldberg-Shprintzen syndrome (previous studies) but the 2 disorders are genetically distinct (previous studies). Goldberg-Shprintzen syndrome is caused by mutation in the KIFBP gene (previous studies) on chromosome 10q." +MONDO_0010008,"Definition: Sarcosinemia is characterized by an increased concentration of sarcosine in plasma and an increased excretion of sarcosine in urine. Sarcosine (N-methylglycine) is enzymatically formed from dimethylglycine by dimethylglycine dehydrogenase (previous studies) and converted to glycine by sarcosine dehydrogenase (SARDH; previous studies; previous studies). Some reports have associated sarcosinemia with mental retardation and neurologic problems, but the disorder is most likely benign and unrelated to significant clinical problems (summary by previous studies)." +MONDO_0013227,"Definition: Plasminogen inhibitor-1 deficiency is a rare autosomal recessive hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of PAI1, which inhibits tissue (PLAT; previous studies) and urinary (PLAU; previous studies) activators of plasminogen (PLG; previous studies) (review by previous studies)." +MONDO_0014714,"Definition: Seizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (summary by previous studies)." +MONDO_0019349,"Definition: Sotos syndrome (SOTOS) is a neurologic disorder characterized by overgrowth from the prenatal stage through childhood, with advanced bone age, an unusual face with large skull, acromegalic features and pointed chin, occasional brain anomalies and seizures, and impaired intellectual development (summary by previous studies). + +Weaver syndrome (previous studies), which shows considerable phenotypic overlap with Sotos syndrome, has been shown to be caused by mutation in the EZH2 gene (previous studies) on chromosome 7q36." +MONDO_0023670,"Definition: Bardet-Biedl syndrome-20 (BBS20), a rare autosomal recessive disorder associated with ciliary dysfunction, is characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity, renal anomalies, and learning disability, as well as hypogonadism in males and genital abnormalities in females (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +Orphanet_51083,"Definition: Short QT syndrome is a cardiac channelopathy associated with a predisposition to atrial fibrillation and sudden cardiac death. Patients have a structurally normal heart, but electrocardiography (ECG) exhibits abbreviated QTc (Bazett's corrected QT) intervals of less than 360 ms (summary by previous studies). + + Genetic Heterogeneity of Short QT Syndrome + +Short QT syndrome-2 (SQT2; previous studies) is caused by mutation in the KCNQ1 gene (previous studies). SQT3 (previous studies) is caused by mutation in the KCNJ2 gene (previous studies). SQT7 (previous studies) is caused by mutation in the SLC4A3 gene (previous studies)." +Orphanet_88637,"Definition: Hypomyelinating leukodystrophy-7 is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability (summary by previous studies). + +See also HLD8 (previous studies), which has similar features and is caused by mutation in the POLR3B gene (previous studies) on chromosome 12q23. The POLR3A and POLR3B genes encode the 2 largest subunits of RNA polymerase III. + +For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see previous studies." +MONDO_0011897,"Definition: Hypomyelinating leukodystrophy-7 is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability (summary by previous studies). + +See also HLD8 (previous studies), which has similar features and is caused by mutation in the POLR3B gene (previous studies) on chromosome 12q23. The POLR3A and POLR3B genes encode the 2 largest subunits of RNA polymerase III. + +For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see previous studies." +Orphanet_137639,"Definition: Hypomyelinating leukodystrophy-7 is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability (summary by previous studies). + +See also HLD8 (previous studies), which has similar features and is caused by mutation in the POLR3B gene (previous studies) on chromosome 12q23. The POLR3A and POLR3B genes encode the 2 largest subunits of RNA polymerase III. + +For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see previous studies." +EFO_0003095,"Definition: The accumulation of excess triglyceride in the liver, a condition known as hepatic steatosis (or fatty liver disease, FLD), is associated with adverse metabolic consequences including insulin resistance and dyslipidemia. Factors promoting deposition of fat in the liver include obesity, diabetes, insulin resistance, and alcohol ingestion. Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in Western countries. In a subset of individuals hepatic steatosis promotes an inflammatory response in the liver, referred to as steatohepatitis, which can progress to cirrhosis and liver cancer (summary by previous studies). + +previous studies reviewed nonalcoholic fatty liver disease. + + Genetic Heterogeneity of Fatty Liver Disease + +Another form of fatty liver disease (FLD2; previous studies) has been associated with variation in the APOC3 gene (previous studies)." +EFO_0010564,"Definition: Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis (NEDBSS) is an autosomal recessive disorder characterized by severely impaired psychomotor development, hypotonia, seizures, and structural brain anomalies, including thin corpus callosum and cerebellar atrophy. Other features include scoliosis, dysmorphic facies, and visual impairment. Affected individuals are usually unable to walk or speak and may require tube feeding in severe cases. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by previous studies). + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +MONDO_0007405,"Definition: Crouzon syndrome is an autosomal dominant disorder characterized by craniosynostosis causing secondary alterations of the facial bones and facial structure. Common features include hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism (previous studies; previous studies)." +Orphanet_207,"Definition: Crouzon syndrome is an autosomal dominant disorder characterized by craniosynostosis causing secondary alterations of the facial bones and facial structure. Common features include hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism (previous studies; previous studies)." +MONDO_0007610,"Definition: Extreme hirsutism with gingival fibromatosis follows a dominant pattern of inheritance (previous studies; previous studies). There is no necessary relationship between the age of development of the gingival changes and the hypertrichosis. The latter may be present at birth but often appears at puberty (previous studies). + +For a discussion of genetic heterogeneity of congenital generalized hypertrichosis, see HTC1 (previous studies)." +MONDO_0008815,"Definition: Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle. Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (previous studies), carbamyl phosphate synthetase deficiency (previous studies), argininosuccinate synthetase deficiency, or citrullinemia (previous studies), argininosuccinate lyase deficiency, and arginase deficiency (previous studies). + +previous studies reviewed argininosuccinic aciduria and progress in understanding it as a monogenic disorder that, like other inborn errors of metabolism, manifests as a multifactorial disorder at the phenotypic level." +MONDO_0010185,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC (MAHCC; previous studies), cblD, cblF (MAHCF; previous studies), and cblJ (MAHCJ; previous studies). + +Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (previous studies), caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (previous studies), caused by mutation in the MMAA gene (previous studies) on 4q31; and MMA cblB (previous studies), caused by mutation in the MMAB gene (previous studies) on 12q24. Another form of isolated MMA (previous studies) can be caused by defect in the transcobalamin receptor (CD320; previous studies)." +Orphanet_79283,"Definition: Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; previous studies) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; previous studies). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC (MAHCC; previous studies), cblD, cblF (MAHCF; previous studies), and cblJ (MAHCJ; previous studies). + +Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (previous studies), caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (previous studies), caused by mutation in the MMAA gene (previous studies) on 4q31; and MMA cblB (previous studies), caused by mutation in the MMAB gene (previous studies) on 12q24. Another form of isolated MMA (previous studies) can be caused by defect in the transcobalamin receptor (CD320; previous studies)." +MONDO_0011266,"Definition: Myotonic dystrophy (DM) is a multisystem disorder and the most common form of muscular dystrophy in adults. Individuals with DM2 have muscle pain and stiffness, progressive muscle weakness, myotonia, male hypogonadism, cardiac arrhythmias, diabetes, and early cataracts. Other features may include cognitive dysfunction, hypersomnia, tremor, and hearing loss (summary by previous studies). + +See also myotonic dystrophy-1 (DM1; previous studies), caused by an expanded CTG repeat in the dystrophia myotonica protein kinase gene (DMPK; previous studies) on 19q13. + +Although originally reported as 2 disorders, myotonic dystrophy-2 and proximal myotonic myopathy are now referred to collectively as DM2 (previous studies)." +Orphanet_606,"Definition: Myotonic dystrophy (DM) is a multisystem disorder and the most common form of muscular dystrophy in adults. Individuals with DM2 have muscle pain and stiffness, progressive muscle weakness, myotonia, male hypogonadism, cardiac arrhythmias, diabetes, and early cataracts. Other features may include cognitive dysfunction, hypersomnia, tremor, and hearing loss (summary by previous studies). + +See also myotonic dystrophy-1 (DM1; previous studies), caused by an expanded CTG repeat in the dystrophia myotonica protein kinase gene (DMPK; previous studies) on 19q13. + +Although originally reported as 2 disorders, myotonic dystrophy-2 and proximal myotonic myopathy are now referred to collectively as DM2 (previous studies)." +MONDO_0012911,"Definition: Pseudohypoparathyroidism type Ic (PHP1C) is characterized by resistance to parathyroid hormone (PTH; previous studies) as well as to other hormones. It is associated with a constellation of physical features referred to as Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation. Laboratory studies in patients with PHP Ic show a decreased cellular cyclic AMP (cAMP) response to infused PTH, but no defect in activity of the erythrocyte Gs protein (previous studies)." +MONDO_0014157,"Definition: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance, and metabolic abnormalities including insulin resistance and diabetes mellitus. Sensorineural deafness occurs late in the first or second decades of life (summary by previous studies)." +MONDO_0030868,"Definition: Spermatogenic failure-49 (SPGF49) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), primarily coiled and short flagella, with markedly reduced or no progressive motility (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see previous studies." +MONDO_0031028,"Definition: Developmental and epileptic encephalopathy-105 with hypopituitarism (DEE105) is an autosomal recessive disorder characterized by the onset of seizures and pituitary insufficiency in the first weeks or months of life. Affected individuals have profoundly impaired development with almost no acquisition of skills. They are hypotonic, unable to sit or speak, and have poor or absent visual fixation. Endocrine workup shows central pituitary dysfunction with low hormone levels. Brain imaging shows cerebral atrophy, thin corpus callosum, and small pituitary gland (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0033642,"Definition: Bachmann-Bupp syndrome (BABS) is a neurometabolic disorder associated with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, dysmorphic features, and characteristic neuroimaging features (summary by previous studies)." +MONDO_0060583,"Definition: Immunodeficiency-71 with inflammatory disease and congenital thrombocytopenia (IMD71) is an autosomal recessive immunologic disorder characterized by the onset of recurrent infections and inflammatory features such as vasculitis and eczema in infancy or early childhood. Infectious agents include bacteria and viruses. Laboratory findings are variable, but usually show thrombocytopenia, sometimes with abnormal platelet morphology, increased serum IgE, IgA, or IgM, leukocytosis, decreased or increased T lymphocytes, and increased eosinophils. Detailed studies show impaired neutrophil and T-cell chemotaxis, as well as impaired T-cell activation due to defects in F-actin (see previous studies) polymerization (summary by previous studies)." +EFO_0009022,"Definition: BBS10 is characterized by progressive retinal dystrophy, obesity, polydactyly, cognitive impairment, and renal dysplasia (previous studies). BBS10 represents a major locus for BBS, with mutations in the BBS10 gene accounting for approximately 20% of BBS patients (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +EFO_1001103,"Definition: The ductus arteriosus is a vital in utero vascular connection between the aorta and pulmonary artery that allows right ventricular output to bypass the nonventilated fetal lungs. Postnatal closure of the ductus arteriosus is an important step in normal cardiopulmonary transition. Failure of ductal closure results in patent ductus arteriosus (PDA), which occurs in approximately 2 to 8 per 10,000 term infants and constitutes 5% to 7% of all congenital heart defects (summary by previous studies). + +For a discussion of genetic heterogeneity of isolated PDA, see PDA1 (previous studies)." +MONDO_0007435,"Definition: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder with protean clinical manifestations consisting of various combinations of myoclonus, seizures, ataxia, choreoathetosis, and dementia. The clinical presentation correlates with the size of the causative CAG repeats, and as such, affected family members can present with very different patterns of the disorder (summary by previous studies)." +Orphanet_101,"Definition: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder with protean clinical manifestations consisting of various combinations of myoclonus, seizures, ataxia, choreoathetosis, and dementia. The clinical presentation correlates with the size of the causative CAG repeats, and as such, affected family members can present with very different patterns of the disorder (summary by previous studies)." +MONDO_0007836,"Definition: IVIC syndrome (IVIC) is an autosomal dominant disorder characterized by upper limb anomalies (radial ray defects, carpal bone fusion), extraocular motor disturbances, and congenital bilateral nonprogressive mixed hearing loss. More variable features include heart involvement, mild thrombocytopenia and leukocytosis (before age 50), shoulder girdle hypoplasia, imperforate anus, kidney malrotation, and rectovaginal fistula (summary by previous studies)." +MONDO_0009529,"Definition: DLD deficiency is an autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). This is the result of E3 being a common component of all 3 mitochondrial multienzyme complexes. Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. E3 deficiency is often associated with increased urinary excretion of alpha-keto acids, such as pyruvate (summary by previous studies). E3 deficiency can also be associated with increased concentrations of branched-chain amino acids, as observed in maple syrup urine disease (MSUD; previous studies), and is sometimes referred to as 'MSUD type III,' although patients with E3 deficiency have additional biochemical defects (previous studies; previous studies)." +MONDO_0013472,Definition: Fatal infantile hypertonic myofibrillar myopathy is a severe autosomal recessive muscular dystrophy with onset in the first weeks of life after a normal neonatal period. Affected infants show rapidly progressive muscular rigidity of the trunk and limbs associated with increasing respiratory difficulty resulting in death before age 3 years (summary by previous studies). +MONDO_0014757,"Definition: Takenouchi-Kosaki syndrome is a highly heterogeneous autosomal dominant complex congenital developmental disorder affecting multiple organ systems. The core phenotype includes delayed psychomotor development with variable intellectual disability, dysmorphic facial features, and cardiac, genitourinary, and hematologic or lymphatic defects, including thrombocytopenia and lymphedema. Additional features may include abnormalities on brain imaging, skeletal anomalies, and recurrent infections. Some patients have a milder disease course reminiscent of Noonan syndrome (see, e.g., NS1, previous studies) (summary by previous studies)." +MONDO_0033655,"Definition: Mitochondrial complex IV deficiency nuclear type 20 (MC4DN20) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show hypotonia, failure to thrive, and global developmental delay. Additional features include elevated liver enzymes, increased serum lactate, metabolic acidosis, and pulmonary arterial hypertension (PAH), which may result in cardiorespiratory failure and early death. Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV (previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0859191,"Definition: Biliary, renal, neurologic, and skeletal syndrome (BRENS) is an autosomal recessive complex ciliopathy with multisystemic manifestations. The most common presentation is severe neonatal cholestasis that progresses to liver fibrosis and cirrhosis. Most patients have additional clinical features suggestive of a ciliopathy, including postaxial polydactyly, hydrocephalus, retinal abnormalities, and situs inversus. Additional features of the syndrome may include congenital cardiac defects, echogenic kidneys with renal failure, ocular abnormalities, joint hyperextensibility, and dysmorphic facial features. Some patients have global developmental delay. Brain imaging typically shows dilated ventricles, hypomyelination, and white matter abnormalities, although some patients have been described with abnormal pituitary development (summary by previous studies and previous studies)." +Orphanet_2523,"Definition: Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present (summary by previous studies and previous studies). + + Genetic Heterogeneity of Diencephalic-Mesencephalic Junction Dysplasia Syndrome + +See also DMJDS2 (previous studies), caused by mutation in the GSX2 gene (previous studies) on chromosome 4q12." +Orphanet_363300,"Definition: Diarrhea-11 (DIAR11) is characterized by onset of intractable malabsorptive diarrhea within the first few weeks of life (previous studies). + +For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (previous studies)." +EFO_0010279,"Definition: GIST-plus syndrome (GISTPS) is an autosomal dominant disorder characterized by incomplete penetrance of multiple mesenchymal tumors of the gastrointestinal tract, including gastrointestinal stromal tumor (GIST), inflammatory fibroid polyps (IFP), and fibroid tumors (FT). Some patients have been reported with coarse facies and skin, broad hands and feet, and premature tooth loss. Isolated GISTs and IFPs are seen in patients with somatic PDGFRA mutations (summary by previous studies)." +EFO_0010643,"Definition: Snijders Blok-Campeau syndrome (SNIBCPS) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development and delayed speech acquisition. Affected individuals tend to have expressive language deficits, with speech apraxia and dysarthria. Other features include macrocephaly and characteristic facial features, such as prominent forehead and hypertelorism, hypotonia, and joint laxity. The severity of the neurologic deficits and presence of nonneurologic features is variable (summary by previous studies)." +EFO_0020034,"Definition: Familial Behcet-like autoinflammatory syndrome-1 (AIFBL1) is an autosomal dominant monogenic autoinflammatory disease characterized predominantly by painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. The onset of symptoms is usually in the first decade, although later onset has been reported. Additional more variable features include skin rash, uveitis, and polyarthritis, consistent with a systemic hyperinflammatory state. Many patients have evidence of autoimmune disease. Rare patients may also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired function of immune cells. The disorder results from a failure of mutant TNFAIP3 to suppress the activation of inflammatory cytokines in the NFKB (see previous studies) signaling pathway; treatment with tumor necrosis factor (TNFA; previous studies) inhibitors may be beneficial. Although some of the clinical features of AIFBL1 resemble those of Behcet disease (previous studies), the more common form of Behcet disease is believed to be polygenic, typically shows later onset in early adulthood, and has symptoms usually restricted to the mucosa (summary by previous studies; previous studies, and previous studies). + + Genetic Heterogeneity of AIFBL + +See also AIFBL2 (previous studies), caused by mutation in the ELF4 gene (previous studies) on chromosome Xq26, and AIFBL3 (previous studies), caused by mutation in the RELA gene (previous studies) on chromosome 11q13." +MONDO_0800045,"Definition: Familial Behcet-like autoinflammatory syndrome-1 (AIFBL1) is an autosomal dominant monogenic autoinflammatory disease characterized predominantly by painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. The onset of symptoms is usually in the first decade, although later onset has been reported. Additional more variable features include skin rash, uveitis, and polyarthritis, consistent with a systemic hyperinflammatory state. Many patients have evidence of autoimmune disease. Rare patients may also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired function of immune cells. The disorder results from a failure of mutant TNFAIP3 to suppress the activation of inflammatory cytokines in the NFKB (see previous studies) signaling pathway; treatment with tumor necrosis factor (TNFA; previous studies) inhibitors may be beneficial. Although some of the clinical features of AIFBL1 resemble those of Behcet disease (previous studies), the more common form of Behcet disease is believed to be polygenic, typically shows later onset in early adulthood, and has symptoms usually restricted to the mucosa (summary by previous studies; previous studies, and previous studies). + + Genetic Heterogeneity of AIFBL + +See also AIFBL2 (previous studies), caused by mutation in the ELF4 gene (previous studies) on chromosome Xq26, and AIFBL3 (previous studies), caused by mutation in the RELA gene (previous studies) on chromosome 11q13." +MONDO_0007690,Definition: Aromatase excess syndrome is an autosomal dominant disorder characterized by increased extraglandular aromatization of steroids that presents with heterosexual precocity in males and isosexual precocity in females (previous studies). +MONDO_0007727,"Definition: Familial periodic fever (FPF) is an autoinflammatory disorder characterized by recurrent fever with localized myalgia and painful erythema. Febrile attacks may last 1 or 2 days but often last longer than 1 week. Arthralgia of large joints, abdominal pain, conjunctivitis, and periorbital edema are common features. During attacks, painless cutaneous lesions may develop on the trunk or extremities and may migrate distally (review by previous studies)." +Orphanet_32960,"Definition: Familial periodic fever (FPF) is an autoinflammatory disorder characterized by recurrent fever with localized myalgia and painful erythema. Febrile attacks may last 1 or 2 days but often last longer than 1 week. Arthralgia of large joints, abdominal pain, conjunctivitis, and periorbital edema are common features. During attacks, painless cutaneous lesions may develop on the trunk or extremities and may migrate distally (review by previous studies)." +MONDO_0009111,"Definition: DPYS deficiency is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by previous studies). + +See also dihydropyrimidine dehydrogenase deficiency (previous studies), a similar disorder." +MONDO_0009894,"Definition: Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by previous studies and previous studies). + +There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, previous studies). + +For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (previous studies)." +MONDO_0012118,"Definition: CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. + +For a general discussion of CDGs, see CDG1A (previous studies)." +MONDO_0014076,"Definition: Dyskeratosis congenita (DKC) is a bone marrow failure syndrome characterized by severely shortened telomeres and diverse clinical symptoms. The classic presentation of DKC includes nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is a severe clinical variant of DKC that is characterized by intrauterine growth failure, microcephaly, developmental delay, immunodeficiency, bone marrow failure, gastrointestinal disease, and cerebellar hypoplasia. Patients with mutations in the RTEL1 gene tend to present with HHS (summary by previous studies). + +For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (previous studies)." +MONDO_0014196,"Definition: Hartsfield syndrome (HRTFDS) classically refers to the triad of holoprosencephaly, ectrodactyly, and cleft/lip palate. Profound mental retardation is also present. Multiple other congenital anomalies usually occur (previous studies). The disorder involves midline and limb field defects (previous studies). + +See also ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC; previous studies), which shows phenotypic similarities." +MONDO_0018264,"Definition: Oculocutaneous albinism (OCA) is a heterogeneous autosomal recessive disorder, with a worldwide prevalence of approximately 1:17,000. It manifests as a reduction or complete loss of melanin in the skin, hair, and eyes, often accompanied by eye symptoms such as photophobia, strabismus, moderate to severe visual impairment, and nystagmus (summary by previous studies). + +For a discussion of genetic heterogeneity of oculocutaneous albinism, see OCA1 (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of variation in skin, hair, and eye pigmentation, see SHEP1 (previous studies)." +MONDO_0030019,"Definition: Anauxetic dysplasia-3 (ANXD3) is characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. Radiographs show short metacarpals, broad middle phalanges, and metaphyseal irregularities. Most patients also exhibit motor and cognitive delays (previous studies). + +For a discussion of genetic heterogeneity of anauxetic dysplasia, see ANXD1 (previous studies)." +MONDO_0032697,"Definition: Neurodevelopmental disorder and language delay with or without structural brain abnormalities (NEDLBA) is characterized by global developmental delay apparent from infancy. The phenotype is highly variable: patients may have hypotonia, behavioral abnormalities, and abnormalities on brain imaging, including enlarged ventricles, thin corpus callosum, and sometimes small brainstem. Many develop seizures, sometimes refractory, and some may have nonspecific dysmorphic features. Intellectual impairment can vary from mild to profound, and some patients may benefit from special education and respond well to speech therapy (summary by previous studies)." +MONDO_0032891,"Definition: Rupture of an intracranial aneurysm (IA), an outpouching or sac-like widening of a cerebral artery, leads to a subarachnoid hemorrhage (SAH), a sudden-onset disease that can lead to severe disability and death. Several risk factors such as smoking, hypertension, and excessive alcohol intake are associated with subarachnoid hemorrhage (summary by previous studies)." +Orphanet_2770,"Definition: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-2 (PLOSL2), or Nasu-Hakola disease, is a recessively inherited presenile frontal dementia with leukoencephalopathy and basal ganglia calcification. In most cases the disorder first manifests in early adulthood as pain and swelling in ankles and feet, followed by bone fractures. Neurologic symptoms manifest in the fourth decade of life as a frontal lobe syndrome with loss of judgment, euphoria, and disinhibition. Progressive decline in other cognitive domains begins to develop at about the same time. The disorder culminates in a profound dementia and death by age 50 years (summary by previous studies). + +For a discussion of genetic heterogeneity of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, see previous studies." +Orphanet_93346,"Definition: The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (summary by previous studies)." +MONDO_0008476,"Definition: The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (summary by previous studies)." +EFO_0004252,"Definition: Nasopharyngeal carcinoma (NPCA) is a malignant tumor that emerges from the epithelium of the nasopharynx. It has a high incidence in southern China, and evidence suggests that there may be a genetic component that underlies familial clustering. Some patients have onset before 20 years of age (summary by previous studies) + +For a general phenotypic description and a discussion of genetic heterogeneity of susceptibility to nasopharyngeal carcinoma, see NPCA1 (previous studies)." +EFO_1000177,"Definition: Choroid plexus tumors are of neuroectodermal origin and range from benign choroid plexus papillomas (CPPs) to malignant choroid carcinomas (CPCs). These rare tumors generally occur in childhood, but have also been reported in adults. Patients typically present with signs and symptoms of increased intracranial pressure including headache, hydrocephalus, papilledema, nausea, vomiting, cranial nerve deficits, gait impairment, and seizures (summary by previous studies)." +MONDO_0007077,Definition: Tietz albinism-deafness syndrome (TADS) is characterized by generalized pigment loss and congenital complete sensorineural hearing loss (summary by previous studies). +MONDO_0007244,"Definition: Caffey disease is an autosomal dominant disorder characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. Painful swelling and systemic fever often accompany the episode, which usually begins before the age of 5 months and resolves before age 2 years. Laboratory findings include an elevated level of alkaline phosphatase and sometimes an elevation in white blood cell count and erythrocyte sedimentation rate. Recurrent episodes are uncommon (summary by previous studies)." +MONDO_0009235,"Definition: Familial benign fleck retina is an autosomal recessive condition associated with a distinctive retinal appearance and no apparent visual or electrophysiologic deficits. Affected individuals are asymptomatic, but fundus examination reveals a striking pattern of diffuse, yellow-white, fleck-like lesions extending to the far periphery of the retina but sparing the foveal region (summary by previous studies)." +MONDO_0010589,"Definition: Aarskog-Scott syndrome, also known as faciogenital dysplasia, is an X-linked disorder characterized by short stature, hypertelorism, shawl scrotum, and brachydactyly, although there is wide phenotypic variability and other features, such as joint hyperextensibility, short nose, widow's peak (previous studies), and inguinal hernia, may also occur. Most patients do not have impaired intellectual development, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature (summary by previous studies)." +MONDO_0012108,"Definition: The Borochowitz-Cormier-Daire type of spondyloepimetaphyseal dysplasia (SEMDBCD) is a rare type of autosomal recessive short-limb short-trunk dwarfism. Affected individuals have significant short stature with pronounced leg bowing, lumbar lordosis, and a waddling gait (summary by previous studies and previous studies)." +MONDO_0014005,"Definition: Nephrotic syndrome type 7 is an autosomal recessive renal disease characterized by onset of nephrotic syndrome with proteinuria usually in the first decade of life. The disorder is progressive, and some patients develop end-stage renal disease within several years. Renal biopsy typically shows membranoproliferative glomerulonephritis. Some patients may benefit from immunosuppressive therapy (summary by previous studies). + +Atypical hemolytic uremic syndrome-7 is characterized by acute onset in the first year of life of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. After the acute episode, most patients develop chronic renal insufficiency. Unlike other genetic forms of aHUS, AHUS7 is not related to abnormal activation of the complement system (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (previous studies)." +MONDO_0014562,"Definition: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth, usually resulting in death. Rare patients may have later onset with a more protracted course. Tissue samples from affected individuals show decreased levels of coenzyme Q10 (CoQ10) (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (previous studies)." +MONDO_0030033,"Definition: Early-onset seizures with neurodegeneration and brain calcifications (SENEBAC) is an autosomal recessive encephalopathy characterized by onset of refractory seizures in the first year of life. Affected individuals tend to have normal or mildly delayed development early in life, but show significant and progressive developmental regression associated with seizure onset. Features include hypotonia, peripheral spasticity, poor eye contact, and absent speech. Most require tube feeding; death in childhood may occur. Brain imaging shows cerebral atrophy, loss of white matter, and punctate calcifications, suggestive of abnormal neuroinflammation (summary by previous studies and previous studies)." +MONDO_0030296,"Definition: Megacystis-microcolon-intestinal hypoperistalsis syndrome-4 (MMIHS4) is a severe early-onset disorder characterized by impaired smooth muscle contractility in the bladder and intestines (previous studies). + +For a discussion of genetic heterogeneity of MMIHS, see previous studies." +MONDO_0030855,"Definition: Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2) is an autosomal dominant generalized connective tissue disorder characterized by features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae) and Ehlers-Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility) (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of combined osteogenesis imperfecta and Ehlers-Danlos syndrome, see previous studies." +MONDO_0030991,"Definition: Bile acid conjugation defect-1 (BACD1) is an autosomal recessive metabolic disorder characterized by onset of symptoms, including jaundice and failure to thrive, in early infancy. The clinical features of the disorder result from impaired absorption of fat-soluble vitamins. Vitamin D deficiency causes rickets with variable growth deficiency, and vitamin K deficiency causes a coagulopathy with decreased production of vitamin K-dependent clotting factors. More variable features may include pruritis, anemia, hepatomegaly, and bile duct proliferation on liver biopsy. Laboratory studies show abnormally increased levels of unconjugated bile acids (summary by previous studies). + +See also familial hypercholanemia (FHCA; previous studies), in which patients have increased serum bile levels of conjugated bile acids." +MONDO_0031054,"Definition: Primary ciliary dyskinesia-48 without situs inversus (CILD48) is an autosomal recessive disorder characterized by recurrent upper and lower respiratory infections due to impaired ciliary movement and clearance. Affected individuals often develop chronic lung disease. Since the defect involves the radial spokes and central pairs of microtubules in motile cilia, situs abnormalities do not occur (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (previous studies)." +MONDO_0032917,Definition: Autosomal dominant deafness-76 (DFNA76) is characterized by progressive or nonprogressive hearing loss with variable age at onset. Hearing loss is more severe at higher frequencies in most patients (previous studies; previous studies; previous studies). +Orphanet_3226,"Definition: Primary lymphedema with myelodysplasia, also known as Emberger syndrome, is a rare disorder characterized by childhood-onset lymphedema of the lower limbs, with lymphoscintigraphy suggestive of lymphatic vessel hypoplasia, and genital lymphatic abnormalities. Myelodysplasia is usually with monosomy 7. Multiple warts, deafness, and minor anomalies (mild hypotelorism, neck webbing, and slender fingers) may also be present (summary by previous studies)." +MONDO_0013540,"Definition: Primary lymphedema with myelodysplasia, also known as Emberger syndrome, is a rare disorder characterized by childhood-onset lymphedema of the lower limbs, with lymphoscintigraphy suggestive of lymphatic vessel hypoplasia, and genital lymphatic abnormalities. Myelodysplasia is usually with monosomy 7. Multiple warts, deafness, and minor anomalies (mild hypotelorism, neck webbing, and slender fingers) may also be present (summary by previous studies)." +Orphanet_48431,"Definition: Congenital cataracts, facial dysmorphism, and neuropathy is an autosomal recessive disorder that is prevalent among Bulgarian Gypsies. Additional features include delayed psychomotor development, skeletal anomalies, and hypogonadism. The predominantly motor neuropathy becomes evident during childhood and progresses to severe disability by the third decade (previous studies). + +CCFDN is genetically distinct from Marinesco-Sjogren syndrome (MSS; previous studies), although the 2 disorders share some overlapping features, including congenital cataracts, delayed psychomotor development, and ataxia (previous studies)." +MONDO_0011402,"Definition: Congenital cataracts, facial dysmorphism, and neuropathy is an autosomal recessive disorder that is prevalent among Bulgarian Gypsies. Additional features include delayed psychomotor development, skeletal anomalies, and hypogonadism. The predominantly motor neuropathy becomes evident during childhood and progresses to severe disability by the third decade (previous studies). + +CCFDN is genetically distinct from Marinesco-Sjogren syndrome (MSS; previous studies), although the 2 disorders share some overlapping features, including congenital cataracts, delayed psychomotor development, and ataxia (previous studies)." +EFO_0004127,"Definition: Familial dysalbuminemic hyperthyroxinemia (FDAH) is an autosomal dominant condition characterized by the presence of a variant serum albumin with preferential affinity for thyroxine (T4) in clinically euthyroid individuals. Individuals have consistently elevated total T4 and elevated or normal free T4 values with normal TSH levels. FDAH is the most commonly inherited euthyroid hyperthyroxinemia in Caucasian populations with an estimated prevalence of 1 in 10,000 individuals. The condition does not cause disease since the concentration of free hormone is normal, but affected individuals may be at risk for unnecessary laboratory testing and possibly even inappropriate treatment (summary by previous studies and previous studies)." +EFO_0020902,"Definition: Two main types of recessive H-deficient red cell phenotypes are recognized: (1) the nonsecretor classic Bombay type (h null and se (FUT2; previous studies) null) with H deficiency of both red cells and saliva, and (2) the secretor Bombay type (h null, Se heterozygous) with H deficiency in red cells but normal ABH in secretions. The latter has been designated para-Bombay phenotype. Under this 2-locus model, the H blood group locus determines expression of the H antigen (as well as the A and/or B antigens) in the erythroid lineage, whereas the SE locus controls H expression (and thus A or B antigen expression) in a variety of secretory epithelia and in saliva. Bombay and para-Bombay individuals display no apparent deleterious phenotype except in circumstances requiring blood transfusion, wherein they are cross-match incompatible with all donors except other H-deficient individuals (summary by previous studies)." +MONDO_0007958,"Definition: Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin (previous studies)-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2 (see previous studies)/familial medullary thyroid carcinoma (FMTC) syndromes (summary by previous studies). Thyroid cancer derived from follicular epithelial cells is referred to as nonmedullary thyroid cancer and comprises several subtypes; see previous studies." +MONDO_0008721,"Definition: Inherited deficiency of medium-chain acyl-CoA dehydrogenase is characterized by intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma with medium-chain dicarboxylic aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels. The disorder may be severe, and even fatal, in young patients (previous studies)." +MONDO_0009261,"Definition: GM1-gangliosidosis type II (GM1G2) is an autosomal recessive lysosomal storage disease characterized by slowly progressive generalized neurodegeneration and mild skeletal changes, with onset between 7 months and 3 years of age. Unlike the severe infantile type I, type II is usually not associated with macular cherry-red spots or organomegaly. Within type II, those with somewhat earlier onset and earlier death are considered to have the 'late-infantile' form, whereas those with slightly later onset and survival into late childhood are referred to as having the 'juvenile' form (previous studies). However, there is no strict age marker to distinguish between these 2 type II forms. GLB1 enzyme activity in type II ranges from approximately 1 to 4% of control values (previous studies; previous studies)." +MONDO_0009479,"Definition: Johanson-Blizzard syndrome is an autosomal recessive disorder characterized by poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency (summary by previous studies)." +MONDO_0009568,"Definition: Mast syndrome (MASTS) is an autosomal recessive complicated form of hereditary spastic paraplegia in which progressive spastic paraparesis is associated in more advanced cases with cognitive decline, dementia, and other neurologic abnormalities. Symptom onset usually occurs in adulthood, and the disorder is progressive with variable severity. Brain imaging shows thinning of the corpus callosum. The disorder occurs with high frequency in the Old Order Amish (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0013607,"Definition: This primary immunodeficiency, designated IMD21, DCML, or MONOMAC, is characterized by profoundly decreased or absent monocytes, B lymphocytes, natural killer (NK) lymphocytes, and circulating and tissue dendritic cells (DCs), with little or no effect on T-cell numbers. Clinical features of IMD21 are variable and include susceptibility to disseminated nontuberculous mycobacterial infections, papillomavirus infections, opportunistic fungal infections, and pulmonary alveolar proteinosis. Bone marrow hypocellularity and dysplasia of myeloid, erythroid, and megakaryocytic lineages are present in most patients, as are karyotypic abnormalities, including monosomy 7 and trisomy 8. In the absence of cytogenetic abnormalities or overt dysplasia, hypoplastic bone marrow may initially be diagnosed as aplastic anemia. Bone marrow transplantation is the only cure. Some patients may have an increased risk of miscarriage. Both autosomal dominant transmission and sporadic cases occur. Less common manifestations of GATA2 deficiency include lymphedema and sensorineural hearing loss, a phenotype usually termed 'Emberger syndrome' (previous studies) (summary by previous studies, previous studies, and previous studies)." +MONDO_0014021,"Definition: Familial episodic pain syndrome-1 is an autosomal dominant neurologic disorder characterized by onset in infancy of episodic debilitating upper body pain triggered by fasting, cold, and physical stress (summary by previous studies). + + Genetic Heterogeneity of Familial Episodic Pain Syndrome + +See also FEPS2 (previous studies), caused by mutation in the SCN10A gene (previous studies) on chromosome 3p22, and FEPS3 (previous studies), caused by mutation in the SCN11A gene (previous studies) on chromosome 3p22." +MONDO_0018996,"Definition: Autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 is a neurodegenerative disorder characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, and increased serum alpha-fetoprotein (AFP; previous studies). Oculomotor apraxia is a common but inconsistent finding, found in about 50% of patients; hence this disorder is sometimes referred to as 'ataxia-oculomotor apraxia-2' (AOA2) (previous studies; summary by previous studies). + +previous studies emphasized that oculomotor apraxia is not a universal finding in this disorder and suggested the name 'spinocerebellar ataxia, autosomal recessive, with axonal neuropathy-2' (SCAN2) to distinguish it from SCAN1 (previous studies). + +For a discussion of genetic heterogeneity of ataxia-oculomotor apraxia, see AOA1 (previous studies). + +For a discussion of genetic heterogeneity of SCAN, see SCAN1 (previous studies)." +Orphanet_64753,"Definition: Autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 is a neurodegenerative disorder characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, and increased serum alpha-fetoprotein (AFP; previous studies). Oculomotor apraxia is a common but inconsistent finding, found in about 50% of patients; hence this disorder is sometimes referred to as 'ataxia-oculomotor apraxia-2' (AOA2) (previous studies; summary by previous studies). + +previous studies emphasized that oculomotor apraxia is not a universal finding in this disorder and suggested the name 'spinocerebellar ataxia, autosomal recessive, with axonal neuropathy-2' (SCAN2) to distinguish it from SCAN1 (previous studies). + +For a discussion of genetic heterogeneity of ataxia-oculomotor apraxia, see AOA1 (previous studies). + +For a discussion of genetic heterogeneity of SCAN, see SCAN1 (previous studies)." +MONDO_0800129,"Definition: X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature (previous studies and previous studies)." +Orphanet_2966,"Definition: Properdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (previous studies)." +MONDO_0010713,"Definition: Properdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (previous studies)." +Orphanet_137754,"Definition: Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by previous studies)." +MONDO_0008673,"Definition: Weyers acrofacial dysostosis (WAD) is an autosomal dominant disorder with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar disorder, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease (summary by previous studies)." +MONDO_0009140,"Definition: Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage (summary by previous studies)." +Orphanet_1865,"Definition: Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage (summary by previous studies)." +MONDO_0011472,"Definition: Ectodermal dysplasia/skin fragility syndrome (EDSFS) is an autosomal recessive genodermatosis characterized by widespread skin fragility, alopecia, nail dystrophy, and focal keratoderma with painful fissures. Hyohidrosis and cheilitis are sometimes present (summary by previous studies)." +MONDO_0032902,"Definition: Joubert syndrome-36 (JBTS36) is an autosomal recessive ciliopathy characterized by global developmental delay, ocular movement abnormalities, and mesoaxial polydactyly. Brain imaging may be normal or show the classic 'molar tooth sign.' There is some phenotypic similarity to and overlap with orofaciodigital syndrome VI (OFD6; previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (previous studies)." +MONDO_0100151,"Definition: Cystinosis has been classified as a lysosomal storage disorder on the basis of cytologic and other evidence pointing to the intralysosomal localization of stored cystine. Cystinosis differs from the other lysosomal diseases inasmuch as acid hydrolysis, the principal enzyme function of lysosomes, is not known to play a role in the metabolic disposition of cystine. The fact that plasma levels are well below saturation indicates that the defect is a cellular one. Within the cell, cystine is compartmentalized with acid phosphatase and is membrane-bound as demonstrated by electron microscopy. Ferritin accumulates in the same organelle which appears to be the lysosome." +EFO_0003778,"Definition: Psoriasis (previous studies) is a chronic inflammatory skin disease that may have an autoimmune basis. The disorder has a strong but complex genetic basis, with a concordance rate of 50 to 70% among monozygotic twins. Psoriatic arthritis affects more than 10% of patients with psoriasis and, in most cases, there is an association between the severity of the arthritis and the skin involvement (previous studies)." +EFO_0009076,"Definition: Y-linked deafness-2 (DFNY2) is characterized by male-limited bilateral progressive sensorineural hearing loss of variable severity, with onset in the third to fifth decades of life (previous studies). + +For a discussion of genetic heterogeneity of Y-linked deafness, see DFNY1 (previous studies)." +EFO_0009150,"Definition: Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Women with ICP are also susceptible to oral contraceptive-induced cholestasis (OCIC). Ursodeoxycholic acid (UDCA) is an effective treatment for conditions caused by ABCB4 mutations (summary by previous studies). + +Mutation in the ABCB4 gene accounts for about 15% of ICP cases (summary by previous studies). + +For a discussion of genetic heterogeneity of ICP, see ICP1 (previous studies)." +MONDO_0007289,"Definition: The i and I antigens of the I blood group system (previous studies) are carbohydrate structures carried on glycolipids and glycoproteins and are characterized as straight or branched glycochains composed of repeating N-acetyllactosamine (LacNAc) units, respectively. Conversion of i antigen into an I-active structure requires the activity of the I-branching enzyme, beta-1,6-N-acetylglucosaminyltransferase (GCNT2; previous studies), which adds the decisive GlcNAc-beta-1-6 branch onto the straight poly-LacNAc chains. Expression of the i and I antigens on red blood cells (RBCs) is reciprocal and developmentally regulated. Adult human RBCs predominantly express I antigen, whereas fetal and neonatal RBCs predominantly express i antigen. After birth, I antigen levels increase gradually as i antigen levels fall, with the normal Ii status of adult RBCs reached after about 13 to 20 months. Mutations that specifically affect 1 of the 3 variants produced by the GCNT2 gene cause the rare adult i phenotype (see previous studies), in which adult RBCs are rich in i antigen and contain low levels of I antigen. Mutations that eliminate all 3 GCNT2 variants cause the adult i phenotype with congenital cataract (review by previous studies)." +MONDO_0007376,"Definition: Fleck corneal dystrophy (CFD) is a rare autosomal dominant disease characterized by numerous tiny, dot-like white flecks scattered in all layers of the corneal stroma. Typically, the stroma located in between the flecks is clear, and the endothelium, the epithelium, Bowman layer, and Descemet membrane are normal. Patients are usually asymptomatic with normal vision, yet a small number of patients report the sensation of a minor photophobia. The flecks in CFD can appear as early as 2 years of age, or sometimes even at birth, and appear not to progress significantly throughout life. Histologically, the corneal flecks appear to correspond to abnormal keratocytes swollen with membrane-limited intracytoplasmic vesicles containing complex lipids and glycosaminoglycans (summary by previous studies)." +MONDO_0008722,"Definition: SCAD deficiency is an autosomal recessive metabolic disorder of fatty acid beta-oxidation. Clinical features are variable: a severe form of the disorder can cause infantile onset of acidosis and neurologic impairment, whereas some patients develop only myopathy. With the advent of screening for inborn errors of metabolism, patients with putative pathogenic mutations but who remain asymptomatic have also been identified (summary by previous studies)." +MONDO_0009112,"Definition: Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 (previous studies) is the most frequent form of RCDP (summary by previous studies). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (previous studies). + +For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see previous studies." +MONDO_0009192,"Definition: Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis, and growth retardation develop at a later age. Other frequent multisystem manifestations include hepatic and renal dysfunction, mental retardation, and cardiovascular abnormalities (summary by previous studies)." +MONDO_0013892,"Definition: C3 glomerulopathy-3 (C3G3) is an autosomal dominant kidney disease characterized by the onset of microscopic or macroscopic hematuria in the first 3 decades of life, followed by variable progression of renal disease. After age 30, about half of patients continue to have episodic hematuria while maintaining normal renal function, whereas the other half develop proteinuria and progressive renal failure or end-stage renal disease. In some cases, renal dysfunction may be triggered or exacerbated by an infectious disease, often an upper respiratory infection or pharyngitis. Some patients may also develop hypertension. Renal biopsy shows glomerular C3 deposition and mesangial proliferation with glomerulonephritis. Membranoproliferative glomerulonephritis (MPGN) may also be observed on renal biopsy. Males tend to have a more severe phenotype than females and are more likely to develop end-stage renal disease, often necessitating dialysis or renal transplant (summary by previous studies). + +For a general description and discussion of genetic heterogeneity of C3G, see C3G1 (previous studies)." +MONDO_0014872,"Definition: Congenital stationary night blindness type 1H (CSNB1H) is an unusual and unique stationary retinal disorder with a dual anomaly in visual processing, characterized by a partial or severe degree of ON bipolar dysfunction and variably reduced cone sensitivity. Patients present with childhood-onset night blindness and middle age-onset photophobia, but have near-normal vision and do not exhibit nystagmus or high myopia (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of congenital stationary night blindness, see CSNB1A (previous studies)." +MONDO_0030746,"Definition: Intermediate junctional epidermolysis bullosa 2A (JEB2A) is an autosomal recessive blistering disease of skin and mucous membranes. Blistering is less severe than in severe JEB (see previous studies). The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Oral mucosa may be involved and nail bed blistering has been reported. Blistering does not affect the life span of affected individuals (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +MONDO_0030805,"Definition: Spinocerebellar ataxia-49 (SCA49) is an autosomal dominant neurologic disorder characterized initially by gait abnormalities, gaze-evoked nystagmus, and hyperreflexia. The age at onset is highly variable, ranging from the second to seventh decades, even within the same family. The disorder is slowly progressive, and later features may include dysarthria, dysmetria, diplopia, pyramidal signs, and axonal peripheral neuropathy. Brain imaging shows cerebellar atrophy and myelination defects (previous studies)." +MONDO_0030938,"Definition: Spermatogenic failure-52 (SPGF52) is characterized by azoospermic infertility resulting from meiotic arrest at the spermatocyte stage (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +Orphanet_165655,"Definition: Chronic idiopathic intestinal pseudoobstruction (CIIP) is caused by severe abnormality of gastrointestinal motility. Patients have recurrent symptoms and signs of intestinal obstruction without any mechanical lesion (previous studies). + +Some primary forms of CIIP are caused by defects of enteric neuronal cells: see Hirschsprung disease (see, e.g., HSCR1; previous studies) and autosomal recessive visceral neuropathy (previous studies) (previous studies)." +Orphanet_1930,"Definition: Herpes simplex virus (HSV)-1 is most often associated with infection of the oral mucosa. Primary infection is most commonly asymptomatic, but it may lead to symptoms usually involving the mucosa and skin. Following replication at the infection site, HSV-1 enters the epithelial endings of sensory neurons and travels up the trigeminal cranial nerves to the trigeminal ganglia, where latent infection is established. Reactivation of HSV-1, usually in the form of herpes labialis (cold sores), may occur in 20 to 40% of the population. HSV-1 seroprevalence is high, with over 85% of adults between the ages of 20 and 40 years infected. HSV-1 rarely infects the central nervous system (CNS), resulting in herpes simplex encephalitis (HSE), with an incidence of 2 to 4 per 1,000,000 people per year. In HSE, HSV-1 invades and replicates in neurons and glial cells, where focal necrotizing infections occur, primarily affecting the temporal and subfrontal regions of the brain. Untreated, HSE is fatal in at least 70% of cases, although the mortality and morbidity have been drastically reduced with antiviral therapy. Approximately one-third of all HSE cases are due to primary infections, and 30% of all HSE cases occur in children under the age of 20 years. Among children, HSE peaks between 3 months and 3 years of age, coinciding with the time of primary infection. In a subset of children, HSE results from a series of monogenic primary immunodeficiencies that impair UNC93B1- and TLR3 (previous studies)-dependent production of IFNA (previous studies)/IFNB (previous studies) and IFNG (previous studies) in the CNS (summary by previous studies). + + Genetic Heterogeneity of Susceptibility to Acute Infection-Induced Encephalopathy, including Herpes Simplex Encephalitis (HSE) + +For other forms of susceptibility to acute infection-induced encephalopathy, see herpes-specific IIAE2 (previous studies), caused by mutation in the TLR3 gene (previous studies) on chromosome 4q35; IIAE3 (previous studies), caused by mutation in the RANBP2 gene (previous studies) on chromosome 2q12; IIAE4 (previous studies), caused by mutation in the CPT2 gene (previous studies) on chromosome 1p32; herpes-specific IIAE5 (previous studies), caused by mutation in the TRAF3 gene (previous studies) on chromosome 14q32; herpes-specific IIAE6 (previous studies), caused by mutation in the TICAM1 gene (previous studies) on chromosome 19p13; herpes-specific IIAE7 (previous studies), caused by mutation in the IRF3 gene (previous studies) on chromosome 19q13; herpes-specific IIAE8 (previous studies), caused by mutation in the TBK1 gene (previous studies) on chromosome 12q14; IIAE9 (previous studies), caused by mutation in the NUP214 gene (previous studies) on chromosome 9q34; herpes-specific IIAE10 (previous studies), caused by mutation in the SNORA31 (previous studies) on chromosome 13q14; and IIAE11 (previous studies), caused by mutation in the DBR1 gene (previous studies) on chromosome 3q22." +MONDO_0010684,"Definition: X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive skeletal muscle disorder characterized by childhood onset of progressive muscle weakness and atrophy primarily affecting the proximal muscles. While onset is usually in childhood, it can range from infancy to adulthood. Many patients lose ambulation and become wheelchair-bound. Other organ systems, including the heart, are clinically unaffected. Muscle biopsy shows intracytoplasmic autophagic vacuoles with sarcolemmal features and a multilayered basal membrane (summary by previous studies; previous studies, and previous studies). + +Danon disease (previous studies), caused by mutation in the LAMP2 gene (previous studies) on chromosome Xq24, is a distinct disorder with similar pathologic features." +MONDO_0012524,"Definition: CMO type II deficiency is an autosomal recessive disorder caused by a defect in the final biochemical step of aldosterone biosynthesis, the 18-hydroxylation of 18-hydroxycorticosterone (18-OHB) to aldosterone. This enzymatic defect results in decreased aldosterone and salt-wasting associated with an increased serum ratio of 18-OHB to aldosterone. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (previous studies). + +The CYP11B2 gene product also catalyzes an earlier step in aldosterone biosynthesis: the 18-hydroxylation of corticosterone to 18-OHB. A defect in that enzymatic step results in CMO type I deficiency (previous studies), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal (previous studies)." +MONDO_0014260,"Definition: Common variable immunodeficiency-10 (CVID10) is an autosomal dominant primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (previous studies)." +MONDO_0014683,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, and congenital muscular dystrophy. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS), which is associated with death in infancy. The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1), collectively known as 'dystroglycanopathies' (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0031045,Definition: Distal arthrogryposis type 11 (DA11) is an autosomal dominant disorder characterized mainly by camptodactyly. Other features include absent flexion creases and limited forearm supination (previous studies). +MONDO_0033043,"Definition: Spastic ataxia-8 with hypomyelinating leukodystrophy is an autosomal recessive progressive neurodegenerative disorder characterized by onset of primarily motor dysfunction within the first year of life. Affected individuals initially have hypotonia and later develop ataxia, spasticity, and a pyramidal syndrome with weakness and loss of ambulation. Other features may include dystonia, dysarthria, and abnormal eye movements. Brain imaging shows cerebellar atrophy and hypomyelinating leukodystrophy. One family with cognitive impairment has also been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (previous studies)." +MONDO_0060577,"Definition: Neurodevelopmental disorder with microcephaly, ataxia, and seizures (NEDMAS) is an autosomal recessive disorder characterized by global developmental delay and early-onset seizures. More variable features may include deafness, cardiomyopathy, and severe febrile decompensations (summary by previous studies)." +Orphanet_280763,"Definition: Spastic paraplegia-47 (SPG47) is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +EFO_0009018,"Definition: Spastic paraplegia-75 (SPG75) is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +MONDO_0007340,"Definition: The main clinical features of cleidocranial dysplasia (CLCD) include persistently open skull sutures with bulging calvaria, hypoplasia or aplasia of the clavicles permitting abnormal facility in apposing the shoulders, wide pubic symphysis, short middle phalanx of the fifth fingers, dental anomalies, and often vertebral malformation. + + Genetic Heterogeneity of Cleidocranial Dysplasia + +CLCD2 (previous studies) is caused by mutation in the CBFB gene (previous studies) on chromosome 16q22. + +See previous studies for a discussion of the combination of cleidocranial dysplasia and parietal foramina. + +previous studies provided a review of the clinical features of cleidocranial dysplasia and the molecular basis of this disorder." +MONDO_0008157,"Definition: Buschke-Ollendorff syndrome (BOS) is an autosomal dominant connective tissue disorder manifest by multiple subcutaneous nevi or nodules. They may be either elastin-rich (elastoma) or collagen-rich (dermatofibrosis lenticularis disseminata) on histologic examination. The lesions are usually nontender and firm. Affected individuals also have osteopoikilosis (OPK), literally meaning 'spotted bones,' which are osteosclerotic foci that occur in the epiphyses and metaphyses of long bones, wrist, foot, ankle, pelvis, and scapula. Some individuals have both skin and bone manifestations, whereas others may lack skin or bone manifestations. Some individuals may also have melorheostosis (previous studies), which is characterized by 'flowing' hyperostosis of the cortex of tubular bones. Most reported cases of BOS and OPK are benign, and the bone lesions are found incidentally, although some patients may have joint pain (reviews by previous studies and previous studies)." +MONDO_0008453,"Definition: Spinal muscular atrophy is characterized by degeneration of the anterior horn cells in the spinal cord, leading to symmetric muscle weakness and wasting. + +See also autosomal recessive adult-onset proximal spinal muscular atrophy (SMA4; previous studies), caused by defect in the SMN1 gene (previous studies), and autosomal dominant childhood-onset proximal SMA (previous studies)." +MONDO_0008734,"Definition: Adrenocortical carcinoma (ADCC) is a rare but aggressive childhood tumor, representing about 0.4% of childhood tumors, with a high incidence of associated tumors. ADCC occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome (previous studies) and is a component tumor in Li-Fraumeni syndrome (LFS; previous studies)." +EFO_1000796,"Definition: Adrenocortical carcinoma (ADCC) is a rare but aggressive childhood tumor, representing about 0.4% of childhood tumors, with a high incidence of associated tumors. ADCC occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome (previous studies) and is a component tumor in Li-Fraumeni syndrome (LFS; previous studies)." +MONDO_0009732,"Definition: The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by previous studies). + +Nephrotic syndrome type 1 (NPHS1) is characterized by prenatal onset of massive proteinuria followed by severe steroid-resistant nephrotic syndrome apparent at birth with rapid progression to end-stage renal failure (previous studies). + +Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature. + + Genetic Heterogeneity of Nephrotic Syndrome and Focal Segmental Glomerulosclerosis + +Nephrotic syndrome and FSGS are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also NPHS2 (previous studies), caused by mutation in the podocin gene (previous studies); NPHS3 (previous studies), caused by mutation in the PLCE1 gene (previous studies); NPHS4 (previous studies), caused by mutation in the WT1 gene (previous studies); NPHS5 (previous studies), caused by mutation in the LAMB2 gene (previous studies); NPHS6 (previous studies), caused by mutation in the PTPRO gene (previous studies); NPHS7 (previous studies), caused by mutation in the DGKE gene (previous studies); NPHS8 (previous studies), caused by mutation in the ARHGDIA gene (previous studies); NPHS9 (previous studies), caused by mutation in the COQ8B gene (previous studies); NPHS10 (previous studies), caused by mutation in the EMP2 gene (previous studies); NPHS11 (previous studies), caused by mutation in the NUP107 gene (previous studies); NPHS12 (previous studies), caused by mutation in the NUP93 gene (previous studies); NPHS13 (previous studies), caused by mutation in the NUP205 gene (previous studies); NPHS14 (previous studies), caused by mutation in the SGPL1 gene (previous studies); NPHS15 (previous studies), caused by mutation in the MAGI2 gene (previous studies); NPHS16 (previous studies), caused by mutation in the KANK2 gene (previous studies), NPHS17 (previous studies), caused by mutation in the NUP85 gene (previous studies); NPHS18 (previous studies), caused by mutation in the NUP133 gene (previous studies); NPHS19 (previous studies), caused by mutation in the NUP160 gene (previous studies); NPHS20 (previous studies), caused by mutation in the TBC1D8B gene (previous studies); NPHS21 (previous studies) caused by mutation in the AVIL gene (previous studies); NPHS22 (previous studies), caused by mutation in the NOS1AP gene (previous studies); NPHS23 (previous studies), caused by mutation in the KIRREL1 gene (previous studies); NPHS24 (previous studies), caused by mutation in the DAAM2 gene (previous studies); and NPHS26 (previous studies), caused by mutation in the LAMA5 gene (previous studies). + +The symbol NPHS25 has been used as an alternative designation for NPHS21. + +See also FSGS1 (previous studies), caused by mutation in the ACTN4 gene (previous studies); FSGS2 (previous studies), caused by mutation in the TRPC6 gene (previous studies); FSGS3 (previous studies), associated with variation in the CD2AP gene (previous studies); FSGS4 (previous studies), mapped to chromosome 22q12; FSGS5 (previous studies), caused by mutation in the INF2 gene (previous studies); FSGS6 (previous studies), caused by mutation in the MYO1E gene (previous studies); FSGS7 (previous studies), caused by mutation in the PAX2 gene (previous studies); FSGS8 (previous studies), caused by mutation in the ANLN gene (previous studies); and FSGS9 (previous studies), caused by mutation in the CRB2 gene (previous studies)." +MONDO_0012193,"Definition: Autosomal dominant limb-girdle muscular dystrophy-3 (LGMDD3) is characterized by slowly progressive proximal muscle weakness affecting the upper and lower limbs. Onset is usually in adulthood, but can occur during the teenage years. Affected individuals may also develop cataracts before age 50 (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (previous studies)." +MONDO_0012999,"Definition: Guanidinoacetate methyltransferase deficiency, an autosomal recessive inborn error of creatine synthesis, is characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, intractable seizures and movement disturbances, severe depletion of creatine/phosphocreatine in the brain, and accumulation of guanidinoacetic acid (GAA) in brain and body fluids (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CCDS, see CCDS1 (previous studies)." +MONDO_0013802,"Definition: Infantile cerebellar-retinal degeneration (ICRD) is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (summary by previous studies). A subset of patients may have a milder phenotype with variable features, including ataxia, developmental delay, and behavioral abnormalities (previous studies). + +Mutation in the ACO2 gene also causes isolated optic atrophy (OPA9; previous studies)." +MONDO_0014401,"Definition: Miura-type epiphyseal chondrodysplasia (ECDM) is an overgrowth syndrome characterized by tall stature, arachnodactyly of the hands, macrodactyly of the great toes, scoliosis, coxa valga, and slipped capital femoral epiphysis (previous studies). Multiple extra epiphyses are present in the hands (previous studies). + +Mutation in the NPR3 gene (previous studies) results in Boudin-Mortier syndrome (BOMOS; previous studies), a similar phenotype of tall stature, arachnodactyly, elongated great toes, and multiple extra epiphyses." +Orphanet_329191,"Definition: Miura-type epiphyseal chondrodysplasia (ECDM) is an overgrowth syndrome characterized by tall stature, arachnodactyly of the hands, macrodactyly of the great toes, scoliosis, coxa valga, and slipped capital femoral epiphysis (previous studies). Multiple extra epiphyses are present in the hands (previous studies). + +Mutation in the NPR3 gene (previous studies) results in Boudin-Mortier syndrome (BOMOS; previous studies), a similar phenotype of tall stature, arachnodactyly, elongated great toes, and multiple extra epiphyses." +MONDO_0014593,"Definition: Developmental and epileptic encephalopathy-29 (DEE29) is an autosomal recessive neurologic disorder characterized by the onset of refractory myoclonic seizures in the first months of life. Affected individuals have poor overall growth, congenital microcephaly with cerebral atrophy and impaired myelination on brain imaging, spasticity with abnormal movements, peripheral neuropathy, and poor visual fixation (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0014906,Definition: Autosomal recessive axonal CMT2A2B is a neurologic disorder characterized by onset of peripheral neuropathy in the first years of life. Patients have difficulty walking due to distal muscle weakness; upper limbs may also be affected. Sensory impairment is more variable. Patients often have optic atrophy (summary by previous studies). +MONDO_0030689,"Definition: Demyelinating Charcot-Marie-Tooth disease-1H (CMT1H) is an autosomal dominant peripheral sensorimotor neuropathy with onset usually in adulthood (third to fifth decades). Affected individuals present with foot deformities, upper or lower limb sensory disturbances, and motor deficits, mainly impaired gait. Of note, many patients complain of unpleasant sensory sensations in the upper extremities and hands. The disorder is slowly progressive and becomes more apparent with age, although patients usually remain ambulatory. Other features include hypo- or areflexia, limb muscle weakness, and impaired gait. Electrophysiologic studies are consistent with a demyelinating polyneuropathy. Rare patients may have hyperelastic skin or develop age-related macular degeneration (summary by previous studies and previous studies) + +For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (previous studies)." +MONDO_0030873,"Definition: Cardiofacioneurodevelopmental syndrome (CFNDS) is characterized by microcephaly, midline facial defects, developmental delay, and cerebellar hypoplasia. Variable cardiac defects may be present, including atrioventricular canal and ventricular septal defects. Heterotaxy has also been reported (previous studies)." +MONDO_0030979,"Definition: Limb-brain ENDOVE syndrome (ENDOVESLB) is characterized by marked mesomelic shortening of the lower limbs due to severe hypoplasia of the tibia and fibula. The talus is absent and foot bones are rudimentary. Hands show short and malformed fingers with a missing digit, and nails are absent on some fingers. In addition, there is cerebellar aplasia with hypoplasia of the brainstem (previous studies)." +MONDO_0032924,"Definition: Primary ciliary dyskinesia-45 (CILD45) is an autosomal recessive disorder characterized by recurrent sinopulmonary infections resulting from defective mucociliary clearance. Affected individuals have onset of symptoms in infancy or early childhood, and the repetitive nature of the disorder may result in bronchiectasis. Nasal nitric oxide may be decreased, but patients do not have situs abnormalities. Male patients have infertility due to immotile sperm (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (previous studies)." +MONDO_0859219,"Definition: Rauch-Steindl syndrome (RAUST) is characterized by poor pre- and postnatal growth, sometimes with short stature and small head circumference, characteristic dysmorphic facial features, and variable developmental delay with delayed motor and speech acquisition and impaired intellectual function that can be mild. Other features may include hypotonia and behavioral abnormalities. The phenotype represents a mild form of Wolf-Hirschhorn syndrome (WHS; previous studies), which is a contiguous gene deletion syndrome caused by heterozygous deletion of several genes on chromosome 4p16. The clinical features of RAUST are similar to but milder than those of WHS, with less severe dysmorphic facial features, less severe developmental disabilities in general, and absence of a seizure disorder. The phenotype and expressivity of RAUST is highly variable (summary by previous studies; previous studies)." +EFO_0009056,"Definition: Spinocerebellar ataxia-38 is an autosomal dominant neurologic disorder characterized by adult-onset of slowly progressive gait ataxia accompanied by nystagmus. Brain MRI shows cerebellar atrophy (summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +EFO_0010248,"Definition: Autosomal recessive spinocerebellar ataxia-27 (SCAR27) is an adult-onset neurologic disorder characterized by gait difficulties and other cerebellar signs, such as eye movement abnormalities, dysarthria, and difficulty writing. The disorder is progressive, and some patients may lose independent ambulation. Additional features include spasticity of the lower limbs and cognitive impairment. Brain imaging shows cerebellar atrophy (summary by previous studies)." +HP_0000545,"Definition: Myopia, or nearsightedness, is a refractive error of the eye. Light rays from a distant object are focused in front of the retina and those from a near object are focused in the retina; therefore distant objects are blurry and near objects are clear (summary by previous studies). + +For a discussion of genetic heterogeneity of susceptibility to myopia, see previous studies." +MONDO_0008513,"Definition: Synpolydactyly (SPD), or syndactyly type II, is defined as a connection between the middle and ring fingers and fourth and fifth toes, variably associated with postaxial polydactyly in the same digits. Minor local anomalies and various metacarpal or metatarsal abnormalities may be present (summary by previous studies). + +In some families with SPD, the foot anomalies are characterized by preaxial as well as postaxial polydactyly, and appear to be fully penetrant. The more severe features of classic SPD, involving 3/4 synpolydactyly in the hands and 4/5 synpolydactyly in the feet, also occur, but at reduced penetrance. This foot phenotype is not seen in patients with classic SPD due to HOXD13 polyalanine tract expansions (previous studies). + +previous studies reviewed the syndactylies, noting that the extreme phenotypic heterogeneity observed in SPD families consists of approximately 18 clinical variants that can be 'lumped' into 3 categories: typical SPD features, minor variants, and unusual phenotypes. + + Genetic Heterogeneity of Synpolydactyly + +See also SPD2 (previous studies), caused by mutation in the fibulin-1 gene (FBLN1; previous studies) on chromosome 22q13, and SPD3 (previous studies), which has been mapped to chromosome 14q11.2-q12." +MONDO_0009166,"Definition: Pontocerebellar hypoplasia (PCH) represents a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. Pontocerebellar hypoplasia type 4 (PCH4) is characterized by severe course and early lethality (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (previous studies)." +MONDO_0009670,"Definition: Autosomal recessive lethal congenital contracture syndrome (LCCS) is the most severe, neonatally lethal, form of arthrogryposis (see previous studies), a disorder characterized by congenital nonprogressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth (summary by previous studies). + + Genetic Heterogeneity of Lethal Congenital Contracture Syndrome + +See also lethal congenital contracture syndrome-2 (LCCS2; previous studies), caused by mutation in the ERBB3 gene (previous studies); LCCS3 (previous studies), caused by mutation in the PIP5K1C gene (previous studies); LCCS4 (previous studies), caused by mutation in the MYBPC1 gene (previous studies); LCCS5 (previous studies), caused by mutation in the DNM2 gene (previous studies); LCCS6 (previous studies), caused by mutation in the ZBTB42 gene (previous studies); LCCS7 (previous studies), caused by mutation in the CNTNAP1 gene (previous studies); LCCS8 (previous studies), caused by mutation in the ADCY6 gene (previous studies); LCCS9 (previous studies), caused by mutation in the ADGRG6 gene (previous studies); LCCS10 (previous studies), caused by mutation in the NEK9 gene (previous studies); and LCCS11 (previous studies), caused by mutation in the GLDN gene (previous studies)." +Orphanet_1486,"Definition: Autosomal recessive lethal congenital contracture syndrome (LCCS) is the most severe, neonatally lethal, form of arthrogryposis (see previous studies), a disorder characterized by congenital nonprogressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth (summary by previous studies). + + Genetic Heterogeneity of Lethal Congenital Contracture Syndrome + +See also lethal congenital contracture syndrome-2 (LCCS2; previous studies), caused by mutation in the ERBB3 gene (previous studies); LCCS3 (previous studies), caused by mutation in the PIP5K1C gene (previous studies); LCCS4 (previous studies), caused by mutation in the MYBPC1 gene (previous studies); LCCS5 (previous studies), caused by mutation in the DNM2 gene (previous studies); LCCS6 (previous studies), caused by mutation in the ZBTB42 gene (previous studies); LCCS7 (previous studies), caused by mutation in the CNTNAP1 gene (previous studies); LCCS8 (previous studies), caused by mutation in the ADCY6 gene (previous studies); LCCS9 (previous studies), caused by mutation in the ADGRG6 gene (previous studies); LCCS10 (previous studies), caused by mutation in the NEK9 gene (previous studies); and LCCS11 (previous studies), caused by mutation in the GLDN gene (previous studies)." +MONDO_0010299,"Definition: Virtually complete deficiency of HPRT residual activity is associated with the Lesch-Nyhan syndrome (LNS; previous studies), whereas partial deficiency (at least 8%) is associated with the Kelley-Seegmiller syndrome. LNS is characterized by abnormal metabolic and neurologic manifestations. In contrast, Kelley-Seegmiller syndrome is usually associated only with the clinical manifestations of excessive purine production. Renal stones, uric acid nephropathy, and renal obstruction are often the presenting symptoms of Kelley-Seegmiller syndrome, but rarely of LNS. After puberty, the hyperuricemia in Kelley-Seegmiller syndrome may cause gout (summary by previous studies)." +MONDO_0010407,"Definition: Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder with a highly variable phenotype. Some affected families show X-linked recessive inheritance, with only males being affected and carrier females having no abnormal findings. In other affected families, males are severely affected, and female mutation carriers show milder cognitive abnormalities or dysmorphic features. In addition, there are female patients with de novo mutations who show the full phenotype, despite skewed X-chromosome inactivation. Affected individuals show global developmental delay from infancy, with variably impaired intellectual development and poor or absent speech, often with delayed walking. Dysmorphic features are common and can include macrocephaly, microcephaly, deep-set eyes, hypotelorism, small palpebral fissures, dysplastic, large, or low-set ears, long face, bitemporal narrowing, high-arched palate, thin upper lip, and scoliosis or mild distal skeletal anomalies, such as brachydactyly or tapered fingers. Males tend to have cryptorchidism. Other features, such as hypotonia, seizures, and delayed bone age, are more variable (summary by previous studies)." +MONDO_0014008,Definition: Phosphohydroxylysinuria (PHLU) is characterized by elevated phosphohydroxylysine in the urine. There is no clinical phenotype associated with this finding other than the urinary metabolites. This was confirmed by population genetic studies performed by previous studies (previous studies). +MONDO_0032790,"Definition: Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities (NEDCFSA) is a developmental disorder characterized by mildly impaired global development apparent from infancy, poor speech acquisition, hypotonia with early feeding difficulties, mildly delayed walking, and variable behavioral abnormalities, such as autistic features, hyperactivity, or attention deficits. Most individuals have coarse facial features, including prominent forehead, large ears, and wide mouth. Other features may include wide hands, thickened fingers, and cutaneous toe syndactyly, as well as joint hyperlaxity. Mutations occur de novo, such that the disorder occurs sporadically in patients with no family history of a similar disorder (summary by previous studies)." +MONDO_0033361,"Definition: Developmental and epileptic encephalopathy-52 (DEE52) is a severe autosomal recessive seizure disorder characterized by infantile onset of refractory seizures with resultant delayed global neurologic development. Affected individuals have impaired intellectual development and may have other persistent neurologic abnormalities, including axial hypotonia and spasticity; death in childhood may occur (summary by previous studies and previous studies). Some patients with DEE52 may have a clinical diagnosis of Dravet syndrome (previous studies), which is characterized by the onset of seizures in the first year or 2 of life after normal early development. Developmental delay, impaired intellectual development, and behavioral abnormalities usually become apparent later between 1 and 4 years of age. Dravet syndrome may also include 'severe myoclonic epilepsy in infancy' (SMEI) (summary by previous studies). + +For a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0033651,"Definition: Mitochondrial complex IV deficiency nuclear type 16 (MC4DN16) is an autosomal recessive metabolic disorder with highly variable manifestations. Common features include failure to thrive with poor overall growth, short stature, and microcephaly. Some patients additionally have neurologic involvement, including developmental regression with severe hypotonia, feeding difficulties, and seizures. Brain imaging in the more severely affected patients shows cerebral and cerebellar atrophy and abnormal lesions in the basal ganglia. In all cases, patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0054843,"Definition: Primary ciliary dyskinesia-38 is an autosomal recessive disorder characterized by chronic airway disease and recurrent sinopulmonary infections beginning in infancy and caused by defective ciliary function. Affected individuals often have neonatal respiratory distress and may later have infertility. About half of patients have laterality defects due to ciliary dysfunction in early embryonic development (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (previous studies)." +Orphanet_631,"Definition: Kowarski syndrome, or short stature associated with bioinactive growth hormone, is characterized clinically by normal or slightly increased GH secretion, pathologically low IGF1 (previous studies) levels, and normal catch-up growth on GH replacement therapy (previous studies)." +MONDO_0009879,"Definition: Kowarski syndrome, or short stature associated with bioinactive growth hormone, is characterized clinically by normal or slightly increased GH secretion, pathologically low IGF1 (previous studies) levels, and normal catch-up growth on GH replacement therapy (previous studies)." +EFO_0020027,"Definition: Acquired partial lipodystrophy is characterized clinically by the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the 'cephalocaudal' sequence, sparing the lower extremities (summary by previous studies). The disorder is not inherited in a classic mendelian pattern; it rather represents a phenotype with a complex etiology. Affected individuals may have genetic susceptibility factors that require the additional presence of environmental factors or acquired disorders to be expressed (summary by previous studies). Most cases are sporadic, family history is negative, and females are more often affected than males (ratio, 4:1). + +There is an association between APLD and autoimmune diseases (previous studies; previous studies), and a subset of patients have APLD associated with low serum complement component C3 and the autoantibody C3 nephritic factor, with or without membranoproliferative glomerulonephritis (APLDC3; previous studies). + +Acquired partial lipodystrophy is distinct from inherited forms of partial lipodystrophy, which are metabolic disorders that show clear mendelian inheritance (see, e.g., FPLD1, previous studies)." +MONDO_0007854,"Definition: Keratolytic winter erythema, also known as Oudtshoorn skin disease, manifests during childhood with recurrent episodes of palmoplantar erythema and centrifugal epidermal peeling. Lateral and dorsal aspects of the hands and feet can be involved. A less common finding is a slowly migratory, annular erythema that is seen mostly on the extremities. Between flares, the skin may appear unremarkable. Hyperhidrosis, associated with a pungent odor, is invariably present, and itching can occur. Peeling is preceded by the formation of dry blisters due to keratolysis, whereas formation of vesicles or bullae is rare. Cold weather, moisture, febrile diseases, and physical and mental stress can trigger exacerbations. In severely affected individuals, skin manifestations persist unremittingly. Penetrance of the disease is high, but expressivity is variable, even within the same family (summary by previous studies)." +MONDO_0009214,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0011257,"Definition: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (previous studies). + +For a discussion of the classification of CDGs, see CDG1A (previous studies). + +CDG Ib is clinically distinct from most other CDGs by the lack of significant central nervous system involvement. The predominant symptoms are chronic diarrhea with failure to thrive and protein-losing enteropathy with coagulopathy. Some patients develop hepatic fibrosis. CDG Ib is also different from other CDGs in that it can be treated effectively with oral mannose supplementation, but can be fatal if untreated (previous studies). Thus, CDG Ib should be considered in the differential diagnosis of patients with unexplained hypoglycemia, chronic diarrhea, liver disease, or coagulopathy in order to allow early diagnosis and effective therapy (previous studies) + +previous studies reviewed CDG Ib and CDG Ic (previous studies). previous studies systematically reviewed the literature concerning liver involvement in CDG." +MONDO_0012873,"Definition: Ehlers-Danlos syndrome spondylodysplastic type 3 is characterized by short stature, hyperelastic skin and hypermobile joints, protuberant eyes with bluish sclerae, finely wrinkled palms, and characteristic radiologic features (previous studies). + +For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see previous studies." +MONDO_0014272,"Definition: Nagashima-type palmoplantar keratoderma is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis, first described by previous studies in the Japanese literature. It is characterized by well-demarcated diffuse erythematous hyperkeratosis that extends onto the dorsal surfaces of the palms and feet and the Achilles tendon area. Involvement of the elbows and knees has also been reported, and there is a high frequency of hyperhidrosis on the palms and soles. In contrast to other types of transgressive diffuse hyperkeratosis such as mal de Meleda (previous studies) and the Gamborg Nielsen type of recessive PPK (PPK Norrbotten; previous studies), PPKN shows only mild hyperkeratosis that is nonprogressive after the second decade and does not involve flexion contractures or constricting bands (summary by previous studies). + +For a discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (previous studies)." +MONDO_0014470,"Definition: Autosomal dominant deafness-65 is characterized by postlingual onset of slowly progressive hearing loss in the third decade. Initially affecting the high frequencies, the hearing loss eventually affects all frequencies and results in severe to profound deafness in the seventh decade. Vestibular function is normal (previous studies)." +MONDO_0025354,"Definition: X-linked spermatogenic failure-3 (SPGFX3) is characterized by male infertility due to multiple morphologic abnormalities of the flagella (MMAF). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0030473,"Definition: Developmental and epileptic encephalopathy-99 (DEE99) is characterized by onset of seizures in early childhood associated with global developmental delay and severely impaired intellectual development. Other features may include hypotonia, quadriparesis, nystagmus, and apnea. Brain imaging may be normal or show nonspecific and variable abnormalities, including cerebral atrophy and polymicrogyria. The severity is variable; some patients die of refractory status epilepticus (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0030970,"Definition: Immunodeficiency-106 (IMD106) is an autosomal recessive immunologic disorder characterized by increased susceptibility to viral infections beginning in infancy or early childhood. Some patients present with recurrent respiratory infections or other viral infections. In many cases, the susceptibility to viral infections due to IMD106 only becomes apparent after initial vaccination with live attenuated viral (LAV) vaccines, most notably MMR and yellow fever. A subset of IMD106 patients who demonstrate adverse reactions to MMR or other LAV vaccinations develop a severe acute hyperinflammatory response reminiscent of hemophagocytic lymphohistiocytosis (HLH) and may show encephalopathy, acute respiratory distress syndrome, and multiorgan failure. However, some patients with IMD106 tolerate MMR vaccination without sequelae. IFNAR1 deficiency may also predispose to severe respiratory infection with SARS-CoV-2 and to herpes simplex virus-1 (HSV1) encephalitis (HSE). The disorder results from an impaired type I interferon signaling response (previous studies)." +Orphanet_169150,"Definition: Patients with C7 deficiency have an increased susceptibility to recurrent bacterial infections, especially meningitis caused by Neisseria meningitidis (previous studies)." +Orphanet_50944,"Definition: Schopf-Schulz-Passarge syndrome (SSPS) is an autosomal recessive disorder characterized by a constellation of multiple eyelid cysts, hypodontia, hypotrichosis, palmoplantar hyperkeratosis, and onychodystrophy (summary by previous studies)." +MONDO_0009145,"Definition: Schopf-Schulz-Passarge syndrome (SSPS) is an autosomal recessive disorder characterized by a constellation of multiple eyelid cysts, hypodontia, hypotrichosis, palmoplantar hyperkeratosis, and onychodystrophy (summary by previous studies)." +EFO_0000365,"Definition: Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by previous studies). + + Genetic Heterogeneity of Colorectal Cancer + +Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; previous studies) and hereditary nonpolyposis colorectal cancer (HNPCC; see previous studies). FAP is caused by mutations in the APC gene (previous studies), whereas HNPCC is caused by mutations in several genes, including MSH2 (previous studies), MLH1 (previous studies), PMS1 (previous studies), PMS2 (previous studies), MSH6 (previous studies), TGFBR2 (previous studies), and MLH3 (previous studies). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, previous studies). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (previous studies), which is caused by mutations in the MUTYH gene (previous studies), and oligodontia-colorectal cancer syndrome (previous studies), which is caused by mutations in the AXIN2 gene (previous studies). + +The CHEK2 gene (previous studies) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (previous studies) was identified in a patient with colorectal cancer. + +Germline susceptibility loci for colorectal cancer have also been identified. CRCS1 (previous studies) is conferred by mutation in the GALNT12 gene (previous studies) on chromosome 9q22; CRCS2 (previous studies) maps to chromosome 8q24; CRCS3 (previous studies) is conferred by variation in the SMAD7 gene (previous studies) on chromosome 18; CRCS4 (previous studies) is conferred by variation on 15q that causes increased and ectopic expression of the GREM1 gene (previous studies); CRCS5 (previous studies) maps to chromosome 10p14; CRCS6 (previous studies) maps to chromosome 8q23; CRCS7 (previous studies) maps to chromosome 11q23; CRCS8 (previous studies) maps to chromosome 14q22; CRCS9 (previous studies) maps to 16q22; CRCS10 (previous studies) is conferred by mutation in the POLD1 gene (previous studies) on chromosome 19q13; CRCS11 (previous studies) maps to chromosome 20p12; and CRCS12 (previous studies) is conferred by mutation in the POLE gene (previous studies) on chromosome 12q24. + +Somatic mutations in many different genes, including KRAS (previous studies), PIK3CA (previous studies), BRAF (previous studies), CTNNB1 (previous studies), FGFR3 (previous studies), AXIN2 (previous studies), AKT1 (previous studies), MCC (previous studies), MYH11 (previous studies), PARK2 (previous studies), RNF43 (previous studies), and BUB1 (previous studies) have been identified in colorectal cancer." +EFO_0004142,"Definition: Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by previous studies). + + Genetic Heterogeneity of Colorectal Cancer + +Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; previous studies) and hereditary nonpolyposis colorectal cancer (HNPCC; see previous studies). FAP is caused by mutations in the APC gene (previous studies), whereas HNPCC is caused by mutations in several genes, including MSH2 (previous studies), MLH1 (previous studies), PMS1 (previous studies), PMS2 (previous studies), MSH6 (previous studies), TGFBR2 (previous studies), and MLH3 (previous studies). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, previous studies). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (previous studies), which is caused by mutations in the MUTYH gene (previous studies), and oligodontia-colorectal cancer syndrome (previous studies), which is caused by mutations in the AXIN2 gene (previous studies). + +The CHEK2 gene (previous studies) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (previous studies) was identified in a patient with colorectal cancer. + +Germline susceptibility loci for colorectal cancer have also been identified. CRCS1 (previous studies) is conferred by mutation in the GALNT12 gene (previous studies) on chromosome 9q22; CRCS2 (previous studies) maps to chromosome 8q24; CRCS3 (previous studies) is conferred by variation in the SMAD7 gene (previous studies) on chromosome 18; CRCS4 (previous studies) is conferred by variation on 15q that causes increased and ectopic expression of the GREM1 gene (previous studies); CRCS5 (previous studies) maps to chromosome 10p14; CRCS6 (previous studies) maps to chromosome 8q23; CRCS7 (previous studies) maps to chromosome 11q23; CRCS8 (previous studies) maps to chromosome 14q22; CRCS9 (previous studies) maps to 16q22; CRCS10 (previous studies) is conferred by mutation in the POLD1 gene (previous studies) on chromosome 19q13; CRCS11 (previous studies) maps to chromosome 20p12; and CRCS12 (previous studies) is conferred by mutation in the POLE gene (previous studies) on chromosome 12q24. + +Somatic mutations in many different genes, including KRAS (previous studies), PIK3CA (previous studies), BRAF (previous studies), CTNNB1 (previous studies), FGFR3 (previous studies), AXIN2 (previous studies), AKT1 (previous studies), MCC (previous studies), MYH11 (previous studies), PARK2 (previous studies), RNF43 (previous studies), and BUB1 (previous studies) have been identified in colorectal cancer." +MONDO_0005575,"Definition: Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by previous studies). + + Genetic Heterogeneity of Colorectal Cancer + +Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; previous studies) and hereditary nonpolyposis colorectal cancer (HNPCC; see previous studies). FAP is caused by mutations in the APC gene (previous studies), whereas HNPCC is caused by mutations in several genes, including MSH2 (previous studies), MLH1 (previous studies), PMS1 (previous studies), PMS2 (previous studies), MSH6 (previous studies), TGFBR2 (previous studies), and MLH3 (previous studies). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, previous studies). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (previous studies), which is caused by mutations in the MUTYH gene (previous studies), and oligodontia-colorectal cancer syndrome (previous studies), which is caused by mutations in the AXIN2 gene (previous studies). + +The CHEK2 gene (previous studies) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (previous studies) was identified in a patient with colorectal cancer. + +Germline susceptibility loci for colorectal cancer have also been identified. CRCS1 (previous studies) is conferred by mutation in the GALNT12 gene (previous studies) on chromosome 9q22; CRCS2 (previous studies) maps to chromosome 8q24; CRCS3 (previous studies) is conferred by variation in the SMAD7 gene (previous studies) on chromosome 18; CRCS4 (previous studies) is conferred by variation on 15q that causes increased and ectopic expression of the GREM1 gene (previous studies); CRCS5 (previous studies) maps to chromosome 10p14; CRCS6 (previous studies) maps to chromosome 8q23; CRCS7 (previous studies) maps to chromosome 11q23; CRCS8 (previous studies) maps to chromosome 14q22; CRCS9 (previous studies) maps to 16q22; CRCS10 (previous studies) is conferred by mutation in the POLD1 gene (previous studies) on chromosome 19q13; CRCS11 (previous studies) maps to chromosome 20p12; and CRCS12 (previous studies) is conferred by mutation in the POLE gene (previous studies) on chromosome 12q24. + +Somatic mutations in many different genes, including KRAS (previous studies), PIK3CA (previous studies), BRAF (previous studies), CTNNB1 (previous studies), FGFR3 (previous studies), AXIN2 (previous studies), AKT1 (previous studies), MCC (previous studies), MYH11 (previous studies), PARK2 (previous studies), RNF43 (previous studies), and BUB1 (previous studies) have been identified in colorectal cancer." +EFO_0009151,"Definition: CRDHL1 is characterized by cone-rod dystrophy and sensorineural hearing loss, with relatively late onset of both ocular and hearing impairment. The funduscopic findings are characteristic, showing ring-shaped atrophy along the major vascular arcades that manifests on fundus autofluorescence as a hypoautofluorescent band along the vascular arcades surrounded by hyperautofluorescent borders (previous studies). + + Genetic Heterogeneity of Cone-Rod Dystrophy and Hearing Loss + +CRDHL2 (previous studies) is caused by mutation in the CEP250 gene (previous studies) on chromosome 20q11." +MONDO_0007883,"Definition: Periodic fever, immunodeficiency, and thrombocytopenia syndrome (PFITS) is an autosomal recessive immunologic disorder with variable manifestations. Common features include early-onset recurrent respiratory infections, stomatitis, and cutaneous infections. Organisms usually include bacteria such as pneumococcus, Staphylococcus, and H. influenzae, but severe viral infections, including varicella, may also occur. Laboratory investigations may show neutropenia, neutrophilia, leukocytosis, or lymphopenia, although levels of immune cells may also be normal. Detailed studies often show impaired neutrophil chemotaxis associated with increased or abnormal F-actin levels, and impaired, normal, or even increased oxidative burst, depending on the stimulus. B- and T-cell abnormalities have also been observed. Some patients develop autoimmune manifestations, including chronic thrombocytopenia, anemia, and periodic fevers, associated with activation of the inflammasome. Early death may occur; however, hematopoietic stem cell transplantation may be curative (summary by previous studies, previous studies, and previous studies)." +MONDO_0007906,"Definition: Familial partial lipodystrophy is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution beginning in late childhood or early adult life. Affected individuals gradually lose fat from the upper and lower extremities and the gluteal and truncal regions, resulting in a muscular appearance with prominent superficial veins. In some patients, adipose tissue accumulates on the face and neck, causing a double chin, fat neck, or cushingoid appearance. Metabolic abnormalities include insulin-resistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently. Familial partial lipodystrophy may also be referred to as lipoatrophic diabetes mellitus, but the essential feature is loss of subcutaneous fat (review by previous studies). + +The disorder may be misdiagnosed as Cushing disease (see previous studies) (previous studies; previous studies). + + Genetic Heterogeneity of Familial Partial Lipodystrophy + +Familial partial lipodystrophy is a clinically and genetically heterogeneous disorder. Types 1 and 2 were originally described as clinical subtypes: type 1 (FPLD1; previous studies), characterized by loss of subcutaneous fat confined to the limbs (previous studies), and FPLD2, characterized by loss of subcutaneous fat from the limbs and trunk (previous studies; previous studies). No genetic basis for FPLD1 has yet been delineated. FPLD3 (previous studies) is caused by mutation in the PPARG gene (previous studies) on chromosome 3p25; FPLD4 (previous studies) is caused by mutation in the PLIN1 gene (previous studies) on chromosome 15q26; FPLD5 (previous studies) is caused by mutation in the CIDEC gene (previous studies) on chromosome 3p25; FPLD6 (previous studies) is caused by mutation in the LIPE gene (previous studies) on chromosome 19q13; and FPLD7 (previous studies) is caused by mutation in the CAV1 gene (previous studies) on chromosome 7q31." +MONDO_0008862,"Definition: 3-Methylcrotonylglycinuria is an autosomal recessive disorder of leucine catabolism. The clinical phenotype is highly variable, ranging from neonatal onset with severe neurologic involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. MCC activity in extracts of cultured fibroblasts of patients is usually less than 2% of control (summary by previous studies). + +Also see 3-methylcrotonylglycinuria I (MCC1D; previous studies), caused by mutation in the alpha subunit of 3-methylcrotonyl-CoA carboxylase (MCCC1; previous studies)." +MONDO_0009953,"Definition: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe psychomotor retardation, mild dysmorphism, and impaired neutrophil motility. It is a member of a group of disorders with a defect in the processing of protein-bound glycans. For a general overview of congenital disorders of glycosylation (CDGs), see CDG1A (previous studies) and CDG2A (previous studies). + +previous studies contended that the neutrophil defect in CDG2C, which has been referred to as 'leukocyte adhesion deficiency type II' (LAD2), is a manifestation of the disorder and that there are no cases of 'primary' LAD II. + +previous studies provided a comprehensive review of both leukocyte adhesion deficiency-1 (LAD1; previous studies) and LAD2. While the functional neutrophil studies are similar in the 2 LADs, the clinical course is milder in LAD2. Furthermore, patients with LAD2 present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism. Delayed separation of the umbilical cord occurs in LAD1. For a discussion of genetic heterogeneity of LAD, see previous studies." +MONDO_0010557,"Definition: Choroideremia is an X-linked disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye (previous studies). The characteristic lesion of choroideremia is chorioretinal scalloped atrophy in the midperipheral fundus, with preservation of the macula (previous studies). + +See also choroideremia, deafness, and mental retardation (previous studies), a contiguous gene deletion syndrome involving the CHM and POU3F4 (previous studies) genes on Xq21. X-linked deafness-2 with stapes fixation (DFNX2; previous studies) is also caused by mutation in the CHM gene." +MONDO_0011275,"Definition: The acromesomelic dysplasias are disorders in which there is disproportionate shortening of skeletal elements, predominantly affecting the middle segments (forearms and forelegs) and distal segments (hands and feet) of the appendicular skeleton. + +Acromesomelic dysplasia-1 (AMD1) is characterized by severe dwarfism (height below 120 cm) with shortening of the middle and distal segments of the limbs. This condition is usually diagnosed at birth and becomes more obvious in the first 2 years of life. X-rays show short broad fingers, square flat feet, and shortening of the long bones (particularly the forearms). The radius is bowed; the ulna is shorter than the radius, and its distal end is occasionally hypoplastic. The skull is dolichocephalic and a shortness of the trunk, with decreased vertebral height and narrowing of the lumbar interpedicular distances, is consistently observed. Facial appearance and intelligence are normal (summary by previous studies). + + Genetic Heterogeneity of Acromesomelic Dysplasia + +Additional autosomal recessive forms of acromesomelic dysplasia include acromesomelic dysplasia-2A (previous studies), -2B (previous studies), and -2C (previous studies), all caused by mutation in the GDF5 gene (previous studies) on chromosome 20q11; AMD3 (previous studies), caused by mutation in the BMPR1B gene (previous studies) on chromosome 4q22; and AMD4 (previous studies), caused by mutation in the PRKG2 gene (previous studies) on chromosome 4q21. + +An autosomal dominant form of acromesomelic dysplasia has also been reported (see previous studies)." +MONDO_0014147,"Definition: Neuronal ceroid lipofuscinosis-13 (CLN13) is an autosomal recessive neurodegenerative disorder characterized by adult onset of progressive cognitive decline and motor dysfunction leading to dementia and often early death. Some patients develop seizures. Neurons show abnormal accumulation of autofluorescent material (summary by previous studies). + +Adult-onset neuronal ceroid lipofuscinosis is sometimes referred to as Kufs disease (see previous studies). In a review of the classification of CLN disease, previous studies noted that the CLN13 phenotype corresponds to 'Kufs type B', which is characterized by dementia and a variety of motor signs (previous studies). + +For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis (CLN), see CLN1 (previous studies)." +Orphanet_352709,"Definition: Neuronal ceroid lipofuscinosis-13 (CLN13) is an autosomal recessive neurodegenerative disorder characterized by adult onset of progressive cognitive decline and motor dysfunction leading to dementia and often early death. Some patients develop seizures. Neurons show abnormal accumulation of autofluorescent material (summary by previous studies). + +Adult-onset neuronal ceroid lipofuscinosis is sometimes referred to as Kufs disease (see previous studies). In a review of the classification of CLN disease, previous studies noted that the CLN13 phenotype corresponds to 'Kufs type B', which is characterized by dementia and a variety of motor signs (previous studies). + +For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis (CLN), see CLN1 (previous studies)." +MONDO_0014154,"Definition: CMTRIC is an autosomal recessive peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. The age at onset and the severity of the disease are variable (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive intermediate CMT, see CMTRIA (previous studies)." +Orphanet_369867,"Definition: CMTRIC is an autosomal recessive peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. The age at onset and the severity of the disease are variable (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive intermediate CMT, see CMTRIA (previous studies)." +MONDO_0014567,"Definition: Neurodevelopmental disorder with spastic paraplegia and microcephaly (NEDSPM) is an autosomal recessive neurologic syndrome characterized by delayed psychomotor development with delayed walking, moderately to severely impaired intellectual development, and poor or absent speech. More severely affected individuals show poor overall growth with progressive microcephaly, axial hypotonia, oromotor dysfunction with drooling, joint contractures, and spastic paraplegia resulting in walking difficulties. Some patients may develop seizures; nonspecific dysmorphic features have also been reported (summary by previous studies and previous studies)." +MONDO_0030118,"Definition: Silver-Russell syndrome-4 (SRS4) is characterized by intrauterine growth retardation followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face and prominent forehead, and relative macrocephaly at birth may be observed (previous studies). + +For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (previous studies)." +MONDO_0030356,"Definition: Short-rib thoracic dysplasia-21 (SRTD21) is characterized by rhizomelic limb shortening with bowing of long bones and metaphyseal abnormalities, narrow chest with short broad ribs, and trident pelvis. Other features include hypotonia and global developmental delay, with corpus callosum hypoplasia and cerebellar vermis abnormalities on brain imaging, which may show the 'molar tooth' sign (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of SRTD, see SRTD1 (previous studies). + +Mutation in the KIAA0753 gene also causes orofaciodigital syndrome (OFD15; previous studies) and Joubert syndrome (JBTS28; previous studies), phenotypes with features overlapping those of SRTD21." +MONDO_0030517,"Definition: Nonphotosensitive trichothiodystrophy-8 (TTD8) is characterized by brittle hair and nails and scaly skin, accompanied by failure to thrive, microcephaly, and neuromotor developmental delay. Hair analysis shows low sulfur content, and skin fibroblasts demonstrate normal DNA repair efficiency after UV irradiation (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of trichothiodystrophy, see TTD1 (previous studies)." +MONDO_0032934,"Definition: Genitourinary and/or brain malformation syndrome (GUBS) is characterized by variable genitourinary anomalies, including disorders of sex differentiation, and brain abnormalities ranging from agenesis of the corpus callosum to anencephaly. Other variable congenital anomalies have been observed, including omphalocele and gastrointestinal tract atresia with aberrant vessels (previous studies)." +Orphanet_51608,"Definition: Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of GACI, see GACI1 (previous studies). + +Pseudoxanthoma elasticum (PXE; previous studies) is an allelic disorder caused by mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (previous studies)." +Orphanet_70595,"Definition: SANDO is an autosomal recessive systemic disorder characterized mainly by adult onset of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) resulting from mitochondrial dysfunction and associated with mtDNA depletion in skeletal muscle and peripheral nerve tissue (previous studies). The phenotype varies widely, even within the same family, and can include myopathy, seizures, and hearing loss, but the common clinical feature appears to be sensory ataxia (review by previous studies). + +Spinocerebellar ataxia with epilepsy (SCAE) is a similar disorder with a higher frequency of migraine headaches and seizures (previous studies)." +MONDO_0011835,"Definition: SANDO is an autosomal recessive systemic disorder characterized mainly by adult onset of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) resulting from mitochondrial dysfunction and associated with mtDNA depletion in skeletal muscle and peripheral nerve tissue (previous studies). The phenotype varies widely, even within the same family, and can include myopathy, seizures, and hearing loss, but the common clinical feature appears to be sensory ataxia (review by previous studies). + +Spinocerebellar ataxia with epilepsy (SCAE) is a similar disorder with a higher frequency of migraine headaches and seizures (previous studies)." +MONDO_0009114,"Definition: Congenital sucrose-isomaltase deficiency (CSID) is an autosomal recessive disorder characterized by absence of sucrase and most of the maltase digestive activity within the sucrase-isomaltase enzyme complex, with the isomaltase activity varying from absent to normal. The large amounts of unabsorbed disaccharides create osmotic-fermatative diarrhea with symptoms such as vomiting, flatulence, and abdominal pain (summary by previous studies)." +MONDO_0009556,"Definition: Malonyl-CoA decarboxylase deficiency is an uncommon inherited metabolic disease. The characteristic phenotype is variable, but may include developmental delay in early childhood, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis, abnormal urinary compounds, lactic acidemia, and hypertrophic cardiomyopathy (previous studies)." +MONDO_0009773,"Definition: Odontoonychodermal dysplasia (OODD) is an autosomal recessive disorder characterized by dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, hyperkeratosis of the palms and soles, hypo- and hyperhidrosis of the skin, and atrophic patches on the face (summary by previous studies; previous studies)." +MONDO_0010466,"Definition: Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by previous studies). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by previous studies, previous studies). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. + +For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (previous studies). + +For a discussion of nomenclature and genetic heterogeneity of DEE, see previous studies. + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +Orphanet_300496,"Definition: Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by previous studies). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by previous studies, previous studies). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. + +For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (previous studies). + +For a discussion of nomenclature and genetic heterogeneity of DEE, see previous studies. + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +MONDO_0010726,"Definition: Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by arrested development between 6 and 18 months of age, regression of acquired skills, loss of speech, stereotypic movements (classically of the hands), microcephaly, seizures, and mental retardation. Rarely, classically affected males with somatic mosaicism or an extra X chromosome have been described (previous studies)." +MONDO_0012794,"Definition: Alopecia, neurologic defects, and endocrinopathy syndrome (ANES) is an autosomal recessive disorder characterized by alopecia with skin involvement including multiple facial nevi and flexural hyperpigmentation; moderately to severely impaired intellectual development; progressive motor decline; and endocrine deficiency (summary by previous studies)." +MONDO_0013408,"Definition: Immunodeficiency-90 with encephalopathy, functional hyposplenia, and hepatic dysfunction (IMD90) is a autosomal recessive complex immunologic disorder with systemic manifestations in addition to primary immunodeficiency. Affected individuals usually present in infancy or early childhood with recurrent fevers and bacterial or viral infections associated with central nervous system symptoms, including irritability, drowsiness, variable seizures, and white matter abnormalities on brain imaging. There is also liver involvement and functional hyposplenism, causing increased susceptibility to invasive pneumococcal infection, which may be fatal. Susceptibility to viral infections likely results from impaired interferon immunity, and bacterial infections likely result from splenic dysfunction. A subset of patients have congenital cardiac malformations. Most individuals demonstrate developmental delay and speech delay. Laboratory findings in affected individuals are similar to those seen in autoimmune lymphoproliferative syndrome (ALPS; previous studies), including high-circulating CD4-/CD8-/TCR-alpha-beta+ (double-negative) T-cell (DNT) counts, and elevated IL10 (previous studies) and FASL (TNFSF6; previous studies) levels, but the clinical features are somewhat different from ALPS: massive lymphadenopathy and autoimmune features are not observed in IMD90 (summary by previous studies, previous studies and previous studies)." +MONDO_0013499,"Definition: Fanconi anemia of complementation group P is an autosomal recessive disorder characterized by increased chromosomal instability and progressive bone marrow failure. Some patients have skeletal anomalies (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of Fanconi anemia (FA), see previous studies." +MONDO_0014746,"Definition: Congenital disorder of glycosylation type IIn (CDG2N) is an autosomal recessive severe multisystem developmental disorder characterized by delayed psychomotor development apparent from infancy, hypotonia, and variable additional features, such as short stature, seizures, visual impairment, and cerebellar atrophy. Serum transferrin analysis shows a CDG type II pattern (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of CDG type II, see CDG2A (previous studies)." +MONDO_0015012,"Definition: MPSPS is an autosomal recessive inborn error of metabolism resulting in a multisystem disorder with features of the mucopolysaccharidosis lysosomal storage diseases (see, e.g., previous studies). Patients present in infancy or early childhood with respiratory difficulties, cardiac problems, anemia, dysostosis multiplex, renal involvement, coarse facies, and delayed psychomotor development. Most patients die of cardiorespiratory failure in the first years of life (summary by previous studies)." +MONDO_0018274,"Definition: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by previous studies). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by previous studies). Not all patients have overt seizures (previous studies)." +MONDO_0859336,"Definition: Congenital muscular dystrophy with or without seizures (MYOS) is an autosomal recessive disorder characterized by severe muscle hypotonia apparent from birth, as well as developmental delay. Laboratory studies show increased serum creatine kinase and muscle biopsy shows nonspecific dystrophic features. Most patients develop seizures or have abnormal epileptiform findings on EEG studies; other variable findings may include feeding difficulties, nystagmus, myopathic facies, areflexia, and brain atrophy on MRI (summary by previous studies and previous studies)." +Orphanet_2238,"Definition: Autosomal dominant hypocalcemia-1 is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by previous studies). + +previous studies noted that patients with gain-of-function mutations in the CASR gene, resulting in generally asymptomatic hypocalcemia with hypercalciuria, have low-normal serum PTH concentrations and have often been diagnosed with hypoparathyroidism because of the insensitivity of earlier PTH assays. Because treatment with vitamin D to correct the hypocalcemia in these patients causes hypercalciuria, nephrocalcinosis, and renal impairment, these patients need to be distinguished from those with other forms of hypoparathyroidism (see previous studies). previous studies suggested the designation 'autosomal dominant hypocalcemic hypercalciuria' for this CASR-related disorder. + + Genetic Heterogeneity of Autosomal Dominant Hypocalcemia + +Autosomal dominant hypocalcemia-2 (HYPOC2; previous studies) is caused by mutation in the GNA11 gene (previous studies) on chromosome 19p13." +MONDO_0011013,"Definition: Autosomal dominant hypocalcemia-1 is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by previous studies). + +previous studies noted that patients with gain-of-function mutations in the CASR gene, resulting in generally asymptomatic hypocalcemia with hypercalciuria, have low-normal serum PTH concentrations and have often been diagnosed with hypoparathyroidism because of the insensitivity of earlier PTH assays. Because treatment with vitamin D to correct the hypocalcemia in these patients causes hypercalciuria, nephrocalcinosis, and renal impairment, these patients need to be distinguished from those with other forms of hypoparathyroidism (see previous studies). previous studies suggested the designation 'autosomal dominant hypocalcemic hypercalciuria' for this CASR-related disorder. + + Genetic Heterogeneity of Autosomal Dominant Hypocalcemia + +Autosomal dominant hypocalcemia-2 (HYPOC2; previous studies) is caused by mutation in the GNA11 gene (previous studies) on chromosome 19p13." +EFO_0003105,"Definition: Neural tube defects are the second most common type of birth defect after congenital heart defects. The 2 most common NTDs are open spina bifida, also known as spina bifida cystica (SBC) or myelomeningocele, and anencephaly (see previous studies) (previous studies). Spina bifida occulta (SBO), a bony defect of the spine covered by normal skin, is a mild form of spina bifida that is often asymptomatic. The term 'spinal dysraphia' refers to both SBC and SBO (previous studies; previous studies). The most severe neural tube defect, craniorachischisis (CRN), leaves the neural tube open from the midbrain or rostral hindbrain to the base of the spine (summary by previous studies). + +Neural tube defects represent a complex trait with multifactorial etiology encompassing both genetic and environmental components (summary by previous studies and previous studies). + +An X-linked form of spina bifida has been suggested; see previous studies. See also folate-sensitive neural tube defects (previous studies), which are caused by genes involved in folate metabolism." +EFO_0010261,"Definition: Paganini-Miozzo syndrome (MRXSPM) is a neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, high myopia, and mild dysmorphic facial features (summary by previous studies)" +MONDO_0008479,"Definition: The corner fracture type of spondylometaphyseal dysplasia (SMDCF) is characterized by flake-like, triangular, or curvilinear ossification centers at the edges of irregular metaphyses that simulate fractures. These 'corner fractures,' which involve the distal tibia, the ulnar aspect of the distal radius, the proximal humerus, and the proximal femur, represent irregular ossification at the growth plates and secondary ossification centers. They become larger in older children and disappear after growth has stopped. In addition, severe scoliosis has been observed in FN1-associated SMDCF, whereas developmental coxa vara is less often seen, and odontoid abnormalities have not been reported (previous studies)." +MONDO_0009210,Definition: Factor V deficiency is a rare autosomal recessive bleeding disorder with variable phenotypic expression (summary by previous studies). +MONDO_0011191,"Definition: Capillary hemangiomas are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births (previous studies). Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma. Hemangiomas are classified as distinct from vascular malformations (see, e.g., CMC1, previous studies; previous studies; and CCM, previous studies), in that the latter are present from birth, tend to grow with the individual, do not regress, and show normal rates of endothelial cell turnover (previous studies; previous studies). previous studies noted that the term 'hemangioma' in adults is considered inaccurate and should be discarded. + +Most hemangiomas occur sporadically, but some families with autosomal dominant inheritance have been reported (previous studies)." +MONDO_0013805,"Definition: Complex cortical dysplasia with other brain malformations-13 (CDCBM13) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development. Brain imaging shows variable neuronal migration defects resulting in cortical malformations, including pachygyria. More variable features include early-onset seizures and dysmorphic features. Some patients may also show signs of peripheral neuropathy, such as abnormal gait, hyporeflexia, and foot deformities (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (previous studies)." +MONDO_0013932,"Definition: The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 5 (CG5, equivalent to CG10 and CGF) have mutations in the PEX2 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0014002,"Definition: Nocturnal frontal lobe epilepsy-5 is an autosomal dominant focal epilepsy syndrome characterized by childhood onset of clusters of motor seizures during sleep. Some patients may develop behavioral or psychiatric manifestations and/or intellectual disability. The phenotype is more severe than observed in other genetic forms of ENFL (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of ENFL, see ENFL1 (previous studies)." +MONDO_0014801,"Definition: EVEN-PLUS syndrome is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (previous studies; previous studies)." +MONDO_0030878,"Definition: Kaya-Barakat-Masson syndrome (KABAMAS) is a severe autosomal recessive neurodevelopmental disorder characterized by profoundly impaired global development with variable motor abnormalities, such as axial hypotonia, peripheral spasticity, dystonia, and poor coordination, resulting in the inability to sit or walk. Affected individuals have impaired intellectual development with absent speech, poor eye contact, and feeding difficulties, resulting in poor overall growth, sometimes with microcephaly. Dysmorphic features are generally not present. Additional more variable features include early-onset seizures, ocular anomalies, foot deformities, and nonspecific brain imaging findings, such as thin corpus callosum and cerebral, cerebellar, or pontine atrophy. Some patients may die in infancy or early childhood (summary by previous studies and previous studies)." +MONDO_0030897,"Definition: Lessel-Kreienkamp syndrome (LESKRES) is a neurodevelopmental disorder characterized by global developmental delay with intellectual disability and speech and language delay apparent from infancy or early childhood. The severity of the disorder is highly variable: some patients have mildly delayed walking and mild cognitive deficits, whereas others are nonambulatory and nonverbal. Most have behavioral disorders. Additional features, including seizures, hypotonia, gait abnormalities, visual defects, cardiac defects, and nonspecific dysmorphic facial features may also be present (summary by previous studies)." +MONDO_0030973,"Definition: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus. Treatment with gamma-IFN (IFNG; previous studies) may be a therapeutic option (summary by previous studies and previous studies)." +EFO_0005571,"Definition: Complex lethal osteochondrodysplasia of the Symoens-Barnes-Gistelinck type is characterized by severe skeletal osteopenia, microcephaly, multiple fractures, and congenital anomalies including ascites, pleural effusion, and intracranial ventriculomegaly (previous studies)." +MONDO_0014821,"Definition: Complex lethal osteochondrodysplasia of the Symoens-Barnes-Gistelinck type is characterized by severe skeletal osteopenia, microcephaly, multiple fractures, and congenital anomalies including ascites, pleural effusion, and intracranial ventriculomegaly (previous studies)." +MONDO_0007032,"Definition: In its rare complete form, 'prune belly' syndrome comprises megacystis (massively enlarged bladder) with disorganized detrusor muscle, cryptorchidism, and thin abdominal musculature with overlying lax skin (summary by previous studies)." +MONDO_0009283,Definition: Glutaric aciduria III is characterized by an isolated accumulation of glutaric acid. It appears to be a 'non-disease' as it is found in healthy individuals and is associated with inconsistent symptoms in others (summary by previous studies). +MONDO_0009943,"Definition: Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by previous studies)." +MONDO_0013487,"Definition: Complement factor D deficiency is an autosomal recessive immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway (summary by previous studies)." +MONDO_0014357,"Definition: Vulto-van Silfout-de Vries syndrome (VSVS) is an intellectual developmental disorder characterized by delayed psychomotor development, poor expressive speech, and behavioral abnormalities, including autistic features and poor eye contact. Most patients have additional nonspecific features, including hypotonia and gait abnormalities, seizures, which may be refractory, high pain threshold, and sleep disturbances (summary by previous studies)." +MONDO_0020852,"Definition: SPGF31 is characterized by male infertility due to oligozoospermia with a high proportion (greater than 90%) of acephalic sperm. Affected couples may overcome infertility with intracytoplasmic sperm injection (previous studies). + +For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see previous studies." +MONDO_0032908,"Definition: CEBALID syndrome is a complex developmental disorder characterized by global developmental delay, variably impaired intellectual development, and craniofacial and structural brain abnormalities. Common features include abnormal skull shape, characteristic facial features with midface hypoplasia, hypertelorism, and high-arched palate, and dysmorphic ears often associated with conductive or sensorineural deafness. Affected individuals have delayed walking and significant expressive speech and language delay, but many can attend special schools. Brain imaging shows crowding of the posterior fossa, including rhombencephalosynapsis (partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres), as well as perisylvian polymicrogyria and cerebellar hypoplasia/dysplasia (summary by previous studies). + +See also Gomez-Lopez-Hernandez syndrome (GLHS; previous studies), which has an overlapping phenotype." +MONDO_0008047,"Definition: Episodic ataxia is a neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia (previous studies). + + Genetic Heterogeneity of Episodic Ataxia + +Episodic ataxia is a genetically heterogeneous disorder. See also EA2 (previous studies), caused by mutation in the CACNA1A gene (previous studies) on chromosome 19p13; EA3 (previous studies), which maps to chromosome 1q42; EA4 (previous studies); EA5, caused by mutation in the CACNB4 gene (previous studies) on chromosome 2q22-q23; EA6 (previous studies), caused by mutation in the SLC1A3 gene (previous studies) on chromosome 5p13; EA7 (previous studies), which maps to chromosome 19q13; EA8 (previous studies), which maps to chromosome 1p36-p34; and EA9 (previous studies), caused by mutation in the SCN2A gene (previous studies) on chromosome 2q24. + +Isolated myokymia-2 (see previous studies) is associated with mutation in the KCNQ2 gene (previous studies)." +MONDO_0010286,"Definition: Siderius-type syndromic intellectual developmental disorder (MRXSSD) is an X-linked disorder in which affected males have mildly impaired intellectual development, mild dysmorphic features, and bilateral or unilateral cleft lip/palate (summary by previous studies)." +Orphanet_85287,"Definition: Siderius-type syndromic intellectual developmental disorder (MRXSSD) is an X-linked disorder in which affected males have mildly impaired intellectual development, mild dysmorphic features, and bilateral or unilateral cleft lip/palate (summary by previous studies)." +MONDO_0010500,"Definition: X-linked syndromic intellectual developmental disorder-33 (MRXS33) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and characteristic facial features (summary by previous studies)." +MONDO_0011134,"Definition: Curry-Jones syndrome (CRJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas (summary by previous studies)." +MONDO_0011393,"Definition: Twenty to 30% of early familial coronary heart disease (CHD) is ascribed to hypoalphalipoproteinemia, or high density lipoprotein deficiency. Although not initially recognized as a predisposing dyslipidemia, extensive epidemiologic work has implicated low high-density lipoprotein cholesterol (HDLC) levels in increased risk of cardiovascular disease, and low HDLC is considered to be a true dyslipidemic syndrome (previous studies). + + Genetic Heterogeneity of Primary Hypoalphalipoproteinemia + +Primary hypoalphalipoproteinemia-2 (previous studies) and intermediate primary hypoalphalipoproteinemia-2 (previous studies) are caused by mutation in the APOA1 gene (previous studies) on chromosome 11q23." +MONDO_0012184,"Definition: Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss (summary by previous studies). + +Mutations in the LAMB2 gene also cause nephrotic syndrome type 5 with or without mild ocular anomalies (NPHS5; previous studies)." +MONDO_0014806,"Definition: Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by previous studies). + + Genetic Heterogeneity of Spinal Muscular Atrophy With Congenital Bone Fractures + +See also SMABF2 (previous studies), caused by mutation in the ASCC1 gene (previous studies) on chromosome 10q22." +MONDO_0030941,"Definition: Erythrokeratodermia variabilis et progressiva-7 (EKVP7) is characterized by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet (transgrediens), as well as erythematous annular skin lesions. Pruritis, woolly hair, and dystrophic nails may also be present (previous studies; previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of EKVP, see EKVP1 (previous studies)." +MONDO_0030998,Definition: DFNA80 is characterized by nonsyndromic congenital deafness associated with absent or malformed cochleae and eighth cranial nerves (previous studies; previous studies). +MONDO_0032764,"Definition: Khan-Khan-Katsanis syndrome (3KS) is an autosomal recessive neurodevelopmental disorder with variable involvement of the ocular, renal, skeletal, and sometimes cardiac systems. Affected individuals present at birth with multiple congenital anomalies, defects in urogenital and limb morphogenesis, poor overall growth with microcephaly, and global developmental delay (summary by previous studies)." +MONDO_0060627,"Definition: GPIBD15 is an autosomal recessive disorder characterized by delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most patients, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by previous studies). + +For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (previous studies)." +Orphanet_3454,"Definition: Female-restricted Wieacker-Wolff syndrome (WRWFFR) is an X-linked dominant syndromic form of neurogenic arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. Affected individuals have decreased fetal movements causing the development of contractures in utero and resulting in AMC and diffuse contractures involving the large and small joints apparent at birth. There is global developmental delay with difficulty walking or inability to walk, hypotonia that often evolves to spasticity, and variably impaired intellectual development with poor or absent speech and language. Dysmorphic facial features, including hypotonic facies, ptosis, microretrognathia, and small mouth, are seen in most patients. Seizures are uncommon; some patients have evidence of a peripheral motor neuropathy with distal muscle weakness. The level of X inactivation in lymphocytes and fibroblasts is often skewed, but may not predict the severity of the phenotype. Most cases occur sporadically; rare X-linked dominant inheritance has been reported in families (summary by previous studies)." +Orphanet_3460,"Definition: Winchester syndrome presents with severe osteolysis in the hands and feet and generalized osteoporosis and bone thinning, similar to multicentric osteolysis, nodulosis, and arthropathy (MONA; previous studies), but subcutaneous nodules are characteristically absent. Various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG changes have been reported (summary by previous studies)." +Orphanet_85196,"Definition: Winchester syndrome presents with severe osteolysis in the hands and feet and generalized osteoporosis and bone thinning, similar to multicentric osteolysis, nodulosis, and arthropathy (MONA; previous studies), but subcutaneous nodules are characteristically absent. Various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG changes have been reported (summary by previous studies)." +Orphanet_90318,"Definition: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (previous studies). There are both severe and mild forms of classic EDS, previously designated EDS I and EDS II, respectively. + +For a general phenotypic description and a discussion of genetic heterogeneity of classic EDS, see previous studies." +MONDO_0019568,"Definition: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (previous studies). There are both severe and mild forms of classic EDS, previously designated EDS I and EDS II, respectively. + +For a general phenotypic description and a discussion of genetic heterogeneity of classic EDS, see previous studies." +EFO_0005569,"Definition: Nanophthalmos is characterized by axial lengths of the ocular globe that are more than 2 SDs smaller than the normal range, or less than 20 mm in adults, with a cornea and lens that are typically of normal size, associated with severe hyperopia (farsightedness) of +7.00 diopters or more. The smaller dimensions of the anterior chamber depth cause the iridocorneal angle to be typically narrow. Abnormal thickening of the scleral connective tissue is often observed (summary by previous studies). + +For a discussion of genetic heterogeneity of nanophthalmos, see NNO1 (previous studies)." +EFO_0010658,"Definition: Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia (NEDBASH) is an autosomal recessive disorder characterized by severely impaired intellectual and motor development, axial and peripheral hypotonia usually with inability to walk, and significant behavioral abnormalities consistent with autism spectrum disorder and reminiscent of Rett syndrome (RTT; previous studies), such as poor communication, stereotypic or repetitive behaviors, hand-wringing, bruxism, and sleep disturbances. Other features include poor overall growth, and joint hypermobility. Rare features include seizures, dystonia, spasticity, and nonspecific brain abnormalities (summary by previous studies and previous studies)." +MONDO_0009263,"Definition: GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (previous studies). previous studies and previous studies noted that optic atrophy is not a consistent feature of the disorder." +MONDO_0011518,"Definition: Wiedemann-Steiner syndrome is a congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, broad nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back (summary by previous studies and previous studies)." +MONDO_0014882,"Definition: Spastic paraplegia-77 (SPG77) is an autosomal recessive neurologic disorder characterized by early-childhood onset of spasticity affecting the lower limbs and resulting in gait difficulties. The disorder is progressive and may be associated with childhood seizures, developmental delay, and mitochondrial dysfunction (previous studies; previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0030433,"Definition: Charcot-Marie-Tooth disease type 2FF (CMT2FF) is an autosomal dominant progressive axonal sensorimotor peripheral neuropathy characterized by early-childhood onset of difficulties walking or running due to atrophy and weakness of the lower limbs. Most patients have foot and ankle deformities, requiring surgery or walking aids. Some patients lose independent ambulation. There is also prominent involvement of the upper limbs, with weakness and atrophy of the forearm, wrist, and intrinsic hand muscles. Proximal muscle function is preserved. Affected individuals have variable distal sensory impairment. Most patients have hyporeflexia, although brisk reflexes, suggesting upper motor involvement, have been described in 1 family. Sural nerve biopsy showed abnormal myelination (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (previous studies)." +MONDO_0033572,"Definition: IDDEBF is a severe disorder characterized by impaired intellectual development, epilepsy, behavioral abnormalities, and coarse facies. Brain MRI findings may include delayed myelination in the deep parietal lobes (previous studies)." +Orphanet_97,"Definition: Episodic ataxia is a genetically heterogeneous neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia. Episodic ataxia type 2 is the most common form of EA (previous studies). + +For a discussion of genetic heterogeneity of episodic ataxia, see EA1 (previous studies)." +MONDO_0007163,"Definition: Episodic ataxia is a genetically heterogeneous neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia. Episodic ataxia type 2 is the most common form of EA (previous studies). + +For a discussion of genetic heterogeneity of episodic ataxia, see EA1 (previous studies)." +EFO_0004994,"Definition: Lumbar disc disease is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders, it has strong genetic determinants (previous studies; previous studies; previous studies)." +EFO_0009316,"Definition: Heterozygous protein C deficiency is characterized by recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic (previous studies). Individuals with decreased amounts of protein C are classically referred to as having type I deficiency and those with normal amounts of a functionally defective protein as having type II deficiency (previous studies). + +Acquired protein C deficiency is a clinically similar disorder caused by development of an antibody against protein C. previous studies reviewed the structural and functional properties of protein C and discussed both hereditary and acquired deficiency of protein C." +MONDO_0007784,"Definition: Selective pituitary resistance to thyroid hormone (PRTH) results in continued thyroid-stimulating hormone (TSH) production driving hypersecretion of T3 and T4 to establish a new equilibrium, with high serum levels of free thyroid hormones together with a nonsuppressed TSH. The presence of a variety of thyrotoxic features, including palpitations, anxiety, tremor, heat intolerance, insomnia, weight loss, and increased stool frequency, suggests that peripheral tissues are less refractory to thyroid hormones than the pituitary (summary by previous studies)." +MONDO_0010383,"Definition: Fragile X syndrome (FXS) is characterized by moderately to severely impaired intellectual development, macroorchidism, and distinct facial features, including long face, large ears, and prominent jaw. In most cases, the disorder is caused by the unstable expansion of a CGG repeat in the FMR1 gene and abnormal methylation, which results in suppression of FMR1 transcription and decreased protein levels in the brain (previous studies). + + Reviews + +Fragile X syndrome accounts for about one-half of cases of X-linked impaired intellectual development and is the second most common cause of mental impairment after trisomy 21 (previous studies) (previous studies). + +previous studies summarized the proceedings of a workshop on the fragile X syndrome held in December 1998. + +previous studies provided a review of fragile X syndrome, which they characterized as a neurodevelopmental disorder, and FXTAS, which they characterized as a neurodegenerative disorder." +MONDO_0011252,"Definition: Shohat-type spondyloepimetaphyseal dysplasia (SEMDSH) is a chondrodysplasia characterized by vertebral, epiphyseal, and metaphyseal abnormalities, including scoliosis with vertebral compression fractures, flattened vertebral bodies, and hypomineralization of long bones. Affected individuals may exhibit a small trunk, short neck, small limbs, joint laxity, bowlegs, and/or abdominal distention with hepatosplenomegaly (summary by previous studies)." +MONDO_0012033,"Definition: Prolonged electroretinal response suppression-1 (PERRS1), also referred to as bradyopsia-1, is an autosomal recessive childhood-onset retinopathy characterized by markedly delayed dark and light adaptation, mild photophobia, difficulty seeing moving objects, moderately reduced visual acuity, normal color vision, normal fundi, and reduced rod and cone responses with prolonged recovery on electrophysiologic assessment (summary by previous studies). + + Genetic Heterogeneity of Prolonged Electroretinal Response Suppression + +PERRS2 (previous studies) is caused by mutation in the RGS9BP gene (previous studies), which encodes the binding partner of RGS9 that anchors it to the photoreceptor out segment disc membrane." +MONDO_0014267,"Definition: Immunodeficiency-15B (IMD15B) is an autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T cells. However, functional studies show impaired differentiation and activation of immune cells (summary by previous studies)." +MONDO_0014704,"Definition: Kosaki overgrowth syndrome (KOGS) is characterized by a facial gestalt involving prominent forehead, proptosis, downslanting palpebral fissures, broad nasal bridge, thin upper lip, and pointed chin. Affected individuals are tall, with an elongated lower segment, and have large hands and feet. Skin is hyperelastic and fragile, and there is progressive neurologic deterioration with white matter lesions on brain imaging (previous studies)." +MONDO_0014805,"Definition: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay, behavioral abnormalities, such as autism, and mild dysmorphic facies. Additional features are variable, but may include hypotonia, feeding problems, delayed walking with unsteady gait, hypogonadism in males, and ocular anomalies, such as strabismus. Some patients develop seizures and some have mild white matter abnormalities on brain imaging (summary by previous studies)." +MONDO_0031007,"Definition: SHILCA is characterized by early-onset retinal degeneration in association with sensorineural hearing loss, short stature, vertebral anomalies, and epiphyseal dysplasia, as well as motor and intellectual delay. Delayed myelination, leukoencephalopathy, and hypoplasia of the corpus callosum and cerebellum have been observed on brain MRI (previous studies)." +MONDO_0035819,"Definition: CIMDAG syndrome (CIMDAG) is a multisystemic disorder characterized by severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination. The associated hematologic abnormalities are variable, but are mostly consistent with congenital dyserythropoietic anemia (CDA) (summary by previous studies and previous studies)." +MONDO_0007105,"Definition: Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) is an autosomal dominant neurodegenerative disorder characterized by adult onset of one or both of these features in an affected individual, with significant intrafamilial variation. The disorder is genetically and pathologically heterogeneous (summary by previous studies). Patients with C9ORF72 repeat expansions tend to show a lower age of onset, shorter survival, bulbar symptom onset, increased incidence of neurodegenerative disease in relatives, and a propensity toward psychosis or hallucinations compared to patients with other forms of ALS and/or FTD (summary by previous studies). Patients with C9ORF72 repeat expansions also show psychiatric disturbances that may predate the onset of dementia (previous studies; previous studies). + +previous studies provided a detailed review of the genes involved in different forms of FTDALS, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration. + +For a general phenotypic description of frontotemporal dementia, also known as frontotemporal lobar degeneration (FTLD), see previous studies. For a general discussion of motor neuron disease (MND), see amyotrophic lateral sclerosis-1 (ALS1; previous studies). + + Genetic Heterogeneity of Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis + +See also FTDALS2 (previous studies), caused by mutation in the CHCHD10 gene (previous studies) on chromosome 22q11; FTDALS3 (previous studies), caused by mutation in the SQSTM1 gene (previous studies) on chromosome 5q35; FTDALS4 (previous studies), caused by mutation in the TBK1 gene (previous studies) on chromosome 12q14; FTDALS5 (previous studies), caused by mutation in the CCNF gene (previous studies) on chromosome 16p13; FTDALS6 (previous studies), caused by mutation in the VCP gene (previous studies) on chromosome 9p13; FTDALS7 (previous studies), caused by mutation in the CHMP2B gene (previous studies) on chromosome 3p11; and FTDALS8 (previous studies), caused by mutation in the CYLD gene (previous studies) on chromosome 16q12." +MONDO_0008745,"Definition: Oculocutaneous albinism is a genetically heterogeneous congenital disorder characterized by decreased or absent pigmentation in the hair, skin, and eyes. The term 'albinism' includes specific ocular changes that are the results of reduced amounts of melanin in the developing eye; these abnormalities in the eye and optic system are specific and necessary for the diagnosis. Aside from decreased pigment in the iris and retina, optic changes include decreased visual acuity, misrouting of the optic nerves at the chiasm, and nystagmus (previous studies). + +Although OCA caused by mutations in the TYR gene was classically known as 'tyrosinase-negative' OCA, previous studies noted that some patients with 'tyrosinase-positive' OCA may indeed have TYR mutations resulting in residual enzyme activity. These patients can be classified as having OCA1B. + + Genetic Heterogeneity of Oculocutaneous Albinism + +OCA1, caused by mutations in the TYR gene, is divided clinically into 2 types: type IA, OCA1A, characterized by complete lack of tyrosinase activity due to production of an inactive enzyme, and type IB (OCA1B; previous studies), characterized by reduced activity of tyrosinase. OCA2 (previous studies), OCA3 (previous studies), and OCA4 (previous studies) are somewhat milder forms of the disorder, caused by mutations in the OCA2 (previous studies), TYRP1 (previous studies), and MATP (SLC45A2; previous studies) genes, respectively. OCA5 (previous studies) has been mapped to chromosome 4q24. OCA6 (see previous studies) is caused by mutation in the SLC24A5 gene (previous studies). OCA7 (previous studies) is caused by mutation in the C10ORF11 gene (previous studies). OCA8 (previous studies) is caused by mutation in the DCT gene (previous studies). + +See also ocular albinism (OA1; previous studies), which is restricted phenotypically to ocular involvement only." +MONDO_0009846,Definition: Essential pentosuria is an inborn error of metabolism in which 1 to 4 gm of the pentose L-xylulose is excreted in the urine each day. It is a benign condition that occurs principally in individuals of Ashkenazi Jewish descent (summary by previous studies). +MONDO_0010015,"Definition: Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by previous studies). + +In sclerocornea there is congenital, nonprogressive corneal opacification that may be peripheral, sectoral, or central in location. Visual prognosis is related to the central corneal involvement. The cornea has a flat curvature. The majority of cases are bilateral (summary by previous studies). + +Isolated sclerocornea is caused by displacement of the limbal arcades and may be associated with cornea plana; in this condition, the anterior chamber is visible and the eye is not microphthalmic. In complex sclerocornea, however, corneal opacification is associated with microphthalmia, cataract, and/or infantile glaucoma. The central cornea is usually relatively clear, but the thickness is normal or increased, never reduced (summary by previous studies)." +Orphanet_289499,"Definition: Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by previous studies). + +In sclerocornea there is congenital, nonprogressive corneal opacification that may be peripheral, sectoral, or central in location. Visual prognosis is related to the central corneal involvement. The cornea has a flat curvature. The majority of cases are bilateral (summary by previous studies). + +Isolated sclerocornea is caused by displacement of the limbal arcades and may be associated with cornea plana; in this condition, the anterior chamber is visible and the eye is not microphthalmic. In complex sclerocornea, however, corneal opacification is associated with microphthalmia, cataract, and/or infantile glaucoma. The central cornea is usually relatively clear, but the thickness is normal or increased, never reduced (summary by previous studies)." +MONDO_0011890,"Definition: For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (previous studies)." +MONDO_0013478,"Definition: Familial partial lipodystrophy type 4 is an autosomal dominant metabolic disorder characterized by childhood or young adult onset of loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin-resistant diabetes mellitus, hypertriglyceridemia, and hypertension (summary by previous studies). Other features may include hepatic steatosis, acanthosis nigricans, polycystic ovary syndrome, and renal disease (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see previous studies." +MONDO_0013511,"Definition: Neonatal cyanosis is characterized by symptoms in the fetus and neonate that gradually abate by 5 to 6 months of age. The disorder is caused by a defect in the fetal hemoglobin chain, which causes reduced affinity for oxygen due to steric inhibition of oxygen binding and/or due to increased oxidation of the fetal hemoglobin molecule to methemoglobin (Hb FM), which has decreased oxygen-binding capacity. Some patients develop anemia resulting from increased destruction of red cells containing abnormal or unstable hemoglobin. The cyanosis resolves spontaneously by 5 to 6 months of age or earlier, as the adult beta-globin chain (HBB; previous studies) is produced and replaces the fetal gamma-globin chain (summary by previous studies)." +MONDO_0030048,"Definition: Harderoporphyria (HARPO) is a rare erythropoietic variant form of hereditary coproporphyria (HCP; previous studies) characterized by neonatal hemolytic anemia, sometimes accompanied by skin lesions, and massive excretion of harderoporphyrin in feces. During childhood and adulthood, a mild residual anemia is chronically observed (review by previous studies)." +MONDO_0060502,"Definition: NDMSBA is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy. Brain imaging may show myelinating abnormalities and white matter lesions consistent with a leukoencephalopathy, as well as structural anomalies, including thin corpus callosum, gyral abnormalities, and cerebral or cerebellar atrophy. Some patients die in early childhood (summary by previous studies and previous studies)." +EFO_0010636,"Definition: Pontocerebellar hypoplasia type 13 (PCH13) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (previous studies)." +MONDO_0007039,"Definition: Vestibular Schwannomatosis (SWNV), also known as neurofibromatosis type II (NF2), is an autosomal dominant multiple neoplasia syndrome characterized by the development of multiple benign nerve sheath tumors, called schwannomas, particularly affecting the vestibular nerve (usually bilaterally), but also involving cranial, spinal, and peripheral/cutaneous nerves. Meningiomas are common, affecting up to 80% of affected individuals. Ependymomas are seen in 20 to 35% of affected individuals. Ocular manifestations, including cataracts, retinal hamartomas, and epiretinal membranes, are also seen (summary by previous studies). + +Schwannoma tumors have been found to be caused by somatic mutations in the NF2 gene. + +For a discussion of genetic heterogeneity of schwannomatosis, see SWN1 (previous studies)." +MONDO_0007804,"Definition: Pallister-Hall syndrome is a pleiotropic autosomal dominant disorder comprising hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and visceral malformations (previous studies)." +MONDO_0007986,"Definition: Metatropic dysplasia (MTD) is characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis. Radiologic features include severe platyspondyly, severe metaphyseal enlargement, and shortening of long bones (previous studies)." +MONDO_0008119,"Definition: The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (previous studies). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (previous studies; previous studies). + +Historically, previous studies proposed a clinical classification for autosomal dominant cerebellar ataxias (ADCAs). ADCA I was characterized by cerebellar ataxia in combination with various associated neurologic features, such as ophthalmoplegia, pyramidal and extrapyramidal signs, peripheral neuropathy, and dementia, among others. ADCA II was characterized by the cerebellar ataxia, associated neurologic features, and the additional findings of macular and retinal degeneration. ADCA III was a pure form of late-onset cerebellar ataxia without additional features. SCA1, SCA2 (previous studies), and SCA3, or Machado-Joseph disease (previous studies), are considered to be forms of ADCA I. These 3 disorders are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. SCA7 (previous studies), caused by a CAG repeat expansion in the ATXN7 gene (previous studies) on chromosome 3p13-p12, is a form of ADCA II. SCA5 (previous studies), SCA31 (previous studies), SCA6 (previous studies), and SCA11 (previous studies) are associated with phenotypes most suggestive of ADCA III. However, previous studies noted that there is significant phenotypic overlap between different forms of SCA as well as significant phenotypic variability within each subtype. + +Classic reviews of olivopontocerebellar atrophies and of inherited ataxias in general include those of previous studies, who identified 5 types of olivopontocerebellar atrophy, previous studies, previous studies, previous studies, and previous studies." +MONDO_0008840,"Definition: Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (previous studies). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (previous studies) and are associated with mutations in the ATM gene." +MONDO_0011274,"Definition: Muenke syndrome is an autosomal dominant disorder characterized by uni- or bicoronal synostosis, macrocephaly, midfacial hypoplasia, and developmental delay. Other more variable features include thimble-shaped middle phalanges, brachydactyly, carpal/tarsal fusion, and deafness. The phenotype is variable and can range from no detectable clinical manifestations to complex findings (summary by previous studies)." +MONDO_0011871,"Definition: Niemann-Pick disease types A and B are caused by an inherited deficiency of acid sphingomyelinase activity. The clinical phenotype ranges from a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age (type A) to a later-onset nonneurologic form (type B) that is compatible with survival into adulthood. Since intermediate cases also have been reported, the disease is best regarded a single entity with a clinical spectrum (summary by previous studies). + +previous studies provided a detailed review of Niemann-Pick disease type B, including clinical management." +MONDO_0013390,"Definition: Autosomal recessive limb-girdle muscular dystrophy-17 (LGMDR17) is characterized by early childhood onset of proximal muscle weakness and atrophy without skin involvement. One family has shown rapid progression of the disorder in adolescence (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (previous studies)." +MONDO_0029137,"Definition: Autosomal dominant deafness-74 (DFNA74) is characterized by nonsyndromic postlingual progressive hearing loss, with onset in the third decade of life in most affected individuals (previous studies)." +MONDO_0030529,"Definition: Autosomal dominant agammaglobulinemia-10 (AGM10) is characterized by early-childhood onset of recurrent viral and bacterial infections affecting various organ systems, particularly the sinopulmonary system. Laboratory studies show low or absent circulating B cells and hypo- or agammaglobulinemia. Affected individuals may have adverse reactions to certain vaccinations, such as the polio vaccine. Treatment with replacement Ig is effective; hematopoietic stem cell transplantation has also been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal agammaglobulinemia, see AGM1 (previous studies)." +MONDO_0033621,"Definition: The James type of infantile spinal muscular atrophy (SMAJI) is a severe neuromuscular disorder with onset of hypotonia in the first weeks or months of life. Some patients may have normal early motor development prior to the onset of symptoms, but all show delayed motor milestones with loss of previous motor skills in the first year of life. There is muscle weakness and atrophy, primarily affecting distal muscles, resulting in the inability to walk independently and causing impairment of fine motor skills of the hands. The disorder is slowly progressive: additional features may include feeding difficulties with failure to thrive, foot deformities, hyperlordosis, scoliosis, vocal cord weakness, and respiratory insufficiency, which may require intervention. Laboratory studies are most consistent with a motor neuronopathy, although skeletal muscle biopsy may also show myopathic features. This disorder is considered to be at the most severe end of the phenotypic spectrum of disorders caused by mutations in the GARS1 gene. The disorder is phenotypically similar to SMA1 (previous studies) (summary by previous studies; previous studies)." +MONDO_0007161,"Definition: Spermatogenic failure-2 (SPGF2) is characterized by male infertility due to azoospermia (previous studies; previous studies). + +For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0007205,"Definition: Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. In 2 families, affected individuals also showed a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Thus, the disorder may be considered a tumor predisposition syndrome (summary by previous studies)." +Orphanet_85182,"Definition: Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. In 2 families, affected individuals also showed a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Thus, the disorder may be considered a tumor predisposition syndrome (summary by previous studies)." +MONDO_0007417,"Definition: Darier-White disease (DAR), also known as keratosis follicularis, is an autosomal dominant skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp, and forehead), palmoplantar pits, and distinctive nail abnormalities (previous studies). Onset is usually before the third decade, and penetrance is complete in adults, although expressivity is variable. Involvement may be severe, with widespread itchy malodorous crusted plaques, painful erosions, blistering, and mucosal lesions. Secondary infection is common. Sun, heat, and sweating exacerbate the symptoms. Darier disease never remits, but oral retinoids may reduce hyperkeratosis. Neuropsychiatric abnormalities, including mild mental retardation and epilepsy, have been described in association with Darier disease in a few families (previous studies); whether this is an association based on pleiotropism of the mutant gene or reflects coincidence is not clear. Histologic findings are (1) mild nonspecific perivascular infiltration in the dermis; (2) dermal villi protruding into the epidermis; (3) suprabasal detachment of the spinal layer leading to the formation of lacunae containing acantholytic cells; (4) in the more superficial epidermis, dyskeratotic round epidermal cells ('corps ronds'), the most distinctive feature; and (5) in the stratum corneum, 'grains' that resemble parakeratotic cells embedded in a hyperkeratotic horny layer. Electron microscopy reveals loss of desmosomal attachments, perinuclear aggregations of keratin filaments, and cytoplasmic vacuolization. Ultrastructural and immunologic studies suggest the disease results from an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion." +MONDO_0007434,"Definition: Primary failure of tooth eruption (PFE) is an autosomal dominant disorder in which nonankylosed posterior teeth fail to move along the eruption path cleared for them, resulting in a posterior open bite. Failure of affected teeth to respond to orthodontic force is a key characteristic (summary by previous studies). + +See also previous studies and previous studies for phenotypes with shared features of PFE." +MONDO_0007796,"Definition: previous studies reviewed the various causes and clinical forms of hypoparathyroidism. They noted that hypoparathyroidism is a clinical disorder characterized by hypocalcemia and hyperphosphatemia. It manifests when parathyroid hormone (PTH; previous studies) secreted from the parathyroid glands is insufficient to maintain normal extracellular fluid calcium concentrations or, less commonly, when PTH is unable to function optimally in target tissues, despite adequate circulating levels. + + Genetic Heterogeneity of Familial Isolated Hypoparathyroidism + +FIH2 (previous studies) is caused by mutation in the GCM2 gene (previous studies). An X-linked form of familial hypoparathyroidism, HYPX (previous studies), is caused by interstitial deletion/insertion on chromosome Xq27.1, which may have a position effect on expression of SOX3 (previous studies). + +Congenital absence of the parathyroid and thymus glands (III and IV pharyngeal pouch syndrome, or DiGeorge syndrome, previous studies) is usually a sporadic condition (previous studies)." +MONDO_0008515,Definition: Syndactyly type IV (SDTY4) is characterized by complete syndactylism of all the fingers accompanied by polydactyly and cup-shaped hands due to flexion of the fingers (summary by previous studies). +MONDO_0008970,"Definition: Blomstrand chondrodysplasia is an autosomal recessive disorder characterized by short limbs, polyhydramnios, hydrops fetalis, facial anomalies, increased bone density, and advanced skeletal maturation (summary by previous studies)." +Orphanet_50945,"Definition: Blomstrand chondrodysplasia is an autosomal recessive disorder characterized by short limbs, polyhydramnios, hydrops fetalis, facial anomalies, increased bone density, and advanced skeletal maturation (summary by previous studies)." +MONDO_0010216,"Definition: For a general description of xeroderma pigmentosum, see XPA (previous studies), and of Cockayne syndrome, see CSA (previous studies). Complementation group G has one of the smallest series of cases (previous studies)." +Orphanet_276267,"Definition: For a general description of xeroderma pigmentosum, see XPA (previous studies), and of Cockayne syndrome, see CSA (previous studies). Complementation group G has one of the smallest series of cases (previous studies)." +MONDO_0011760,"Definition: The mucopolysaccharidoses are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function. + +Deficiency of alpha-L-iduronidase can result in a wide range of phenotypic involvement with 3 major recognized clinical entities: Hurler (MPS IH; previous studies), Hurler-Scheie (MPS IH/S; previous studies), and Scheie (MPS IS) syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression (previous studies)." +MONDO_0012401,"Definition: Congenital stromal corneal dystrophy (CSCD) is a rare autosomal dominant eye disease characterized by diffuse bilateral corneal clouding with flake-like whitish opacities throughout the stroma. These small flakes and spots are present at or shortly after birth and are thought to become more numerous with age. Some affected individuals may have strabismus or nystagmus. Normal corneal thickness, horizontal diameter, and endothelial function distinguish the condition from congenital corneal opacifications such as posterior polymorphous dystrophy (see previous studies) and congenital glaucoma (see previous studies). Most individuals undergo a penetrating keratoplasty in late adolescence or in early adulthood with good results (summary by previous studies and previous studies)." +MONDO_0013749,"Definition: Ventricular septal defect (VSD) is the most common form of congenital cardiovascular anomaly, occurring in nearly 50% of all infants with a congenital heart defect and accounting for 14 to 16% of cardiac defects that require invasive treatment within the first year of life. Congenital VSDs may occur alone or in combination with other cardiac malformations. Large VSDs that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death (summary by previous studies). + +Other congenital cardiac defects caused by mutation in the NKX2-5 gene include atrial septal defect with or without atrioventricular conduction defects (ASD7; previous studies), tetralogy of Fallot (see TOF, previous studies), conotruncal malformations (see previous studies), and hypoplastic left heart syndrome (HLHS2; previous studies). + +For a discussion of genetic heterogeneity of ventricular septal defect, see VSD1 (previous studies)." +MONDO_0014206,Definition: Interstitial lung and liver disease is an autosomal recessive disorder characterized by onset of respiratory insufficiency and progressive liver disease in infancy or early childhood. Pathologic examination of lung lavage is consistent with pulmonary alveolar proteinosis (summary by previous studies). +Orphanet_1460,"Definition: Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (previous studies; previous studies). + + Genetic Heterogeneity of Mitochondrial Complex III Deficiency + +Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (previous studies), caused by mutation in the TTC19 gene (previous studies) on chromosome 17p12; MC3DN3 (previous studies), caused by mutation in the UQCRB gene (previous studies) on chromosome 8q; MC3DN4 (previous studies), caused by mutation in the UQCRQ gene (previous studies) on chromosome 5q31; MC3DN5 (previous studies), caused by mutation in the UQCRC2 gene (previous studies) on chromosome 16p12; MC3DN6 (previous studies), caused by mutation in the CYC1 gene (previous studies) on chromosome 8q24; MC3DN7 (previous studies), caused by mutation in the UQCC2 gene (previous studies) on chromosome 6p21; MC3DN8 (previous studies), caused by mutation in the LYRM7 gene (previous studies) on chromosome 5q23; MC3DN9 (previous studies), caused by mutation in the UQCC3 gene (previous studies) on chromosome 11q12; and MC3DN10 (previous studies), caused by mutation in the UQCRFS1 gene (previous studies) on chromosome 19q12. + +See also MTYCB (previous studies) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene." +MONDO_0007415,"Definition: Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (previous studies; previous studies). + + Genetic Heterogeneity of Mitochondrial Complex III Deficiency + +Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (previous studies), caused by mutation in the TTC19 gene (previous studies) on chromosome 17p12; MC3DN3 (previous studies), caused by mutation in the UQCRB gene (previous studies) on chromosome 8q; MC3DN4 (previous studies), caused by mutation in the UQCRQ gene (previous studies) on chromosome 5q31; MC3DN5 (previous studies), caused by mutation in the UQCRC2 gene (previous studies) on chromosome 16p12; MC3DN6 (previous studies), caused by mutation in the CYC1 gene (previous studies) on chromosome 8q24; MC3DN7 (previous studies), caused by mutation in the UQCC2 gene (previous studies) on chromosome 6p21; MC3DN8 (previous studies), caused by mutation in the LYRM7 gene (previous studies) on chromosome 5q23; MC3DN9 (previous studies), caused by mutation in the UQCC3 gene (previous studies) on chromosome 11q12; and MC3DN10 (previous studies), caused by mutation in the UQCRFS1 gene (previous studies) on chromosome 19q12. + +See also MTYCB (previous studies) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene." +Orphanet_254902,"Definition: Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (previous studies; previous studies). + + Genetic Heterogeneity of Mitochondrial Complex III Deficiency + +Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (previous studies), caused by mutation in the TTC19 gene (previous studies) on chromosome 17p12; MC3DN3 (previous studies), caused by mutation in the UQCRB gene (previous studies) on chromosome 8q; MC3DN4 (previous studies), caused by mutation in the UQCRQ gene (previous studies) on chromosome 5q31; MC3DN5 (previous studies), caused by mutation in the UQCRC2 gene (previous studies) on chromosome 16p12; MC3DN6 (previous studies), caused by mutation in the CYC1 gene (previous studies) on chromosome 8q24; MC3DN7 (previous studies), caused by mutation in the UQCC2 gene (previous studies) on chromosome 6p21; MC3DN8 (previous studies), caused by mutation in the LYRM7 gene (previous studies) on chromosome 5q23; MC3DN9 (previous studies), caused by mutation in the UQCC3 gene (previous studies) on chromosome 11q12; and MC3DN10 (previous studies), caused by mutation in the UQCRFS1 gene (previous studies) on chromosome 19q12. + +See also MTYCB (previous studies) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene." +Orphanet_35858,"Definition: Imerslund-Grasbeck syndrome-1 (IGS1) is an autosomal recessive disorder characterized by onset of megaloblastic anemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Low molecular weight (LMW) proteinuria is frequently present, but sometimes occurs later and is usually mild or subclinical. Patients often present with vague symptoms, including failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Some patients may present later in childhood with neurologic abnormalities related to B12 deficiency, such as sensorimotor neuropathy and/or cognitive disturbances. Treatment with vitamin B12 results in sustained clinical improvement of the anemia and resolution of the neurologic symptoms, if present. The proteinuria is nonprogressive, and affected individuals do not have deterioration of kidney function; correct diagnosis is important to prevent unnecessary treatment. The disorder results from a combination of vitamin B12 deficiency due to selective malabsorption of the vitamin, and impaired reabsorption of LMW proteins in the proximal renal tubule. These defects are caused by disruption of the AMN (previous studies)/CUBN complex that forms the 'cubam' receptor responsible for intestinal uptake of B12/GIF (CBLIF; previous studies). In the kidney, AMN/CUBN interacts with the endocytic receptor megalin (LRP2; previous studies), which is important for the reabsorption of plasma proteins (summary by previous studies, previous studies, previous studies). + + Genetic Heterogeneity of Imerslund-Grasbeck Syndrome + +See also IGS2 (previous studies), caused by mutation in the AMN gene (previous studies) on chromosome 14q32. + +Congenital pernicious anemia (previous studies), a distinct disorder with overlapping features, is caused by mutation in the GIF (CBLIF) gene (previous studies). Adult pernicious anemia (previous studies) is another distinct autoimmune disorder associated with plasma autoantibodies to gastric parietal cells or gastric intrinsic factor." +Orphanet_400008,"Definition: Maternal genes play a critical role in the very early stages of embryonic development because of the lag in transcribing genes derived from the male pronucleus. TLE6 mutations are a rare cause of human female-limited fertility and appear to represent the earliest known human embryonic lethality that is due to a single gene mutation. In affected women, ovulation proceeds normally and the retrieved oocytes appear normal, but zygote formation is severely impaired (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of OZEMA, see previous studies." +EFO_0009531,"Definition: Aortic valve disease-3 (AOVD3) is characterized by aortic stenosis and/or bicuspid aortic valve (BAV), associated in some patients with aneurysm of the aortic root and/or ascending aorta. Atrial septal defect (ASD) has also been observed in some individuals (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of aortic valve disease, see AOVD1 (previous studies)." +MONDO_0008760,"Definition: Alpha-methylacetoacetic aciduria, also known as 3-ketothiolase deficiency, is an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone." +MONDO_0009588,"Definition: Langer mesomelic dysplasia (LMD) is characterized by severe limb aplasia or severe hypoplasia of the ulna and fibula, and a thickened and curved radius and tibia. These changes can result in displacement deformities of the hands and feet. Hypoplasia of the mandible is also observed (previous studies). + +See also Leri-Weill dyschondrosteosis (previous studies), a less severe phenotype that results from heterozygous defect in the SHOX or SHOXY genes." +MONDO_0009728,"Definition: Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. It is the most frequent genetic cause of renal failure in children. NPHP may be combined with extrarenal manifestations, such as liver fibrosis, situs inversus, or cardiac malformations. When nephronophthisis is combined with retinitis pigmentosa, the disorder is known as Senior-Loken syndrome (SLSN1; previous studies); when it is combined with cerebellar vermis hypoplasia, the disorder is known as Joubert syndrome (JBTS1; previous studies); and when it is combined with multiple developmental and neurologic abnormalities, the disorder is often known as Meckel-Gruber syndrome (MKS1; previous studies). Because most NPHP gene products localize to the cilium or its associated structures, nephronophthisis and the related syndromes have been termed 'ciliopathies' (summary by previous studies). + +Clinical features of familial juvenile nephronophthisis include anemia, polyuria, polydipsia, isosthenuria, and death in uremia. previous studies provided a detailed review of nephronophthisis, including a discussion of clinical features and molecular genetics. previous studies provided a review of NPHP, including clinical features, pathophysiology, and therapeutic approaches. + + Genetic Heterogeneity of Nephronophthisis + +NPHP2 (previous studies) is caused by mutation in the INVS gene (previous studies) on chromosome 9q31; NPHP3 (previous studies) is caused by mutation in the NPHP3 gene (previous studies) on chromosome 3q22; NPHP4 (previous studies) is caused by mutation in the NPHP4 gene (previous studies) on chromosome 1p36; NPHP7 (previous studies) is caused by mutation in the GLIS2 gene (previous studies) on chromosome 16p13; NPHP9 (previous studies) is caused by mutation in the NEK8 gene (previous studies) on chromosome 17q11; NPHP11 (previous studies) is caused by mutation in the TMEM67 gene (previous studies) on chromosome 8q22; NPHP12 (previous studies) is caused by mutation in the TTC21B gene (previous studies) on chromosome 2q24; NPHP13 (previous studies) is caused by mutation in the WDR19 gene (previous studies) on chromosome 4p14; NPHP14 (previous studies) is caused by mutation in the ZNF423 gene (previous studies) on chromosome 16; NPHP15 (previous studies) is caused by mutation in the CEP164 gene (previous studies) on chromosome 11q; NPHP16 (previous studies) is caused by mutation in the ANKS6 gene (previous studies) on chromosome 9q22; NPHP18 (previous studies) is caused by mutation in the CEP83 gene (previous studies) on chromosome 12q22; NPHP19 (previous studies) is caused by mutation in the DCDC2 gene (previous studies) on chromosome 6p22; and NPHP20 (previous studies) is caused by mutation in the MAPKBP1 gene (previous studies) on chromosome 15q13. + +Two disorders have been phenotypically described as 'NPHP-like' due to variable unique features: NPHPL1 (previous studies), caused by mutation in the XPNPEP3 gene (previous studies) on chromosome 22q13, and NPHPL2 (previous studies), caused by mutation in the SLC41A1 gene (previous studies) on chromosome 1q32." +MONDO_0010308,Definition: XLTDA is an X-linked recessive hematologic disorder characterized by thrombocytopenia and abnormal platelet morphology and function due to defective platelet maturation. Some patients have a variable severity of dyserythropoietic anemia (summary by previous studies). +MONDO_0010854,"Definition: Oculoectodermal syndrome (OES) is characterized by the association of epibulbar dermoids and aplasia cutis congenita. Affected individuals exhibit congenital scalp lesions which are atrophic, nonscarring, hairless regions that are often multiple and asymmetric in distribution, and may have associated hamartomas. Ectodermal changes include linear hyperpigmentation that may follow the lines of Blaschko and, rarely, epidermal nevus-like lesions. Epibulbar dermoids may be uni- or bilateral. Additional ocular anomalies such as skin tags of the upper eyelid and rarely optic nerve or retinal changes or microphthalmia can be present. Phenotypic expression is highly variable, and various other abnormalities have occasionally been reported, including growth failure, lymphedema, and cardiovascular defects, as well as neurodevelopmental symptoms such as developmental delay, epilepsy, learning difficulties, and behavioral abnormalities. Benign tumor-like lesions such as nonossifying fibromas of the long bones and giant cell granulomas of the jaws have repeatedly been observed and appear to be age-dependent, becoming a common manifestation in individuals aged 5 years or older (summary by previous studies)." +MONDO_0011213,"Definition: Pierpont syndrome (PRPTS) is a multiple congenital anomaly syndrome associated with learning disability. Key features include distinctive facial characteristics, especially when smiling, plantar fat pads, and other limb anomalies (summary by previous studies)." +MONDO_0011683,"Definition: Oculocutaneous albinism type IV (OCA4) is an autosomal recessive disorder of pigmentation of skin, hair, and eyes. The degree of hypopigmentation varies from mild to severe. Hair color ranges from white through yellow and blond to brown, with gray, blue-gray, or brown irides. Nystagmus may be present (previous studies). Other ocular abnormalities include decreased visual acuity, macular hypoplasia, optic dysplasia, or atypical choroidal vessels (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of oculocutaneous albinism, see OCA1 (previous studies)." +MONDO_0012172,"Definition: The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death (SIDS; previous studies), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy (previous studies). + +Some patients with MTP deficiency show a protracted progressive course associated with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy. These patients tend to survive into adolescence and adulthood (previous studies). + + Genetic Heterogeneity of Mitochondrial Trifunctional Protein Deficiency + +See also MTPD2 (previous studies), caused by mutation in the HADHB gene, the beta subunit of the mitochondrial trifunctional protein." +MONDO_0013279,"Definition: Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (previous studies). + +For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (previous studies)." +MONDO_0033557,"Definition: Immune dysregulation and systemic hyperinflammation syndrome (IMDYSHI) is an autosomal recessive immunologic disorder characterized by systemic hyperinflammation in the absence of an infectious agent or autoimmune trigger. Features include lymphadenopathy, hepatosplenomegaly, recurrent fever, and laboratory evidence of immune dysregulation with abnormal immune cell populations and increased serum levels of inflammatory cytokines. The phenotype is reminiscent of relapsing hemophagocytic lymphohistiocytosis (HLH; see FHL1, previous studies) (summary by previous studies)." +Orphanet_1195,Definition: Atransferrinemia is characterized by microcytic anemia and by iron loading. It can be treated effectively by plasma infusions (summary by previous studies). +MONDO_0008846,Definition: Atransferrinemia is characterized by microcytic anemia and by iron loading. It can be treated effectively by plasma infusions (summary by previous studies). +Orphanet_319547,"Definition: IMD28 is caused by autosomal recessive (AR) IFNGR2 deficiency, a rare molecular cause of susceptibility to mycobacterial disease. The clinical presentation of complete AR IFNGR2 deficiency resembles that of complete IFNGR1 deficiency (IMD27A; previous studies). The disease manifests early in life, with severe, often fatal, infection. The most commonly encountered pathogens include M. bovis bacillus Calmette-Guerin (BCG), M. avium, and M. fortuitum. Complete AR IFNGR2 deficiency is characterized by an undetectable cellular response to interferon-gamma (IFNG; previous studies). There is also a rare partial form of AR IFNGR2 deficiency, reported in 1 child, who retained a residual cellular response to IFNG and presented with a relatively mild infection by M. bovis BCG and M. abscessus (review by previous studies)." +EFO_0005269,"Definition: Multiple types of congenital heart defects-2 (CHTD2) is characterized by variable congenital heart defects, primarily involving the valves, but also including septal defects or aneurysms, and complex defects such as tetralogy of Fallot. Dilated cardiomyopathy and myocardial noncompaction have been reported in some patients. In addition, some affected individuals exhibit facial dysmorphism and features of connective tissue disease (previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of CHTD, see previous studies." +EFO_0009050,"Definition: Smith-Kingsmore syndrome (SKS) is a rare autosomal dominant syndromic intellectual disability syndrome characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features including frontal bossing, midface hypoplasia, small chin, hypertelorism with downslanting palpebral fissures, depressed nasal bridge, smooth philtrum, and thin upper lip (previous studies; previous studies)." +MONDO_0009231,"Definition: Acromesomelic dysplasia-2B (AMD2B) is characterized by normal head and trunk, hypoplastic/dysplastic or absent fibulae, and severe hypoplastic/dysplastic hand/feet abnormalities. Mental development is normal (summary by previous studies)." +MONDO_0011405,"Definition: Poikiloderma with neutropenia (PN) is an autosomal recessive syndrome characterized by poikiloderma, hyperkeratotic nails, generalized hyperkeratosis on palms and soles, noncyclic neutropenia, short stature, and recurrent pulmonary infections (previous studies)." +MONDO_0011537,"Definition: Macrocephaly/autism syndrome is an autosomal dominant disorder characterized by increased head circumference, abnormal facial features, and delayed psychomotor development resulting in autistic behavior or mental retardation (previous studies). Some patients may have a primary immunodeficiency disorder with recurrent infections associated with variably abnormal T- and B-cell function (previous studies)." +MONDO_0012905,"Definition: Hypomyelinating leukodystrophy-6, also known as hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum, is a neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen. The disorder usually shows sporadic occurrence, but sibs may be affected if a parent is somatic mosaic for the mutation (summary by previous studies). + +Hypomyelinating leukodystrophies (HLD) comprise a genetically heterogeneous entity in which there is a substantial permanent deficit in myelin deposition within the brain, resulting in neurologic deficits (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see previous studies." +Orphanet_139441,"Definition: Hypomyelinating leukodystrophy-6, also known as hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum, is a neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen. The disorder usually shows sporadic occurrence, but sibs may be affected if a parent is somatic mosaic for the mutation (summary by previous studies). + +Hypomyelinating leukodystrophies (HLD) comprise a genetically heterogeneous entity in which there is a substantial permanent deficit in myelin deposition within the brain, resulting in neurologic deficits (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see previous studies." +MONDO_0014421,"Definition: Generalized glucocorticoid resistance is an autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of clinical stigmata of Cushing syndrome. The clinical expression of the disease is variable. Common features include hypoglycemia, hypertension, and metabolic alkalosis. In females, overproduction of adrenal androgens has been associated with infertility, male-pattern baldness, hirsutism, and menstrual irregularities. Other features include chronic fatigue and profound anxiety (summary by previous studies; previous studies)." +MONDO_0014702,"Definition: Autosomal recessive SPG9B is a neurologic disorder characterized by early-onset complex spastic paraplegia. Affected individuals had delayed psychomotor development, intellectual disability, and severe motor impairment. More variable features include dysmorphic facial features, tremor, and urinary incontinence (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (previous studies)." +MONDO_0030856,"Definition: Developmental and epileptic encephalopathy-89 (DEE89) is a severe autosomal recessive disorder characterized by profound global developmental delay with impaired intellectual development, absent speech, inability to sit or walk due to axial hypotonia and spastic quadriparesis, and onset of seizures in the first days or months of life. EEG shows suppression-burst pattern or hypsarrhythmia, consistent with DEE or a clinical diagnosis of West syndrome. More variable features include joint contractures with foot deformities, dysmorphic facial features with cleft palate, and omphalocele. Affected individuals have poor motor skills, poor eye contact, and lack of language development; some die in infancy or early childhood. Brain imaging may be normal or show nonspecific abnormalities (summary by previous studies)." +MONDO_0032819,"Definition: Nongoitrous congenital hypothyroidism-7 (CHNG7) is characterized by normal-to-low T4 and normal-to-high thyrotropin (TSH; see previous studies) levels, with reduced or absent pituitary responsiveness to thyrotropin-releasing hormone (TRH; previous studies). Patients may exhibit short stature, growth retardation, and delayed bone age, as well as lethargy or fatigue (previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of congenital nongoitrous hypothyroidism, see previous studies." +MONDO_0032886,"Definition: Liang-Wang syndrome (LIWAS) is a polymalformation syndrome apparent from birth that shows large phenotypic variability and severity. However, all patients have some degree of neurologic dysfunction. The most severely affected individuals have severe global developmental delay with impaired intellectual development and poor or absent speech, marked craniofacial dysmorphism, and visceral and connective tissue abnormalities affecting the bones and vessels. The least severely affected individuals lack seizures, significant dysmorphism, and visceral involvement; they come to attention for neurologic signs and symptoms, including developmental delay with speech delay, strabismus, and/or ataxia. About half of patients have brain imaging anomalies, notably cerebral and cerebellar atrophy and thin corpus callosum, whereas the other half have normal brain imaging (summary by previous studies)." +MONDO_0100352,"Definition: Paroxysmal kinesigenic choreoathetosis (PKC) is an autosomal dominant neurologic condition characterized by recurrent and brief attacks of involuntary movement triggered by sudden voluntary movement. These attacks usually have onset during childhood or early adulthood and can involve dystonic postures, chorea, or athetosis. Symptoms become less severe with age and show favorable response to anticonvulsant medications such as carbamazepine or phenytoin. It is the most common type of paroxysmal movement disorder. The condition is often misdiagnosed as an epileptic manifestation (summary by previous studies). + +PKC shares some clinical features with benign familial infantile convulsions (BFIC2; previous studies) and infantile convulsions and paroxysmal choreoathetosis (ICCA; previous studies), which are allelic disorders. + +See also rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (previous studies), which maps to chromosome 16p12-p11.2. + + Genetic Heterogeneity of Episodic Kinesigenic Dyskinesia + +See also EKD2 (previous studies), which maps to chromosome 16q13-q22.1, and EKD3 (previous studies), caused by mutation in the TMEM151A gene (previous studies) on chromosome 11q13." +Orphanet_2850,"Definition: Alopecia-intellectual disability syndrome (APMR) is a rare autosomal recessive disorder in which affected individuals show loss of hair on the scalp, absence of eyebrows, eyelashes, and axillary and pubic hair, and mildly to severely impaired intellectual development (summary by previous studies). + + Genetic Heterogeneity of Alopecia-Intellectual Disability Syndrome + +Loci for alopecia-intellectual disability syndrome have been mapped to chromosome 3q26.2-q26.31 (APMR2; previous studies) and chromosome 18q11.2-q12.2 (APMR3; previous studies). APMR4 (previous studies) is caused by mutation in the LSS gene (previous studies) on chromosome 21q22." +Orphanet_79322,"Definition: Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. + +For a general discussion of CDGs, see CDG Ia (previous studies) and CDG Ib (previous studies)." +MONDO_0012123,"Definition: Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. + +For a general discussion of CDGs, see CDG Ia (previous studies) and CDG Ib (previous studies)." +MONDO_0007400,Definition: Jackson-Weiss syndrome (JWS) is an autosomal dominant condition consisting of craniosynostosis characterized by premature fusion of the cranial sutures as well as radiographic anomalies of the feet (summary by previous studies). +MONDO_0008559,"Definition: Thrombophilia is a multifactorial disorder of inappropriate clot formation resulting from an interaction of genetic, acquired, and circumstantial predisposing factors. Venous thromboembolism most commonly manifests as deep vein thrombosis, which may progress to pulmonary embolism if the clot dislodges and travels to the lung. Other manifestations include thromboses of the cerebral or visceral veins and recurrent pregnancy loss (summary by previous studies and previous studies). + + Genetic Heterogeneity of Thrombophilia + +THPH2 (previous studies) is caused by mutation in the F5 gene (previous studies) on chromosome 1q23; THPH3 (previous studies) and THPH4 (previous studies) are both caused by mutation in the PROC gene (previous studies) on 2q; THPH5 (previous studies) and THPH6 (previous studies) are caused by mutation in the PROS1 gene (previous studies) on 3q11; THPH7 (previous studies) is caused by mutation in the AT3 gene (previous studies) on 1q25; THPH8 (previous studies) is caused by mutation in the F9 gene (previous studies) on Xq27; THPH9 (previous studies) is associated with decreased release of tissue plasminogen activator (PLAT; previous studies); THPH10 (previous studies) is caused by mutation in the HCF2 gene (previous studies) on 22q11; THPH11 (previous studies) is caused by mutation in the HRG gene (previous studies) on 3q27; and THPH12 (previous studies) is associated with variation in the THBD gene (previous studies) on 20p11. + +Susceptibility to thrombosis has also been associated with variation in additional genes, including MTHFR (previous studies); F13B (previous studies); plasminogen activator inhibitor (SERPINE1; previous studies); and several genes encoding fibrinogen (FGA, previous studies; FGB, previous studies; FGG, previous studies). Variation in the SERPINA10 (see previous studies), KNG1 (previous studies) and HABP2 (previous studies) genes has also been reported. + +Protection against venous thrombosis is associated with variation in the F13A1 gene (previous studies) on 6p25." +MONDO_0009655,"Definition: The Sanfilippo syndrome, or mucopolysaccharidosis III, is an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate (previous studies). The disorder is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. Type A has been reported (previous studies) to be the most severe, with earlier onset and rapid progression of symptoms and shorter survival. + + Genetic Heterogeneity of Mucopolysaccharidosis Type III + +MPS III includes 4 types, each due to the deficiency of a different enzyme: heparan N-sulfatase (type A); alpha-N-acetylglucosaminidase (type B; previous studies); acetyl CoA:alpha-glucosaminide acetyltransferase (type C; previous studies); and N-acetylglucosamine 6-sulfatase (type D; previous studies)." +MONDO_0009669,"Definition: Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy (summary by previous studies). + +Four types of SMA are recognized depending on the age of onset, the maximum muscular activity achieved, and survivorship: type I, severe infantile acute SMA, or Werdnig-Hoffman disease; type II (previous studies), or infantile chronic SMA; type III (previous studies), juvenile SMA, or Wohlfart-Kugelberg-Welander disease; and type IV (previous studies), or adult-onset SMA. All types are caused by recessive mutations in the SMN1 gene. + +previous studies provided a detailed review of clinical features, molecular pathogenesis, and therapeutic strategies for SMA." +MONDO_0011688,"Definition: MDDGB5 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and structural brain abnormalities (previous studies). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (previous studies)." +MONDO_0012239,"Definition: Congenital myopathy-4B (CMYP4B) is an autosomal recessive disorder of the skeletal muscle characterized by the onset of muscle weakness in infancy or early childhood. The severity and pattern of muscle weakness varies, but most affected individuals show congenital contractures, delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty walking or inability to walk. Affected individuals have respiratory insufficiency due to muscle weakness, which may be life-threatening. Other common features include myopathic facies, chest deformities, distal joint laxity, and scoliosis. Variable histologic findings on skeletal muscle biopsy are observed, including nemaline rods, type 1 fiber predomination, and centralized nuclei (previous studies; previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0012423,"Definition: Impaired intellectual development, truncal obesity, retinal dystrophy, and micropenis syndrome (MORMS) is an autosomal recessive disorder characterized by these findings (previous studies)." +MONDO_0012496,"Definition: Koolen-De Vries syndrome is characterized by moderate to severe intellectual disability, hypotonia, friendly demeanor, and highly distinctive facial features, including tall, broad forehead, long face, upslanting palpebral fissures, epicanthal folds, tubular nose with bulbous nasal tip, and large ears. More variable features include cardiac or genitourinary anomalies and seizures (summary by previous studies)." +MONDO_0013301,"Definition: Aromatase deficiency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens. If a fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, and is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. Affected females are usually diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotropic hypogonadism. Affected males do not present with obvious defects at birth. Their clinical symptoms include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions, and excess adiposity. Estrogen replacement therapy reverses the symptoms in males and females (summary by previous studies)." +MONDO_0014994,"Definition: GDACCF is an intellectual disability syndrome apparent soon after birth with neonatal hypotonia, poor feeding, and respiratory insufficiency followed by delayed psychomotor development and intellectual disability with poor speech. Brain imaging shows aplasia or hypoplasia of the corpus callosum. Affected individuals have variable dysmorphic facial features, and some may have dysplastic, cystic kidneys or mild cardiac defects (summary by previous studies)." +MONDO_0032737,"Definition: Spastic paraplegia-80 (SPG80) is an autosomal dominant juvenile-onset neurologic disorder characterized by onset of progressive spasticity and hyperreflexia affecting mainly the lower limbs and resulting in difficulty walking or loss of independent ambulation, sometimes as early as the second decade. Some patients may have cerebellar signs and mild cognitive impairment, but most have a pure form of the disorder (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (previous studies)." +Orphanet_101992,"Definition: Complement factor H deficiency (CFHD) has a variable phenotype. Some patients present with recurrent infections, including increased susceptibility to meningococcal infections, whereas others develop renal disease manifest primarily as C3 glomerulopathy. Affected individuals usually present in the first decades of life with nonspecific findings such as hematuria and may progress to chronic renal failure. As complement factor H is the key regulator of the alternative pathway of the complement system, CFH deficiency results in inappropriate activation of the alternative complement pathway. Laboratory features usually include decreased serum levels of factor H, due to the genetic defect, as well as secondarily decreased levels of complement component C3 (previous studies) and other alternative pathway components, consistent with consumption of these factors. The renal phenotype is now considered to be a form of C3 glomerulopathy (C3G), which is a pathologic entity in which C3 is deposited within the kidney glomerulus in the mesangial or intramembranous space; this occurs in the absence of immune complexes or immunoglobulins. Terms used to describe this disease include membranoproliferative glomerulonephritis type II (MPGN II), mesangial glomerulonephritis, dense deposit disease (DDD), and C3 glomerulonephritis (summary by previous studies, reviews by previous studies and previous studies). + + Nomenclature and Classification + +Several reviews (previous studies, previous studies, previous studies) have noted that the definition and classification of C3G continues to evolve. Historically, C3G has been referred to as type II membranoproliferative glomerulonephritis (MPGN) or dense deposit disease (DDD) with mesangial or intramembranous deposition of electron dense material. In contrast, MPGN types I and III, which are usually associated with immune complex deposition, tend to show subendothelial and subepithelial electron dense deposits. However, there is significant variability, and the differentiation and distinction between these terms is often unclear. previous studies also discussed the role of complement in renal disease. + +A subgroup of patients with MGPN II who do not have mutations in the CFH gene are positive for serum C3 nephritic factor (C3NeF), which is an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. Presence of C3NeF prolongs the half-life of C3 convertase, which also results in inappropriate activation of the complement cascade (summary by previous studies). + + Genetic Heterogeneity of C3G + +C3G2 (previous studies) is caused by mutation in the CFI gene (previous studies) on chromosome 4q25, and C3G3 (previous studies) is caused by mutation in the CFHR5 gene (previous studies) on chromosome 1q31." +MONDO_0012350,"Definition: Complement factor H deficiency (CFHD) has a variable phenotype. Some patients present with recurrent infections, including increased susceptibility to meningococcal infections, whereas others develop renal disease manifest primarily as C3 glomerulopathy. Affected individuals usually present in the first decades of life with nonspecific findings such as hematuria and may progress to chronic renal failure. As complement factor H is the key regulator of the alternative pathway of the complement system, CFH deficiency results in inappropriate activation of the alternative complement pathway. Laboratory features usually include decreased serum levels of factor H, due to the genetic defect, as well as secondarily decreased levels of complement component C3 (previous studies) and other alternative pathway components, consistent with consumption of these factors. The renal phenotype is now considered to be a form of C3 glomerulopathy (C3G), which is a pathologic entity in which C3 is deposited within the kidney glomerulus in the mesangial or intramembranous space; this occurs in the absence of immune complexes or immunoglobulins. Terms used to describe this disease include membranoproliferative glomerulonephritis type II (MPGN II), mesangial glomerulonephritis, dense deposit disease (DDD), and C3 glomerulonephritis (summary by previous studies, reviews by previous studies and previous studies). + + Nomenclature and Classification + +Several reviews (previous studies, previous studies, previous studies) have noted that the definition and classification of C3G continues to evolve. Historically, C3G has been referred to as type II membranoproliferative glomerulonephritis (MPGN) or dense deposit disease (DDD) with mesangial or intramembranous deposition of electron dense material. In contrast, MPGN types I and III, which are usually associated with immune complex deposition, tend to show subendothelial and subepithelial electron dense deposits. However, there is significant variability, and the differentiation and distinction between these terms is often unclear. previous studies also discussed the role of complement in renal disease. + +A subgroup of patients with MGPN II who do not have mutations in the CFH gene are positive for serum C3 nephritic factor (C3NeF), which is an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. Presence of C3NeF prolongs the half-life of C3 convertase, which also results in inappropriate activation of the complement cascade (summary by previous studies). + + Genetic Heterogeneity of C3G + +C3G2 (previous studies) is caused by mutation in the CFI gene (previous studies) on chromosome 4q25, and C3G3 (previous studies) is caused by mutation in the CFHR5 gene (previous studies) on chromosome 1q31." +Orphanet_178464,"Definition: Myofibrillar myopathy-9 with early respiratory failure (MFM9) is an autosomal dominant muscle disorder characterized by adult onset of slowly progressive muscle weakness with diaphragmatic involvement causing respiratory insufficiency. Patients present between 20 and 70 years of age with distal or proximal muscle weakness, mainly affecting the lower limbs with foot drop or difficulty walking. The age at onset is highly variable, even within families. Nearly all patients eventually develop significant proximal and distal weakness, as well as respiratory insufficiency requiring nocturnal ventilation. Additional, more variable features may include axial weakness, neck muscle weakness, and rarely, cardiac involvement. Muscle biopsy shows myopathic or dystrophic changes with fiber splitting, eosinophilic cytoplasmic inclusions consistent with myofibrillar myopathy, rimmed vacuoles, and increased connective or fatty tissue (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (previous studies)." +EFO_0010828,"Definition: Myofibrillar myopathy-9 with early respiratory failure (MFM9) is an autosomal dominant muscle disorder characterized by adult onset of slowly progressive muscle weakness with diaphragmatic involvement causing respiratory insufficiency. Patients present between 20 and 70 years of age with distal or proximal muscle weakness, mainly affecting the lower limbs with foot drop or difficulty walking. The age at onset is highly variable, even within families. Nearly all patients eventually develop significant proximal and distal weakness, as well as respiratory insufficiency requiring nocturnal ventilation. Additional, more variable features may include axial weakness, neck muscle weakness, and rarely, cardiac involvement. Muscle biopsy shows myopathic or dystrophic changes with fiber splitting, eosinophilic cytoplasmic inclusions consistent with myofibrillar myopathy, rimmed vacuoles, and increased connective or fatty tissue (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (previous studies)." +MONDO_0011362,"Definition: Myofibrillar myopathy-9 with early respiratory failure (MFM9) is an autosomal dominant muscle disorder characterized by adult onset of slowly progressive muscle weakness with diaphragmatic involvement causing respiratory insufficiency. Patients present between 20 and 70 years of age with distal or proximal muscle weakness, mainly affecting the lower limbs with foot drop or difficulty walking. The age at onset is highly variable, even within families. Nearly all patients eventually develop significant proximal and distal weakness, as well as respiratory insufficiency requiring nocturnal ventilation. Additional, more variable features may include axial weakness, neck muscle weakness, and rarely, cardiac involvement. Muscle biopsy shows myopathic or dystrophic changes with fiber splitting, eosinophilic cytoplasmic inclusions consistent with myofibrillar myopathy, rimmed vacuoles, and increased connective or fatty tissue (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (previous studies)." +Orphanet_273,"Definition: Myotonic dystrophy is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. The genetic defect in DM1 results from an amplified trinucleotide repeat in the 3-prime untranslated region of a protein kinase gene. Disease severity varies with the number of repeats: normal individuals have 5 to 37 repeats, mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with onset at birth can have more than 2,000 repeats. The disorder shows genetic anticipation, with expansion of the repeat number dependent on the sex of the transmitting parent. Alleles of 40 to 80 repeats are usually expanded when transmitted by males, whereas only alleles longer than 80 repeats tend to expand in maternal transmissions. Repeat contraction events occur 4.2 to 6.4% of the time (previous studies). + + Genetic Heterogeneity of Myotonic Dystrophy + +See also myotonic dystrophy-2 (DM2; previous studies), which is caused by mutation in the ZNF9 gene (previous studies) on chromosome 3q21." +MONDO_0008056,"Definition: Myotonic dystrophy is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. The genetic defect in DM1 results from an amplified trinucleotide repeat in the 3-prime untranslated region of a protein kinase gene. Disease severity varies with the number of repeats: normal individuals have 5 to 37 repeats, mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with onset at birth can have more than 2,000 repeats. The disorder shows genetic anticipation, with expansion of the repeat number dependent on the sex of the transmitting parent. Alleles of 40 to 80 repeats are usually expanded when transmitted by males, whereas only alleles longer than 80 repeats tend to expand in maternal transmissions. Repeat contraction events occur 4.2 to 6.4% of the time (previous studies). + + Genetic Heterogeneity of Myotonic Dystrophy + +See also myotonic dystrophy-2 (DM2; previous studies), which is caused by mutation in the ZNF9 gene (previous studies) on chromosome 3q21." +Orphanet_98869,"Definition: Congenital dyserythropoietic anemia type I is an autosomal recessive hematologic disorder characterized by congenital macrocytic anemia secondary to ineffective erythropoiesis. The bone marrow shows erythroid hyperplasia, with nuclear abnormalities in most erythroblasts. Up to 3% of erythroblasts have interchromatin bridges, and erythroblast nuclei are abnormally electron dense with spongy ('Swiss cheese-like') heterochromatin on electron microscopy. Some reported patients have distal digital abnormalities (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of CDA, see CDAN1A (previous studies)." +MONDO_0007176,"Definition: Sveinsson chorioretinal atrophy (SCRA) is characterized by bilateral, well-defined, tongue-shaped strips of atrophic retina and choroid that extend from the optic nerve into the peripheral ocular fundus. The lesions may be evident at birth and usually progress at a variable rate, sometimes leading to central visual loss. Separate small distinct circular atrophic lesions are observed in the peripheral ocular fundus in some patients. Congenital anterior polar cataracts are found in approximately 25% of affected individuals (summary by previous studies)." +MONDO_0009257,"Definition: Galactosemia III (GALAC3), or epimerase-deficiency galactosemia, was originally described as a benign condition in which GALE impairment is restricted to circulating red and white blood cells (previous studies). Fibroblasts, liver, phytohemagglutinin-stimulated leukocytes, and Epstein Barr virus-transformed lymphoblasts from these patients all demonstrated normal or near-normal levels of GALE, leading to the designation 'peripheral' (or 'isolated') epimerase deficiency. A second form of epimerase deficiency became apparent in which a patient, despite normal GALT activity, presented with symptoms reminiscent of classic galactosemia and demonstrated severely impaired GALE activity in both red blood cells and fibroblasts (previous studies). This form was designated 'generalized' epimerase deficiency. previous studies demonstrated that epimerase deficiency is in fact not a binary condition but is, rather, a continuum disorder. + +For a discussion of genetic heterogeneity of galactosemia, see GALAC1 (previous studies)." +MONDO_0010367,"Definition: Idiopathic short stature is usually defined as a height below the third percentile for chronological age or minus 2 standard deviations (SD) of national height standards in the absence of specific causative disorders (previous studies). + +For a discussion of genetic heterogeneity of quantitative trait loci for stature, see STQTL1 (previous studies)." +MONDO_0011223,"Definition: Juvenile amyotrophic lateral sclerosis-4 (ALS4) is an autosomal dominant disorder characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs, with onset of symptoms before the age of 25 years, a slow rate of progression, and a normal life span (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (previous studies)." +MONDO_0012561,"Definition: Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a broad spectrum of renal and urinary tract malformations. CAKUT structural anomalies range from complete renal agenesis (the most severe), to renal hypodysplasia, multicystic kidney dysplasia, duplex renal collecting system, ureteropelvic junction obstruction (UPJO), megaureter, posterior urethral valves (PUV), and vesicoureteral reflux (VUR). Renal abnormalities are observed in close relatives of up to 10% of CAKUT patients, although these are frequently asymptomatic. The phenotype often does not follow classic mendelian inheritance: family members with the same genetic defect may have variable phenotypes, ranging from severe renal insufficiency to asymptomatic anomalies. CAKUT occurs in about 1 in 500 live births, but are severe enough to cause neonatal death in about 1 in 2,000 births. In addition, CAKUT can occur in syndromic disorders in association with other congenital anomalies, such as papillorenal syndrome (previous studies) (summary by previous studies). + + Genetic Heterogeneity of Congenital Anomalies of Kidney and Urinary Tract + +Also see CAKUT2 (previous studies), caused by mutation in the TBX18 gene (previous studies) on chromosome 6q14, and CAKUT3 (previous studies), caused by mutation in the NRIP1 gene (previous studies) on chromosome 21q." +Orphanet_183539,"Definition: Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a broad spectrum of renal and urinary tract malformations. CAKUT structural anomalies range from complete renal agenesis (the most severe), to renal hypodysplasia, multicystic kidney dysplasia, duplex renal collecting system, ureteropelvic junction obstruction (UPJO), megaureter, posterior urethral valves (PUV), and vesicoureteral reflux (VUR). Renal abnormalities are observed in close relatives of up to 10% of CAKUT patients, although these are frequently asymptomatic. The phenotype often does not follow classic mendelian inheritance: family members with the same genetic defect may have variable phenotypes, ranging from severe renal insufficiency to asymptomatic anomalies. CAKUT occurs in about 1 in 500 live births, but are severe enough to cause neonatal death in about 1 in 2,000 births. In addition, CAKUT can occur in syndromic disorders in association with other congenital anomalies, such as papillorenal syndrome (previous studies) (summary by previous studies). + + Genetic Heterogeneity of Congenital Anomalies of Kidney and Urinary Tract + +Also see CAKUT2 (previous studies), caused by mutation in the TBX18 gene (previous studies) on chromosome 6q14, and CAKUT3 (previous studies), caused by mutation in the NRIP1 gene (previous studies) on chromosome 21q." +MONDO_0012991,"Definition: Kahrizi syndrome is an autosomal recessive neurodevelopmental disorder characterized by mental retardation, cataracts, coloboma, kyphosis, and coarse facial features (summary by previous studies). + +See also congenital disorder of glycosylation type Iq (CDG1Q; previous studies), an allelic disorder with overlapping features." +MONDO_0014789,"Definition: Congenital disorder of glycosylation type IIo (CDG2O) is an autosomal recessive metabolic disorder characterized by infantile onset of progressive liver failure, hypotonia, and delayed psychomotor development. Laboratory abnormalities include elevated liver enzymes, coagulation factor deficiencies, hypercholesterolemia, and low ceruloplasmin. Serum isoelectric focusing of proteins shows a combined defect of N- and O-glycosylation, suggestive of a Golgi defect (summary by previous studies). + +For a general discussion of CDGs, see CDG1A (previous studies)." +MONDO_0030070,"Definition: Visceral heterotaxy-9 (HTX9) is an autosomal recessive disorder characterized by randomization of organ laterality, resulting in defects such as situs inversus and dextrocardia. Affected males are infertile mainly due to defective sperm motility, whereas affected females do not appear to have fertility problems. The disorder results from impaired function of the embryonic nodal cilia and sperm flagella. However, patients do not have classic respiratory symptoms of primary ciliary dyskinesia (see, e.g., CILD; previous studies). The phenotype is highly variable; some affected individuals may be identified incidentally (summary by previous studies and previous studies). + +For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (previous studies)." +MONDO_0032574,"Definition: Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum (previous studies)." +MONDO_0032728,"Definition: Charcot-Marie-Tooth disease type 2EE (CMT2EE) is an autosomal recessive sensorimotor peripheral axonal neuropathy with onset in the first or second decades of life. The disorder primarily affects the lower limbs and is slowly progressive, sometimes resulting in loss of ambulation, with later onset of upper limb involvement. There is significant distal muscle weakness and atrophy, usually with foot or hand deformities. Skeletal muscle biopsy shows findings of disturbed mitochondrial maintenance. Cognition is unaffected, and chronic liver disease is absent (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (previous studies)." +MONDO_0100095,"Definition: Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. Patient have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy (summary by previous studies)." +Orphanet_136,"Definition: Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a progressive disorder of the small arterial vessels of the brain manifest by migraine, strokes, and white matter lesions, with resultant cognitive impairment in some patients (review by previous studies). + + Genetic Heterogeneity of Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy + +CADASIL2 (previous studies) is caused by mutation in the HTRA1 gene (previous studies) on chromosome 10q26." +Orphanet_1541,"Definition: Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by previous studies). + +For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (previous studies)." +MONDO_0011481,"Definition: Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by previous studies). + +For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (previous studies)." +MONDO_0013580,"Definition: Patients with pyruvate dehydrogenase E1-beta deficiency (PDHBD) present with typical clinical, biochemical and neuroradiological features: encephalopathy, hypotonia, respiratory difficulties, seizures, and lactic acidosis. Agenesis of the corpus callosum is often present. Patients with a severe clinical course die in infancy (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase deficiency, see previous studies." +MONDO_0013772,"Definition: Congenital cataracts, hearing loss, and neurodegeneration (CCHLND) is an autosomal recessive disorder characterized by congenital cataracts, severe psychomotor retardation, and hearing loss associated with decreased serum ceruloplasmin and copper. Brain MRI shows cerebral and cerebellar atrophy and hypomyelination (summary by previous studies)." +MONDO_0014367,"Definition: Aicardi-Goutieres syndrome-7 (AGS7) is an autosomal dominant inflammatory disorder characterized by severe neurologic impairment. Most patients present in infancy with delayed psychomotor development, axial hypotonia, spasticity, and brain imaging changes, including basal ganglia calcification, cerebral atrophy, and deep white matter abnormalities. Laboratory evaluation shows increased alpha-interferon (IFNA1; previous studies) activity with upregulation of interferon signaling and interferon-stimulated gene expression. Some patients may have normal early development followed by episodic neurologic regression (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (previous studies)." +MONDO_0014532,"Definition: Autosomal dominant isolated mitochondrial myopathy (IMMD) is characterized by onset of proximal lower limb weakness and exercise intolerance in the first decade of life. The disorder is slowly progressive, with later involvement of facial muscles, muscles of the upper limbs, and distal muscles. Patients may also have respiratory compromise (previous studies) or develop severe fatal cardiomyopathy (previous studies)." +MONDO_0014658,Definition: SADDAN dysplasia (severe achondroplasia with developmental delay and acanthosis nigricans) is a very rare skeletal dysplasia characterized by the constellation of these features. Radiology reveals 'ram's horn' shaped clavicles and reverse bowing of lower limbs. Approximately half of patients die before the fourth week of life secondary to respiratory failure (summary by previous studies). +MONDO_0014661,"Definition: Autosomal recessive generalized intermediate epidermolysis bullosa simplex 5D (EBS5D) is characterized by generalized skin blistering that heals with scarring and hyperpigmentation. Nail dystrophy is severe. Mucous membranes, heart, and muscle are spared (previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0030491,"Definition: Immunodeficiency-91 and hyperinflammation (IMD91) is an autosomal recessive complex immunologic disorder characterized by both immunodeficiency and recurrent infections, often to viruses or mycobacteria, as well as by hyperinflammation with systemic involvement. Affected individuals present in infancy with variable features, including fever, infection, thrombocytopenia, renal or hepatic dysfunction, recurrent infections, or seizures. Most patients eventually develop hepatic or renal failure, compromised neurologic function, lymphadenopathy or hepatosplenomegaly, and multiorgan failure resulting in death. More variable features may include intermittent monocytosis, features of hemophagocytic lymphohistiocytosis (HLH), and serologic evidence of hyperinflammation. The disorder is thought to result from dysregulation of the interferon response to viral stimulation in the innate immune system (summary by previous studies; previous studies)." +MONDO_0030936,"Definition: Progressive myoclonic epilepsy-12 (EPM12) is an autosomal recessive neurologic disorder characterized by onset of tonic-clonic seizures and/or myoclonus in the second decade of life. Affected individuals develop cerebellar ataxia associated with progressive cerebral and cerebellar atrophy on brain imaging. Most patients lose ambulation and become wheelchair-bound. Additional more variable features include mild cognitive dysfunction or psychiatric manifestations, such as depression or anxiety (summary by previous studies). + +For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (previous studies)." +MONDO_0030994,"Definition: Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is characterized by global developmental delay apparent in infancy, impaired intellectual development, and speech delay. Some patients develop seizures, and may show regression after onset of seizures. Others have autistic features or behavioral abnormalities. Additional variable systemic features may also be present, such as cardiac defects, failure to thrive, or brain imaging anomalies (summary by previous studies)." +MONDO_0859518,"Definition: Hypomyelinating leukodystrophy-26 with chondrodysplasia (HLD26) is characterized by severe psychomotor delay, predominantly involving motor and expressive language development, with cerebral and cerebellar atrophy and corpus callosum hypoplasia. In addition, patients show pre- and postnatal growth retardation, early-onset scoliosis, and dislocations of large joints (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see HLD1 (previous studies)." +MONDO_0859578,"Definition: Lacrimoauriculodentodigital syndrome-3 (LADD3) is a multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies (summary by previous studies)." +MONDO_0008547,"Definition: Thanatophoric dysplasia is a severe short-limb dwarfism syndrome that is usually lethal in the perinatal period. previous studies classified cases of TD into subtypes based on the presence of curved as opposed to straight femurs; patients with straight, relatively long femurs always had associated severe cloverleaf skull and were designated TD type II (TD2), whereas TD cases with curved, short femurs with or without cloverleaf skull were designated TD type I (TD1; previous studies) (previous studies)." +MONDO_0008827,"Definition: Progressive pseudorheumatoid dysplasia (PPRD) is an autosomal recessive skeletal dysplasia with radiographic changes similar to those of spondyloepiphyseal dysplasia tarda, and clinical, but not radiographic, resemblance to rheumatoid arthritis. It is a progressive chondropathy affecting primarily the articular cartilage with characteristic skeletal abnormalities notably in the spine (summary by previous studies). Signs and symptoms, typically consisting of stiffness and swelling of joints, motor weakness, and joint contractures, usually develop between 3 and 8 years of age (summary by previous studies)." +MONDO_0009712,"Definition: Congenital myopathy-1B (CMYP1B) is an autosomal recessive disorder of skeletal muscle characterized by severe hypotonia and generalized muscle weakness apparent soon after birth or in early childhood with delayed motor development, generalized muscle weakness and atrophy, and difficulty walking or running. Affected individuals show proximal muscle weakness with axial and shoulder girdle involvement, external ophthalmoplegia, and bulbar weakness, often resulting in feeding difficulties and respiratory insufficiency. Orthopedic complications such as joint laxity, distal contractures, hip dislocation, cleft palate, and scoliosis are commonly observed. Serum creatine kinase is normal. The phenotype is variable in severity (previous studies; previous studies). Some patients show symptoms in utero, including reduced fetal movements, polyhydramnios, and intrauterine growth restriction. The most severely affected patients present in utero with fetal akinesia, arthrogryposis, and lung hypoplasia resulting in fetal or perinatal death (previous studies). Skeletal muscle biopsy of patients with recessive RYR1 mutations can show variable features, including multiminicores (previous studies), central cores (previous studies), congenital fiber-type disproportion (CFTD) (previous studies), and centronuclear myopathy (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0010292,"Definition: Uruguay faciocardiomusculoskeletal syndrome (FCMSU) is an X-linked disorder in which affected males have a distinctive facial appearance, muscular hypertrophy, and cardiac ventricular hypertrophy leading to premature death. Additional features include large, broad, and deformed hands and feet, congenital hip dislocation, and scoliosis (summary by previous studies)." +MONDO_0010559,"Definition: The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of previous studies and previous studies. Some forms of SPG are considered 'uncomplicated,' i.e., progressive spasticity occurs in isolation; others are considered 'complicated,' i.e., progressive spasticity occurs with other neurologic features. X-linked, autosomal dominant (see previous studies), and autosomal recessive (see previous studies) forms of SPG have been described. + +Spastic paraplegia-1 is usually called MASA syndrome, the designation originally suggested by previous studies, because the main clinical features are summarized by the acronym MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs). The shuffling gait is probably caused by spasticity of the lower limbs, and all affected males have been reported to have increased reflexes. The adducted thumbs are thought to be caused by hypoplastic or absent extensor pollicis longus or brevis muscles. In affected males, the onset of speech is delayed (previous studies). + +See previous studies for isolated X-linked congenital clasped thumb and previous studies for an autosomal adducted thumbs syndrome. + + Genetic Heterogeneity of X-linked Spastic Paraplegia + +Other forms of X-linked spastic paraplegia include SPG2 (previous studies), caused by mutation in the myelin proteolipid protein gene (PLP1; previous studies); SPG16 (previous studies), mapped to Xq11.2-q23; and SPG34 (previous studies), mapped to Xq24-q25." +MONDO_0010758,"Definition: Wieacker-Wolff syndrome (WRWF) is a severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia), which results in arthrogryposis multiplex congenita (AMC) apparent at birth. Affected boys are born with severe contractures, show delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and foot deformities. Additional features include global developmental delay with poor or absent speech and impaired intellectual development, feeding difficulties and poor growth, hypotonia, hypogenitalism, and spasticity. Carrier females may be unaffected or have mild features of the disorder (summary by previous studies and previous studies)." +MONDO_0011842,"Definition: FTLD-TDP is clinically characterized by frontotemporal dementia (see FTD; previous studies), which shows variable phenotypic expression but most commonly presents with social, behavioral, or language deterioration, rather than memory or motor deficits. Other variations of the phenotype have been referred to as 'dysphasic disinhibition dementia' and 'primary progressive aphasia' (PPA) (previous studies; previous studies; previous studies). Some patients may present with a clinical diagnosis of Alzheimer disease (AD; previous studies) or Parkinson disease (PD; previous studies), which are part of the phenotypic spectrum of this disorder (previous studies). + + Genetic Heterogeneity of FTLD-TDP + +The specific presence of TDP43 (TARDBP; previous studies)-positive inclusions on neuropathologic examination defines a genetically heterogeneous group of dementias known collectively as 'FTLD-TDP.' FTLD-TDP is a neuropathologic diagnosis; only about 20% of patients with this neuropathologic diagnosis have GRN mutations (review by previous studies). + +TDP43-positive inclusions also occur in ALS10 (previous studies), caused by mutation in the TARDBP gene (previous studies); IBMPFD (previous studies), caused by mutation in the VCP gene (previous studies); and FTDALS (previous studies), caused by mutation in the C9ORF72 gene (previous studies). + +previous studies provided a detailed review of the molecular genetics of FTLD, with special emphasis on FTLDU. previous studies reviewed the molecular pathology and genetic heterogeneity of FTLD, including FTLD-TDP, and also noted that FTLDU is now referred to as FTLD-TDP." +MONDO_0013579,"Definition: Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by previous studies)." +Orphanet_289307,"Definition: Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by previous studies)." +MONDO_0014043,"Definition: Primary microcephaly-10 (MCPH10) is an autosomal recessive disorder characterized by extremely small head size (-9 SD) at birth and death usually by 1 year of age. Neuropathologic examination shows severe loss of neurons as well as neuronal loss of polarity and abnormal dendritic maturation (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (previous studies)." +MONDO_0030480,Definition: Autosomal recessive deafness-119 (DFNB119) is characterized by nonsyndromic mild to profound sensorineural hearing loss (previous studies). +MONDO_0030714,"Definition: Osteogenesis imperfecta comprises a group of connective tissue disorders characterized clinically by bone fragility, low bone mass, and increased susceptibility to fractures. Osteogenesis imperfecta type XXII (OI22) is a severe recessive form of the disease (previous studies)." +MONDO_0030798,"Definition: Immunodeficiency-99 with hypogammaglobulinemia and autoimmune cytopenias (IMD99) is an autosomal recessive immunologic disorder characterized by the onset of recurrent sinopulmonary infections in early childhood. Laboratory studies reveal hypogammaglobulinemia with decreased memory B cells that show impaired class-switch recombination (CSR) and decreased somatic hypermutation (SHM). Due to abnormal antibody production and impaired self-tolerance, patients may develop autoimmune cytopenias, such as thrombocytopenia, or autoimmune features, such as vitiligo. There are also defects in the T-cell compartment (previous studies)." +MONDO_0030846,"Definition: Spermatogenic failure-48 (SPGF48) is characterized by male infertility due to a variable spectrum of severely impaired spermatogenesis, primarily at meiosis and resulting in azoospermia. However, sparse postmeiotic germ cell development and retrieval of sperm in some cases has been reported (previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see previous studies." +MONDO_0030982,"Definition: Sulfide:quinone oxidoreductase-deficiency (SQORD) is characterized by a variable phenotype ranging from no clinical symptoms to episodes of encephalopathy and Leigh syndrome-like (see previous studies) brain lesions, with acute symptoms triggered by infections and fasting. Other features may include lactic acidosis and decreased mitochondrial respiratory chain complex IV activity in tissues. Most affected individuals are asymptomatic. Patients with encephalopathy may recover or die in childhood (previous studies)." +MONDO_0032766,"Definition: Primary hypoalphalipoproteinemia-2 is an autosomal recessive disorder characterized by dysfunctional apoA-I production, resulting in undetectable levels of apoA-I in serum and in markedly low levels of serum high density lipoprotein cholesterol (HDL-C). The disorder is associated with extensive atherosclerosis, xanthomas, and corneal opacities (summary by previous studies). + +For a discussion of genetic heterogeneity of primary hypoalphalipoproteinemia, see previous studies." +MONDO_0032936,"Definition: Congenital myopathy-9A (CMYP9A) is an autosomal recessive early-onset severe muscular disorder resulting in early death. Affected individuals present at birth with neonatal hypotonia, poor feeding, fractures of the long bones, and respiratory insufficiency. Laboratory investigations are consistent with a defect in early muscle development (summary by previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +EFO_0000341,"Definition: Chronic obstructive pulmonary disease (COPD) is a common, complex disorder associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction due to chronic bronchitis, emphysema, and/or small airways disease. Airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) (previous studies; previous studies)." +EFO_0000538,Definition: Familial hypertrophic cardiomyopathy-3 (CMH3) is an autosomal dominant disorder characterized by increased myocardial mass with myocyte and myofibrillar disarray (previous studies). +EFO_0009036,"Definition: Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is an autosomal recessive multisystemic disorder with highly variable manifestations, even within the same family. Some patients present in infancy with hypotonia and global developmental delay with poor or absent motor skill acquisition and poor growth, whereas others present as young adults with exercise intolerance and muscle weakness. All patients have signs of a peripheral neuropathy, usually demyelinating, with distal muscle weakness and atrophy and distal sensory impairment; many become wheelchair-bound. Additional features include spasticity, extensor plantar responses, contractures, cerebellar signs, seizures, short stature, and rare involvement of other organ systems, including the heart, pancreas, and kidney. Biochemical analysis may show deficiencies in mitochondrial respiratory complex enzyme activities in patient tissue, although this is not always apparent. Lactate is frequently increased, suggesting mitochondrial dysfunction (previous studies; previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +EFO_0010168,"Definition: The Kondo-Fu type of spondyloepiphyseal dysplasia (SEDKF) is characterized by severely retarded growth and skeletal anomalies, including spondyloepiphyseal dysplasia with associated kyphosis and reduced bone mineral density. Elevated levels of blood lysosomal enzymes have also been observed (previous studies)." +MONDO_0009109,"Definition: Lysinuric protein intolerance is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine, and orotic aciduria (previous studies). + +See also dibasic amino aciduria I (previous studies)." +MONDO_0009910,"Definition: Wiedemann-Rautenstrauch syndrome (WDRTS) is a rare autosomal recessive neonatal progeroid disorder characterized by intrauterine growth retardation, failure to thrive, short stature, a progeroid appearance, hypotonia, and variable mental impairment (summary by previous studies). Average survival in WDRTS is 7 months, although survival into the third decade of life has been reported (previous studies)." +MONDO_0011176,"Definition: Familial hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder characterized by very low serum magnesium levels. Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by previous studies). + + Genetic Heterogeneity of Hypomagnesemia + +A form of hypomagnesemia due to kidney defects and high urinary magnesium excretion associated with hypocalciuria (HOMG2; previous studies) is caused by mutation in the FXYD2 gene (previous studies). Renal hypomagnesemia-3 (HOMG3; previous studies), associated with hypercalciuria and nephrocalcinosis, is caused by mutation in the CLDN16 gene (previous studies). Renal hypomagnesemia-4 (HOMG4; previous studies), which is normocalciuric, is caused by mutation in the EGF gene (previous studies). Renal hypomagnesemia-5 (HOMG5; previous studies), associated with hypercalciuria, nephrocalcinosis, and severe ocular involvement, is caused by mutation in the CLDN19 gene (previous studies). Renal hypomagnesemia-6 (HOMG6; previous studies) is caused by mutation in the CNNM2 gene (previous studies). Renal hypomagnesemia-7 with or without dilated cardiomyopathy (HOMG7; previous studies) is caused by mutation in the RRAGD gene (previous studies). + +Patients with Gitelman syndrome (previous studies) and Bartter syndrome (see previous studies) also show hypomagnesemia, and steatorrhea and severe chronic diarrhea states, such as Crohn disease (see previous studies) and Whipple disease, that can result in severe hypomagnesemia." +Orphanet_30924,"Definition: Familial hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder characterized by very low serum magnesium levels. Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by previous studies). + + Genetic Heterogeneity of Hypomagnesemia + +A form of hypomagnesemia due to kidney defects and high urinary magnesium excretion associated with hypocalciuria (HOMG2; previous studies) is caused by mutation in the FXYD2 gene (previous studies). Renal hypomagnesemia-3 (HOMG3; previous studies), associated with hypercalciuria and nephrocalcinosis, is caused by mutation in the CLDN16 gene (previous studies). Renal hypomagnesemia-4 (HOMG4; previous studies), which is normocalciuric, is caused by mutation in the EGF gene (previous studies). Renal hypomagnesemia-5 (HOMG5; previous studies), associated with hypercalciuria, nephrocalcinosis, and severe ocular involvement, is caused by mutation in the CLDN19 gene (previous studies). Renal hypomagnesemia-6 (HOMG6; previous studies) is caused by mutation in the CNNM2 gene (previous studies). Renal hypomagnesemia-7 with or without dilated cardiomyopathy (HOMG7; previous studies) is caused by mutation in the RRAGD gene (previous studies). + +Patients with Gitelman syndrome (previous studies) and Bartter syndrome (see previous studies) also show hypomagnesemia, and steatorrhea and severe chronic diarrhea states, such as Crohn disease (see previous studies) and Whipple disease, that can result in severe hypomagnesemia." +MONDO_0014764,"Definition: Spastic paraplegia and psychomotor retardation with or without seizures is an autosomal recessive complex neurodevelopmental disorder with onset in infancy. Affected children show hypotonia followed by severely impaired global development and significant motor disability. Most develop seizures in childhood and have speech delay. Other features, such as ocular abnormalities, foot deformities, hypoplasia of the corpus callosum, and decreased white matter, are more variable (summary by previous studies)." +MONDO_0015019,"Definition: Yao syndrome (YAOS) is an autoinflammatory disease characterized by periodic fever, dermatitis, arthritis, and swelling of the distal extremities, as well as gastrointestinal and sicca-like symptoms. The disorder is associated with specific NOD2 variants (previous studies)." +MONDO_0030045,"Definition: Liberfarb syndrome is a progressive disorder involving connective tissue, bone, retina, ear, and brain. Patients exhibit severe short stature and scoliosis with thoracic kyphosis and lumbar hyperlordosis. Severe joint laxity results in dislocations of elbows, hips, and knees. Eye findings are consistent with early-onset retinal degeneration, and there is moderate to severe early-onset hearing loss. Microcephaly is apparent by school age, and patients exhibit developmental delay and intellectual deficits (previous studies). Clinical variability has been observed, with some patients presenting differences in the severity and location of skeletal dysplasia involvement as well as variation in other features of the syndrome (previous studies; previous studies)." +MONDO_0030887,"Definition: Dilated cardiomyopathy-2G (CMD2G) is characterized by early-onset severe dilated cardiomyopathy that progresses rapidly to heart failure in the neonatal period without evidence of intervening hypertrophy. Cardiac tissue exhibits markedly shortened thin filaments, disorganized myofibrils, and reduced contractile force generation, resulting in the severe ventricular dysfunction observed. There is no evidence of skeletal muscle hypertrophy (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see previous studies." +MONDO_0030929,"Definition: Autosomal dominant primary microcephaly-27 (MCPH27) is characterized by small head circumference apparent in early childhood and associated with global developmental delay manifest as delayed walking, inability to walk, impaired intellectual development, and poor or absent speech. Most patients have variable and nonspecific additional features, including facial dysmorphism, hypotonia, limb hypertonia, poor feeding, and distal skeletal anomalies. Brain imaging may show enlarged ventricles or gyral abnormalities, but most have normal imaging (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (previous studies)." +MONDO_0100296,"Definition: Olmsted syndrome-1 (OLMS1) is a rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma (PPK) and periorificial keratotic plaques with severe pruritus of lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas (summary by previous studies). The digital constriction ('pseudoainhum') may progress to autoamputation of fingers and toes (previous studies). + + Genetic Heterogeneity of Olmsted Syndrome + +OLMS2 (previous studies) is caused by mutation in the PERP gene (previous studies) on chromosome 6q23. + +An X-linked form of Olmsted syndrome (OLMSX; previous studies) is caused by mutation in the MBTPS2 gene (previous studies) on chromosome Xp22." +Orphanet_7,"Definition: The 3C syndrome, also known as Ritscher-Schinzel syndrome, is a developmental malformation syndrome characterized by craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations. Facial features include prominent occiput, prominent forehead, low-set ears, downslanting palpebral fissures, depressed nasal bridge, and micrognathia. Cardiac defects can include septal defects and aortic stenosis, among others, and brain imaging shows Dandy-Walker malformation, cerebellar vermis hypoplasia, posterior fossa cysts, and ventricular dilatation. Affected individuals have delayed psychomotor development (summary by previous studies; previous studies). + + Genetic Heterogeneity of Ritscher-Schinzel Syndrome + +See also RTSC2 (previous studies), caused by mutation in the CCDC22 gene (previous studies) on chromosome Xp11; RTSC3 (previous studies), caused by mutation in the VPS35L gene (previous studies) on chromosome 16p12; and RTSC4 (previous studies), caused by mutation in the DPYSL5 gene (previous studies) on chromosome 2p23." +MONDO_0009292,"Definition: Glycogen storage disease IV (GSD4) is a clinically heterogeneous disorder. The typical 'classic' hepatic presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular presentation of GSD IV is distinguished by age at onset into 4 groups: perinatal, presenting as fetal akinesia deformation sequence (FADS) and perinatal death; congenital, with hypotonia, neuronal involvement, and death in early infancy; childhood, with myopathy or cardiomyopathy; and adult, with isolated myopathy or adult polyglucosan body disease (previous studies). The enzyme deficiency results in tissue accumulation of abnormal glycogen with fewer branching points and longer outer branches, resembling an amylopectin-like structure, also known as polyglucosan (previous studies). + +previous studies provided a review of the neuromuscular forms of glycogen branching enzyme deficiency." +MONDO_0009706,"Definition: Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive muscular disorder characterized by childhood onset of exercise intolerance with muscle tenderness, cramping, dyspnea, and palpitations. Biochemical features include lactic acidosis and, rarely, rhabdomyolysis. It is a chronic disorder with remission and exacerbation of the muscle phenotype (summary by previous studies)." +MONDO_0014527,"Definition: previous studies reported a Moroccan boy with a chromosomal breakage who died of hepatocellular carcinoma at age 17 years. The boy was noted to have growth retardation at age 3 years; at age 7 he was found to have thoracic kyphosis, frontal bossing, and a delayed bone age of approximately 3 years. He underwent surgery for severe bilateral posterior subcapsular cataracts at age 14. Examination at age 15 showed short stature and low weight, with premature graying of scalp hair, small frontotemporal diameter, small deep-set eyes, bulbous nose with high nasal bridge, small upper lip, and micrognathia. In addition, he had thoracic kyphoscoliosis, sloping shoulders, mild pectus excavatum, moderate bilateral contractures of both elbows, bilateral clinodactyly, and pes planus. At age 17, he developed abdominal pain, and ultrasonography revealed a liver mass; biopsy confirmed hepatocellular carcinoma. Because of the advanced stage, no treatment was possible, and he died 2 months later. Although his parents were not known to be consanguineous, they originated from the same small Moroccan village. + +previous studies studied 2 brothers from a nonconsanguineous Australian family of European ancestry who exhibited low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age, and mild joint restrictions in the fingers and elbows. In addition, both brothers developed early-onset hepatocellular carcinoma, at ages 16 and 14 years, respectively. The older brother died at age 18 from complications of acute fulminant hepatic failure. Analysis of patient tumor biopsies showed strong focal accumulations of cancer biomarkers as well as a high proliferative index compared to healthy liver or to cells from idiopathic hepatocellular carcinoma." +MONDO_0014711,"Definition: Charcot-Marie-Tooth disease type 2W is an autosomal dominant neurologic disorder characterized by a peripheral neuropathy mainly affecting the lower limbs and resulting in gait difficulties and distal sensory impairment, although most patients also have upper limb involvement. The age at onset is highly variable, ranging from childhood to late adulthood (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0859255,"Definition: Childhood-onset biotin-responsive peripheral motor neuropathy (COMNB) is an autosomal recessive disorder characterized predominantly by the onset of distal muscle weakness and atrophy late in the first decade of life. The disorder predominantly affects the upper limbs and hands, resulting in difficulties with fine motor skills. Some patients may have lower limb involvement, resulting in gait difficulties. Electrophysiologic studies and muscle biopsy are consistent with chronic denervation with axonal and demyelinating features. Rare patients may have additional neurologic signs, including spasticity, ataxia, and cerebellar signs. Sensation is intact, and patients have normal cognitive development. Treatment with biotin, pantothenic acid, and lipoic acid may result in clinical improvement (previous studies)." +Orphanet_276432,"Definition: Ogden syndrome (OGDNS) is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Many patients also have cardiac malformations or arrhythmias (summary by previous studies)." +MONDO_0010457,"Definition: Ogden syndrome (OGDNS) is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Many patients also have cardiac malformations or arrhythmias (summary by previous studies)." +EFO_0000183,"Definition: Classic Hodgkin lymphoma is a lymph node cancer of germinal center B-cell origin. Hodgkin lymphoma tumors consist of a minority of malignant cells, known as 'Reed-Sternberg' (RS) cells, mixed with reactive lymphocytes and other benign inflammatory cells. A defining feature of RS cells is the presence of 2 nuclei (summary by previous studies)." +MONDO_0009348,"Definition: Classic Hodgkin lymphoma is a lymph node cancer of germinal center B-cell origin. Hodgkin lymphoma tumors consist of a minority of malignant cells, known as 'Reed-Sternberg' (RS) cells, mixed with reactive lymphocytes and other benign inflammatory cells. A defining feature of RS cells is the presence of 2 nuclei (summary by previous studies)." +MONDO_0007041,"Definition: Apert syndrome is a congenital disorder characterized primarily by craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet with a tendency to fusion of bony structures. Most cases are sporadic, but autosomal dominant inheritance has been reported (previous studies). + +previous studies provided a review of all the 'craniosynostosis syndromes.'" +MONDO_0009964,"Definition: Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by previous studies and previous studies). + +There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, previous studies). + +For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (previous studies)." +MONDO_0012208,"Definition: Ichthyosis with confetti (IWC), also known as congenital reticular ichthyosiform erythroderma (CRIE), is a rare skin condition characterized by slowly enlarging islands of normal skin surrounded by erythematous ichthyotic patches in a reticulated pattern. The condition starts in infancy as a lamellar ichthyosis, with small islands of normal skin resembling confetti appearing in late childhood and at puberty. Histopathologic findings include band-like parakeratosis, psoriasiform acanthosis, and vacuolization of keratinocytes with binucleated cells in the upper epidermis, sometimes associated with amyloid deposition in the dermis. Ultrastructural abnormalities include perinuclear shells formed from a network of fine filaments in the upper epidermis (summary by previous studies)." +MONDO_0013532,"Definition: Protein Z serves as a cofactor for the downregulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI; previous studies). Evidence also suggests that protein Z may promote the assembly of thrombin with phospholipid surfaces, thus enhancing coagulation. There is a wide variation of protein Z levels in human plasma, and studies have reported conflicting results of the clinical consequences of protein Z deficiency in humans. Most studies have reported an association between decreased protein Z levels and thrombosis, including stroke, venous thrombosis, and obstetric complications, although early reports suggested an association between protein Z deficiency and bleeding tendency (previous studies). Overall, a role for protein Z in the pathogenesis of hemostatic disorders in humans is controversial and remains unclear (review by previous studies and previous studies). + +Protein Z deficiency has been shown to exacerbate the thrombotic phenotype in patients with thrombophilia due to factor V Leiden (see previous studies)." +MONDO_0014715,Definition: Immunodeficiency-44 (IMD44) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to viral infections and adverse multisystemic reaction to vaccination in some patients. Affected individuals appear to have defects in mitochondrial fission and fusion (summary by previous studies). +MONDO_0030801,"Definition: Monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2) is an autosomal dominant hematologic disorder characterized by onset of pancytopenia, acute myelogenous leukemia (AML), and variable features of myelodysplastic syndrome (MDS) usually in the first decades of life. Bone marrow cells show monosomy 7. Germline mutations in the SAMD9 gene, located on chromosome 7q, have a gain-of-function suppressive effect on the cell cycle, resulting in decreased cellular proliferation. It is hypothesized that this germline defect leads to selective pressure favoring somatic loss of the chromosome 7 harboring the mutant allele (adaptation by aneuploidy) (summary by previous studies). + +For a discussion of genetic heterogeneity of monosomy 7 myelodysplasia and leukemia syndrome, see previous studies." +MONDO_0033374,"Definition: Developmental and epileptic encephalopathy-65 (DEE65) is characterized by onset of intractable seizures of various types usually within the first months or years of life, severe to profound psychomotor developmental delay, and mild facial dysmorphism (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +EFO_0009060,"Definition: Spinocerebellar ataxia-43 is an autosomal dominant, slowly progressive neurologic disorder characterized by adult-onset gait and limb ataxia and often associated with peripheral neuropathy mainly affecting the motor system, although some patients may have distal sensory impairment (summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0007970,"Definition: Melorheostosis (MEL) is characterized by 'flowing' hyperostosis of the cortex of tubular bones. The lesions are usually asymmetric and involve only 1 limb or correspond to a particular sclerotome. They may be accompanied by abnormalities of adjacent soft tissue, including joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangiomas (review by previous studies). The designation combines root words meaning 'limb,' 'flow,' and 'bone.' + +Melorheostosis may sometimes be a feature of Buschke-Ollendorff syndrome (BOS; previous studies), a benign disorder which is caused by mutation in the LEMD3 gene (previous studies). Although germline or somatic LEMD3 mutations had been postulated to cause isolated melorheostosis (previous studies; previous studies; previous studies; previous studies), several studies have not been able to prove this (previous studies; previous studies; previous studies)." +MONDO_0008830,"Definition: Aspartylglucosaminuria (AGU) is a severe autosomal recessive lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. The disorder is caused by deficient activity of the lysosomal enzyme glycosylasparaginase, which results in body fluid and tissue accumulation of a series of glycoasparagines, i.e., glycoconjugates with an aspartylglucosamine moiety at the reducing end. AGU belongs to the group of disorders commonly referred to as the Finnish disease heritage (summary by previous studies and previous studies)." +MONDO_0008913,"Definition: Cardiac valvular dysplasia-1 (CVDP1) is characterized by congenital malformations of the pulmonic, tricuspid, and mitral valves. Structural cardiac defects, including atrial and ventricular septal defects, single left ventricle, and hypoplastic right ventricle have also been observed in affected individuals (previous studies). + + Genetic Heterogeneity of Cardiac Valvular Dysplasia + +CVDP2 (previous studies) is caused by mutation in the ADAMTS19 gene (previous studies) on chromosome 5q23." +MONDO_0009281,"Definition: Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (previous studies). + +previous studies provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I." +MONDO_0010160,"Definition: Tyrosinemia type II (TYRSN2) is an autosomal recessive disorder characterized by keratitis, painful palmoplantar hyperkeratosis, mental retardation, and elevated serum tyrosine levels. The disorder is caused by deficiency of hepatic tyrosine aminotransferase (previous studies)." +Orphanet_28378,"Definition: Tyrosinemia type II (TYRSN2) is an autosomal recessive disorder characterized by keratitis, painful palmoplantar hyperkeratosis, mental retardation, and elevated serum tyrosine levels. The disorder is caused by deficiency of hepatic tyrosine aminotransferase (previous studies)." +MONDO_0010178,"Definition: Congenital bilateral absence of the vas deferens is found in more than 25% of men with obstructive azoospermia, involving a complete or partial defect of the Wolffian duct derivatives. In 80% of men with CBAVD, mutations are identified in the CFTR gene (summary by previous studies). + + Genetic Heterogeneity of Congenital Bilateral Aplasia of Vas Deferens + +Also see CBAVDX (previous studies), caused by mutation in the ADGRG2 gene (previous studies)." +MONDO_0010441,"Definition: CK syndrome (CKS) is an X-linked recessive disorder characterized by mild to severe cognitive impairment, seizures, microcephaly, cerebral cortical malformations, dysmorphic facial features, and thin body habitus. It is named after the first identified patient (summary by previous studies). + +CHILD syndrome (previous studies) is an allelic disorder with a different phenotype." +MONDO_0010691,"Definition: Norrie disease is an X-linked recessive disorder characterized by very early childhood blindness due to degenerative and proliferative changes of the neuroretina. Approximately 50% of patients show some form of progressive mental disorder, often with psychotic features, and about one-third of patients develop sensorineural deafness in the second decade. In addition, some patients have more complex phenotypes, including growth failure and seizures (previous studies). + +previous studies noted confusion of the terms 'pseudoglioma' and microphthalmia with Norrie disease in the literature. 'Pseudoglioma' is a nonspecific term for any condition resembling retinoblastoma and can have diverse causes, including inflammation, hemorrhage, trauma, neoplasia, or congenital malformation, and often shows unilateral involvement. Thus, 'pseudoglioma' is not an acceptable clinical or pathologic diagnosis (previous studies)." +MONDO_0010753,"Definition: X-linked cardiac valvular dysplasia (CVDPX) is a rare form of heart disease characterized by multivalvular dysplasia and regurgitation, which can lead to lethal heart failure in some patients. Heterozygous females are more mildly affected than hemizygous males. Some patients also exhibit features of Ehler-Danlos syndrome (EDS; see previous studies), with hyperextensible skin and joint hypermobility, whereas others have stiffening of joints from early childhood (previous studies; previous studies; previous studies)." +MONDO_0010803,"Definition: Eiken syndrome (EKNS) is an autosomal recessive skeletal dysplasia characterized by delayed ossification of bones, epiphyseal dysplasia, and bone remodeling abnormalities. Type A1 brachydactyly (see previous studies), supernumerary epiphyses of proximal phalanges and metacarpals, and failure of eruption of primary teeth have also been described. Defining radiologic features include delayed ossification of epiphyses and primary ossification centers of short tubular bones, modeling abnormalities of tubular bones, and angel-shaped phalanges (previous studies). + +See previous studies for a disorder with similar radiologic features." +MONDO_0012465,"Definition: Glycosylphosphatidylinositol is a glycolipid that anchors more than 150 proteins to the cell surface, and these proteins, termed GPI-anchored proteins (GPI-APs), perform a variety of functions as enzymes, adhesion molecules, complement regulators, and coreceptors in signal transduction pathways. Reduced surface levels of GPI-APs or abnormal GPI-AP structure can therefore result in variable manifestations. Glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1) is characterized predominantly by portal hypertension due to portal vein thrombosis. Most patients have absence seizures, cerebral thrombosis, and macrocephaly. Some patients have mildly to moderately impaired intellectual development (summary by previous studies; previous studies). + + Genetic Heterogeneity of Glycosylphosphatidylinositol Biosynthesis Defects + +Also see GPIBD2 (previous studies), caused by mutation in the PIGV gene (previous studies); GPIBD3 (previous studies), caused by mutation in the PIGN gene (previous studies); GPIBD4 (previous studies), caused by mutation in the PIGA gene (previous studies); GPIBD5 (previous studies), caused by mutation in the PIGL gene (previous studies); GPIBD6 (previous studies), caused by mutation in the PIGO gene (previous studies); GPIBD7 (previous studies), caused by mutation in the PIGT gene (previous studies); GPIBD8 (previous studies), caused by mutation in the PGAP2 gene (previous studies); GPIBD9 (previous studies), caused by mutation in the PGAP1 gene (previous studies); GPIBD10 (previous studies), caused by mutation in the PGAP3 gene (previous studies); GPIBD11 (previous studies), caused by mutation in the PIGW gene (previous studies); GPIBD12 (previous studies), caused by mutation in the PIGY gene (previous studies); GPIBD13 (previous studies), caused by mutation in the PIGG gene (previous studies); GPIBD14 (previous studies), caused by mutation in the PIGP gene (previous studies); GPIBD15 (previous studies), caused by mutation in the GPAA1 gene (previous studies); GPIBD16 (previous studies), caused by mutation in the PIGC gene (previous studies); GPIBD17 (previous studies), caused by mutation in the PIGH gene (previous studies); GPIBD18 (previous studies), caused by mutation in the PIGS gene (previous studies); GPIBD19 (previous studies), caused by mutation in the PIGQ gene (previous studies); GPIBD20 (previous studies), caused by mutation in the PIGB gene (previous studies); GPIBD21 (previous studies), caused by mutation in the PIGU gene (previous studies); GPIBD22 (previous studies), caused by mutation in the PIGK gene (previous studies); GPIBD23 (previous studies), caused by mutation in the ARV1 gene (previous studies); GPIBD24 (previous studies), caused by mutation in the PIGF gene (previous studies); and GPIBD25 (previous studies), caused by mutation in the C18ORF32 gene (previous studies)." +MONDO_0012658,"Definition: Brachydactyly type B2 (BDB2) is a subtype of brachydactyly characterized by hypoplasia/aplasia of distal phalanges in combination with distal symphalangism, fusion of carpal/tarsal bones, and partial cutaneous syndactyly (summary by previous studies)." +MONDO_0013714,"Definition: Mannose-binding lectin (MBL) deficiency, defined as MBL protein level of less than 100 ng/ml, is present in about 5% of people of European descent and in about 10% of sub-Saharan Africans. Most MBL-deficient adults appear healthy, but low levels of MBL are associated with increased risk of infection in toddlers, in cancer patients undergoing chemotherapy, and in organ-transplant patients receiving immunosuppressive drugs, particularly recipients of liver transplants (review by previous studies). MBL is a soluble molecule that can activate the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by previous studies). + + Genetic Heterogeneity of Lectin Complement Activation Pathway Defects + +See also LCAPD2 (previous studies), caused by variation in the MASP2 gene (previous studies) on chromosome 1p36, and LCAPD3 (previous studies), caused by variation in the FCN3 gene (previous studies) on chromosome 1p36." +MONDO_0021018,"Definition: Autosomal dominant limb-girdle muscular dystrophy is characterized by proximal and/or distal muscle weakness and atrophy. The age at onset is variable and can range from the first to the sixth decade, although later onset is less common. Most patients present with proximal muscle weakness that progresses to distal involvement, but some can present with distal impairment. The severity is variable: patients with a more severe phenotype can lose ambulation after several decades and have facial weakness with bulbar and respiratory involvement. Muscle biopsy shows dystrophic changes with protein aggregates, myofibrillar degeneration, and rimmed vacuoles (summary by previous studies). + + Genetic Heterogeneity of Autosomal Dominant Limb-Girdle Muscular Dystrophy + +Other forms of autosomal dominant LGMD include LGMDD2 (previous studies), previously LGMD1F, caused by mutation in the TNPO3 gene (previous studies) on chromosome 7q32; LGMDD3 (previous studies), previously LGMD1G, caused by mutation in the HNRNPDL gene (previous studies) on chromosome 4q21; and LGMDD4 (previous studies), previously LGMD1I, caused by mutation in the CAPN3 gene (previous studies) on chromosome 15q15. + +For a discussion of autosomal recessive LGMD, see previous studies." +Orphanet_34516,"Definition: Autosomal dominant limb-girdle muscular dystrophy is characterized by proximal and/or distal muscle weakness and atrophy. The age at onset is variable and can range from the first to the sixth decade, although later onset is less common. Most patients present with proximal muscle weakness that progresses to distal involvement, but some can present with distal impairment. The severity is variable: patients with a more severe phenotype can lose ambulation after several decades and have facial weakness with bulbar and respiratory involvement. Muscle biopsy shows dystrophic changes with protein aggregates, myofibrillar degeneration, and rimmed vacuoles (summary by previous studies). + + Genetic Heterogeneity of Autosomal Dominant Limb-Girdle Muscular Dystrophy + +Other forms of autosomal dominant LGMD include LGMDD2 (previous studies), previously LGMD1F, caused by mutation in the TNPO3 gene (previous studies) on chromosome 7q32; LGMDD3 (previous studies), previously LGMD1G, caused by mutation in the HNRNPDL gene (previous studies) on chromosome 4q21; and LGMDD4 (previous studies), previously LGMD1I, caused by mutation in the CAPN3 gene (previous studies) on chromosome 15q15. + +For a discussion of autosomal recessive LGMD, see previous studies." +MONDO_0030063,"Definition: Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, severe to profound intellectual impairment, early-onset refractory seizures, hypotonia, failure to thrive, and progressive microcephaly. Brain imaging shows cerebral atrophy, thin corpus callosum, and myelination defects. Death in childhood may occur (summary by previous studies)." +MONDO_0031030,"Definition: Immunodeficiency-107 with susceptibility to invasive Staphylococcus aureus infection (IMD107) is an autosomal dominant immunologic disorder characterized most often by the development of invasive and severe life-threatening infections with S. aureus affecting the skin and/or lungs. There is incomplete penetrance (about 30%) and variable expressivity. In some patients with heterozygous OTULIN mutations, an infectious agent is not identified, suggesting that low-grade infectious or even noninfectious triggers may play a role in development of the disease. The levels and function of immune cells appear normal; the molecular defect resides in fibroblasts and possibly other nonhematopoietic barrier cells that show increased susceptibility to the detrimental effects of the S. aureus alpha-toxin (previous studies)." +MONDO_0060490,"Definition: NMIHBA is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay apparent from infancy and profoundly impaired intellectual development. Affected individuals have microcephaly with accompanying dysmorphic features, truncal hypotonia, peripheral spasticity, and lack of independent ambulation or speech acquisition. Brain imaging shows variable abnormalities, including cortical atrophy, thin corpus callosum, cerebellar hypoplasia, and delayed myelination (summary by previous studies)." +Orphanet_107,"Definition: Branchiootorenal syndrome is an autosomal dominant disorder characterized by sensorineural, conductive, or mixed hearing loss, structural defects of the outer, middle, and inner ear, branchial fistulas or cysts, and renal abnormalities ranging from mild hypoplasia to complete absence. Reduced penetrance and variable expressivity has been observed (previous studies). + + Genetic Heterogeneity of Branchiootorenal Syndrome + +See also BOR2 (previous studies), caused by mutation in the SIX5 gene (previous studies) on chromosome 19q13. previous studies stated that approximately 40% of patients with BOR have mutations in the EYA1 gene and 5% have mutations in the SIX5 gene. + +See also branchiootic (BO) syndrome-1 (BOS1; previous studies) and the otofaciocervical syndrome (OFC; previous studies), allelic disorders showing overlapping phenotypes but without renal anomalies. See also previous studies for a discussion of the BOR-Duane-hydrocephalus contiguous gene syndrome as described by previous studies. + +Although previous studies maintained that the BOR syndrome is distinct from the BO syndrome because in the latter condition renal anomaly is absent and deafness is not a constant feature, previous studies concluded that the 2 syndromes are in fact a single entity." +EFO_0010278,"Definition: Shukla-Vernon syndrome (SHUVER) is an X-linked recessive neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development, and behavioral abnormalities, including autism spectrum disorder and ADHD. Dysmorphic features are common and may include tall forehead, downslanting palpebral fissures, and tapering fingers. Some patients may have seizures and/or cerebellar atrophy on brain imaging. Carrier mothers may have mild manifestations, including learning disabilities (summary by previous studies)." +MONDO_0008287,"Definition: Greig cephalopolysyndactyly syndrome is characterized by frontal bossing, scaphocephaly, and hypertelorism associated with pre- and postaxial polydactyly and variable syndactyly. The phenotype shows variable expressivity and can also include craniosynostosis. Affected individuals usually have normal psychomotor development (summary by previous studies)." +MONDO_0009384,"Definition: Leydig cell hypoplasia is an autosomal recessive disorder in which loss of function of the LHCGR gene in the male prevents normal sexual development. Two types of LCH have been defined (previous studies). Type I, a severe form caused by complete inactivation of LHCGR, is characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high LH levels, total lack of responsiveness to LH/CG challenge, lack of breast development, and absent development of secondary male sex characteristics. Type II, a milder form caused by partial inactivation of the gene, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. Females with inactivating mutations in the LHCGR gene display a mild phenotype characterized by defective follicular development and ovulation, amenorrhea, and infertility (review by previous studies). + + Reviews + +previous studies noted that the clinical manifestations of female patients with hypogonadotropic hypogonadism due to isolated LH deficiency (HH23; previous studies) are very similar to those of women with hypergonadotropic hypogonadism due to inactivating mutations of the LH receptor: all have female external genitalia, spontaneous development of normal pubic hair and breasts at puberty, and normal to late menarche followed by oligoamenorrhea and infertility. Pelvic ultrasound shows a small or normal uterus and normal or enlarged ovaries with cysts. However, women with LHB (previous studies) mutations can be treated with luteinizing hormone or chorionic gonadotropin (CG; previous studies) replacement therapy; women with LH receptor mutations are resistant to LH, and no treatment is effective in recovering their fertility." +MONDO_0010356,"Definition: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. The syndrome manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypoosmolality, and natriuresis. SIADH occurs in a setting of normal blood volume, without evidence of renal disease or deficiency of thyroxine or cortisol. Although usually transient, SIADH may be chronic; it is often associated with drug use or a lesion in the central nervous system or lung. When the cardinal features of SIADH were defined by previous studies, levels of AVP could not be measured. Subsequently, radioimmunoassays revealed that SIADH is usually associated with measurably elevated serum levels of AVP. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is characterized by a clinical picture similar to SIADH, but is associated with undetectable levels of AVP (previous studies)." +MONDO_0010733,"Definition: The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of previous studies and previous studies. Some forms of SPG are considered 'uncomplicated,' i.e., progressive spasticity occurs in isolation; others are considered 'complicated,' i.e., progressive spasticity occurs with other neurologic features. X-linked, autosomal dominant (see previous studies), and autosomal recessive (see previous studies) forms of SPG have been described. + +For discussion of genetic heterogeneity of X-linked SPG, see previous studies." +Orphanet_99015,"Definition: The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of previous studies and previous studies. Some forms of SPG are considered 'uncomplicated,' i.e., progressive spasticity occurs in isolation; others are considered 'complicated,' i.e., progressive spasticity occurs with other neurologic features. X-linked, autosomal dominant (see previous studies), and autosomal recessive (see previous studies) forms of SPG have been described. + +For discussion of genetic heterogeneity of X-linked SPG, see previous studies." +MONDO_0010735,"Definition: Kennedy disease is an X-linked recessive form of spinal muscular atrophy. It occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. The disorder is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia (previous studies). The disorder is clinically similar to, but genetically distinct from, classic forms of autosomal spinal muscular atrophy (see, e.g., SMA1; previous studies)." +MONDO_0014405,"Definition: STING-associated vasculopathy with onset in infancy is an autoinflammatory vasculopathy causing severe skin lesions, particularly affecting the face, ears, nose, and digits, and resulting in ulceration, eschar formation, necrosis, and, in some cases, amputation. Many patients have interstitial lung disease. Tissue biopsy and laboratory findings show a hyperinflammatory state, with evidence of increased beta-interferon (IFNB1; previous studies) signaling (summary by previous studies)." +MONDO_0021056,"Definition: Familial adenomatous polyposis-1 is an autosomal dominant disorder characterized by predisposition to cancer. Affected individuals usually develop hundreds to thousands of adenomatous polyps of the colon and rectum, a small proportion of which will progress to colorectal carcinoma if not surgically treated. Gardner syndrome is a variant of FAP in which desmoid tumors, osteomas, and other neoplasms occur together with multiple adenomas of the colon and rectum (previous studies). + +previous studies reviewed the genetics of hereditary colon cancer, including APC. + + Genetic Heterogeneity of Familial Adenomatous Polyposis + +See also autosomal recessive FAP2 (previous studies), caused by mutation in the MUTYH gene (previous studies) on chromosome 1p34; autosomal recessive FAP3 (previous studies), caused by mutation in the NTHL1 gene (previous studies) on chromosome 16p13; and autosomal recessive FAP4 (previous studies), caused by mutation in the MSH3 gene (previous studies) on chromosome 5q11." +MONDO_0030074,"Definition: Spondylometaphyseal dysplasia with corneal dystrophy (SMDCD) is characterized by short stature due to short proximal and distal long bones. Affected individuals also exhibit narrow thorax with pulmonary hypoplasia and respiratory failure, as well as corneal dystrophy. Severe developmental delay has been observed (previous studies)." +MONDO_0030747,"Definition: Severe junctional epidermolysis bullosa 2B (JEB2B) is an autosomal recessive skin blistering disorder characterized by extreme fragility of the skin and epithelia of various extracutaneous tissues. Skin blisters and erosions are present at birth. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Oral mucosal blistering and laryngeal and esophageal mucosal involvement can occur. Patients usually die before 1 year of age (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +MONDO_0030925,"Definition: Oocyte/zygote/embryo maturation arrest-10 (OZEMA10) is characterized by high rates of abnormal fertilization of mature oocytes, with development of multiple pronuclei or absent pronucleus. Morphologically normal zygotes often undergo early embryonic arrest, and surviving embryos fail to establish a successful pregnancy after implantation (previous studies). + +For a discussion of genetic heterogeneity of OZEMA, see previous studies." +MONDO_0008477,Definition: SMD Kozlowski (SMDK) is an autosomal dominant disorder characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles (previous studies). +MONDO_0008689,"Definition: Dehydrated hereditary stomatocytosis (DHS), also known as hereditary xerocytosis, is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. DHS erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. DHS patients typically exhibit mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration (summary by previous studies). Patients may also show perinatal edema and pseudohyperkalemia due to loss of K+ from red cells stored at room temperature. A minor proportion of red cells appear as stomatocytes on blood films. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur. The course of DHS is frequently associated with iron overload, which may lead to hepatosiderosis (summary by previous studies). + +Dehydrated red blood cells, including those from hereditary xerocytosis patients, show delayed infection rates to Plasmodium in vitro, suggesting a potential protective mechanism against malaria (previous studies). A polymorphism in PIEZO1 that is enriched in populations of African descent and results in xerocytosis conferred resistance to Plasmodium infection in vitro (see previous studies). + +The 'leaky red blood cells' in familial pseudohyperkalemia show a temperature-dependent loss of potassium when stored at room temperature, manifesting as apparent hyperkalemia. The red blood cells show a reduced life span in vivo, but there is no frank hemolysis. Studies of cation content and transport show a marginal increase in permeability at 37 degrees C and a degree of cellular dehydration, qualitatively similar to the changes seen in dehydrated hereditary stomatocytosis. Physiologic studies show that the passive leak of potassium has an abnormal temperature dependence, such that the leak is less sensitive to temperature than that in normal cells (summary by previous studies). + +previous studies noted that 3 clinical forms of pseudohyperkalemia unassociated with hematologic manifestations, based predominantly on the leak-temperature dependence curve, had been reported: (1) pseudohyperkalemia Edinburgh, in which the curve has a shallow slope; (2) pseudohyperkalemia Chiswick or Falkirk (see previous studies), in which the curve is shouldered; and (3) pseudohyperkalemia Cardiff (see previous studies), in which the temperature dependence of the leak shows a 'U-shaped' profile with a minimum at 23 degrees C. previous studies stated that potassium-flux temperature profiles are consistent both from year to year in an individual as well as consistent within affected members of a pedigree. + + Genetic Heterogeneity of Hereditary Stomatocytosis + +Dehydrated hereditary stomatocytosis-2 (DHS2; previous studies) is caused by mutation in the KCNN4 gene (previous studies) on chromosome 19q13. Another form of stomatocytosis, involving familial pseudohyperkalemia with minimal hematologic abnormalities (PSHK2; previous studies), is caused by mutation in the ABCB6 gene (previous studies) on chromosome 2q35. Cryohydrocytosis (CHC; previous studies) is caused by mutation in the SLC4A1 gene (previous studies) on chromosome 17q21, and stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN; previous studies) is caused by mutation in the SLC2A1 gene (previous studies) on chromosome 1p34. An overhydrated form of hereditary stomatocytosis (OHST; previous studies) is caused by mutation in the RHAG gene (previous studies) on chromosome 6p12. + +See previous studies for a discussion of the association of familial stomatocytosis and hypertrophic gastritis in the dog, an autosomal recessive syndrome. + + Reviews + +previous studies reviewed genetic disorders of red cell membrane permeability to monovalent cations, noting 'inevitable' overlap between entities based on clinical phenotype. + +previous studies provided a review of hereditary stomatocytosis and cation-leaky red cells, stating that consistent features include hemolytic anemia, a monovalent cation leak, and changes in red cell morphology that appear to follow a continuum, from normal discocyte to stomatocyte to echinocyte in DHS, and from discocyte to stomatocyte to spherocyte to fragmentation in OHST. previous studies suggested that the underlying pathologic mechanism might involve misfolded mutant proteins that escape the quality control system of the cell and reach the red cell membrane, where they disrupt the red cell membrane structure and cause a cation leak that alters the hydration of the red cell, thereby changing the morphology and viability of the cell. + +previous studies provided an overview of 2 groups of nonimmune hereditary red cell membrane disorders caused by defects in membrane proteins located in distinct layers of the red cell membrane: red cell cytoskeleton disorders, including hereditary spherocytosis (see previous studies), hereditary elliptocytosis (see previous studies), and hereditary pyropoikilocytosis (previous studies); and cation permeability disorders of the red cell membrane, or hereditary stomatocytoses, including DHS, OHST, CHC, and PSHK. The authors noted that because there is no specific screening test for the hereditary stomatocytoses, a preliminary diagnosis is based on the presence of a compensated hemolytic anemia, macrocytosis, and a temperature- or time-dependent pseudohyperkalemia in some patients. previous studies reported the International Council for Standardization in Haematology (ICSH) guidelines for laboratory diagnosis of nonimmune hereditary red cell membrane disorders." +MONDO_0009934,"Definition: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity (previous studies). Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period (previous studies). Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs (previous studies)." +Orphanet_210122,"Definition: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity (previous studies). Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period (previous studies). Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs (previous studies)." +MONDO_0010438,"Definition: Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired hemolytic anemia that often manifests with hemoglobinuria, abdominal pain, smooth muscle dystonias, fatigue, and thrombosis. The disease results from the expansion of hematopoietic stem cells harboring a mutation in the PIGA gene, which encodes a protein required for the biosynthesis of glycosylphosphatidylinositol (GPI), a lipid moiety that attaches dozens of proteins to the cell surface. Thus, PNH cells are deficient in cell surface GPI-anchored proteins. This deficiency on erythrocytes leads to intravascular hemolysis, since certain GPI-anchored proteins (i.e., CD55 (previous studies) and CD59 (previous studies)) normally function as complement regulators. Free hemoglobin released from intravascular hemolysis leads to circulating nitrous oxide depletion and is responsible for many of the clinical manifestations of PNH, including fatigue, erectile dysfunction, esophageal spasm, and thrombosis (review by previous studies). + + Genetic Heterogeneity of Paroxysmal Nocturnal Hemoglobinuria + +See also PNH2 (previous studies), which may be caused by germline and somatic mutation in the PIGT gene (previous studies) on chromosome 20q13." +MONDO_0010632,"Definition: Developmental and epileptic encephalopathy-1 (DEE1) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of DEE1 patients progress to tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (previous studies). + +DEE1 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; previous studies) to Proud syndrome (previous studies) to infantile spasms without brain malformations (DEE) to syndromic (previous studies) and nonsyndromic (previous studies) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (previous studies; previous studies). + + Reviews + +previous studies reviewed the genetics of epilepsy syndromes starting in the first year of life and included a diagnostic algorithm. + + Genetic Heterogeneity of Developmental and Epileptic Encephalopathy + +Also see DEE2 (previous studies), caused by mutation in the CDKL5 gene (previous studies); DEE3 (previous studies), caused by mutation in the SLC25A22 gene (previous studies); DEE4 (previous studies), caused by mutation in the STXBP1 gene (previous studies); DEE5 (previous studies), caused by mutation in the SPTAN1 gene (previous studies); DEE6A (previous studies), also known as Dravet syndrome, caused by mutation in the SCN1A gene (previous studies); DEE6B (previous studies), also caused by mutation in the SCN1A gene; DEE7 (previous studies), caused by mutation in the KCNQ2 gene (previous studies); DEE8 (previous studies), caused by mutation in the ARHGEF9 gene (previous studies); DEE9 (previous studies), caused by mutation in the PCDH19 gene (previous studies); DEE10 (previous studies), caused by mutation in the PNKP gene (previous studies); DEE11 (previous studies), caused by mutation in the SCN2A gene (previous studies); DEE12 (previous studies), caused by mutation in the PLCB1 gene (previous studies); DEE13 (previous studies), caused by mutation in the SCN8A gene (previous studies); DEE14 (previous studies), caused by mutation in the KCNT1 gene (previous studies); DEE15 (previous studies), caused by mutation in the ST3GAL3 gene (previous studies); DEE16 (previous studies), caused by mutation in the TBC1D24 gene (previous studies); DEE17 (previous studies), caused by mutation in the GNAO1 gene (previous studies); DEE18 (previous studies), caused by mutation in the SZT2 gene (previous studies); DEE19 (previous studies), caused by mutation in the GABRA1 gene (previous studies); DEE20 (previous studies), caused by mutation in the PIGA gene (previous studies); DEE21 (previous studies), caused by mutation in the NECAP1 gene (previous studies); DEE22 (previous studies), caused by mutation in the SLC35A2 gene (previous studies); DEE23 (previous studies), caused by mutation in the DOCK7 gene (previous studies); DEE24 (previous studies), caused by mutation in the HCN1 gene (previous studies); DEE25 (previous studies), caused by mutation in the SLC13A5 gene (previous studies); DEE26 (previous studies), caused by mutation in the KCNB1 gene (previous studies); DEE27 (previous studies), caused by mutation in the GRIN2B gene (previous studies); DEE28 (previous studies), caused by mutation in the WWOX gene (previous studies); DEE29 (previous studies), caused by mutation in the AARS gene (previous studies); DEE30 (previous studies), caused by mutation in the SIK1 gene (previous studies); DEE31A (previous studies) and DEE31B (previous studies), caused by mutation in the DNM1 gene (previous studies); DEE32 (previous studies), caused by mutation in the KCNA2 gene (previous studies); DEE33 (previous studies), caused by mutation in the EEF1A2 gene (previous studies); DEE34 (previous studies), caused by mutation in the SLC12A5 gene (previous studies); DEE35 (previous studies), caused by mutation in the ITPA gene (previous studies); DEE36 (previous studies), caused by mutation in the ALG13 gene (previous studies); DEE37 (previous studies), caused by mutation in the FRRS1L gene (previous studies); DEE38 (previous studies), caused by mutation in the ARV1 gene (previous studies); DEE39 (previous studies), caused by mutation in the SLC25A12 gene (previous studies); DEE40 (previous studies), caused by mutation in the GUF1 gene (previous studies); DEE41 (previous studies), caused by mutation in the SLC1A2 gene (previous studies); DEE42 (previous studies), caused by mutation in the CACNA1A gene (previous studies); DEE43 (previous studies), caused by mutation in the GABRB3 gene (previous studies); DEE44 (previous studies), caused by mutation in the UBA5 gene (previous studies); DEE45 (previous studies), caused by mutation in the GABRB1 gene (previous studies); DEE46 (previous studies), caused by mutation in the GRIN2D gene (previous studies); DEE47 (previous studies), caused by mutation in the FGF12 gene (previous studies); DEE48 (previous studies), caused by mutation in the AP3B2 gene (previous studies); DEE49 (previous studies), caused by mutation in the DENND5A gene (previous studies); DEE50 (previous studies) caused by mutation in the CAD gene (previous studies); DEE51 (previous studies), caused by mutation in the MDH2 gene (previous studies); DEE52 (previous studies), caused by mutation in the SCN1B gene (previous studies); DEE53 (previous studies), caused by mutation in the SYNJ1 gene (previous studies); DEE54 (previous studies), caused by mutation in the HNRNPU gene (previous studies); DEE55 (previous studies), caused by mutation in the PIGP gene (previous studies); DEE56 (previous studies), caused by mutation in the YWHAG gene (previous studies); DEE57 (previous studies), caused by mutation in the KCNT2 gene (previous studies); DEE58 (previous studies), caused by mutation in the NTRK2 gene (previous studies); DEE59 (previous studies), caused by mutation in the GABBR2 gene (previous studies); DEE60 (previous studies), caused by mutation in the CNPY3 gene (previous studies); DEE61 (previous studies), caused by mutation in the ADAM22 gene (previous studies); DEE62 (previous studies), caused by mutation in the SCN3A gene (previous studies); DEE63 (previous studies), caused by mutation in the CPLX1 gene (previous studies); DEE64 (previous studies), caused by mutation in the RHOBTB2 gene (previous studies); DEE65 (previous studies), caused by mutation in the CYFIP2 gene (previous studies); DEE66 (previous studies), caused by mutation in the PACS2 gene (previous studies); DEE67 (previous studies), caused by mutation in the CUX2 gene (previous studies); DEE68 (previous studies), caused by mutation in the TRAK1 gene (previous studies); DEE69 (previous studies), caused by mutation in the CACNA1E gene (previous studies); DEE70 (previous studies) caused by mutation in the PHACTR1 gene (previous studies); DEE71 (previous studies), caused by mutation in the GLS gene (previous studies); DEE72 (previous studies), caused by mutation in the NEUROD2 gene (previous studies); DEE73 (previous studies), caused by mutation in the RNF13 gene (previous studies); DEE74 (previous studies), caused by mutation in the GABRG2 gene (previous studies); DEE75 (previous studies), caused by mutation in the PARS2 gene (previous studies); DEE76 (previous studies), caused by mutation in the ACTL6B gene (previous studies); DEE77 (previous studies), caused by mutation in the PIGQ gene (previous studies); DEE78 (previous studies), caused by mutation in the GABRA2 gene (previous studies); DEE79 (previous studies), caused by mutation in the GABRA5 gene (previous studies); DEE80 (previous studies), caused by mutation in the PIGB gene (previous studies); DEE81 (previous studies), caused by mutation in the DMXL2 gene (previous studies); DEE82 (previous studies), caused by mutation in the GOT2 gene (previous studies); DEE83 (previous studies), caused by mutation in the UGP2 gene (previous studies); DEE84 (previous studies), caused by mutation in the UGDH gene (previous studies); DEE85 (previous studies), caused by mutation in the SMC1A gene (previous studies); DEE86 (previous studies), caused by mutation in the DALRD3 gene (previous studies); DEE87 (previous studies), caused by mutation in the CDK19 gene (previous studies); DEE88 (previous studies), caused by mutation in the MDH1 gene (previous studies); DEE89 (previous studies), caused by mutation in the GAD1 gene (previous studies); DEE90 (previous studies), caused by mutation in the FGF13 gene (previous studies); DEE91 (previous studies), caused by mutation in the PPP3CA gene (previous studies); DEE92 (previous studies), caused by mutation in the GABRB2 gene (previous studies); DEE93 (previous studies), caused by mutation in the ATP6V1A gene (previous studies); DEE94 (previous studies), caused by mutation in the CHD2 gene (previous studies); DEE95 (previous studies), caused by mutation in the PIGS gene (previous studies); DEE96 (previous studies), caused by mutation in the NSF gene (previous studies); DEE97 (previous studies), caused by mutation in the iCELF2 gene (previous studies); DEE98 (previous studies), caused by mutation in the ATP1A2 gene (previous studies); DEE99 (previous studies), caused by mutation in the ATP1A3 gene (previous studies); DEE100 (previous studies), caused by mutation in the FBXO28 gene (previous studies); DEE101 (previous studies), caused by mutation in the GRIN1 gene (previous studies); DEE102 (previous studies), caused by mutation in the SLC38A3 gene (previous studies); DEE103 (previous studies), caused by mutation in the KCNC2 gene (previous studies); DEE104 (previous studies), caused by mutation in the ATP6V0A1 gene (previous studies); DEE105 (previous studies), caused by mutation in the HID1 gene (previous studies); DEE106 (previous studies), caused by mutation in the UFSP2 gene (previous studies); DEE107 (previous studies), caused by mutation in the NAPB gene (previous studies); DEE108 (previous studies), caused by mutation in the MAST3 gene (previous studies); DEE109 (previous studies), caused by mutation in the FZR1 gene (previous studies); and DEE110 (previous studies), caused by mutation in the CACNA2D1 gene (previous studies). + +The phenotype is also observed in other genetic disorders, including GLUT1 deficiency syndrome (previous studies); glycine encephalopathy (previous studies); Aicardi-Goutieres syndrome (previous studies); and in males with MECP2 mutations (previous studies), among others. + +For associations pending confirmation, see MOLECULAR GENETICS." +Orphanet_3175,"Definition: Developmental and epileptic encephalopathy-1 (DEE1) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of DEE1 patients progress to tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (previous studies). + +DEE1 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; previous studies) to Proud syndrome (previous studies) to infantile spasms without brain malformations (DEE) to syndromic (previous studies) and nonsyndromic (previous studies) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (previous studies; previous studies). + + Reviews + +previous studies reviewed the genetics of epilepsy syndromes starting in the first year of life and included a diagnostic algorithm. + + Genetic Heterogeneity of Developmental and Epileptic Encephalopathy + +Also see DEE2 (previous studies), caused by mutation in the CDKL5 gene (previous studies); DEE3 (previous studies), caused by mutation in the SLC25A22 gene (previous studies); DEE4 (previous studies), caused by mutation in the STXBP1 gene (previous studies); DEE5 (previous studies), caused by mutation in the SPTAN1 gene (previous studies); DEE6A (previous studies), also known as Dravet syndrome, caused by mutation in the SCN1A gene (previous studies); DEE6B (previous studies), also caused by mutation in the SCN1A gene; DEE7 (previous studies), caused by mutation in the KCNQ2 gene (previous studies); DEE8 (previous studies), caused by mutation in the ARHGEF9 gene (previous studies); DEE9 (previous studies), caused by mutation in the PCDH19 gene (previous studies); DEE10 (previous studies), caused by mutation in the PNKP gene (previous studies); DEE11 (previous studies), caused by mutation in the SCN2A gene (previous studies); DEE12 (previous studies), caused by mutation in the PLCB1 gene (previous studies); DEE13 (previous studies), caused by mutation in the SCN8A gene (previous studies); DEE14 (previous studies), caused by mutation in the KCNT1 gene (previous studies); DEE15 (previous studies), caused by mutation in the ST3GAL3 gene (previous studies); DEE16 (previous studies), caused by mutation in the TBC1D24 gene (previous studies); DEE17 (previous studies), caused by mutation in the GNAO1 gene (previous studies); DEE18 (previous studies), caused by mutation in the SZT2 gene (previous studies); DEE19 (previous studies), caused by mutation in the GABRA1 gene (previous studies); DEE20 (previous studies), caused by mutation in the PIGA gene (previous studies); DEE21 (previous studies), caused by mutation in the NECAP1 gene (previous studies); DEE22 (previous studies), caused by mutation in the SLC35A2 gene (previous studies); DEE23 (previous studies), caused by mutation in the DOCK7 gene (previous studies); DEE24 (previous studies), caused by mutation in the HCN1 gene (previous studies); DEE25 (previous studies), caused by mutation in the SLC13A5 gene (previous studies); DEE26 (previous studies), caused by mutation in the KCNB1 gene (previous studies); DEE27 (previous studies), caused by mutation in the GRIN2B gene (previous studies); DEE28 (previous studies), caused by mutation in the WWOX gene (previous studies); DEE29 (previous studies), caused by mutation in the AARS gene (previous studies); DEE30 (previous studies), caused by mutation in the SIK1 gene (previous studies); DEE31A (previous studies) and DEE31B (previous studies), caused by mutation in the DNM1 gene (previous studies); DEE32 (previous studies), caused by mutation in the KCNA2 gene (previous studies); DEE33 (previous studies), caused by mutation in the EEF1A2 gene (previous studies); DEE34 (previous studies), caused by mutation in the SLC12A5 gene (previous studies); DEE35 (previous studies), caused by mutation in the ITPA gene (previous studies); DEE36 (previous studies), caused by mutation in the ALG13 gene (previous studies); DEE37 (previous studies), caused by mutation in the FRRS1L gene (previous studies); DEE38 (previous studies), caused by mutation in the ARV1 gene (previous studies); DEE39 (previous studies), caused by mutation in the SLC25A12 gene (previous studies); DEE40 (previous studies), caused by mutation in the GUF1 gene (previous studies); DEE41 (previous studies), caused by mutation in the SLC1A2 gene (previous studies); DEE42 (previous studies), caused by mutation in the CACNA1A gene (previous studies); DEE43 (previous studies), caused by mutation in the GABRB3 gene (previous studies); DEE44 (previous studies), caused by mutation in the UBA5 gene (previous studies); DEE45 (previous studies), caused by mutation in the GABRB1 gene (previous studies); DEE46 (previous studies), caused by mutation in the GRIN2D gene (previous studies); DEE47 (previous studies), caused by mutation in the FGF12 gene (previous studies); DEE48 (previous studies), caused by mutation in the AP3B2 gene (previous studies); DEE49 (previous studies), caused by mutation in the DENND5A gene (previous studies); DEE50 (previous studies) caused by mutation in the CAD gene (previous studies); DEE51 (previous studies), caused by mutation in the MDH2 gene (previous studies); DEE52 (previous studies), caused by mutation in the SCN1B gene (previous studies); DEE53 (previous studies), caused by mutation in the SYNJ1 gene (previous studies); DEE54 (previous studies), caused by mutation in the HNRNPU gene (previous studies); DEE55 (previous studies), caused by mutation in the PIGP gene (previous studies); DEE56 (previous studies), caused by mutation in the YWHAG gene (previous studies); DEE57 (previous studies), caused by mutation in the KCNT2 gene (previous studies); DEE58 (previous studies), caused by mutation in the NTRK2 gene (previous studies); DEE59 (previous studies), caused by mutation in the GABBR2 gene (previous studies); DEE60 (previous studies), caused by mutation in the CNPY3 gene (previous studies); DEE61 (previous studies), caused by mutation in the ADAM22 gene (previous studies); DEE62 (previous studies), caused by mutation in the SCN3A gene (previous studies); DEE63 (previous studies), caused by mutation in the CPLX1 gene (previous studies); DEE64 (previous studies), caused by mutation in the RHOBTB2 gene (previous studies); DEE65 (previous studies), caused by mutation in the CYFIP2 gene (previous studies); DEE66 (previous studies), caused by mutation in the PACS2 gene (previous studies); DEE67 (previous studies), caused by mutation in the CUX2 gene (previous studies); DEE68 (previous studies), caused by mutation in the TRAK1 gene (previous studies); DEE69 (previous studies), caused by mutation in the CACNA1E gene (previous studies); DEE70 (previous studies) caused by mutation in the PHACTR1 gene (previous studies); DEE71 (previous studies), caused by mutation in the GLS gene (previous studies); DEE72 (previous studies), caused by mutation in the NEUROD2 gene (previous studies); DEE73 (previous studies), caused by mutation in the RNF13 gene (previous studies); DEE74 (previous studies), caused by mutation in the GABRG2 gene (previous studies); DEE75 (previous studies), caused by mutation in the PARS2 gene (previous studies); DEE76 (previous studies), caused by mutation in the ACTL6B gene (previous studies); DEE77 (previous studies), caused by mutation in the PIGQ gene (previous studies); DEE78 (previous studies), caused by mutation in the GABRA2 gene (previous studies); DEE79 (previous studies), caused by mutation in the GABRA5 gene (previous studies); DEE80 (previous studies), caused by mutation in the PIGB gene (previous studies); DEE81 (previous studies), caused by mutation in the DMXL2 gene (previous studies); DEE82 (previous studies), caused by mutation in the GOT2 gene (previous studies); DEE83 (previous studies), caused by mutation in the UGP2 gene (previous studies); DEE84 (previous studies), caused by mutation in the UGDH gene (previous studies); DEE85 (previous studies), caused by mutation in the SMC1A gene (previous studies); DEE86 (previous studies), caused by mutation in the DALRD3 gene (previous studies); DEE87 (previous studies), caused by mutation in the CDK19 gene (previous studies); DEE88 (previous studies), caused by mutation in the MDH1 gene (previous studies); DEE89 (previous studies), caused by mutation in the GAD1 gene (previous studies); DEE90 (previous studies), caused by mutation in the FGF13 gene (previous studies); DEE91 (previous studies), caused by mutation in the PPP3CA gene (previous studies); DEE92 (previous studies), caused by mutation in the GABRB2 gene (previous studies); DEE93 (previous studies), caused by mutation in the ATP6V1A gene (previous studies); DEE94 (previous studies), caused by mutation in the CHD2 gene (previous studies); DEE95 (previous studies), caused by mutation in the PIGS gene (previous studies); DEE96 (previous studies), caused by mutation in the NSF gene (previous studies); DEE97 (previous studies), caused by mutation in the iCELF2 gene (previous studies); DEE98 (previous studies), caused by mutation in the ATP1A2 gene (previous studies); DEE99 (previous studies), caused by mutation in the ATP1A3 gene (previous studies); DEE100 (previous studies), caused by mutation in the FBXO28 gene (previous studies); DEE101 (previous studies), caused by mutation in the GRIN1 gene (previous studies); DEE102 (previous studies), caused by mutation in the SLC38A3 gene (previous studies); DEE103 (previous studies), caused by mutation in the KCNC2 gene (previous studies); DEE104 (previous studies), caused by mutation in the ATP6V0A1 gene (previous studies); DEE105 (previous studies), caused by mutation in the HID1 gene (previous studies); DEE106 (previous studies), caused by mutation in the UFSP2 gene (previous studies); DEE107 (previous studies), caused by mutation in the NAPB gene (previous studies); DEE108 (previous studies), caused by mutation in the MAST3 gene (previous studies); DEE109 (previous studies), caused by mutation in the FZR1 gene (previous studies); and DEE110 (previous studies), caused by mutation in the CACNA2D1 gene (previous studies). + +The phenotype is also observed in other genetic disorders, including GLUT1 deficiency syndrome (previous studies); glycine encephalopathy (previous studies); Aicardi-Goutieres syndrome (previous studies); and in males with MECP2 mutations (previous studies), among others. + +For associations pending confirmation, see MOLECULAR GENETICS." +MONDO_0011969,"Definition: CDGs, previously called carbohydrate-deficient glycoprotein syndromes, grew from hereditary multisystem disorders first recognized by previous studies. The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. For a general discussion of CDGs, see CDG1A (previous studies). + +CDG1H is a severe form of CDG. The majority of patients have brain involvement, liver pathology, gastrointestinal symptoms, dysmorphism (including brachydactyly), eye involvement (especially cataract), and skin symptoms. Most patients die within the first year of life (summary by previous studies)." +MONDO_0012549,"Definition: Autosomal recessive spinocerebellar ataxia-8 (SCAR8) is a slowly progressive neurodegenerative disorder characterized by gait ataxia and other cerebellar signs, such as nystagmus and dysarthria. The age at onset is highly variable, and but most often is in the second or third decades. The disorder was initially identified in patients of French Canadian descent, most of whom have a relatively 'pure' form of the disorder. However, subsequent studies have shown that SCAR8 occurs worldwide and most commonly manifests with additional features, including spasticity, secondary musculoskeletal abnormalities, and ocular movement anomalies, consistent with a 'complicated' phenotype. Brain imaging typically shows cerebellar atrophy, sometimes with pontine involvement. Rare patients may have an early-onset multisystemic disorder with impaired intellectual development and respiratory dysfunction (summary by previous studies)." +MONDO_0013017,"Definition: Hypotrichosis-5 (HYPT5), also known as Marie Unna hereditary hypotrichosis-2 (MUHH2), is a form of hereditary hypotrichosis characterized by twisting hair. Affected individuals have little or no scalp hair at birth, wiry and irregular scalp hair in childhood, and sparse or no forehead and parietal hair at puberty. Eyebrows and eyelashes are thin, and pubic and axillary hair fails to develop. Scarring alopecia is modest, and vertex hair is normal (summary by previous studies). + +For a general phenotypic description of Marie Unna hereditary hypotrichosis, see MUHH1 (previous studies). + +For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see previous studies." +MONDO_0013865,"Definition: COXPD10 is an autosomal recessive disorder resulting in variable defects of mitochondrial oxidative respiration. Affected individuals present in infancy with hypertrophic cardiomyopathy and lactic acidosis. The severity is variable, but can be fatal in the most severe cases (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0014022,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. The brain shows cobblestone lissencephaly, a cortical malformation. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0014313,"Definition: Immunodeficiency-20 is a rare autosomal recessive primary immunodeficiency characterized by functional deficiency of NK cells. Patient NK cells are defective in spontaneous cell cytotoxicity, but retain antibody-dependent cellular cytotoxicity. Patients typically present early in childhood with severe herpes viral infections, particularly Epstein Barr virus (EBV), and human papillomavirus (HPV) (summary by previous studies)." +MONDO_0014699,"Definition: Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features (NEDHILD) is a rare neurodevelopmental disorder associated with impaired intellectual development, speech and language impairment, microcephaly, seizures, hypotonia, ophthalmologic issues, constipation/gastroesophageal reflux, and behavioral problems, including autism and sleep disturbances (summary by previous studies)." +MONDO_0014916,"Definition: Developmental and epileptic encephalopathy-41 (DEE41) is a neurologic disorder characterized by the onset of seizures in the first days or weeks of life. Affected infants show severely impaired psychomotor development with hypotonia, spasticity, lack of speech, poor visual fixation, feeding difficulties sometimes necessitating tube feeding, poor overall growth and microcephaly, and contractures. Brain imaging may show delayed myelination, thin corpus callosum, and cerebral atrophy (summary by the previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0031052,"Definition: Developmental and epileptic encephalopathy-106 (DEE106) is an autosomal recessive disorder characterized by the onset of various types of frequent, often refractory, seizures within the first year of life. Affected individuals demonstrate profound global developmental delay with limited ability to move and severely impaired intellectual development with absent speech. Nonspecific brain abnormalities may be observed on MRI (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +EFO_0004125,"Definition: Mutations in the AIP gene have been found predominantly in growth hormone (GH)-secreting adenomas, but have also been found in adrenocorticotropic hormone (ACTH)-secreting, thyroid hormone (TSH)-secreting, and prolactin (PRL)-secreting pituitary tumors. + +Pituitary adenomas are benign monoclonal neoplasms of the anterior pituitary gland, accounting for approximately 15% of intracranial tumors. Growth hormone (previous studies)-secreting adenomas, also known as somatotropinomas, which clinically result in acromegaly, comprise about 20% of all pituitary tumors and are the second most common hormone-secreting pituitary tumor after prolactin (previous studies)-secreting tumors, which account for 40 to 45% of pituitary tumors. ACTH-secreting tumors, which result in Cushing disease, and thyrotropin (TSHB; previous studies)-secreting tumors are much less common. Nonsecreting pituitary tumors, which account for about 33%, can cause symptoms due to local compressive effects of tumor growth (previous studies; previous studies; previous studies). + +Acromegaly is characterized by coarse facial features, protruding jaw, and enlarged extremities (previous studies). Familial isolated somatotropinoma (FIS) is defined as the occurrence of at least 2 cases of acromegaly or gigantism in a family that does not exhibit features of other endocrine syndromes. FIS patients tend to have onset about 4 to 10 years earlier than patients with sporadic disease (previous studies; previous studies). + +Cushing disease is characterized by central obesity, moon facies, diabetes, 'buffalo hump,' hypertension, fatigue, easy bruising, depression, and reproductive disorders. Cushing disease is associated with increased morbidity and mortality, mainly due to cardiovascular or cerebrovascular disease and infections (summary by previous studies). + +Familial isolated pituitary adenoma (FIPA) and pituitary adenoma predisposition (PAP) are terms referring to families in which 2 or more individuals develop pituitary tumors. Within a family, tumor types can be heterogeneous, with members of the same family having GH-secreting, prolactin-secreting, ACTH-secreting, or nonsecreting adenomas; in contrast, some families are homogeneous with regard to tumor type. Familial isolated somatotropinoma refers specifically to GH-secreting tumors and is usually associated with an acromegaly phenotype. Thus, FIS is a subset of FIPA or PAP (previous studies). + +previous studies discussed prolactinoma in general terms as a clinical, diagnostic, and therapeutic problem. + + Genetic Heterogeneity of Pituitary Adenomas + +Also see pituitary adenoma-2 (PITA2; previous studies), caused by mutation in the GPR101 gene (previous studies); pituitary adenoma-3 (PITA3; previous studies), caused by somatic activating mutations in the GNAS1 gene (previous studies); pituitary adenoma-4 (PITA4; previous studies), caused by somatic mutation in the USP8 gene (previous studies); and pituitary adenoma-5 (PITA5; previous studies), caused by mutation in the CDH23 gene (previous studies). + +Patients with the chromosome Xq26.3 microduplication syndrome (previous studies) have growth hormone-secreting adenomas. + +Familial acromegaly can also occur in association with multiple endocrine neoplasia type I (MEN1; previous studies), Carney complex (CNC1; previous studies), and the McCune-Albright syndrome (previous studies). + +previous studies performed a retrospective analysis of 208 patients with pituitary gigantism due to pituitary adenoma or hyperplasia. Most patients (78.4%) were male, and the median onset of rapid growth was 13 years of age for boys and 11 years for girls. Of the 143 patients who consented to genetic testing, 29% had AIP mutations, and microduplication at Xq26.3 (XLAG; previous studies) was present in 2 familial isolated pituitary adenoma kindreds and in 10 sporadic patients. previous studies noted that no genetic etiology was identified in more than 50% of the cases, and that the genetically unexplained cases showed more aggressive disease in terms of invasion, hormone levels, and lower control rates." +MONDO_0007055,"Definition: Acromicric dysplasia is an autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have distinct facial features, including round face, well-defined eyebrows, long eyelashes, bulbous nose with anteverted nostrils, long and prominent philtrum, and thick lips with a small mouth. Other characteristic features include hoarse voice and pseudomuscular build, and there are distinct skeletal features as well, including an internal notch of the femoral head, internal notch of the second metacarpal, and external notch of the fifth metacarpal (summary by previous studies). + +Allelic disorders with overlapping skeletal and joint features include geleophysic dysplasia-2 (GPHYSD2; previous studies) and the autosomal dominant form of Weill-Marchesani syndrome (previous studies)." +MONDO_0007410,"Definition: Cryptophthalmos is a condition of eyelid malformation with an underlying malformed eye. Complete, incomplete, and symblepharon varieties exist. The skin in complete cryptophthalmos extends uninterrupted from the forehead to the cheek. In the incomplete form, there is medial eyelid fusion, but coincident intact lateral structures. The symblepharon variety presents with fusion of the upper eyelid skin to the superior aspect of the globe. The complete variety is the most common form (summary by previous studies)." +MONDO_0008373,Definition: Familial retinal arterial tortuosity is characterized by marked tortuosity of second- and third-order retinal arteries with normal first-order arteries and venous system. Two-thirds of patients experience variable degrees of symptomatic transient vision loss due to retinal hemorrhage following minor stress or trauma (summary by previous studies). +MONDO_0009179,"Definition: Autosomal recessive dystrophic epidermolysis bullosa is a severe skin disorder beginning at birth and characterized by recurrent blistering at the level of the sublamina densa beneath the cutaneous basement membrane. This results in mutilating scarring and contractures of the hands, feet, and joints. Patients also developed strictures of the gastrointestinal tract from mucosal involvement, which can lead to poor nutrition. Affected individuals have an increased risk of developing aggressive squamous cell carcinoma (previous studies; previous studies). + +Allelic disorders include autosomal dominant DEB (DDEB; previous studies), in which the phenotype is less severe, and nonsyndromic congenital nail disorder-8 (NDNC8; previous studies), which has been found to segregate as an autosomal dominant trait in heterozygous carriers in some families with recessive DEB." +MONDO_0011136,"Definition: Quebec platelet disorder is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. The disorder shows a favorable therapeutic response to fibrinolytic inhibitors (summary by previous studies)." +MONDO_0011449,"Definition: Sialic acid storage diseases are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or as a slowly progressive adult form that is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia, and mental retardation; visceromegaly and coarse features are also present in the infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by MRI. Enlarged lysosomes are seen on electron microscopic studies, and patients excrete large amounts of free sialic acid in the urine (previous studies)." +MONDO_0012034,"Definition: Autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2) is a myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients. Affected individuals also have distal muscle weakness of the hands and lower leg muscles. There is variability in presentation and progression. Some patients present in early childhood with mildly delayed walking and difficulty running and jumping, whereas others present as adults with mainly pelvic-girdle weakness. Patients with early onset tend to have a more severe disorder, and may develop contractures, loss of independent ambulation, and respiratory insufficiency. Muscle biopsy shows dystrophic changes with abnormal nuclei, rimmed vacuoles, and filamentous inclusions (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (previous studies)." +MONDO_0013050,"Definition: Growth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness (summary by previous studies)." +MONDO_0013056,"Definition: Developmental and epileptic encephalopathy-39 with leukodystrophy (DEE39) is an autosomal recessive neurologic syndrome characterized clinically by global developmental delay apparent in early infancy, early-onset seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Other features include absent speech and inability to walk; spasticity and hyperreflexia has also been reported. Although there is significant hypomyelination on brain imaging, the disorder was not classified as a primary leukodystrophy. The myelination defect was thought to stem from primary neuronal dysfunction due to impaired mitochondrial transport activity (summary by previous studies and previous studies). However, serial brain imaging in a patient with DEE39 by previous studies suggested that the mechanism of disease is consistent with a leukoaxonopathy type of leukodystrophy. + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +Orphanet_353217,"Definition: Developmental and epileptic encephalopathy-39 with leukodystrophy (DEE39) is an autosomal recessive neurologic syndrome characterized clinically by global developmental delay apparent in early infancy, early-onset seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Other features include absent speech and inability to walk; spasticity and hyperreflexia has also been reported. Although there is significant hypomyelination on brain imaging, the disorder was not classified as a primary leukodystrophy. The myelination defect was thought to stem from primary neuronal dysfunction due to impaired mitochondrial transport activity (summary by previous studies and previous studies). However, serial brain imaging in a patient with DEE39 by previous studies suggested that the mechanism of disease is consistent with a leukoaxonopathy type of leukodystrophy. + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0014072,"Definition: Combined D-2- and L-2-hydroxyglutaric aciduria (D-2-HG and L-2-HG) is an autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts (summary by previous studies). + +See also isolated L-2-hydroxyglutaric aciduria (previous studies) and isolated D-2-hydroxyglutaric aciduria (see previous studies)." +MONDO_0026733,"Definition: Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD) is an X-linked recessive phenotype characterized by global developmental delay with hypotonia, delayed speech, and mildly delayed walking associated with somatic marfanoid features, including tall stature, long fingers, and mildly dysmorphic facies. Some patients may have cardiac defects, such as mitral valve regurgitation, as well as other anomalies related to connective tissue defects, such as scoliosis (summary by previous studies)." +Orphanet_53696,"Definition: Congenital arthrogryposis with anterior horn cell disease (CAAHD) is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by previous studies and previous studies). + + Distinction from Lethal Congenital Contracture Syndrome 1 + +Biallelic mutation in the GLE1 gene can also cause LCCS1, which is lethal in utero. However, distinguishing between LCCS1 and CAAHD is controversial. previous studies suggested that differentiating between the 2 disorders has limited utility, and that they may represent a genotype/phenotype correlation rather than 2 different disease entities. In contrast, previous studies concluded that LCCS1 represents a distinct clinical entity in which all affected individuals die prenatally and exhibit no fetal movements. + +previous studies differentiated CAAHD from LCCS1, noting that both are prevalent in Finland. LCCS1 is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. In LCCS1, the spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with CAAHD survive longer than those with LCCS1, and when present, hydrops and intrauterine growth retardation are mild. The macroscopic findings of the central nervous system and skeletal muscles are closer to normal, although microscopic analysis also shows degeneration of anterior horn cells. In addition, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS1." +MONDO_0012750,"Definition: Congenital arthrogryposis with anterior horn cell disease (CAAHD) is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by previous studies and previous studies). + + Distinction from Lethal Congenital Contracture Syndrome 1 + +Biallelic mutation in the GLE1 gene can also cause LCCS1, which is lethal in utero. However, distinguishing between LCCS1 and CAAHD is controversial. previous studies suggested that differentiating between the 2 disorders has limited utility, and that they may represent a genotype/phenotype correlation rather than 2 different disease entities. In contrast, previous studies concluded that LCCS1 represents a distinct clinical entity in which all affected individuals die prenatally and exhibit no fetal movements. + +previous studies differentiated CAAHD from LCCS1, noting that both are prevalent in Finland. LCCS1 is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. In LCCS1, the spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with CAAHD survive longer than those with LCCS1, and when present, hydrops and intrauterine growth retardation are mild. The macroscopic findings of the central nervous system and skeletal muscles are closer to normal, although microscopic analysis also shows degeneration of anterior horn cells. In addition, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS1." +MONDO_0007083,"Definition: Palmoplantar keratoderma and congenital alopecia-1 (PPKCA1) is a rare autosomal dominant disorder characterized by severe hyperkeratosis and congenital alopecia. Nail changes occur in some patients (summary by previous studies). + +Also see PPKCA2 (previous studies), an autosomal recessive disorder characterized by congenital alopecia and progressive hyperkeratosis resulting in sclerodactyly, severe contractures and tapering of the digits, and pseudoainhum formation." +MONDO_0008259,"Definition: Primary spontaneous pneumothorax (PSP) is a condition in which air enters the pleural space and causes secondary lung collapse. It is mostly sporadic but also occurrs in families. It is associated with bullae in the lungs of most patients (summary by previous studies). + +Birt-Hogg-Dube syndrome (BHD; previous studies), which is characterized by spontaneous pneumothorax as well as by fibrofolliculomas of the skin and increased risk of renal and colonic tumors, is also caused by mutation in the FLCN gene. previous studies suggested that isolated primary spontaneous pneumothorax associated with FLCN mutations may be part of the clinical spectrum of BHD, showing incomplete disease penetrance. + +Spontaneous pneumothorax is a complication of certain heritable disorders of connective tissue, particularly the Marfan syndrome (previous studies) and the Ehlers-Danlos syndrome (see, e.g., previous studies). Pulmonary bullae can also occur with alpha-1-antitrypsin deficiency (previous studies)." +MONDO_0008729,"Definition: Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursors 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension (previous studies). + +CAH due to 11-beta-hydroxylase deficiency accounts for approximately 5 to 8% of all CAH cases; approximately 90% of cases are caused by 21-hydroxylase deficiency (previous studies) (previous studies)." +MONDO_0008753,"Definition: Alkaptonuria is an autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of the cardiac valves (summary by previous studies). + +Alkaptonuria enjoys the historic distinction of being one of the first conditions in which mendelian recessive inheritance was proposed (by previous studies, on the suggestion of Bateson) and of being 1 of the 4 conditions in the charter group of inborn errors of metabolism. The manifestations are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and arthritis, especially characteristic in the spine." +MONDO_0008798,"Definition: Congenital anonychia is defined as the absence of fingernails and toenails. Anonychia and its milder phenotypic variant, hyponychia, usually occur as a feature of genetic syndromes, in association with significant skeletal and limb anomalies. Isolated nonsyndromic congenital anonychia/hyponychia is a rare entity that usually follows autosomal recessive inheritance with variable expression, even within a given family. The nail phenotypes observed range from no nail field to a nail field of reduced size with an absent or rudimentary nail (summary by previous studies). This form of nail disorder is referred to here as nonsyndromic congenital nail disorder-4 (NDNC4). + +For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (previous studies)." +Orphanet_94150,"Definition: Congenital anonychia is defined as the absence of fingernails and toenails. Anonychia and its milder phenotypic variant, hyponychia, usually occur as a feature of genetic syndromes, in association with significant skeletal and limb anomalies. Isolated nonsyndromic congenital anonychia/hyponychia is a rare entity that usually follows autosomal recessive inheritance with variable expression, even within a given family. The nail phenotypes observed range from no nail field to a nail field of reduced size with an absent or rudimentary nail (summary by previous studies). This form of nail disorder is referred to here as nonsyndromic congenital nail disorder-4 (NDNC4). + +For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (previous studies)." +MONDO_0008954,"Definition: The peroxisome biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 2 (CG2) have mutations in the PEX5 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0011216,"Definition: Juvenile, or type 2, hemochromatosis is an autosomal recessive inborn error of iron metabolism that leads to severe iron loading and organ failure before 30 years of age. The common complications of iron overload, including liver cirrhosis, cardiac disease, endocrine failure, diabetes, arthropathy, and skin pigmentation, are similar to those of adult-onset hereditary hemochromatosis, but hypogonadism and cardiomyopathy are the most common symptoms at presentation. Heart failure and/or major arrhythmias are usually the cause of death in the absence of treatment. Early detection of the disorder is important because iron depletion by phlebotomy can prevent organ damage and all disease manifestations (summary by previous studies). + + Genetic Heterogeneity of Hemochromatosis Type 2 + +Hemochromatosis type 2B (HFE2B; previous studies) is caused by mutation in the hepcidin gene (HAMP; previous studies) on chromosome 19q13." +MONDO_0011466,"Definition: Welander distal myopathy (WDM) is an autosomal dominant disorder characterized by adult onset of distal muscle weakness predominantly affecting the distal long extensors of the hands, with slow progression to involve all small hand muscles and the lower legs. Skeletal muscle biopsy shows myopathic changes and prominent rimmed vacuoles. Rare homozygous patients showed earlier onset, faster progression, and proximal muscle involvement. This disorder is common in Sweden and Finland (summary by previous studies)." +MONDO_0013074,"Definition: Encephalocraniocutaneous lipomatosis (ECCL) is a neurocutaneous disorder characterized by ocular anomalies, skin lesions, and central nervous system (CNS) anomalies (previous studies). + +The malformations in ECCL are patchy and asymmetric. The most characteristic skin anomaly is nevus psiloliparus, a well-demarcated, alopecic fatty tissue nevus on the scalp, seen in 80% of affected individuals. Other dermatologic features include frontotemporal or zygomatic subcutaneous fatty lipomas, nonscarring alopecia, focal dermal hypoplasia or aplasia of the scalp, periocular skin tags, and pigmentary abnormalities following the lines of Blaschko. Choristomas of the eye (epibulbar dermoids or lipodermoids) are also present in 80% of patients, and can be unilateral or bilateral. Characteristic CNS features in ECCL include intracranial and intraspinal lipomas, seen in 61% of patients, and less often cerebral asymmetry, arachnoid cysts, enlarged ventricles, and leptomeningeal angiomatosis. A predisposition to low-grade gliomas has also been observed. Seizures and intellectual disability are common, but one-third of affected individuals have normal intellect. Skeletal manifestations include bone cysts and jaw tumors, such as odontomas, osteomas, and ossifying fibromas (summary by previous studies)." +MONDO_0013176,"Definition: Weill-Marchesani syndrome is a rare connective tissue disorder characterized by microspherophakia, severe myopia, acute and/or chronic glaucoma, and cataract. Other features include brachydactyly and short stature. Patients may also have stiff joints and thickened skin, especially on the hands. Occasionally, cardiac defects or an abnormal heart rhythm is present (summary by previous studies). + +For a discussion of genetic heterogeneity of Weill-Marchesani syndrome, see WMS1 (previous studies)." +Orphanet_363992,"Definition: Weill-Marchesani syndrome is a rare connective tissue disorder characterized by microspherophakia, severe myopia, acute and/or chronic glaucoma, and cataract. Other features include brachydactyly and short stature. Patients may also have stiff joints and thickened skin, especially on the hands. Occasionally, cardiac defects or an abnormal heart rhythm is present (summary by previous studies). + +For a discussion of genetic heterogeneity of Weill-Marchesani syndrome, see WMS1 (previous studies)." +MONDO_0013352,"Definition: Intellectual developmental disorder with language impairment and with or without autistic features is a neurodevelopmental disorder characterized by global developmental delay with moderate to severe speech delay that particularly affects expressive speech. Most patients have articulation defects, but frank verbal dyspraxia is not observed. Common dysmorphic features include broad forehead, downslanting palpebral fissures, short nose with broad tip, relative macrocephaly, frontal hair upsweep, and prominent digit pads. Gross motor skills are also delayed. Some patients have autistic features and/or behavioral problems. All reported cases have occurred de novo (review by previous studies)." +EFO_1001500,"Definition: Intellectual developmental disorder with language impairment and with or without autistic features is a neurodevelopmental disorder characterized by global developmental delay with moderate to severe speech delay that particularly affects expressive speech. Most patients have articulation defects, but frank verbal dyspraxia is not observed. Common dysmorphic features include broad forehead, downslanting palpebral fissures, short nose with broad tip, relative macrocephaly, frontal hair upsweep, and prominent digit pads. Gross motor skills are also delayed. Some patients have autistic features and/or behavioral problems. All reported cases have occurred de novo (review by previous studies)." +MONDO_0013423,"Definition: MASP2 deficiency, classically defined as MASP2 protein level of less than 100 ng/ml, occurs in about 4% of Caucasians and up to 18% of some African populations. Some MASP2-deficient individuals have increased risk of infection or autoimmune disease, but most are asymptomatic. MASP2 plays a role in activation of the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of lectin complement activation pathway defects, see LCAPD1 (previous studies)." +MONDO_0013877,Definition: Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by previous studies). +MONDO_0014886,"Definition: Neurodevelopmental disorder with microcephaly and gray sclerae (NEDMIGS) is a severe autosomal recessive disorder characterized by impaired global development with hypotonia often precluding independent ambulation, profoundly impaired intellectual development with poor or absent language, mild microcephaly, and abnormal visual fixation. Patients also have gray sclerae and may have coarse facial features. Most affected individuals have seizures; some may have brain imaging abnormalities (summary by previous studies and previous studies)." +MONDO_0030983,"Definition: Waardenburg syndrome type 2F (WS2F) is characterized by congenital or neonatal-onset sensorineural hearing loss and altered pigmentation of the iris, hair, and skin. Variable expressivity has been reported, even among patients with the same mutation (previous studies; previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of WS2, as well as a brief description of other clinical variants of Waardenburg syndrome (WS1, previous studies; WS3, previous studies; and WS4, previous studies), see WS2A (previous studies)." +MONDO_0032684,"Definition: IMAGEI is an autosomal recessive disorder characterized by intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency. Patients exhibit distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency (previous studies). + +An autosomal dominant form of the disorder, without immunodeficiency (IMAGE; previous studies), is caused by mutation in the CDKN1C gene (previous studies) on chromosome 11p15." +MONDO_0032930,"Definition: Intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA) is an autosomal recessive neurologic disorder characterized by global developmental delay apparent from infancy, hypotonia, and poor overall growth, sometimes with borderline microcephaly. The phenotype is highly variable: some patients may show ataxia and some may have seizures (summary by previous studies)." +MONDO_0033654,"Definition: Mitochondrial complex IV deficiency nuclear type 19 (MC4DN19) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy or early childhood. Affected individuals show global developmental delay and developmental regression with a loss of acquired motor and language skills. Additional features include motor dysfunction, such as hypokinesia and pyramidal signs. More variable features may include recurrent infections with immunodeficiency and possibly protein-losing enteropathy. Serum lactate is increased; T2-weighted lesions in the medulla oblongata have also been reported. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0044792,"Definition: Congenital melanocytic nevus syndrome is characterized by pigmentary skin defects apparent at birth. Most individuals have 1 or more large or giant lesions greater than 20 cm and up to over 60 cm in diameter, which may cover up to 80% of total body area. These lesions may or may not be hairy. Smaller 'satellite' pigmented lesions numbering in the hundreds may also be present all over the body. Congenital melanocytic nevi (CMN) can be associated with malignant melanoma (see CMM1, previous studies), but the risk appears to be low, ranging from 1 to 2% for all individuals, but rising to 10 to 15% in those with very large nevi (greater than 40 cm). A small subset of patients with CMNS have abnormalities of the central nervous system, known as 'neurocutaneous melanosis' or 'neuromelanosis' (previous studies), which may be symptomatic. Patients with CMNS also tend to have a characteristic facial appearance, including wide or prominent forehead, periorbital fullness, small short nose with narrow nasal bridge, round face, full cheeks, prominent premaxilla, and everted lower lip (summary by previous studies; previous studies). + +Spitz nevi are benign melanocytic melanomas composed of epithelioid or spindle cell melanocytes. They usually present as solitary skin tumors but can occur in multiple patterns, having agminated, dermatomal, and disseminated forms (summary by previous studies). Nevus spilus, also known as speckled lentiginous nevus, is a congenital hyperpigmented patch that progressively evolves, with affected individuals developing dark macules and papules during childhood and adolescence. Over time, nevus spilus may give rise to common lentigines, melanocytic nevi, Spitz nevi, and melanomas (summary by previous studies)." +MONDO_0100250,"Definition: A disorder of sex development (DSD) is a 'congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical.' 46,XX DSD is a disorder of gonadal (ovarian) development, which may be complete or partial (previous studies). Sex-reversed 46,XX individuals can present as phenotypically normal males, as men with genital ambiguities, or as true hermaphrodites (previous studies). + +46,XX male sex reversal is a condition in which a phenotypically normal male has a female genotype. A 'true hermaphrodite' must have both mature ovarian and mature testicular tissue with histologic evidence of follicles and tubules, respectively (previous studies). It is a genetically heterogeneous condition. + + Genetic Heterogeneity of 46,XX Sex Reversal + +Another form of 46,XX sex reversal (SRXX2; previous studies) is caused by duplication or triplication in a regulatory region upstream of the SOX9 gene (previous studies) on chromosome 17q24. SRXX3 (previous studies) is caused by duplications or deletions in the SOX3 (previous studies) regulatory region on chromosome Xq26. SRXX4 (previous studies) is caused by mutation in the NR5A1 gene (previous studies) on chromosome 9q33. SRXX5 (previous studies) is caused by mutation in the NR2F2 gene (previous studies) on chromosome 15q26." +MONDO_0859263,"Definition: Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (DEDISB) is a neurodevelopmental disorder characterized by variably impaired skill acquisition apparent from infancy or early childhood. Affected individuals have predominant language delay with mild fine and gross motor deficits, although they usually are ambulatory by around 3 years of age. Most patients have mild to moderately impaired intellectual development and behavioral abnormalities, including aggression, hyperactivity, and autism spectrum disorder. About half of individuals develop various types of seizures that may be refractory in some. More variable features include dysmorphic facial features, mild ocular anomalies, and nonspecific findings on brain imaging (previous studies)." +Orphanet_860,"Definition: Multiple types of congenital heart defects are associated with mutation in the GDF1 gene, including tetralogy of fallot (TOF), transposition of the great arteries (TGA), double-outlet right ventricle (DORV), total anomalous pulmonary venous return (TAPVR), pulmonary stenosis or atresia, atrioventricular canal, ventricular septal defect (VSD), and hypoplastic left or right ventricle (previous studies). + +For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see previous studies." +MONDO_0007375,"Definition: Epithelial basement membrane corneal dystrophy (EBMD) is a common bilateral epithelial dystrophy characterized mainly by sheet-like areas of basement membrane originating from the basal epithelial cells of the corneal epithelium and extending superficially into the epithelium. Slit lamp examination may reveal dots, maps, grayish epithelial fingerprint lines, blebs, nets, or any combination of these patterns. Histologic analysis shows abnormal redundant basement membrane and intraepithelial lacunae filled with cellular debris. Most patients are asymptomatic before the age of 30 years; some may have recurrent erosions, the frequency of which declines with age, and a loss of vision due to surface irregularity (summary by previous studies)." +Orphanet_98956,"Definition: Epithelial basement membrane corneal dystrophy (EBMD) is a common bilateral epithelial dystrophy characterized mainly by sheet-like areas of basement membrane originating from the basal epithelial cells of the corneal epithelium and extending superficially into the epithelium. Slit lamp examination may reveal dots, maps, grayish epithelial fingerprint lines, blebs, nets, or any combination of these patterns. Histologic analysis shows abnormal redundant basement membrane and intraepithelial lacunae filled with cellular debris. Most patients are asymptomatic before the age of 30 years; some may have recurrent erosions, the frequency of which declines with age, and a loss of vision due to surface irregularity (summary by previous studies)." +MONDO_0008246,Definition: Pigmented paravenous chorioretinal atrophy is a stationary disease of the ocular fundus in which bone corpuscle pigmentation is seen in a paravenous distribution. Patients are usually asymptomatic; diagnosis is based on the characteristic fundus appearance. Most cases have been reported in males (summary by previous studies). +MONDO_0013118,"Definition: Nijmegen breakage syndrome-like disorder (NBSLD) is an autosomal recessive disorder characterized by severe prenatal growth retardation and persistent postnatal growth restriction, congenital microcephaly, borderline to mildly impaired intellectual development, normal sexual development, and radioresistant DNA synthesis with no immunodeficiency, myelodysplasia, or early neurodegeneration (summary by previous studies)." +MONDO_0013836,"Definition: Primary coenzyme Q10 deficiency-6 is an autosomal recessive disorder characterized by onset in infancy of severe progressive nephrotic syndrome resulting in end-stage renal failure and sensorineural deafness. Renal biopsy usually shows focal segmental glomerulosclerosis (FSGS). Some patients may show a favorable response to oral coenzyme Q supplementation (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of focal segmental glomerulosclerosis and nephrotic syndrome, see FSGS1 (previous studies) and NPHS1 (previous studies)." +MONDO_0014244,"Definition: Hereditary sensory and autonomic neuropathy type VII (HSAN7) is characterized by congenital absence of pain sensation resulting in recurrent injuries and self-inflicted wounds. Severe pruritis, intestinal dysmotility, and hyperhydrosis may be present (previous studies; previous studies). + +For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (previous studies)." +MONDO_0014526,"Definition: Polyglucosan body myopathy-2 is an autosomal recessive disorder characterized by proximal muscle weakness of the lower limbs resulting in gait disturbances. Some patients also have involvement of the upper limbs and/or distal muscle weakness. The age at onset is highly variable, and the disorder is slowly progressive. Muscle biopsy shows accumulation of polyglucosan, which contains abnormally long and poorly branched glucosyl chains and is variably resistant to digestion by alpha-amylase (summary by previous studies). + +For a discussion of genetic heterogeneity of PGBM, see PGBM1 (previous studies)." +MONDO_0014888,"Definition: MIRAGE syndrome (MIRAGE) is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection (previous studies)." +MONDO_0014984,"Definition: LICS is an autosomal recessive chromosome breakage syndrome characterized by failure to thrive in infancy, immune deficiency, and fatal progressive pediatric lung disease induced by viral infection. Some patients may have mild dysmorphic features (summary by previous studies)." +MONDO_0032904,"Definition: Meesmann corneal dystrophy-2 (MECD2) is characterized by fragility of the anterior corneal epithelium and the presence of intraepithelial microcysts. Although the disease is generally mild and affected individuals are often asymptomatic, some suffer from recurrent erosions leading to lacrimation, photophobia, and deterioration in visual acuity (summary by previous studies). + +For a discussion of genetic heterogeneity of Meesmann corneal dystrophy, see MECD1 (previous studies)." +MONDO_0859149,"Definition: Hypertriglyceridemia-2 (HYTG2) is characterized by moderately to severely elevated plasma triglyceride levels, increased total cholesterol levels, and low levels of high density lipoprotein (HDL) cholesterol. Reduced penetrance has been observed (previous studies; previous studies)." +Orphanet_329224,"Definition: Schuurs-Hoeijmakers syndrome (SHMS) is characterized by impaired intellectual development, distinct craniofacial features, and variable additional congenital abnormalities (summary by previous studies)." +MONDO_0014006,"Definition: Schuurs-Hoeijmakers syndrome (SHMS) is characterized by impaired intellectual development, distinct craniofacial features, and variable additional congenital abnormalities (summary by previous studies)." +EFO_0021797,"Definition: Hypophosphatasia (HPP) is an inborn error of metabolism characterized clinically by defective bone mineralization and biochemically by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. + +previous studies classified forms of hypophosphatasia according to age of onset: perinatal, infantile, childhood (previous studies), and adult (previous studies). previous studies indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (see previous studies). All of these forms are allelic." +MONDO_0007572,"Definition: Familial erythrocytosis-1 is an autosomal dominant disorder characterized by increased serum red blood cell mass and hemoglobin concentration, hypersensitivity of erythroid progenitors to EPO (previous studies), and low serum levels of EPO. There is no increase in platelets or leukocytes and the disorder does not progress to leukemia (previous studies). + + Genetic Heterogeneity of Familial Erythrocytosis + +See also ECYT2 (previous studies), caused by mutation in the VHL gene (previous studies) on chromosome 3p25; ECYT3 (previous studies), caused by mutation in the EGLN1 gene (previous studies) on chromosome 1q42; ECYT4 (previous studies), caused by mutation in the EPAS1 gene (previous studies) on chromosome 2p21; ECYT5 (previous studies), caused by mutation in the EPO gene (previous studies) on chromosome 7q22; ECYT6 (previous studies), caused by mutation in the HBB gene (previous studies) on chromosome 11q15; ECYT7 (previous studies), caused by mutation in the HBA genes (previous studies; previous studies) on chromosome 16p13; and ECYT8 (previous studies), caused by mutation in the BPGM gene (previous studies) on chromosome 7q33. + +previous studies reviewed causes of familial erythrocytosis and noted that the disorder may result from defects in the regulation of 2,3-diphosphoglycerate (see previous studies and previous studies). + +Erythrocytosis may also be caused by somatic mutation in the JAK2 (previous studies) or the SH2B3 (previous studies) gene on chromosome 9p24 and 12q24, respectively. + +For a review of the genetics of congenital erythrocytosis, see previous studies." +MONDO_0007747,Definition: Isolated hyperchlorhidrosis (HYCHL) is an autosomal recessive condition in which excessive salt wasting in sweat can result in severe infantile hyponatremic dehydration and hyperkalemia (summary by previous studies). +MONDO_0008953,"Definition: Zellweger syndrome is an autosomal recessive systemic disorder characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life (summary by previous studies). + +'Zellweger syndrome' is the prototype of a large group of peroxisomal disorders, which can be classified into 2 main groups: (1) disorders of peroxisome biogenesis and (2) single peroxisomal enzyme deficiencies (see previous studies). The peroxisome biogenesis disorders (PBDs) fall into 4 main phenotypic classes. Three of them, Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), have multiple complementation groups and form a spectrum of overlapping features, with the most severe being the Zellweger syndrome and the least severe infantile Refsum disease. The fourth group, rhizomelic chondrodysplasia punctata (RCDP1; previous studies), is a distinct PBD phenotype (summary by previous studies, previous studies). + +Heimler syndrome, a rare autosomal recessive disorder encompassing sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities, represents a discrete phenotypic entity at the mildest end of the PBD spectrum (previous studies). + + Genetic Heterogeneity of Zellweger Syndrome + +Zellweger syndrome (denoted by the suffix 'A' in the symbol) is a genetically heterogeneous disorder and can be caused by mutation in any one of several genes, known as pexins, involved in peroxisome biogenesis. The pexin (PEX) genes encode proteins essential for the assembly of functional peroxisomes (summary by previous studies). Forms of Zellweger syndrome include PBD1A, caused by mutation in the PEX1 gene on chromosome 7q21; PBD2A (previous studies), caused by mutation in the PEX5 (previous studies) gene on chromosome 12p13; PBD3A (previous studies), caused by mutation in the PEX12 (previous studies) gene on chromosome 17; PBD4A (previous studies), caused by mutation in the PEX6 (previous studies) gene on chromosome 6p21; PBD5A (previous studies), caused by mutation in the PEX2 (previous studies) gene on chromosome 8q21; PBD6A (previous studies), caused by mutation in the PEX10 (previous studies) gene on chromosome 1p36; PBD7A (previous studies), caused by mutation in the PEX26 (previous studies) gene on chromosome 22q11; PBD8A (previous studies), caused by mutation in the PEX16 (previous studies) gene on chromosome 11p12; PBD10A (previous studies), caused by mutation in the PEX3 (previous studies) gene on chromosome 6q23-q24; PBD11A (previous studies), caused by mutation in the PEX13 (previous studies) gene on chromosome 2p15; PBD12A (previous studies), caused by mutation in the PEX19 (previous studies) gene on chromosome 1q22; and PBD13A (previous studies), caused by mutation in the PEX14 gene (previous studies) on chromosome 1p36.2. + +Mutation in the pexin genes also causes the less severe phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD); see PBD1B (previous studies) for a phenotypic description and discussion of genetic heterogeneity of these PBDs. + +Heimler syndrome-1 (HMLR1; previous studies) and -2 (HMLR2; previous studies) are caused by mutation in the PEX1 and PEX6 genes, respectively. + +The rhizomelic chondrodysplasia subtype of PBD (RCDP1, PBD9; previous studies), and a PBD without rhizomelia (PBD9B; previous studies), are caused by mutation in the PEX7 gene (previous studies) on chromosome 6q22-q24. + +In addition to the defects in peroxisome assembly, previous studies noted that peroxisomal disorders include a number of single peroxisomal enzyme deficiencies: X-linked adrenoleukodystrophy (ALD; previous studies), acyl-coenzyme A oxidase deficiency (previous studies), DHAPAT deficiency (previous studies), alkyl-DHAP synthase deficiency (previous studies), glutaric aciduria type III (previous studies), classic Refsum disease (previous studies), hyperoxaluria type I (previous studies), and acatalasia (previous studies). A peroxisomal and mitochondrial fission defect results in a lethal encephalopathy (EMPF; previous studies)." +MONDO_0011303,"Definition: Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in several renal disorders that manifest clinically as proteinuria and progressive decline in renal function. Some patients with FSGS develop the clinical entity called 'nephrotic syndrome' (see NPHS1; previous studies), which includes massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. However, patients with FSGS may have proteinuria in the nephrotic range without other features of the nephrotic syndrome (summary by previous studies; previous studies). + +previous studies provided a detailed review of FSGS, emphasizing that the disorder results from defects of the podocyte. + +Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature. + + Genetic Heterogeneity of Focal Segmental Glomerulosclerosis and Nephrotic Syndrome + +Focal segmental glomerulosclerosis and nephrotic syndrome are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also FSGS2 (previous studies), caused by mutation in the TRPC6 gene (previous studies); FSGS3 (previous studies), associated with variation in the CD2AP gene (previous studies); FSGS4 (previous studies), mapped to chromosome 22q12; FSGS5 (previous studies), caused by mutation in the INF2 gene (previous studies); FSGS6 (previous studies), caused by mutation in the MYO1E gene (previous studies); FSGS7 (previous studies), caused by mutation in the PAX2 gene (previous studies); FSGS8 (previous studies), caused by mutation in the ANLN gene (previous studies); FSGS9 (previous studies), caused by mutation in the CRB2 gene (previous studies); and FSGS10 (previous studies), caused by mutation in the LMX1B gene (previous studies). + +See also NPHS1 (previous studies), caused by mutation in the NPHS1 gene (previous studies); NPHS2 (previous studies), caused by mutation in the podocin gene (previous studies); NPHS3 (previous studies), caused by mutation in the PLCE1 gene (previous studies); NPHS4 (previous studies), caused by mutation in the WT1 gene (previous studies); NPHS5 (previous studies), caused by mutation in the LAMB2 gene (previous studies); NPHS6 (previous studies), caused by mutation in the PTPRO gene (previous studies); NPHS7 (previous studies), caused by mutation in the DGKE gene (previous studies); NPHS8 (previous studies), caused by mutation in the ARHGDIA gene (previous studies); NPHS9 (previous studies), caused by mutation in the COQ8B gene (previous studies); NPHS10 (previous studies), caused by mutation in the EMP2 gene (previous studies); NPHS11 (previous studies), caused by mutation in the NUP107 gene (previous studies); NPHS12 (previous studies), caused by mutation in the NUP93 gene (previous studies); NPHS13 (previous studies), caused by mutation in the NUP205 gene (previous studies); NPHS14 (previous studies), caused by mutation in the SGPL1 gene (previous studies); NPHS15 (previous studies), caused by mutation in the MAGI2 gene (previous studies); NPHS16 (previous studies), caused by mutation in the KANK2 gene (previous studies), NPHS17 (previous studies), caused by mutation in the NUP85 gene (previous studies); NPHS18 (previous studies), caused by mutation in the NUP133 gene (previous studies); NPHS19 (previous studies), caused by mutation in the NUP160 gene (previous studies); NPHS20 (previous studies), caused by mutation in the TBC1D8B gene (previous studies); and NPHS21 (previous studies) caused by mutation in the AVIL gene (previous studies)." +MONDO_0013359,"Definition: This form of hyperaldosteronism is characterized by hypertension secondary to massive adrenal mineralocorticoid production. Like patients with glucocorticoid-remediable aldosteronism (GRA, or FH I; previous studies), patients with FH III present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. However, hypertension and aldosteronism in FH III are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension (previous studies). + + Reviews + +previous studies reviewed the role of KCNJ5 in adrenal pathophysiology and provided an overview of the clinical and biochemical phenotypes resulting from KCNJ5 mutations in patients with sporadic and familial primary aldosteronism. The authors stated that the prevalence of FH III appeared to be 7% of patients with familial aldosteronism and 0.3% of all cases of primary hyperaldosteronism. In addition, they noted that the total prevalence of reported KCNJ5 mutations in aldosterone-producing adrenal adenomas (APAs) was 40%." +MONDO_0013467,"Definition: Individuals with ficolin-3 deficiency have highly variable manifestations and a variable age of symptom onset. Some patients may show increased susceptibility to infection in the perinatal or neonatal period, whereas others may show autoimmune features as adults. Ficolin-3, also known as H-ficolin, can activate the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of lectin complement activation pathway defects, see LCAPD1 (previous studies)." +MONDO_0013615,"Definition: CRSDA is an autosomal recessive disorder characterized by craniosynostosis, maxillary hypoplasia, and dental anomalies, including malocclusion, delayed and ectopic tooth eruption, and/or supernumerary teeth. Some patients also display minor digit anomalies, such as syndactyly and/or clinodactyly (summary by previous studies)." +MONDO_0014863,"Definition: Macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) is an autosomal recessive neurodevelopmental disorder characterized by large head and somatic overgrowth apparent at birth followed by global developmental delay. Affected individuals have characteristic dysmorphic facial features and persistently large head, but increased birth weight normalizes with age. Additional neurologic features, including seizures, hypotonia, and gait ataxia, may also occur. Patients show severe intellectual impairment (summary by previous studies)." +MONDO_0014921,"Definition: Developmental and epileptic encephalopathy-43 (DEE43) is a neurologic disorder characterized by the onset of various types of seizures usually in the first year of life. The age at onset is highly variable, ranging from the neonatal period to about 12 months of age. Later onset may rarely occur. Seizure types include febrile, infantile spasms, focal, tonic-clonic, and myoclonic; they tend to be refractory to treatment. Affected individuals show global developmental delay with mild to moderate intellectual disability, although some may have normal early development before the onset of seizures. EEG shows focal, multifocal, or generalized sharp waves associated with seizures, sometimes with hypsarrhythmia. Additional more variable features include tube feeding, hypotonia, peripheral hypertonia, ataxia, dyskinesia, and behavioral difficulties, including aggression, ADHD, stereotypic, and impulsive behavior (summary by the previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0030866,"Definition: Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) is an autosomal recessive multisystemic disorder characterized by global neurodevelopmental delay, severely impaired intellectual development, poor overall growth, and spasticity of the lower limbs resulting in gait difficulties. Most affected individuals also develop progressive hypertrophic cardiomyopathy in childhood or have cardiac developmental anomalies. Additional more variable features include dysmorphic facies and axonal sensory peripheral neuropathy. Brain imaging tends to show thin corpus callosum and polymicrogyria (summary by previous studies)." +MONDO_0032937,"Definition: Congenital myopathy-9B (CMYP9B) is an autosomal recessive early-onset skeletal muscle disorder mainly affecting proximal muscles. Affected individuals have neonatal hypotonia followed by mildly delayed walking in childhood. Muscle weakness is slowly progressive, resulting in positive Gowers sign and difficulty running or climbing, but most patients remain ambulatory. Some patients develop respiratory involvement requiring ventilatory support, whereas cardiac function is unaffected. Muscle biopsy shows type 1 fiber predominance with disorganized Z-lines and multiminicore myopathy (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +Orphanet_2780,"Definition: Osteopathia striata with cranial sclerosis is an X-linked dominant sclerosing bone dysplasia that presents in females with macrocephaly, cleft palate, mild learning disabilities, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae (previous studies). In males, the disorder is usually associated with fetal or neonatal lethality. Occasional surviving males have, in addition to hyperostosis, cardiac, intestinal, and genitourinary malformations. Osteosclerosis in the cranial and facial bones leads to disfigurement and to disability due to pressure on cranial nerves, e.g., deafness. Osteopathia striata is a frequent feature of focal dermal hypoplasia (FDH; previous studies). + +Although early reports of familial cases of this disorder appeared to suggest autosomal dominant inheritance (see, e.g., previous studies and previous studies), reappraisal of the literature (previous studies; previous studies) and the finding of a molecular basis for the disorder by previous studies confirms that the inheritance pattern is X-linked dominant. Affected males who survive have a more severe phenotype than affected females, and sporadic male cases may result from somatic mosaicism (previous studies)." +MONDO_0010310,"Definition: Osteopathia striata with cranial sclerosis is an X-linked dominant sclerosing bone dysplasia that presents in females with macrocephaly, cleft palate, mild learning disabilities, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae (previous studies). In males, the disorder is usually associated with fetal or neonatal lethality. Occasional surviving males have, in addition to hyperostosis, cardiac, intestinal, and genitourinary malformations. Osteosclerosis in the cranial and facial bones leads to disfigurement and to disability due to pressure on cranial nerves, e.g., deafness. Osteopathia striata is a frequent feature of focal dermal hypoplasia (FDH; previous studies). + +Although early reports of familial cases of this disorder appeared to suggest autosomal dominant inheritance (see, e.g., previous studies and previous studies), reappraisal of the literature (previous studies; previous studies) and the finding of a molecular basis for the disorder by previous studies confirms that the inheritance pattern is X-linked dominant. Affected males who survive have a more severe phenotype than affected females, and sporadic male cases may result from somatic mosaicism (previous studies)." +EFO_0000479,"Definition: Thrombocythemia-3 is an autosomal dominant hematologic disorder characterized by increased platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic episodes, such as cerebrovascular events or myocardial infarction (summary by previous studies). + +For a discussion of genetic heterogeneity of thrombocythemia, see THCYT1 (previous studies)." +EFO_0005532,"Definition: Approximately 40 million people take ACE inhibitors (ACEi) to treat hypertension and cardiovascular disease. A small proportion of white patients who take ACEi (0.1-0.7%) develop angioedema (AEACEI) (previous studies; previous studies), a potentially life-threatening side effect characterized by swelling of the face, lips, tongue, and airway that can lead to suffocation and death if severe. ACEi-associated angioedema is 4 to 5 times more prevalent among African Americans (previous studies; previous studies). Other risk factors include female sex, smoking, immunosuppressant therapy, and seasonal allergies. The pathophysiology of ACEi-associated angioedema is thought to be related to increased circulating bradykinin, which is normally degraded by ACE. During pharmacologic ACE inhibition, bradykinin is primarily degraded by aminopeptidase P (summary by previous studies and previous studies). Aminopeptidase P is encoded by 3 genes: XPNPEP1 (previous studies) on chromosome 10q25, XPNPEP2 (previous studies) on chromosome Xq25, and XPNPEP3 (previous studies) on chromosome 22q13." +MONDO_0010060,"Definition: Mitochondrial DNA depletion syndrome-7 is an autosomal recessive severe neurodegenerative disorder characterized primarily by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy. Although originally classified as a form of spinocerebellar ataxia (see, e.g., SCA1, previous studies) (previous studies), it has been reclassified as a mitochondrial DNA depletion syndrome (previous studies) based on the finding of mtDNA depletion in the brain and liver of affected individuals. + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0012136,"Definition: Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. The neonatal form presents shortly after birth with respiratory distress, seizures, altered mental status, hepatomegaly, cardiomegaly, cardiac arrhythmia, and, in many cases, dysmorphic features, renal dysgenesis, and migration defects. This form is rapidly fatal (summary by previous studies). + +See also the infantile (previous studies) and adult-onset (previous studies) forms of the disorder, which are also caused by mutation in the CPT2 gene." +MONDO_0013659,"Definition: The microcephaly-capillary malformation syndrome is a congenital disorder characterized by severe progressive microcephaly, early-onset refractory epilepsy, profound developmental delay, and multiple small capillary malformations spread diffusely on the body. Additional more variable features include dysmorphic facial features, distal limb abnormalities, and mild heart defects (summary by previous studies and previous studies)." +MONDO_0014922,"Definition: Myofibrillar myopathy-7 (MFM7) is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness that primarily affects the lower limbs and is associated with joint contractures (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (previous studies)." +MONDO_0020735,"Definition: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands. Although some familial cases have been reported, the vast majority of AIMAH cases are sporadic. Patients typically present in the fifth and sixth decades of life, approximately 10 years later than most patients with other causes of Cushing syndrome (previous studies; previous studies). + +Approximately 10 to 15% of adrenal Cushing syndrome is due to primary bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD, see previous studies), which is often a component of the Carney complex (previous studies) and associated with mutations in the PRKAR1A gene (previous studies) on chromosome 17q23-q24. AIMAH is rare, representing less than 1% of endogenous causes of Cushing syndrome (previous studies; previous studies). + +See also ACTH-independent Cushing syndrome (previous studies) due to somatic mutation in the PRKACA gene (previous studies). + +Cushing 'disease' (previous studies) is an ACTH-dependent disorder caused in most cases by pituitary adenomas that secrete excessive ACTH. + + Genetic Heterogeneity of ACTH-Independent Macronodular Adrenal Hyperplasia + +AIMAH2 (previous studies) is caused by germline mutation of 1 allele of the ARMC5 gene (previous studies) coupled with a somatic mutation in the other allele." +MONDO_0020745,"Definition: Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS) is characterized by syncope, cardiac arrest, and/or sudden unexpected death. Polymorphic ventricular tachycardia and ventricular fibrillation have been documented in these patients. Symptoms generally occur with physical activity or emotional stress, but unlike typical catecholaminergic ventricular tachycardia (CPVT), arrhythmias are not reproducible on exercise stress testing or adrenaline challenge (previous studies). + +Mutation in the RYR2 gene also causes catecholaminergic polymorphic ventricular tachycardia-1 (CPVT1; previous studies)." +MONDO_0023655,"Definition: Autosomal recessive primary immunodeficiency-14B (IMD14B) is characterized by onset of recurrent infections in early childhood. Most patients have respiratory infections, but some may develop inflammatory bowel disease or osteomyelitis. Laboratory studies tend to show hypogammaglobulinemia and decreased levels of B cells. Although NK cell and T cell numbers are normal, there may be evidence of impaired immune-mediated cytotoxicity and defective T-cell function (summary by previous studies and previous studies)." +MONDO_0030034,"Definition: Progressive myoclonic epilepsy-11 (EPM11) is a neurodegenerative disorder characterized by onset of developmental regression and various types of seizures around 2 years of age after relatively normal early development. The seizures are usually refractory to treatment and are associated with multiple abnormalities on EEG. During the first and second decades, affected individuals develop additional neurologic signs and symptoms, including pyramidal, extrapyramidal, and cerebellar signs such as spasticity, loss of independent ambulation, myoclonus, tremor, and ataxia. Cognitive impairment is severe, and patients can speak only a few words or are non-verbal (summary by previous studies). + +For discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (previous studies)." +MONDO_0032655,"Definition: Visual impairment and progressive phthisis bulbi is characterized by poor vision at birth, with development of bilateral phthisis by adulthood (previous studies)." +EFO_0000625,"Definition: Epidermal nevi are congenital lesions that affect about 1 in 1,000 people. They appear at or shortly after birth as localized epidermal thickening with hyperpigmentation that frequently follow the lines of Blaschko, suggesting that they result from postzygotic somatic mutation in the skin (previous studies). + +A rare subgroup of epidermal nevi is clinically indistinguishable from other epidermal nevi, but displays histopathologic features typical of epidermolytic hyperkeratosis (see EHK, previous studies), and patients with this type of epidermal nevi sometimes have offspring with generalized EHK (previous studies). + +Woolly hair nevus is a rare condition characterized by the development of woolly hair in a restricted area on the scalp, either present at birth or becoming evident later in life when scalp hair begins to grow. Woolly hair nevus can be an isolated finding or can occur in association with additional ectodermal defects; epidermal nevi have been reported in association with woolly hair nevi (summary by previous studies). + +Nevus sebaceous, a benign congenital skin lesion that preferentially affects the scalp and face, is characterized by hairless, yellow-orange plaques of various size and shape. Histology shows that nevus sebaceous is a hamartoma consisting of epidermal, sebaceous, and apocrine elements. About 24% of nevi develop secondary tumors, some of which may be malignant (summary by previous studies). + +Also see giant pigmented hairy nevus (previous studies) and malignant melanoma (previous studies)." +MONDO_0008093,"Definition: Epidermal nevi are congenital lesions that affect about 1 in 1,000 people. They appear at or shortly after birth as localized epidermal thickening with hyperpigmentation that frequently follow the lines of Blaschko, suggesting that they result from postzygotic somatic mutation in the skin (previous studies). + +A rare subgroup of epidermal nevi is clinically indistinguishable from other epidermal nevi, but displays histopathologic features typical of epidermolytic hyperkeratosis (see EHK, previous studies), and patients with this type of epidermal nevi sometimes have offspring with generalized EHK (previous studies). + +Woolly hair nevus is a rare condition characterized by the development of woolly hair in a restricted area on the scalp, either present at birth or becoming evident later in life when scalp hair begins to grow. Woolly hair nevus can be an isolated finding or can occur in association with additional ectodermal defects; epidermal nevi have been reported in association with woolly hair nevi (summary by previous studies). + +Nevus sebaceous, a benign congenital skin lesion that preferentially affects the scalp and face, is characterized by hairless, yellow-orange plaques of various size and shape. Histology shows that nevus sebaceous is a hamartoma consisting of epidermal, sebaceous, and apocrine elements. About 24% of nevi develop secondary tumors, some of which may be malignant (summary by previous studies). + +Also see giant pigmented hairy nevus (previous studies) and malignant melanoma (previous studies)." +EFO_0010565,"Definition: Congenital myopathy-19 (CMYP19) is an autosomal recessive skeletal muscle disorder characterized by infantile-onset of progressive muscle weakness and atrophy associated with scoliosis, variably impaired walking, and dysmorphic facial features (previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0007363,"Definition: Congenital contractural arachnodactyly is a rare, autosomal dominant connective tissue disorder characterized by contractures, arachnodactyly, scoliosis, and crumpled ears (previous studies). It shares overlapping features with Marfan syndrome (previous studies), which is caused by mutation in the gene encoding fibrillin-1 (FBN1; previous studies)." +MONDO_0007566,"Definition: Individuals with multiple self-healing squamous epithelioma (MSSE) develop multiple invasive skin tumors that undergo spontaneous regression leaving pitted scars. Age at onset is highly variable, ranging from 8 to 62 years. The disorder shows autosomal dominant inheritance, and most affected families have originated from western Scotland (previous studies). MSSE has been considered to be a variety of multiple keratoacanthoma (previous studies; previous studies)." +MONDO_0010191,"Definition: Von Willebrand disease is a bleeding disorder resulting from a defect in platelet aggregation due to defects in the von Willebrand factor protein. Type 3 von Willebrand disease, which is inherited as an autosomal recessive disorder, is associated with a severe quantitative defect or virtual absence of VWF in plasma, a prolonged bleeding time, and more severe bleeding tendencies compared to the other types of VWD. Type 3 accounts for about 1% of patients with VWD. Bleeding usually starts in infancy and can include epistaxis, recurrent mucocutaneous bleeding, bleeding after surgery, and hemarthroses. Since VWF also serves as a carrier protein for coagulation factor VIII (F8; previous studies), affected individuals also have very low levels of plasma F8, resembling hemophilia A (previous studies) (summary by previous studies; reviews by previous studies and previous studies). + +For a general description and a classification of the types of von Willebrand disease, see VWD type 1 (previous studies)." +MONDO_0012237,"Definition: Nemaline myopathy-6 is an autosomal dominant skeletal muscle disorder characterized by childhood onset of slowly progressive proximal muscle weakness, exercise intolerance, and slow movements with stiff muscles. Patients are unable to run or correct themselves from falling over. Histopathologic changes seen on skeletal muscle biopsy include nemaline rods, cores devoid of oxidative enzyme activity, and predominance of hypertrophic type 1 fibers. There is no cardiac or respiratory involvement (summary by previous studies)." +MONDO_0013550,"Definition: Williams distal myopathy is an autosomal dominant slowly progressive muscular disorder characterized by distal muscle weakness and atrophy affecting the upper and lower limbs. Onset occurs around the third to fourth decades of life, and patients remain ambulatory even after long disease duration. Muscle biopsy shows nonspecific changes with no evidence of rods, necrosis, or inflammation (summary by previous studies). + +Mutation in the FLNC gene can also cause myofibrillar myopathy-5 (MFM5; previous studies), which shows a different pattern of muscle involvement and different histologic changes." +MONDO_0014743,"Definition: Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life (summary by previous studies). + +For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see previous studies." +MONDO_0032763,"Definition: Immunodeficiency-62 (IMD62) is an autosomal recessive primary immunologic disorder clinically characterized by onset of recurrent upper and lower respiratory infections late in the first decade of life. Patients may also have increased viral susceptibility to varicella zoster virus (VZV) or herpes simplex virus (HSV). Laboratory studies show impaired antibody response to vaccination, low levels of circulating memory B cells, and almost undetectable antibodies. There is also evidence of secondary T-cell dysfunction. The disorder may result from disturbed actin cytoskeleton dynamics causing impaired lymphocyte migration (summary by previous studies)." +Orphanet_293822,"Definition: Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by previous studies). + +For a discussion of genetic heterogeneity of cutaneous malignant melanoma, see CMM1 (previous studies)." +EFO_0010277,"Definition: O'Donnell-Luria-Rodan syndrome (ODLURO) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, variably delayed intellectual development, and subtle dysmorphic features. Some patients may have autism, seizures, hypotonia, and/or feeding difficulties (summary by previous studies)." +MONDO_0010514,"Definition: IMD50 is an X-linked recessive primary immunodeficiency characterized by the onset of recurrent bacterial or varicella zoster virus (VZV) infections in early childhood. Laboratory studies show profound lymphopenia, hypogammaglobulinemia, poor immune response to vaccine antigens, and fluctuating neutropenia. The disorder does not affect overall patient survival (summary by previous studies)." +MONDO_0010592,"Definition: Focal dermal hypoplasia is inherited as an X-linked dominant with in utero lethality in males. The features include atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, and multiple papillomas of the mucous membranes or skin. In addition, digital anomalies consist of syndactyly, polydactyly, camptodactyly, and absence deformities. Oral anomalies, in addition to lip papillomas, include hypoplastic teeth. Ocular anomalies (coloboma of iris and choroid, strabismus, microphthalmia) have also been present in some cases. Mental retardation occurs in some patients. Striated bones are probably a nearly constant feature (previous studies; previous studies). + +Reports from the International Research Symposium on Goltz Syndrome in 2013 were published in the American Journal of Medical Genetics; the authors and subjects of the reports are listed in an introduction by previous studies." +MONDO_0011335,"Definition: Spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2) is characterized by short stature, distinctive midface retrusion, progressive knee malalignment (genu valgum and/or varum), generalized ligamentous laxity, and mild spinal deformity. Intellectual development is not impaired. Radiographic characteristics include significantly retarded epiphyseal ossification that evolves into epiphyseal dysplasia and precocious osteoarthritis, metaphyseal irregularities and vertical striations, constricted femoral neck, slender metacarpals and metatarsals, and mild thoracolumbar kyphosis or scoliosis with normal or mild platyspondyly (summary by previous studies). + +For a discussion of genetic heterogeneity of SEMD with joint laxity, see SEMDJL1 (previous studies)." +MONDO_0014402,"Definition: Progressive encephalopathy with or without lipodystrophy is a severe neurodegenerative disorder characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade. Patients may show a mild or typical lipodystrophic appearance (summary by previous studies)." +MONDO_0014546,"Definition: Vacuolar myopathy with CASQ1 aggregates is an autosomal dominant mild muscle disorder characterized by adult onset of muscle cramping and weakness as well as increased levels of serum creatine kinase (CK). The disorder is not progressive, and some patients may be asymptomatic (summary by previous studies)." +MONDO_0014566,"Definition: Charcot-Marie-Tooth disease type 2U (CMT2U) is an autosomal dominant neurologic disorder characterized by late-adult onset of distal sensory impairment resulting in distal muscle weakness and atrophy affecting the upper and lower limbs. The disorder is slowly progressive (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +Orphanet_397735,"Definition: Charcot-Marie-Tooth disease type 2U (CMT2U) is an autosomal dominant neurologic disorder characterized by late-adult onset of distal sensory impairment resulting in distal muscle weakness and atrophy affecting the upper and lower limbs. The disorder is slowly progressive (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0030890,"Definition: Pontocerebellar hypoplasia type 17 (PCH17) is a severe autosomal recessive developmental disorder characterized by neonatal hypotonia, severe feeding difficulties, and respiratory insufficiency. Brain imaging shows cerebellar and brainstem hypoplasia. Most affected individuals die in infancy. Those who survive show variable developmental delay. Other features of the disorder include distal hypertonia, poor overall growth, visual defects, autonomic problems, dysmorphic features, and seizures (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (previous studies)." +Orphanet_140927,"Definition: Benign familial neonatal-infantile seizures is an autosomal dominant disorder in which afebrile seizures occur in clusters during the first year of life, without neurologic sequelae (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of benign familial infantile seizures, see BFIS1 (previous studies)." +Orphanet_1997,"Definition: The blepharocheilodontic syndrome is a rare autosomal dominant disorder characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. An additional rare manifestation is imperforate anus (summary by previous studies)." +MONDO_0007765,"Definition: Hyperostosis cranialis interna is a bone disorder characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base. The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII (previous studies)." +MONDO_0010659,"Definition: Intellectual developmental disorder-109 (MRX109) is characterized by mildly to moderately impaired intellectual development associated with learning difficulties, communication deficits, attention problems, hyperactivity, and autistic behavior (summary by previous studies). The disorder, which is associated with a fragile site on chromosome Xq28 (FRAXE), can be caused either by silencing of the FMR2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene (previous studies)." +MONDO_0011376,"Definition: Ventricular fibrillation (VF) is said to cause more than 300,000 sudden deaths each year in the US alone. In approximately 5 to 12% of cases, there are no demonstrable cardiac or noncardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). Patients with a distinct form of VF called Brugada syndrome (see previous studies) present with a characteristic electrocardiographic pattern, with right bundle branch block (RBBB) and elevation of ST segment in leads V1 to V3 and may account for 40 to 60% of all IVF cases (review by previous studies). Mutations in the SCN5A gene were identified in patients with Brugada syndrome-1 (previous studies). + + Genetic Heterogeneity of Paroxysmal Familial Ventricular Fibrillation + +Another familial form of VF (VF2; previous studies) is caused by mutation in the DPP6 gene (previous studies) on chromosome 7q26." +Orphanet_228140,"Definition: Ventricular fibrillation (VF) is said to cause more than 300,000 sudden deaths each year in the US alone. In approximately 5 to 12% of cases, there are no demonstrable cardiac or noncardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). Patients with a distinct form of VF called Brugada syndrome (see previous studies) present with a characteristic electrocardiographic pattern, with right bundle branch block (RBBB) and elevation of ST segment in leads V1 to V3 and may account for 40 to 60% of all IVF cases (review by previous studies). Mutations in the SCN5A gene were identified in patients with Brugada syndrome-1 (previous studies). + + Genetic Heterogeneity of Paroxysmal Familial Ventricular Fibrillation + +Another familial form of VF (VF2; previous studies) is caused by mutation in the DPP6 gene (previous studies) on chromosome 7q26." +MONDO_0011803,"Definition: Hereditary spastic paraplegia (SPG) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. There is considerable genetic heterogeneity. Inheritance is most often autosomal dominant (see previous studies), but X-linked (see previous studies) and autosomal recessive (see previous studies) forms occur. + +SPG7 shows phenotypic variability between families. Some cases are pure, whereas other are complicated with additional neurologic features (previous studies)." +MONDO_0012222,"Definition: Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder with atypical features. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy (previous studies); type II, also known as Kanzaki disease, is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder (see previous studies) with mild to moderate neurologic manifestations (previous studies)." +MONDO_0013111,"Definition: Acute infantile liver failure resulting from TRMU mutation is a transient disorder of hepatic function. In addition to elevated liver enzymes, jaundice, vomiting, coagulopathy, and hyperbilirubinemia, the presence of increased serum lactate is consistent with a defect in mitochondrial respiratory function. With supportive care, patients who survive the initial acute episode can recover and show normal development (previous studies). + +See also transient infantile mitochondrial myopathy (MMIT; previous studies), which is a similar disorder. + +A more severe, permanent disorder with some overlapping features is associated with mitochondrial DNA depletion (previous studies). + +See ILFS1 (previous studies) for information on syndromic infantile liver failure." +MONDO_0014289,Definition: Autosomal recessive intellectual developmental disorder-41 (MRT41) is characterized by macrocephaly and global developmental delay. Some patients have seizures (previous studies). +MONDO_0014947,"Definition: Developmental and epileptic encephalopathy-46 (DEE46) is a neurologic disorder characterized by the onset of intractable seizures in the first months or years of life. Affected individuals show global developmental delay with failure to thrive, hypotonia, and hyperreflexia with variably impaired intellectual development. More severely affected individuals have almost no developmental progress and are unable to sit or speak, whereas others may achieve some milestones (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0024770,"Definition: X-linked familial Behcet-like autoinflammatory syndrome-2 (AIFBL2) is an X-linked recessive disorder characterized by the onset of inflammatory symptoms in the first decade of life in male patients. Affected males often present with oral mucosal ulceration and skin inflammation. More variable features may include gastrointestinal ulceration, arthritis, recurrent fevers, and iron deficiency anemia. Laboratory studies are consistent with immune dysregulation manifest as increased inflammatory markers and variable immune cell abnormalities, such as decreased NK cells and low memory B cells. One patient presented with recurrent infections and immunodeficiency in addition to autoinflammation. The disorder results from a defect in ELF4, which normally acts as a negative regulator of inflammatory disease. Symptoms may respond to blockade of IL1 (see previous studies) or TNFA (previous studies) (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of AIFBL, see AIFBL1 (previous studies)." +MONDO_0030835,"Definition: Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN) is a complex neurologic disorder characterized by impaired motor and intellectual development, hypotonia, poor overall growth, usually with short stature and microcephaly, and subtly dysmorphic facial features. Affected individuals have distal muscle weakness and muscle atrophy resulting in delayed acquisition of motor skills and persistent gait abnormalities. Although many patients have clinical and/or electrophysiologic features consistent with an axonal sensorimotor peripheral neuropathy, such as hyporeflexia, impaired sensation, foot drop, and pes cavus, the signs and severity are highly variable. Additional features may include hearing loss, pigmentary retinopathy, and abnormalities on brain imaging, including cerebral or cerebellar atrophy, hypomyelination, and lesions in the basal ganglia or brainstem. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN syndrome), which highlights the expanding clinical spectrum associated with MORC2 mutations and may render classification of patients into one or the other disorder challenging (summary by previous studies)." +MONDO_0030895,"Definition: Nephrotic syndrome type 22 (NPHS22) is an autosomal recessive renal disease characterized by onset of progressive kidney dysfunction in infancy. Affected individuals usually present with edema associated with hypoproteinemia, proteinuria, and microscopic hematuria. Renal biopsy shows effacement of the podocyte foot processes, glomerulosclerosis, and thickening of the glomerular basement membrane. The disease is steroid-resistant and progressive, resulting in end-stage renal disease usually necessitating kidney transplant (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (previous studies)." +MONDO_0032931,"Definition: Neonatal lethal pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome (PHRINL) is an autosomal recessive multisystem disorder with onset in utero and death in the neonatal period. Rare patients may survive a few months. Affected infants show respiratory insufficiency and almost no spontaneous movement at birth, usually requiring mechanical ventilation and admission to the neonatal intensive care unit. Additional features include corneal clouding, seizures, dysmorphic facies, contractures, and progressive pontocerebellar hypoplasia with simplified gyral pattern and white matter abnormalities. Some patients may have cardiac anomalies or cardiac hypertrophy. Laboratory studies show evidence consistent with mitochondrial defects and/or abnormal cholesterol or lipid metabolism. Depending on the type of mutation or deletion, some patients may have a less severe disorder (see GENOTYPE/PHENOTYPE CORRELATIONS) (summary by previous studies)." +MONDO_0033615,"Definition: Coenzyme Q10 deficiency-9 (COQ10D9) is an autosomal recessive disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in the first decade of life. Some patients may have additional neurologic signs and symptoms, including intellectual disability and seizures. Treatment with CoQ10 may offer clinical benefit (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (previous studies)." +MONDO_0036193,"Definition: Parkinsonism with polyneuropathy (PKNPY) is an autosomal dominant disorder characterized by asymmetrical tremor-dependent parkinsonism. The age of onset ranges from the late forties to mid-sixties, and patients have a good response to levodopa (summary by previous studies)." +MONDO_0800132,"Definition: Autoinflammatory-pancytopenia syndrome (AIPCS) is an autosomal recessive disorder characterized by severe anemia and thrombocytopenia apparent from early infancy, hepatosplenomegaly, and recurrent fevers associated with a hyperinflammatory state. Additional systemic features may include chronic diarrhea, proteinuria with renal disease, liver fibrosis with elevated liver enzymes, deforming arthropathy, and vasculitic skin lesions. Some patients may have motor delay or learning difficulties associated with subcortical white matter lesions on brain imaging. Laboratory studies show increased levels of proinflammatory cytokines and increased expression of interferon-stimulated genes (ISGs), consistent with a type I interferonopathy (previous studies). Treatment with a JAK (see previous studies) inhibitor (baricitinib) may be effective (previous studies)." +MONDO_0800167,"Definition: Knobloch syndrome-1 (KNO1) is an autosomal recessive developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia (summary by previous studies). + + Genetic Heterogeneity of Knobloch Syndrome + +KNO2 (previous studies) is caused by mutation in the PAK2 gene (previous studies) on chromosome 3q29." +MONDO_0859139,"Definition: Blepharophimosis-impaired intellectual development syndrome (BIS) is a congenital disorder characterized by a distinct facial appearance with blepharophimosis and global development delay. Affected individuals have delayed motor skills, sometimes with inability to walk, and impaired intellectual development with poor or absent speech; some patients show behavioral abnormalities. There are recognizable facial features, including epicanthal folds, sparse eyebrows, broad nasal bridge, short nose with downturned tip, and open mouth with thin upper lip. Other more variable features include distal skeletal anomalies, feeding difficulties with poor growth, respiratory infections, and hypotonia with peripheral spasticity (summary by previous studies)." +Orphanet_75840,"Definition: Ullrich congenital muscular dystrophy-2 (UCMD2) is a severe autosomal recessive disorder characterized by joint hypermobility, proximal contractures, and muscle weakness precluding ambulation (summary by previous studies). + +For a discussion of genetic heterogeneity of Ullrich congenital muscular dystrophy, see UCMD1 (previous studies)." +MONDO_0014654,"Definition: Ullrich congenital muscular dystrophy-2 (UCMD2) is a severe autosomal recessive disorder characterized by joint hypermobility, proximal contractures, and muscle weakness precluding ambulation (summary by previous studies). + +For a discussion of genetic heterogeneity of Ullrich congenital muscular dystrophy, see UCMD1 (previous studies)." +EFO_0009016,"Definition: Ataxia-oculomotor apraxia-4 (AOA4) is an autosomal recessive neurologic disorder characterized by onset of dystonia and ataxia in the first decade. Additional features include oculomotor apraxia and peripheral neuropathy. Some patients may show cognitive impairment. The disorder is progressive, and most patients become wheelchair-bound in the second or third decade (summary by previous studies). + +For a discussion of genetic heterogeneity of ataxia-oculomotor apraxia, see AOA1 (previous studies)." +MONDO_0008278,"Definition: The JPHT syndrome includes the features of both the juvenile polyposis syndrome (JPS; previous studies) and hereditary hemorrhagic telangiectasia (HHT; previous studies) in a single individual. JPS is characterized by hamartomatous polyps occurring throughout the gastrointestinal tract, resulting in an increased risk of gastrointestinal cancer, and HHT is a vascular dysplasia characterized by telangiectases of the skin, and oral and nasal mucosa, epistaxis, and arteriovenous malformations (AVMs) of the lungs, liver, brain, and gastrointestinal tract (summary by previous studies)." +MONDO_0009203,"Definition: The focal dermal dysplasias (FFDDs) are a group of related developmental defects characterized by bitemporal or preauricular skin lesions resembling aplasia cutis congenita. FFFD3 is an autosomal recessive disorder characterized by bitemporal skin lesions with variable facial findings, including thin and puckered periorbital skin, distichiasis and/or absent eyelashes, upslanting palpebral fissures, a flat nasal bridge with a broad nasal tip, large lips, and redundant facial skin (summary by previous studies). + +FFDD2 (previous studies) is characterized by the same facial features as FFDD3, but the inheritance is autosomal dominant. + +For a classification and a discussion of genetic heterogeneity of FFDD, see FFDD1 (previous studies)." +MONDO_0013362,"Definition: Beaulieu-Boycott-Innes syndrome (BBIS) is an autosomal recessive neurodevelopmental disorder characterized by delayed development, moderate to severe intellectual disability, and dysmorphic facial features. Other developmental anomalies, such as cardiac and renal defects, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis, may also be present (summary by previous studies and previous studies)." +MONDO_0013692,"Definition: Tumor predisposition syndrome-1 (TPDS1) is inherited in an autosomal dominant pattern. Individuals carrying heterozygous BAP1 mutations are at high-risk for the development of a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma (previous studies), cutaneous melanoma (previous studies), malignant mesothelioma on exposure to asbestos (previous studies), and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma (summary by previous studies, previous studies, previous studies, and previous studies). + + Genetic Heterogeneity of Tumor Predisposition Syndrome + +See also TPDS2 (previous studies), caused by mutation in the MBD4 gene (previous studies) on chromosome 3q21." +MONDO_0013936,"Definition: Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see previous studies. + +Individuals with PBDs of complementation group 7 (CG7, equivalent to CGB) have mutations in the PEX10 gene. For information on the history of PBD complementation groups, see previous studies." +MONDO_0030332,"Definition: Primary ciliary dyskinesia-46 (CILD46) is characterized by recurrent sinus and respiratory infections, with reduced pulmonary function and uncoordinated beating of respiratory cilia. No situs abnormalities have been observed (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (previous studies)." +MONDO_0044738,"Definition: Gabriele-de Vries syndrome is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variable cognitive impairment, often with behavioral problems, feeding problems, some movement abnormalities, and dysmorphic facial features. Affected individuals may also have a variety of congenital abnormalities (summary by previous studies)." +Orphanet_158681,"Definition: Epidermolysis bullosa simplex 2E with migratory circinate erythema (EBS2E) is a skin disorder in which multiple vesicles are present from birth onward and acquire over time a typical migratory circinate pattern on an erythematous background. Postinflammatory hyperpigmentation develops gradually and may have a mottled pattern (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0012258,"Definition: Epidermolysis bullosa simplex 2E with migratory circinate erythema (EBS2E) is a skin disorder in which multiple vesicles are present from birth onward and acquire over time a typical migratory circinate pattern on an erythematous background. Postinflammatory hyperpigmentation develops gradually and may have a mottled pattern (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +Orphanet_352479,"Definition: Autosomal recessive limb-girdle muscular dystrophy-21 (LGMDR21) is characterized by progressive limb-girdle weakness with age of onset ranging from congenital to adult. Muscle imaging shows a specific and selective pattern of fatty muscle degeneration (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive LGMD, see LGMDR1 (previous studies)." +Orphanet_85448,"Definition: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported (previous studies)." +MONDO_0007097,"Definition: The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including lattice corneal dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported (previous studies)." +EFO_0010264,"Definition: SMALED2B is a severe neuromuscular disorder with onset in utero. Affected individuals show decreased fetal movements and are usually born with congenital contractures consistent with arthrogryposis multiplex congenita (AMC). After birth, they have severe hypotonia and muscle atrophy as well as respiratory insufficiency due to muscle weakness. Some patients may have dysmorphic facial features and/or abnormalities on brain imaging. Many patients die in early childhood (summary by previous studies) + +For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (previous studies)." +MONDO_0007272,"Definition: In hypercarotenemia and vitamin A deficiency (HCVAD), serum beta-carotene levels are very high, but serum vitamin A levels are low to low-normal. Yellow or orange discoloration of skin may be present (summary by previous studies). + +See also previous studies for possible autosomal recessive inheritance." +MONDO_0007621,"Definition: Floating-Harbor syndrome (FLHS) is a rare genetic disorder characterized by proportionate short stature, delayed bone age, delayed speech development, and typical facial features. The face is triangular with deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, and thin lips (previous studies). + +Rubinstein-Taybi syndrome (see previous studies), which shows phenotypic overlap with Floating-Harbor syndrome, is caused by mutation in the CREBBP gene (previous studies), for which SRCAP is a coactivator." +MONDO_0008995,"Definition: Yunis-Varon syndrome is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by previous studies)." +MONDO_0009354,"Definition: Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase (MTR; previous studies). Clinical features are somewhat variable, but include delayed psychomotor development, hypotonia, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE and CblG (previous studies) (previous studies). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by previous studies). + +CblG is caused by mutation in the MTR gene." +MONDO_0011939,"Definition: Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (previous studies). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (previous studies). previous studies also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family. + + Classification of the Enchondromatoses + +In their classification of the enchondromatoses, previous studies called Ollier disease and Maffucci syndrome types I and II enchondromatosis, respectively; metachondromatosis (previous studies), type III; and spondyloenchondrodysplasia (SPENCD), also called spondyloenchondromatosis, type IV; enchondromatosis with irregular vertebral lesions, type V; and generalized enchondromatosis, type VI. previous studies added 3 tentative categories to the 6 in the classification of previous studies. + +previous studies suggested a new classification of enchondromatosis (multiple enchondromas)." +MONDO_0012221,"Definition: Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy; type II, also known as Kanzaki disease (previous studies), is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder with mild to moderate neurologic manifestations (previous studies)." +MONDO_0014952,"Definition: Neurodevelopmental disorder with hypotonia and impaired expressive language and with or without seizures (NEDHELS) is an autosomal recessive disorder characterized by hypotonia, poor feeding, and global developmental delay apparent from infancy. Most patients have poor overall growth, poor eye contact, sleep disturbances, and severely impaired expressive language. Affected individuals also tend to have behavioral problems, microcephaly, and variable dysmorphic features; many develop seizures. Brain imaging may show enlarged ventricles, thin corpus callosum and brainstem, and white matter abnormalities. The phenotype is variable (summary by previous studies)." +MONDO_0030060,"Definition: Neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB) is characterized by impaired intellectual development or developmental delay, behavioral abnormalities including autistic features, and language impairment. Other features include seizures and developmental regression (previous studies)." +MONDO_0033565,"Definition: Oocyte/zygote/embryo maturation arrest-9 (OZEMA9) is characterized by female infertility due to oocyte meiotic arrest at metaphase I in most patients. Abnormal zygotic cleavage has also been observed (previous studies). + +For a discussion of genetic heterogeneity of OZEMA, see previous studies." +EFO_0004255,"Definition: NPHS17, a disease of the renal glomerular filter, is characterized by proteinuria, edema, and hypoalbuminemia. It does not respond to drug treatment and inevitably progresses to end-stage renal disease, thus requiring dialysis or renal transplantation for survival. Renal histology shows focal segmental glomerulosclerosis (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (previous studies)." +EFO_0009021,"Definition: Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by previous studies). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by previous studies). + + Genetic Heterogeneity of Bardet-Biedl Syndrome + +BBS1 is caused by mutation in a gene on chromosome 11q13 (previous studies); BBS2 (previous studies), by mutation in a gene on 16q13 (previous studies); BBS3 (previous studies), by mutation in the ARL6 gene on 3q11 (previous studies); BBS4 (previous studies), by mutation in a gene on 15q22 (previous studies); BBS5 (previous studies), by mutation in a gene on 2q31 (previous studies); BBS6 (previous studies), by mutation in the MKKS gene on 20p12 (previous studies); BBS7 (previous studies), by mutation in a gene on 4q27 (previous studies); BBS8 (previous studies), by mutation in the TTC8 gene on 14q32 (previous studies); BBS9 (previous studies), by mutation in a gene on 7p14 (previous studies); BBS10 (previous studies), by mutation in a gene on 12q21 (previous studies); BBS11 (previous studies), by mutation in the TRIM32 gene on 9q33 (previous studies); BBS12 (previous studies), by mutation in a gene on 4q27 (previous studies); BBS13 (previous studies), by mutation in the MKS1 gene (previous studies) on 17q23; BBS14 (previous studies), by mutation in the CEP290 gene (previous studies) on 12q21, BBS15 (previous studies), by mutation in the WDPCP gene (previous studies) on 2p15; BBS16 (previous studies), by mutation in the SDCCAG8 gene (previous studies) on 1q43; BBS17 (previous studies), by mutation in the LZTFL1 gene (previous studies) on 3p21; BBS18 (previous studies), by mutation in the BBIP1 gene (previous studies) on 10q25; BBS19 (previous studies), by mutation in the IFT27 gene (previous studies) on 22q12; BBS20 (previous studies), by mutation in the IFT172 gene (previous studies) on 9p21; BBS21 (previous studies), by mutation in the CFAP418 gene (previous studies) on 8q22; and BBS22 (previous studies), by mutation in the IFT74 gene (previous studies) on 9p21. + +The CCDC28B gene (previous studies) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; previous studies), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. + +Although BBS had originally been thought to be a recessive disorder, previous studies demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While previous studies called this 'triallelic inheritance,' previous studies suggested the term 'recessive inheritance with a modifier of penetrance.' previous studies found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, previous studies found heterozygosity in a mutation of the BBS3 gene (previous studies) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (previous studies). + +Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (previous studies), caused by TTC8 mutation, and RP55 (previous studies), caused by ARL6 mutation." +EFO_0010663,"Definition: Neurooculocardiogenitourinary syndrome (NOCGUS) is a multisystem disorder characterized by poor growth and anomalies of the ocular, craniofacial, neurologic, cardiovascular, genitourinary, skeletal, and gastrointestinal systems. Lethality before 2 years of age has been observed (previous studies)." +MONDO_0010401,"Definition: X-linked myopathy with postural muscle atrophy (XMPMA) is a progressive muscular dystrophy with onset in adulthood. Affected individuals develop a proximal myopathy characterized by specific atrophy of postural muscles, limited neck flexion, bent spine, contractures of the Achilles tendon, respiratory problems, and cardiomyopathy. Patients may show muscle hypertrophy in the early stages of the disorder (previous studies). + +The clinical features of Emery-Dreifuss muscular dystrophy (see EDMD1; previous studies) classically include the triad of muscle weakness, joint contractures, and cardiac involvement, thus showing clinical overlap with XMPMA (previous studies)." +MONDO_0011816,"Definition: Lathosterolosis (LATHOS) is an autosomal recessive disorder characterized by a recognizable pattern of multiple congenital anomalies involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage. It is caused by a defect of cholesterol biosynthesis due to sterol C5-desaturase deficiency (summary by previous studies)." +MONDO_0011915,"Definition: Patients with MVP2 have nonsyndromic MVP of variable severity inherited as an autosomal dominant trait. + +For a general phenotypic description and discussion of genetic heterogeneity of mitral valve prolapse, see MVP1 (previous studies)." +MONDO_0012699,"Definition: MDDGC4 is an autosomal recessive muscular dystrophy with onset in infancy or early childhood. Cognition and brain structure are usually normal (previous studies). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies)." +MONDO_0032594,"Definition: Intellectual developmental disorder and retinitis pigmentosa (IDDRP) is characterized by mild to moderate intellectual disability and typical features of RP. Patients experience reduced night vision, constriction of visual fields, and reduced visual acuity; optic disc pallor, attenuated retinal blood vessels, and bone-spicule pigmentation are seen on funduscopy. Attention-deficit/hyperactivity disorder is observed in some patients (previous studies)." +MONDO_0060641,"Definition: NEDSGA is an autosomal dominant disorder characterized by global developmental delay apparent from infancy or early childhood, resulting in variable intellectual disability that can range from profound with absent speech to mild with an ability to attend special schools. Most affected individuals show irritability, stiffness, and hypertonia early in life, which progresses to spasticity and impaired gait later. Some patients may develop seizures of variable severity early in life (summary by previous studies)." +MONDO_0100219,"Definition: Autosomal dominant growth hormone insensitivity syndrome with immune dysregulation-2 (GHISID2) is a congenital disorder characterized by short stature due to insensitivity to growth hormone (GH1; previous studies). Affected individuals usually have delayed bone age, delayed puberty, and decreased serum IGF1 (previous studies). Some patients may have features of mild immune dysregulation, such as eczema, increased serum IgE, asthma, or celiac disease (summary by previous studies)." +MONDO_0007057,"Definition: Hajdu-Cheney syndrome (HJCYS) is a rare autosomal dominant skeletal disorder characterized by short stature, coarse and dysmorphic facies, bowing of the long bones, and vertebral anomalies. Facial features include hypertelorism, bushy eyebrows, micrognathia, small mouth with dental anomalies, low-set ears, and short neck. There is progressive focal bone destruction, including acroosteolysis and generalized osteoporosis. Additional and variable features include hearing loss, renal cysts, and cardiovascular anomalies (summary by previous studies; previous studies; previous studies)." +MONDO_0008783,"Definition: Tangier disease (TGD) is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (previous studies)." +MONDO_0009064,"Definition: Ocular nonnephropathic cystinosis, a variant of the classic nephropathic type of cystinosis (previous studies), is an autosomal recessive lysosomal storage disorder characterized by photophobia due to corneal cystine crystals but absence of renal disease (summary by previous studies)." +MONDO_0009667,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (previous studies), collectively known as 'dystroglycanopathies' (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0009877,"Definition: Laron syndrome is an autosomal recessive disorder characterized by marked short stature that results from failure to generate insulin-like growth factor I (IGF1; previous studies) in response to growth hormone (GH; previous studies). GH levels are normal or increased. The disorder is caused by dysfunction of the growth hormone receptor. + +A Laron syndrome-like phenotype associated with immunodeficiency (previous studies) is caused by a postreceptor defect, i.e., mutation in the STAT5B gene (previous studies). + +Patients with mutations in the GHR gene that cause only partial insensitivity to growth hormone have a form of short stature (previous studies)." +MONDO_0010501,"Definition: X-linked syndromic intellectual developmental disorder-34 (MRXS34) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum (summary by previous studies)." +MONDO_0012565,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0013000,Definition: ALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (previous studies). +MONDO_0020820,"Definition: Distal arthrogryposis is a clinically and genetically heterogeneous disorder characterized by clenched fist, overlapping fingers, camptodactyly, ulnar deviation, and positional foot deformities from birth. It is a disorder of primary limb malformation without primary neurologic or muscle disease. DA1 is not associated with other abnormalities, whereas other forms of DA have additional phenotypic features (previous studies). The congenital contractures in DA2B (Sheldon-Hall syndrome, SHS) are similar to those observed in DA1, but affected individuals tend to have more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth. DA2B is thought to be the most common of the distal arthrogryposis disorders (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (previous studies)." +MONDO_0060554,"Definition: VCRL1 is an autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal defects, and distal mild limb defects. Additional features are variable (summary by previous studies). + + Genetic Heterogeneity of Vertebral, Cardiac, Renal, and Limb Defects Syndrome + +See also VCRL2 (previous studies), caused by mutation in the KYNU gene (previous studies) on chromosome 2q22, and VCRL3 (previous studies), caused by mutation in the NADSYN1 gene (previous studies) on chromosome 11q13." +MONDO_0100316,"Definition: Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (previous studies). + +A form of torsade de pointes in which the first beat has a short coupling interval has been described (previous studies). + + Genetic Heterogeneity of Long QT Syndrome + +Other forms of LQT syndrome (LQTS) are LQT2 (previous studies), caused by mutation in the KCNH2 gene (previous studies); LQT3 (previous studies), caused by mutation in the SCN5A gene (previous studies); LQT4 (see previous studies), caused by mutation in the ANK2 gene (previous studies); LQT5 (previous studies), caused by mutation in the KCNE1 gene (previous studies); LQT6 (previous studies), caused by mutation in the KCNE2 gene (previous studies); LQT7 (Andersen cardiodysrhythmic periodic paralysis, previous studies), caused by mutation in the KCNJ2 gene (previous studies); LQT8 (previous studies), caused by mutation in the CACNA1C gene (previous studies); LQT9 (previous studies), caused by mutation in the CAV3 gene (previous studies); LQT10 (previous studies), caused by mutation in the SCN4B gene (previous studies); LQT11 (previous studies), caused by mutation in the AKAP9 gene (previous studies); LQT12 (previous studies), caused by mutation in the SNTA1 gene (previous studies); LQT13 (previous studies), caused by mutation in the KCNJ5 gene (previous studies); LQT14 (previous studies), caused by mutation in the CALM1 gene (previous studies), LQT15 (previous studies), caused by mutation in the CALM2 gene (previous studies); and LQT16 (previous studies), caused by mutation in the CALM3 gene (previous studies). + +Approximately 10% of LQTS patients in whom a mutation is identified in one ion channel gene carry a second mutation in the same gene or in another ion channel gene (previous studies). + + Reviews + +previous studies reviewed the role of Ca(2+) cycling in cardiac repolarization and in the pathogenesis of long QT-associated cardiac arrhythmias." +EFO_0004253,"Definition: previous studies reviewed aspects of renal stone disease. Nephrolithiasis and urolithiasis remain major public health problems of largely unknown cause. While disorders such as cystinuria (previous studies) and primary hyperoxaluria (see previous studies) that have nephrolithiasis as a major feature have advanced understanding of the metabolic and physiologic processes of stone formation in general, they have not addressed the etiology of calcium oxalate stone formation, responsible for approximately 75% of urolithiasis cases in humans. Men are affected twice as often as women, but children show no such gender bias. The recurrence rate is also high. In populations of European ancestry, 5 to 10% of adults experience the painful precipitation of calcium oxalate in their urinary tracts. + +previous studies noted that between 35 and 65% of hypercalciuric stone formers and up to 70% of subjects with hypercalciuria have relatives with nephrolithiasis, and twin studies have estimated the heritability of kidney stones to be 56%. + + Genetic Heterogeneity of Calcium Oxalate Nephrolithiasis + +See also CAON2 (previous studies), caused by mutation in the OXGR1 gene (previous studies) on chromosome 13q32." +MONDO_0007168,"Definition: Atelosteogenesis type III (AO3) is an autosomal dominant skeletal dysplasia with vertebral abnormalities, disharmonious skeletal maturation, poorly modeled long bones, and joint dislocations. Craniofacial abnormalities, vertebral fusions, and carpal, tarsal, and phalangeal abnormalities are present (previous studies). There is considerable phenotypic overlap with AO1 (previous studies), but patients with AO3 have less delay in normal ossification, with better ossification of vertebrae, fibulae, metacarpals, and phalanges. Infants with AO3 often have respiratory and feeding difficulties, and respiratory complications and cervical spine instability are the apparent causes of death in reported cases (summary by previous studies)." +MONDO_0008150,"Definition: Osteoglophonic dysplasia (OGD) is characterized by rhizomelic dwarfism, nonossifying bone lesions, craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge (summary by previous studies)." +MONDO_0008795,"Definition: Gillespie syndrome (GLSP) is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (summary by previous studies and previous studies)." +Orphanet_1065,"Definition: Gillespie syndrome (GLSP) is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (summary by previous studies and previous studies)." +MONDO_0008860,Definition: Beta-aminoisobutyric acid (BAIB) is a product of pyrimidine catabolism. Excretion of BAIB in urine is a benign 'metabolic polymorphism' present in many human populations (previous studies). +MONDO_0011945,Definition: Perinatal lethal Gaucher disease is considered to be a distinct form of type II Gaucher disease (previous studies) (previous studies). +MONDO_0014744,"Definition: Autosomal recessive spinocerebellar ataxia-21 is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur (summary by previous studies). + +The phenotype is highly variable: all patients appear to have episodic and severe liver dysfunction in early childhood that tends to resolve with age. Affected individuals also show mild developmental or language delay and/or later onset of variable neurologic features, such as motor dysfunction (summary by previous studies)." +MONDO_0016369,"Definition: Rothmund-Thomson syndrome type 2 (RTS2) is an autosomal recessive disorder characterized by poikiloderma, congenital bone defects, and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose, and congenital radial ray defects) and/or subtle (visible only by radiographic analysis) (summary by previous studies). + + Genetic Heterogeneity of Rothmund-Thomson Syndrome + +Rothmund-Thomson syndrome type 1 (previous studies) is caused by mutation in the ANAPC1 gene (previous studies) on chromosome 2q13." +MONDO_0030733,"Definition: Spermatogenic failure-70 (SPGF70) is characterized by male infertility due to azoospermia or sperm immotility and necrozoospermia (previous studies). Hypospermatogenesis and meiotic arrest have also been observed (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0032798,"Definition: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity (previous studies). In addition, patients exhibit mild facial dysmorphism (previous studies)." +MONDO_0100220,"Definition: Rajab interstitial lung disease with brain calcifications-2 (RILDBC2) is an autosomal recessive disorder characterized by growth delay, interstitial lung disease, liver disease, and abnormal brain MRI findings, including brain calcifications and periventricular cysts (previous studies). + +For a discussion of genetic heterogeneity of RILDBC, see RILDBC1 (previous studies)." +MONDO_0008234,"Definition: Multiple endocrine neoplasia type IIA is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas. MEN2B (previous studies), characterized by MTC with or without pheochromocytoma and with characteristic clinical abnormalities such as ganglioneuromas of the lips, tongue and colon, but without hyperparathyroidism, is also caused by mutation in the RET gene (summary by previous studies). + +For a discussion of genetic heterogeneity of multiple endocrine neoplasia, see MEN1 (previous studies)." +MONDO_0009212,"Definition: Factor X deficiency is a rare autosomal recessive bleeding disorder showing variable phenotypic severity. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. The disorder can be caused either by reduced levels of the factor X protein or by synthesis of a dysfunctional factor X protein (summary by previous studies)." +MONDO_0010035,"Definition: Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital malformation and mental retardation syndrome. Although historically a clinical distinction was often made between a classic 'type I' disorder and a more severe 'type II' disorder, in reality the syndrome constitutes a clinical and biochemical continuum from mild to severe (previous studies; previous studies; previous studies). + +The discovery of the deficiency of 7-dehydrocholesterol reductase as a causative factor of the SLO syndrome (previous studies) made this syndrome the first true metabolic syndrome of multiple congenital malformations. A multidisciplinary National Institute of Child Health and Human Development (NICHD) conference of the SLO syndrome reviewed different implications of this discovery and proposed further studies in this field. A detailed report on this conference and abstracts of presentations were provided by previous studies. Observations presented at an NICHD RSH/SLOS conference in September 1995 were reviewed by previous studies. previous studies referred to SLOS as a metabolic malformation syndrome, but suggested that this may be an exception. Most mutations that had been related to multiple congenital malformation syndromes, i.e., disturbances of the body plan, have not been disorders of intermediary metabolism but, instead, mutations of homeobox genes and other transcriptional regulators and signaling systems. + +previous studies gave a presumedly complete bibliography of the SLO syndrome, which was updated by previous studies and included almost 200 references. They concluded that lumping SLO syndrome with the Pallister-Hall hamartoblastoma syndrome (PHS; previous studies) is not justified. In a given severe case, differentiation from the Meckel syndrome (previous studies) may be a challenge. + +previous studies reviewed the cholesterol biosynthetic pathway and the 6 disorders involving enzyme defects in post-squalene cholesterol biosynthesis: SLOS, desmosterolosis (previous studies), X-linked dominant chondrodysplasia punctata (CDPX2; previous studies), CHILD syndrome (previous studies), lathosterolosis (previous studies), and hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM; previous studies)." +MONDO_0011428,"Definition: Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome-3 (ECC3) is an autosomal dominant disorder comprising absence of the central parts of the hands and feet, resulting in split-hand/foot malformation, ectodermal dysplasia, and cleft lip with or without cleft palate (summary by previous studies). + +Also see EEC1 (previous studies), which has been mapped to chromosome 7q11." +MONDO_0011797,"Definition: Infantile-onset ascending spastic paralysis is an autosomal recessive neurodegenerative disorder characterized by onset in the first years of life of progressive upper and lower motor neuron degeneration resulting in loss of ability to walk in childhood. It initially affects the lower limbs and then ascends to the upper limbs and bulbar muscles, causing dysarthria and dysphagia. Cognition is unaffected (summary by previous studies)." +MONDO_0013110,"Definition: NCFTD is an autosomal recessive disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function (previous studies)." +MONDO_0013156,"Definition: MDDGB4 is a rare autosomal recessive congenital muscular dystrophy that is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies.' In contrast to most dystroglycanopathies, impaired intellectual development is not a feature of MDDGB4 (previous studies). + +For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (previous studies)." +MONDO_0014353,"Definition: IMD23 is an autosomal recessive primary immunodeficiency syndrome characterized by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity (summary by previous studies and previous studies)." +MONDO_0018663,Definition: Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly (SKPHA) is an autosomal recessive disorder characterized by rhizomelic skeletal dysplasia of variable severity with or without abnormal nuclear shape and chromatin organization in blood granulocytes (previous studies; previous studies; previous studies). Initial skeletal features may improve with age (previous studies). +MONDO_0020795,"Definition: Silver-Russell syndrome-5 (SRS5) is characterized by intrauterine growth retardation, with feeding difficulties in early childhood and postnatal growth failure. Relative macrocephaly may be present at birth. Other dysmorphic features include triangular face with prominent forehead (previous studies). + +For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (previous studies)." +MONDO_0033619,"Definition: Myopathy, epilepsy, and progressive cerebral atrophy (MEPCA) is a severe autosomal recessive disorder with onset in utero or at birth. Affected individuals have hypotonia with respiratory or feeding difficulties apparent from birth and often associated with contractures of the large joints. There is little spontaneous movement: skeletal muscle biopsy and electrophysiologic studies are consistent with a myopathy or myasthenic disorder. Patients also develop refractory seizures with burst-suppression pattern or hypsarrhythmia on EEG. Brain imaging shows progressive cerebral atrophy and myelination defects. All patients reported to date died within the first year of life (summary by previous studies)." +MONDO_0859240,Definition: Intellectual developmental disorder with or without peripheral neuropathy (IDDPN) is an autosomal recessive neurologic disorder characterized by global developmental delay with mildly impaired intellectual development apparent from infancy or early childhood. Affected individuals have hypotonia and delayed walking with an unsteady gait and frequent falls. Some patients develop a progressive length-dependent sensorimotor peripheral neuropathy. Additional features may include dysarthria and subtle dysmorphic facial features (previous studies). +MONDO_0008959,"Definition: CHAND syndrome is characterized by ankyloblepharon, sparse, curly, and woolly hair, nail dysplasia, and oral frenula (summary by previous studies)." +MONDO_0010386,"Definition: Immunodeficiency-33 (IMD33) is an X-linked recessive disorder that affects only males. It is characterized by early-onset severe infections, usually due to pneumococcus, H. influenzae, and atypical mycobacteria, although other organisms have also been detected. Immunologic investigations may show variable abnormalities or may be normal. Disturbances include dysgammaglobulinemia with hypogammaglobulinemia, decreased IgG2, aberrant levels of IgM and IgA, and decreased class-switched memory B cells. There is often poor, but variable, response to vaccination; in particular, most patients do not develop antibodies to certain polysaccharide vaccines, notably pneumococcus. Other immunologic abnormalities may include impaired NK cytotoxic function, impaired cytokine production upon stimulation with IL1B (previous studies) or TNFA (previous studies), low IL6 (previous studies), low IL12 (see previous studies), and decreased IFNG (previous studies). Patients do not have overt abnormalities of T-cell proliferation, although signaling pathways, such as CD40LG (previous studies)/CD40 (previous studies), may be disturbed. There is heterogeneity in the immunologic phenotype, resulting in highly variable clinical courses, most likely due to the different effects of hypomorphic mutations. Treatment with antibiotics and IVIg is usually beneficial; hematopoietic stem cell transplantation may not be necessary, but can be effective. Features of hypohidrotic ectodermal dysplasia are generally not present, although some patients may have conical teeth or hypodontia (summary by previous studies, previous studies, previous studies, previous studies)." +MONDO_0010979,"Definition: Timothy syndrome (TS) is characterized by multiorgan dysfunction, including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism (previous studies). + +previous studies reviewed the genetic and clinical findings in published reports of Timothy syndrome, noting that although classically TS is characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay, an increasing number of identified TS-causing variants are associated with complex and variable symptom profiles, including some cases exhibiting only cardiac features. Potential mechanisms for the variability observed in clinical features include mosaicism, genetic background, isoform complexity of CACNA1C with differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. The authors proposed a TS nomenclature based on specific mutation designations, but noted that the case reports could also be grouped as a single entity, Timothy syndrome, with the recognition that there is a broad and variable phenotypic spectrum." +MONDO_0012516,"Definition: Mandibulofacial dysostosis with microcephaly is a rare syndrome comprising progressive microcephaly, midface and malar hypoplasia, micrognathia, microtia, dysplastic ears, preauricular skin tags, significant developmental delay, and speech delay. Many patients have major sequelae, including choanal atresia that results in respiratory difficulties, conductive hearing loss, and cleft palate (summary by previous studies)." +MONDO_0014933,"Definition: Developmental and epileptic encephalopathy-44 (DEE44) is an autosomal recessive neurologic disorder characterized by the onset of refractory infantile spasms or myoclonus usually in the first weeks or months of life, up to about 12 months of age. Affected infants may have normal or mildly delayed development before the onset of seizures, but thereafter show developmental stagnation and severe neurologic impairment. EEG in some patients shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Additional features include poor feeding and poor overall growth with microcephaly, axial hypotonia with peripheral hypertonia or spasticity, abnormal movements, limited eye contact, and profoundly impaired intellectual development with absent language. Many patients require tube feeding, and some die in childhood (summary by previous studies; previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0030046,"Definition: Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity (NEDBASS) is an autosomal recessive neurologic disorder characterized by global developmental delay apparent from early infancy, poor overall growth often with microcephaly, impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum. Early death may occur (summary by previous studies)." +MONDO_0030266,Definition: Immunodeficiency-80 with or without congenital cardiomyopathy (IMD80) is an autosomal recessive immunologic disorder with variable manifestations. One patient with infantile-onset of chronic cytomegalovirus (CMV) infection associated with severely decreased NK cells has been reported. Another family with 3 affected fetuses showing restrictive cardiomyopathy and hypoplasia of the spleen and thymus has also been reported (summary by previous studies). +MONDO_0030902,"Definition: Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome (see previous studies). Patient tissue showed isolated mitochondrial complex I deficiency. Death may occur in childhood (previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see previous studies." +MONDO_0033533,"Definition: Combined oxidative phosphorylation deficiency-45 (COXPD45) is an autosomal recessive multisystem disorder characterized by poor overall growth apparent from infancy, global developmental delay, seizures, and acute progressive neurologic deterioration with loss of skills. Other features may include dysmorphic facies and lesions on brain imaging. Laboratory studies show increased serum lactate and COXPD in patient tissues, consistent with a mitochondrial defect (summary by previous studies). + +For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0033637,"Definition: Mitochondrial complex IV deficiency nuclear type 7 (MC4DN7) is an autosomal recessive metabolic encephalomyopathic disorder with highly variable manifestations. Only a few patients have been reported. Some patients have normal early development then show rapid neurodegeneration with progressive muscle weakness, gait disturbances, and cognitive decline in mid to late childhood. Other features may include seizures and visual impairment. Brain imaging shows progressive leukodystrophy with cystic lesions. In contrast, at least 1 patient has been reported who presented in the neonatal period with metabolic acidosis, hydrocephalus, hypotonia, and cortical blindness. This patient developed hypertrophic cardiomyopathy resulting in early death. All patients had increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0044304,"Definition: Mild non-BH4-deficient hyperphenylalaninemia (HPANBH4) is an autosomal recessive disorder characterized by increased serum phenylalanine (HPA) usually detected by newborn screening and associated with highly variable neurologic defects, including movement abnormalities, such as dystonia, and variably impaired intellectual development. Laboratory analysis shows dopamine and serotonin deficiencies in the cerebrospinal fluid, and normal tetrahydrobiopterin (BH4) metabolism. Evidence suggests that treatment with BH4 and neurotransmitter precursors can lead to clinical improvement or even prevent the neurologic defects if started in infancy (summary by previous studies). + +The phenotype is highly variable: some patients may present with later onset of juvenile or young adult nonprogressive dopa-responsive parkinsonism reminiscent of early-onset Parkinson disease (previous studies). These patients benefit from treatment with L-dopa (summary by previous studies). + +In a review of HPA, previous studies noted that molecular screening for DNAJC12 mutations should be mandatory in patients in whom deficiencies of PAH (previous studies) and BH4 metabolism have been excluded." +MONDO_0859345,"Definition: Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH) is an autosomal dominant disorder characterized by choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. Additional features may include developmental delay, impaired intellectual development, and growth failure/retardation (summary by previous studies and previous studies)." +Orphanet_83473,"Definition: This disorder comprises megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome (MCAP; previous studies) (summary by previous studies). + + Genetic Heterogeneity of the Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome + +See also MPPH2 (previous studies), caused by mutation in the AKT3 gene (previous studies) on chromosome 1q43-q44; and MPPH3 (previous studies), caused by mutation in the CCND2 gene (previous studies) on chromosome 12p13." +MONDO_0007949,"Definition: Marshall syndrome (MRSHS) is characterized by midfacial hypoplasia, cleft palate, ocular anomalies including high myopia and cataracts, sensorineural hearing loss, short stature with spondyloepiphyseal dysplasia, and arthropathy. In contrast to Stickler syndrome type II, it has less severe eye findings but striking ocular hypertelorism, more pronounced maxillary hypoplasia, and ectodermal abnormalities (summary by previous studies and previous studies)." +MONDO_0008147,"Definition: Osteogenesis imperfecta type II (OI2) is a connective tissue disorder characterized by bone fragility, with many perinatal fractures, severe bowing of long bones, undermineralization, and death in the perinatal period due to respiratory insufficiency (previous studies; previous studies). + +Also see osteogenesis imperfecta type VII (OI7; previous studies), an autosomal recessive form of lethal OI caused by mutation in the CRTAP gene (previous studies)." +MONDO_0009705,Definition: CPT I deficiency is an autosomal recessive metabolic disorder of long-chain fatty acid oxidation characterized by severe episodes of hypoketotic hypoglycemia usually occurring after fasting or illness. Onset is in infancy or early childhood (previous studies) +MONDO_0010653,"Definition: Renpenning syndrome is an X-linked mental retardation syndrome with clinically recognizable features. Affected individuals have microcephaly, short stature, small testes, and dysmorphic facies, including tall narrow face, upslanting palpebral fissures, abnormal nasal configuration, cupped ears, and short philtrum. The nose may appear long or bulbous, with overhanging columella. Less consistent manifestations include ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. previous studies proposed that the various X-linked mental retardation syndromes due to PQBP1 mutations be combined under the name of Renpenning syndrome." +MONDO_0013512,"Definition: Hemoglobin H disease is a subtype of alpha-thalassemia (see previous studies) in which patients have compound heterozygosity for alpha(+)-thalassemia, caused by deletion of one alpha-globin gene, and for alpha(0)-thalassemia, caused by deletion in cis of 2 alpha-globin genes (summary by previous studies). When 3 alpha-globin genes become inactive because of deletions with or without concomitant nondeletional mutations, the affected individual has only 1 functional alpha-globin gene. These people usually have moderate anemia and marked microcytosis and hypochromia. In affected adults, there is an excess of beta-globin chains within erythrocytes that will form beta-4 tetramers, also known as hemoglobin H (summary by previous studies). + +Hb H disease is usually caused by the combination of alpha(0)-thalassemia with deletional alpha(+)-thalassemia, a combination referred to as 'deletional' Hb H disease. In a smaller proportion of patients, Hb H disease is caused by an alpha(0)-thalassemia plus an alpha(+)-thalassemia point mutation or small insertion/deletion. Such a situation is labeled 'nondeletional' Hb H disease. Patients with nondeletional Hb H disease are usually more anemic, more symptomatic, more prone to have significant hepatosplenomegaly, and more likely to require transfusions (summary by previous studies)." +MONDO_0013541,"Definition: Complex cortical dysplasia with other brain malformations (CDCBM) is a disorder of aberrant neuronal migration and disturbed axonal guidance. Affected individuals have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Brain imaging shows variable malformations of cortical development, including polymicrogyria, gyral disorganization, and fusion of the basal ganglia, as well as thin corpus callosum, hypoplastic brainstem, and dysplastic cerebellar vermis. Extraocular muscles are not involved (summary by previous studies). + +Mutation in the TUBB3 gene can also cause congenital fibrosis of extraocular muscles-3A (CFEOM3A; previous studies), a milder and somewhat different neurologic phenotype. + + Genetic Heterogeneity of Complex Cortical Dysplasia With Other Brain Malformations + +See also CDCBM2 (previous studies), caused by mutation in the KIF5C gene (previous studies) on chromosome 2q23; CDCBM3 (previous studies), caused by mutation in the KIF2A gene (previous studies) on chromosome 5q12; CDCBM4 (previous studies), caused by mutation in the TUBG1 gene (previous studies) on chromosome 17q21; CDCBM5 (previous studies), caused by mutation in the TUBB2A gene (previous studies) on chromosome 6p25; CDCBM6 (previous studies), caused by mutation in the TUBB gene (previous studies) on chromosome 6p21; CDCBM7 (previous studies), caused by mutation in the TUBB2B gene (previous studies) on chromosome 6p25; CDCBM9 (previous studies), caused by mutation in the CTNNA2 gene (previous studies) on chromosome 2p12; CDCBM10 (previous studies), caused by mutation in the APC2 gene (previous studies) on chromosome 19p13; CDCBM11 (previous studies), caused by mutation in the KIF26A gene (previous studies) on chromosome 14q32; CDCBM12 (previous studies), caused by mutation in the CAMSAP1 gene (previous studies) on chromosome 9q34; and CDCBM13 (previous studies), caused by mutation in the DYNC1H1 gene (previous studies) on chromosome 14q32. + +The designation CDCBM8 was previously used to represent a phenotype caused by mutation in the TUBA8 gene (see previous studies) on chromosome 22q11; the patients with this phenotype were subsequently found to have a homozygous mutation in the SNAP29 gene (previous studies), also on chromosome 22q11, that was likely responsible for a similar disorder, CEDNIK syndrome (previous studies). + +See also lissencephaly (e.g., LIS1, previous studies), which shows overlapping features and may result from mutation in tubulin genes." +Orphanet_300570,"Definition: Complex cortical dysplasia with other brain malformations (CDCBM) is a disorder of aberrant neuronal migration and disturbed axonal guidance. Affected individuals have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Brain imaging shows variable malformations of cortical development, including polymicrogyria, gyral disorganization, and fusion of the basal ganglia, as well as thin corpus callosum, hypoplastic brainstem, and dysplastic cerebellar vermis. Extraocular muscles are not involved (summary by previous studies). + +Mutation in the TUBB3 gene can also cause congenital fibrosis of extraocular muscles-3A (CFEOM3A; previous studies), a milder and somewhat different neurologic phenotype. + + Genetic Heterogeneity of Complex Cortical Dysplasia With Other Brain Malformations + +See also CDCBM2 (previous studies), caused by mutation in the KIF5C gene (previous studies) on chromosome 2q23; CDCBM3 (previous studies), caused by mutation in the KIF2A gene (previous studies) on chromosome 5q12; CDCBM4 (previous studies), caused by mutation in the TUBG1 gene (previous studies) on chromosome 17q21; CDCBM5 (previous studies), caused by mutation in the TUBB2A gene (previous studies) on chromosome 6p25; CDCBM6 (previous studies), caused by mutation in the TUBB gene (previous studies) on chromosome 6p21; CDCBM7 (previous studies), caused by mutation in the TUBB2B gene (previous studies) on chromosome 6p25; CDCBM9 (previous studies), caused by mutation in the CTNNA2 gene (previous studies) on chromosome 2p12; CDCBM10 (previous studies), caused by mutation in the APC2 gene (previous studies) on chromosome 19p13; CDCBM11 (previous studies), caused by mutation in the KIF26A gene (previous studies) on chromosome 14q32; CDCBM12 (previous studies), caused by mutation in the CAMSAP1 gene (previous studies) on chromosome 9q34; and CDCBM13 (previous studies), caused by mutation in the DYNC1H1 gene (previous studies) on chromosome 14q32. + +The designation CDCBM8 was previously used to represent a phenotype caused by mutation in the TUBA8 gene (see previous studies) on chromosome 22q11; the patients with this phenotype were subsequently found to have a homozygous mutation in the SNAP29 gene (previous studies), also on chromosome 22q11, that was likely responsible for a similar disorder, CEDNIK syndrome (previous studies). + +See also lissencephaly (e.g., LIS1, previous studies), which shows overlapping features and may result from mutation in tubulin genes." +MONDO_0014918,"Definition: Thauvin-Robinet-Faivre syndrome is an autosomal recessive disorder characterized by generalized overgrowth, mainly of height, and mildly delayed psychomotor development with mild or severe learning difficulties. More variable features may include congenital heart defects, kidney abnormalities, and skeletal defects. Patients may have an increased risk for Wilms tumor (summary by previous studies)." +MONDO_0030353,"Definition: Joubert syndrome-38 (JBTS38) is characterized by hypotonia, global developmental delay, oculomotor apraxia, and breathing abnormalities, with a 'molar tooth sign' on brain MRI. Patients also exhibit pituitary abnormalities with growth hormone deficiency (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (previous studies)." +MONDO_0030976,"Definition: Oculomotor-abducens synkinesis (OCABSN) is an autosomal recessive disorder characterized by a specific anomaly of extraocular muscle movements involving the oculomotor nerve (cranial nerve III) and the abducens nerve (cranial nerve VI). The superior branch of CN3 innervates the levator palpebrae superioris muscle, which raises the eyelid, and CN6 innervates the lateral rectus muscle, which controls lateral eye movement. Affected individuals show ptosis as well as elevation of the eyelid on ipsilateral abduction. The features indicate abnormal innervation of these muscles and suggest synkinesis of the oculomotor and abducens nerves. The disorder can be classified as a congenital cranial dysinnervation disorder (CCDD), and also shows features of congenital fibrosis of the extraocular muscles (CFEOM; see previous studies) (summary by previous studies and previous studies). + +See also oculomotor-levator synkinesis (OCLEVS; previous studies), a similar disorder." +MONDO_0032893,"Definition: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (PAMDDFS) is an autosomal recessive neurologic disorder characterized by progressive microcephaly associated with abnormal facial features, hypotonia, and variable global developmental delay with impaired intellectual development. Brain imaging shows variable malformation of cortical development on the lissencephaly spectrum, mainly pachygyria and thin corpus callosum (summary by previous studies)." +Orphanet_1429,"Definition: Benign hereditary chorea (BHC) is an autosomal dominant movement disorder that manifests before age 5 years and has a stationary or only slightly progressive course. Intelligence is normal or slightly below normal and mental deterioration is not seen. In some families, the choreic movements decrease during adolescence or early adulthood (summary by previous studies)." +EFO_0004152,"Definition: Benign hereditary chorea (BHC) is an autosomal dominant movement disorder that manifests before age 5 years and has a stationary or only slightly progressive course. Intelligence is normal or slightly below normal and mental deterioration is not seen. In some families, the choreic movements decrease during adolescence or early adulthood (summary by previous studies)." +Orphanet_2995,"Definition: BRWS is a rare developmental phenotype characterized by the combination of hypertelorism, broad nose with large tip and prominent root, congenital nonmyopathic ptosis, ridged metopic suture, arched eyebrows, iris or retinal coloboma, sensorineural deafness, shoulder girdle muscle bulk and progressive joint stiffness, and pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Intellectual disability and epilepsy are variable in severity and largely correlate with central nervous system anomalies (summary by previous studies). previous studies and previous studies suggested that BRWS, Fryns-Aftimos syndrome, and cerebrofrontofacial syndrome represent the same clinical entity. The phenotype is highly variable (summary by previous studies). + + Genetic Heterogeneity of Baraitser-Winter Syndrome + +Baraitser-Winter syndrome-2 (BRWS2; previous studies) is caused by heterozygous mutation in the ACTG1 gene (previous studies) on chromosome 17q25." +MONDO_0007507,"Definition: Complete congenital absence of dermatoglyphs is a rare syndrome characterized by autosomal dominant inheritance of the lack of ridges on palms and soles, neonatal acral blisters and facial milia, adult traumatic blistering and fissuring, absent or reduced sweating of palms and soles, and contracture of digits. Additional features may include single palmar transverse crease, palmoplantar keratoderma, and nail grooving (summary by previous studies)." +Orphanet_1658,"Definition: Complete congenital absence of dermatoglyphs is a rare syndrome characterized by autosomal dominant inheritance of the lack of ridges on palms and soles, neonatal acral blisters and facial milia, adult traumatic blistering and fissuring, absent or reduced sweating of palms and soles, and contracture of digits. Additional features may include single palmar transverse crease, palmoplantar keratoderma, and nail grooving (summary by previous studies)." +MONDO_0008275,"Definition: Familial expansile osteolysis is an autosomal dominant bone dysplasia characterized by increased bone remodeling with osteolytic lesions mainly affecting the appendicular skeleton. There is medullary and cortical expansion of the bone without sclerosis, leading to painful and disabling deformities and tendency to pathologic fracture. Clinical features include onset of conductive hearing loss in childhood, premature loss of teeth, and variably increased serum alkaline phosphatase (summary by previous studies and previous studies)." +MONDO_0008501,"Definition: Sturge-Weber syndrome is characterized by an intracranial vascular anomaly, leptomeningeal angiomatosis, most often involving the occipital and posterior parietal lobes. The most common symptoms and signs are facial cutaneous vascular malformations (port-wine stains), seizures, and glaucoma. Stasis results in ischemia underlying the leptomeningeal angiomatosis, leading to calcification and laminar cortical necrosis. The clinical course is highly variable and some children experience intractable seizures, mental retardation, and recurrent stroke-like episodes (review by previous studies)." +MONDO_0009544,"Definition: Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by previous studies and previous studies). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by previous studies)." +MONDO_0009666,"Definition: Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (summary by previous studies). + +Also see biotinidase deficiency (previous studies), another form of MCD with a later onset. + +Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (previous studies) or prolonged parenteral alimentation without supplemental biotin (previous studies)." +MONDO_0011735,"Definition: HIGM3, first described in humans by previous studies, is characterized by hypogammaglobulinemia with normal or elevated levels of IgM. + +For a general phenotypic description and a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (previous studies)." +MONDO_0014689,"Definition: Klippel-Feil syndrome-4 with nemaline myopathy and facial dysmorphism (KFS4) is an autosomal recessive disorder characterized mainly by severe hypotonia apparent from infancy. Klippel-Feil anomaly is primarily defined by fusion of the cervical spine, with associated low posterior hairline and limited neck mobility being observed in about half of patients (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of Klippel-Feil syndrome, see KFS1 (previous studies)." +MONDO_0014958,"Definition: Harel-Yoon syndrome is a syndromic neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, truncal hypotonia, spasticity, and peripheral neuropathy. Other more variable features such as optic atrophy may also occur. Laboratory studies in some patients show evidence of mitochondrial dysfunction (summary by previous studies)." +Orphanet_83418,"Definition: Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetric muscle weakness and atrophy (summary by previous studies)." +MONDO_0009673,"Definition: Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetric muscle weakness and atrophy (summary by previous studies)." +EFO_0009075,"Definition: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals may also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements such as ataxia, dysmetria, and myoclonus (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (previous studies)." +MONDO_0014671,"Definition: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals may also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements such as ataxia, dysmetria, and myoclonus (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (previous studies)." +MONDO_0009216,"Definition: Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (previous studies). Because no underlying enzymatic defect in carbohydrate metabolism had been identified and because metabolism of both glucose and galactose is impaired, a primary defect of monosaccharide transport across the membranes had been suggested (previous studies; previous studies; previous studies; previous studies). + +Use of the term glycogenosis type XI introduced by previous studies is to be discouraged because glycogen accumulation is not due to the proposed functional defect of phosphoglucomutase, an essential enzyme in the common degradative pathways of both glycogen and galactose, but is secondary to nonfunctional glucose transport." +MONDO_0009229,"Definition: Hyaline fibromatosis syndrome is an autosomal recessive condition characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. The severity is variable. Some individuals present in infancy and have additional visceral or systemic involvement, which can lead to early death. These patients may show intractable diarrhea and increased susceptibility to infection. Other patients have later onset of a milder disorder affecting only the face and digits. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Histologic analysis of skin lesions shows proliferation of spindle-shaped cells forming strands in a homogeneous and hyaline eosinophilic extracellular material in the dermis (summary by previous studies)." +MONDO_0010362,"Definition: Glycogen storage disease IXd (GSD9D) is an X-linked recessive, relatively mild metabolic disorder characterized by variable exercise-induced muscle weakness or stiffness. Most patients have adult onset of symptoms, and some remain asymptomatic even in late adulthood. The phenotype is usually only apparent with intense exercise (summary by previous studies). + +For a discussion of genetic heterogeneity of GSD IX, see GSD9A (previous studies)." +MONDO_0010704,"Definition: Otopalatodigital syndrome-1 is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. The disorders, which include frontometaphyseal dysplasia (FMD1; previous studies), otopalatodigital syndrome-2 (OPD2; previous studies), and Melnick-Needles syndrome (MNS; previous studies), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD is characterized by a generalized skeletal dysplasia, deafness and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by previous studies). previous studies suggested that these disorders constitute a single entity, which they termed 'frontootopalatodigital osteodysplasia.'" +MONDO_0011423,"Definition: Limb-girdle muscular dystrophies are characterized clinically by predominantly proximal muscle weakness of variable severity and dystrophic changes on muscle biopsy. LGMDR4 is in general a severe form of the disorder, with some patients developing symptoms before 8 years of age and losing the ability to ambulate in their second decade. Some patients have a milder course, with weakness evident in the teenage years and loss of walking ability in their fourth decade (summary by previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (previous studies)." +MONDO_0013170,"Definition: Cutis laxa is a collection of disorders that are typified by loose and/or wrinkled skin that imparts a prematurely aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The skin lacks elastic recoil, in marked contrast to the hyperelasticity apparent in classic Ehlers-Danlos syndrome (see previous studies). These properties are nearly always attributable to loss, fragmentation, or severe disorganization of dermal elastic fibers (summary by previous studies). + +Patients with autosomal recessive cutis laxa type IC exhibit generalized cutis laxa in association with impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development (summary by previous studies). + +For general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (previous studies)." +MONDO_0013483,Definition: OBHD is a neurodevelopmental disorder characterized by global developmental delay and hyperphagia resulting in obesity. Some patients may develop seizures (summary by previous studies). +MONDO_0013485,"Definition: Spinocerebellar ataxia-35 is an autosomal dominant adult-onset neurologic disorder characterized by difficulty walking due to cerebellar ataxia. The age at onset ranges from teenage years to late adulthood, and the disorder is slowly progressive. Additional features may include hand tremor, dysarthria, hyperreflexia, and saccadic eye movements (summary by previous studies)." +MONDO_0013967,"Definition: PBD14B is an autosomal recessive peroxisome biogenesis disorder characterized clinically by mild intellectual disability, congenital cataracts, progressive hearing loss, and polyneuropathy (previous studies), all of which had been observed in patients with mild peroxisomal biogenesis disorders (e.g., previous studies; previous studies). Additionally, recurrent migraine-like episodes following mental stress or physical exertion, not a common feature in peroxisome disorders, was reported. + +previous studies classified the disorder described by previous studies in their patient as a mild 'Zellweger syndrome (previous studies) spectrum' (ZSS) disorder. See PBD1B (previous studies) for a phenotypic description and discussion of genetic heterogeneity of less severe phenotypes on the Zellweger syndrome spectrum. See PBD9B (previous studies) for another atypical peroxisome biogenesis disorder." +MONDO_0013972,"Definition: Perrault syndrome-2 is an autosomal recessive disorder characterized by sensorineural deafness in both males and females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile (summary by previous studies). + +For a discussion of genetic heterogeneity of Perrault syndrome, see PRLTS1 (previous studies)." +MONDO_0014077,"Definition: Lissencephaly-5 (LIS5) is an autosomal recessive brain malformation characterized by cobblestone changes in the cortex, more severe in the posterior region, and subcortical band heterotopia. Affected individuals have hydrocephalus, seizures, and severely delayed psychomotor development (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (previous studies)." +MONDO_0033635,"Definition: Mitochondrial complex IV deficiency nuclear type 3 (MC4DN3) is an autosomal recessive multisystem metabolic disorder with a highly variable phenotype. Some patients present with encephalomyopathic features in early infancy, whereas others may present later in infancy or the first years of life after normal early development. Affected individuals show hypotonia, failure to thrive, and developmental delay or regression with poor eye contact and loss of motor skills with ataxia. Additional features observed in some patients include proximal renal tubulopathy, macrocytic anemia, sensorineural hearing loss, nystagmus, and hypertrophic cardiomyopathy, consistent with systemic involvement. Brain imaging in most patients shows lesions consistent with Leigh syndrome (see previous studies). Laboratory studies show increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV. Most patients die in infancy (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +MONDO_0054741,"Definition: COXPD34 is an autosomal recessive disorder resulting from a defect in mitochondrial function. The phenotype is variable, but may include congenital sensorineural deafness, increased serum lactate, and hepatic and renal dysfunction. Neurologic function is relatively preserved (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0054742,"Definition: COXPD35 is an autosomal recessive disorder characterized mainly by global developmental delay with intellectual disability, microcephaly, and early-onset myoclonic and other types of seizures. Affected individuals have variable deficiencies of mitochondrial respiratory enzyme complexes resulting from a defect in mitochondrial metabolism (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +EFO_0004138,"Definition: Progressive familial heart block type I (PFHBI, PFHB1) is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block (previous studies; previous studies; previous studies). It is defined on electrocardiogram by evidence of bundle branch disease, i.e., right bundle branch block, left anterior or posterior hemiblock, or complete heart block, with broad QRS complexes. Progression has been shown from a normal electrocardiogram to right bundle branch block and from the latter to complete heart block. These electrocardiographic features differentiate PFHB type I from progressive familial heart block type II (PFHBII, PFHB2; previous studies), in which the onset of complete heart block is associated with narrow complexes. Electrocardiographically the changes represent, respectively, bundle branch disease (PFHB1) and atrioventricular nodal disease with an atrioventricular block and an idionodal escape rhythm (PFHB2). PFHBI is manifested symptomatically when complete heart block supervenes, either with dyspnea, syncopal episodes, or sudden death. Treatment, which is best managed by regular electrocardiographic follow-up, is by the timely implantation of a pacemaker (previous studies). + + Genetic Heterogeneity of Progressive Familial Heart Block Type I + +Progressive familial heart block type IB (PFHB1B; previous studies) is caused by mutation in the TRPM4 gene (previous studies) on chromosome 19q13.32." +EFO_0010167,"Definition: Squalene synthase deficiency (SQSD) is an autosomal recessive disorder characterized by profound developmental delay, brain abnormalities, 2/3 syndactyly of the toes, and facial dysmorphisms, as well as low total and LDL-cholesterol and abnormal urine organic acids (previous studies)." +MONDO_0007104,"Definition: Amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam is a neurodegenerative disorder with unusually high incidence among the Chamorro people of Guam. Both ALS and parkinsonism-dementia are chronic, progressive, and uniformly fatal disorders in this population. Both diseases are known to occur in the same kindred, the same sibship, and even the same individual." +MONDO_0008135,"Definition: Optic atrophy-13 with retinal and foveal abnormalities (OPA13) is an autosomal dominant disorder characterized by decreased visual acuity due to bilateral optic atrophy. Difficulties with color vision may also be apparent. The age at onset varies widely: most patients have onset in the first decade, but later onset even into adulthood has been reported. In addition to optic atrophy, most patients develop retinal pigmentary involvement and abnormal appearance of the fovea. Some patients may develop additional systemic features, including sensorineural deafness and progressive nephropathy resulting in renal failure. The disorder is associated with variable signs of mitochondrial dysfunction, including altered morphology, mtDNA depletion, and defective mtDNA replication (summary by previous studies, previous studies)." +MONDO_0009271,"Definition: Geroderma osteodysplasticum (GO) is an autosomal recessive disorder characterized by skin wrinkling limited to the dorsa of hands and feet and to the abdomen, bowed long bones, and osteopenia with frequent fractures. There is a distinctive facial appearance with droopy skin at the cheeks, maxillary hypoplasia, and large ears. Adult patients appear prematurely aged (summary by previous studies)." +MONDO_0010714,"Definition: Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay (summary by previous studies). + + Genetic Heterogeneity of Hypomyelinating Leukodystrophy + +Other forms of hypomyelinating leukodystrophy include HLD2 (previous studies), caused by mutation in the GJC2/GJA12 gene (previous studies) on chromosome 1q41; HLD3 (previous studies), caused by mutation in the AIMP1 gene (previous studies) on chromosome 4q24; HLD4 (previous studies), caused by mutation in the HSPD1 gene (previous studies) on chromosome 2q33.1; HLD5 (previous studies), caused by mutation in the FAM126A gene (previous studies) on chromosome 7p15; HLD6 (previous studies), caused by mutation in the TUBB4A gene (previous studies) on chromosome 19p13; HLD7 (previous studies), caused by mutation in the POLR3A gene (previous studies) on chromosome 10q22; HLD8 (previous studies), caused by mutation in the POLR3B gene (previous studies) on chromosome 12q23; HLD9 (previous studies), caused by mutation in the RARS gene (previous studies) on chromosome 5; HLD10 (previous studies), caused by mutation in the PYCR2 gene (previous studies) on chromosome 1q42; HLD11 (previous studies), caused by mutation in the POLR1C gene (previous studies) on chromosome 6p21; HLD12 (previous studies), caused by mutation in the VPS11 gene (previous studies) on chromosome 11q23; HLD13 (previous studies) caused by mutation in the HIKESHI gene (previous studies) on chromosome 11q14; HLD14 (previous studies), caused by mutation in the UFM1 gene (previous studies) on chromosome 13q13; HLD15 (previous studies), caused by mutation in the EPRS gene (previous studies) on chromosome 1q41; HLD16 (previous studies), caused by mutation in the TMEM106B gene (previous studies) on chromosome 7p21; HLD17 (previous studies), caused by mutation in the AIMP2 gene (previous studies) on chromosome 7p22; HLD18 (previous studies), caused by mutation in the DEGS1 gene (previous studies) on chromosome 1q42; HLD19 (previous studies), caused by mutation in the TMEM63A gene (previous studies) on chromosome 1q42; HLD20 (previous studies), caused by mutation in the CNP gene (previous studies) on chromosome 17q21; HLD21 (previous studies), caused by mutation in the POLR3K gene (previous studies) on chromosome 16p13; HLD22 (previous studies), caused by mutation in the CLDN11 gene (previous studies) on chromosome 3q26; HLD23 (previous studies), caused by mutation in the RNF220 gene (previous studies) on chromosome 1p34; HLD24 (previous studies), caused by mutation in the ATP11A gene (previous studies) on chromosome 13q34; HLD25 (previous studies), caused by mutation in the TMEM163 gene (previous studies) on chromosome 2q21; and HLD26 (previous studies), caused by mutation in the SLC35B2 gene (previous studies) on chromosome 6p21." +MONDO_0011026,"Definition: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by previous studies). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (previous studies). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; previous studies) (previous studies). + +NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by previous studies). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by previous studies). + +In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (previous studies)." +MONDO_0011421,"Definition: A distinct group of inborn defects of complex V (ATP synthase) is represented by the enzyme deficiency due to nuclear genome mutations characterized by a selective inhibition of ATP synthase biogenesis. Biochemically, the patients show a generalized decrease in the content of ATP synthase complex which is less than 30% of normal. Most cases present with neonatal-onset hypotonia, lactic acidosis, hyperammonemia, hypertrophic cardiomyopathy, and 3-methylglutaconic aciduria. Many patients die within a few months or years (summary by previous studies). + + Genetic Heterogeneity of Mitochondrial Complex V Deficiency + +Other nuclear types of mitochondrial complex V deficiency include MC5DN2 (previous studies), caused by mutation in the TMEM70 gene (previous studies) on chromosome 8q21; MC5DN3 (previous studies), caused by mutation in the ATP5E gene (ATP5F1E; previous studies) on chromosome 20q13; MC5DN4A (previous studies) and MC5DN4B (previous studies), both caused by mutation in the ATP5A1 gene (ATP5F1A; previous studies) on chromosome 18q; MC5DN5 (previous studies), caused by mutation in the ATP5D gene (ATP5F1D; previous studies) on chromosome 19p13; MC5DN6 (previous studies), caused by mutation in the USMG5 gene (ATP5MD; previous studies) on chromosome 10q24; and MC5DN7 (previous studies), caused by mutation in the ATP5PO gene (previous studies) on chromosome 21q22. + +Mutations in the mitochondrial-encoded MTATP6 (previous studies) and MTATP8 (previous studies) genes can also cause mitochondrial complex V deficiency (see, e.g., previous studies)." +MONDO_0012793,"Definition: Renal hypouricemia is a common inherited disorder characterized by impaired renal urate reabsorption and subsequent low serum urate levels. It may be associated with severe complications such as exercise-induced acute renal failure (EIARF) and nephrolithiasis (summary by previous studies). + +For additional phenotypic information and a discussion of genetic heterogeneity of renal hypouricemia, see RHUC1 (previous studies)." +MONDO_0013155,"Definition: MDDGB3 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and mild brain abnormalities (previous studies). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (previous studies). + +For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (previous studies)." +MONDO_0013806,"Definition: Patients with this syndrome develop cutaneous telangiectases in infancy with patchy alopecia over areas of affected skin, thinning of the lateral eyebrows, and mild dental and nail anomalies. Affected individuals are at increased risk of developing oropharyngeal cancer, and other malignancies have been reported as well (previous studies)." +MONDO_0013835,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0014951,"Definition: MRT74 is characterized by intellectual impairment, macrocephaly, and dysmorphic features. Epilepsy with eyelid myoclonus has also been reported (previous studies; previous studies)." +MONDO_0015000,"Definition: Developmental and epileptic encephalopathy-48 (DEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech; poor, if any, motor development; and onset of seizures usually in the first year of life, although later onset has been reported. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0015009,"Definition: LMPHM7 is an autosomal dominant disorder with variable expressivity. Some patients may develop severe nonimmune lymphatic-related hydrops fetalis (LRHF) in utero, resulting in early death, whereas others may have milder manifestations, such as atrial septal defect (ASD) or varicose veins as adults. The hydrops and/or swelling improves spontaneously in those who survive the neonatal period (summary by previous studies). + +For a discussion of genetic heterogeneity of lymphatic malformation, see previous studies." +MONDO_0030260,"Definition: Pontocerebellar hypoplasia type 1E (PCH1E) is an autosomal recessive neurologic disorder characterized by severe hypotonia and respiratory insufficiency apparent soon after birth. Virtually all patients die in the first days or weeks of life. Postmortem examination and brain imaging show pontocerebellar atrophy and loss of anterior motor neurons in the spinal cord. Additional more variable features may include optic atrophy, peripheral neuropathy, dysmorphic features, congenital contracture or foot deformities, and seizures (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (previous studies)." +Orphanet_276264,"Definition: Xeroderma pigmentosum is an autosomal recessive disorder characterized by sun sensitivity and increased skin sensitivity to UV light, as well as an increased risk of skin cancer associated with a defect in nucleotide excision repair (NER). The XPF form of XP is usually relatively mild compared to other forms. Patients with XPF tend to have later onset of skin cancer. Some patients with XPF may develop neurologic impairment or growth defects, and are then classified as having Cockayne syndrome (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of xeroderma pigmentosa, see XPA (previous studies), and of Cockayne syndrome, see CSA (previous studies)." +MONDO_0010215,"Definition: Xeroderma pigmentosum is an autosomal recessive disorder characterized by sun sensitivity and increased skin sensitivity to UV light, as well as an increased risk of skin cancer associated with a defect in nucleotide excision repair (NER). The XPF form of XP is usually relatively mild compared to other forms. Patients with XPF tend to have later onset of skin cancer. Some patients with XPF may develop neurologic impairment or growth defects, and are then classified as having Cockayne syndrome (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of xeroderma pigmentosa, see XPA (previous studies), and of Cockayne syndrome, see CSA (previous studies)." +MONDO_0008294,"Definition: Porphyrias are inherited defects in the biosynthesis of heme. Acute intermittent porphyria, the most common form of porphyria, is an autosomal dominant disorder characterized by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurologic disturbances. In the classic form of AIP, both the ubiquitous 'nonerythroid' housekeeping HMBS isoform and the 'erythroid' HMBS isoform are deficient. However, about 5% of families have the 'nonerythroid variant' of AIP, with a defect only in the ubiquitous nonerythroid HMBS isoform and normal levels of the erythroid HMBS isoform. Clinical characteristics in the 2 forms are identical; diagnostic methods based on the level of enzyme in erythrocytes are ineffective (previous studies; previous studies; previous studies). + +There are several other forms of porphyria: see porphyria cutanea tarda (previous studies), variegata porphyria (previous studies), coproporphyria (previous studies), acute hepatic porphyria (previous studies), and congenital erythropoietic porphyria (previous studies)." +MONDO_0008725,"Definition: Lipoid congenital adrenal hyperplasia, the most severe disorder of steroid hormone biosynthesis, is caused by a defect in the conversion of cholesterol to pregnenolone, the first step in adrenal and gonadal steroidogenesis. All affected individuals are phenotypic females with a severe salt-losing syndrome that is fatal if not treated in early infancy (summary by previous studies and previous studies)." +MONDO_0009173,"Definition: Deficiency of enterokinase, a sequence-specific protease that activates trypsinogen (see previous studies) and has a major role in protein digestion, is an autosomal recessive disorder characterized by severe protein malabsorption in early infancy, with failure to thrive, chronic diarrhea, and generalized edema. In adulthood, patients have normal body weight and no gastrointestinal symptoms, even when pancreatic enzyme supplements are discontinued (summary by previous studies)." +MONDO_0009842,"Definition: Immunodeficiency-108 with autoinflammation (IMD108) is an autosomal recessive disorder characterized mainly by features of autoinflammation, often manifest as onset of recurrent episodes of abdominal pain associated with fever and elevated inflammatory markers around adolescence. Affected individuals also have recurrent infections, particularly of the skin and nails; poor wound healing; and mild bleeding tendencies. Peripheral blood examination shows hypolobulated neutrophils, suggesting a defect in myeloid differentiation and function. However, neutrophil primary and secondary granules are normal (summary by previous studies)." +MONDO_0011731,"Definition: Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by previous studies)." +MONDO_0012235,"Definition: Autosomal recessive spinocerebellar ataxia is a neurologic disorder characterized by onset of progressive gait difficulties, eye movement abnormalities, and dysarthria in the first or second decade of life (summary by previous studies)." +MONDO_0012747,Definition: Aldolase A deficiency is an autosomal recessive disorder associated with hereditary hemolytic anemia (previous studies). +MONDO_0014455,"Definition: CAGSSS, which comprises cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, is an autosomal recessive multisystemic disorder with a highly variable phenotypic spectrum. Not all of these features are always present, and almost all the features may present at different times and/or become more apparent with age. The skeletal features are consistent with spondyloepimetaphyseal dysplasia (SEMD) (summary by previous studies). + +One family had a distinctive presentation with infantile-onset intractable seizures and cortical abnormalities reminiscent of Leigh syndrome (see previous studies). The correlation between genotype and phenotype remains unclear, but since the IARS2 gene is involved in mitochondrial function, heterogeneous manifestations can be expected (previous studies)." +MONDO_0024525,"Definition: Fanconi renotubular syndrome is an autosomal dominant renal disorder resulting from decreased solute and water reabsorption in the proximal tubule of the kidney. Patients have polydipsia and polyuria with phosphaturia, glycosuria, and aminoaciduria. They may develop hypophosphatemic rickets or osteomalacia, renal acidosis, and a tendency toward dehydration. Common laboratory abnormalities include glucosuria with a normal serum glucose, hyperaminoaciduria, hypophosphatemia, progressive renal insufficiency, renal sodium and potassium wasting, acidosis, uricosuria, and low molecular weight proteinuria. The disorder is progressive, and some patients will eventually develop renal insufficiency (summary by previous studies). + + Genetic Heterogeneity of Fanconi Renotubular Syndrome + +See also FRTS2 (previous studies), caused by mutation in the SLC34A1 gene (previous studies) on chromosome 5q35; FRTS3 (previous studies), caused by mutation in the EHHADH gene (previous studies) on chromosome 3q27; FRTS4 (previous studies), which is associated with maturity-onset diabetes of the young (MODY), caused by mutation in the HNF4A gene (previous studies) on chromosome 20q13; and FRTS5 (previous studies), caused by mutation in the NDUFAF6 gene (previous studies) on chromosome 8q22." +MONDO_0030043,"Definition: Congenital disorder of glycosylation type IIt (CDG2t) is an autosomal recessive multisystemic metabolic disorder characterized by global developmental delay, poor overall growth, severely impaired intellectual development with absent language, and behavioral abnormalities. Most patients develop early-onset seizures; brain imaging tends to show white matter abnormalities. Variable dysmorphic features, including long face, almond-shaped eyes, protruding maxilla, and short philtrum, are also present. The disorder, which is associated with low levels of HDL cholesterol, results from defective posttranslational O-linked glycosylation of certain plasma lipids and proteins (summary by previous studies). + +For an overview of congenital disorders of glycosylation, see CDG1A (previous studies) and CDG2A (previous studies)." +Orphanet_2268,"Definition: Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is an autosomal recessive disorder characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable (summary by previous studies). + +For a discussion of genetic heterogeneity of immunodeficiency-centromeric instability-facial anomalies syndrome, see ICF1 (previous studies)." +Orphanet_3057,Definition: Brunner syndrome is a recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with MAOA deficiency (previous studies). +MONDO_0010379,Definition: Brunner syndrome is a recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with MAOA deficiency (previous studies). +MONDO_0008146,"Definition: Osteogenesis imperfecta type I (OI1) is a dominantly inherited, generalized connective tissue disorder characterized mainly by bone fragility and blue sclerae. In most cases, 'functional null' alleles of COL1A1 on chromosome 17 or COL1A2 on chromosome 7 lead to reduced amounts of normal collagen I." +MONDO_0009431,"Definition: Hereditary hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by previous studies)." +MONDO_0010120,"Definition: Thrombocytopenia-3 (THC3) is an autosomal recessive hematologic disorder characterized by onset of small-platelet thrombocytopenia in infancy. Patients may show variable bleeding tendency, manifest as petechiae, epistaxis, or heavy menstrual bleeding (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see previous studies." +MONDO_0010933,"Definition: DFNB4 with enlarged vestibular aqueduct is characterized by pre- or perilingual onset of sensorineural or mixed hearing loss, which may be fluctuating or progressive. The hearing loss is associated with temporal bone abnormalities, most commonly enlargement of the vestibular aqueduct, but it can also include the more severe Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2.5 turns is replaced by a hypoplastic coil of 1.5 turns (summary by previous studies and previous studies). Enlarged vestibular aqueduct is the most common form of inner ear abnormality and can be associated with disequilibrium symptoms in a minority of patients (previous studies; previous studies; previous studies; previous studies; previous studies; previous studies)." +MONDO_0012392,"Definition: 2-Methylbutyryl-CoA dehydrogenase deficiency is an autosomal recessive metabolic disorder of impaired isoleucine degradation. It is most often ascertained via newborn screening and is usually clinically asymptomatic, although some patients have been reported to have delayed development and neurologic signs. Therefore, the clinical relevance of the deficiency is unclear (previous studies)." +MONDO_0012593,"Definition: Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) is an autosomal dominant disorder characterized by onset of this triad of features in infancy. Movement abnormalities begin with muscular hypotonia followed by the development of chorea, athetosis, dystonia, ataxia, and dysarthria. Some patients show neonatal respiratory distress and developmental delay. The phenotype is variable both between and within families (summary by previous studies)." +Orphanet_280633,"Definition: Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by previous studies). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (previous studies). + + Genetic Heterogeneity of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome + +MCAHS2 (previous studies) is caused by mutation in the PIGA gene (previous studies) on chromosome Xp22, MCAHS3 (previous studies) is caused by mutation in the PIGT gene (previous studies) on chromosome 20q13, and MCAHS4 (previous studies) is caused by mutation in the PIGQ gene (previous studies) on chromosome 16p13. + +previous studies provided a review of the main clinical features of the different types of MCAHS, noting that patients with mutations in the PIGN, PIGA, and PIGT genes have distinct patterns of facial anomalies that can be detected by computer-assisted comparison. Some individuals with MCAHS may have variable increases in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. previous studies concluded that a distinction between MCAHS and HPMRS1 (previous studies), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified together under the more encompassing term of 'GPI biosynthesis defects' (GPIBD)." +MONDO_0013563,"Definition: Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by previous studies). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (previous studies). + + Genetic Heterogeneity of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome + +MCAHS2 (previous studies) is caused by mutation in the PIGA gene (previous studies) on chromosome Xp22, MCAHS3 (previous studies) is caused by mutation in the PIGT gene (previous studies) on chromosome 20q13, and MCAHS4 (previous studies) is caused by mutation in the PIGQ gene (previous studies) on chromosome 16p13. + +previous studies provided a review of the main clinical features of the different types of MCAHS, noting that patients with mutations in the PIGN, PIGA, and PIGT genes have distinct patterns of facial anomalies that can be detected by computer-assisted comparison. Some individuals with MCAHS may have variable increases in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. previous studies concluded that a distinction between MCAHS and HPMRS1 (previous studies), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified together under the more encompassing term of 'GPI biosynthesis defects' (GPIBD)." +EFO_0000768,"Definition: Interstitial lung disease (ILD) comprises a heterogeneous group of rare diseases affecting the distal part of the lung and characterized by a progressive remodeling of the alveolar interstitium. The manifestations form a spectrum ranging from idiopathic interstitial pneumonia (IIP) or pneumonitis to the more severe idiopathic pulmonary fibrosis (IPF). IPF is associated with an increased risk of developing lung cancer, which occurs in a subset of patients with ILD. Clinical features of ILD include dyspnea, clubbing of the fingers, and restrictive lung capacity. Imaging typically shows ground glass opacities and inter- and intraseptal thickening, while histologic studies usually show a pattern consistent with 'usual interstitial pneumonia' (UIP) (review by previous studies; summary by previous studies). + +Idiopathic pulmonary fibrosis is one of a family of idiopathic pneumonias sharing clinical features of shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees in inflammation, fibrosis, or both on lung biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Although older studies included several forms of interstitial pneumonia under the term 'idiopathic pulmonary fibrosis,' the clinical label of 'idiopathic pulmonary fibrosis' should be reserved for patients with a specific form of fibrosing interstitial pneumonia referred to as usual interstitial pneumonia (previous studies). It is estimated that 0.5 to 2.2% of cases of idiopathic pulmonary fibrosis are familial (previous studies). previous studies reviewed idiopathic pulmonary fibrosis, emphasizing definition, pathogenesis, diagnosis, natural history, and therapy. previous studies provided a 'top ten list' of references pertaining to etiopathogenesis, prognosis, diagnosis, therapy, and other aspects of idiopathic pulmonary fibrosis. + +For a discussion of genetic heterogeneity of ILD, see ILD1 (previous studies). + +Pulmonary fibrosis can also be a feature in patients with mutations in the TERT (previous studies) or the TERC (previous studies) gene; see PFBMFT1 (previous studies) and PFBMFT2 (previous studies). + +Some patients with surfactant protein C deficiency (previous studies) who survive to adulthood manifest features of pulmonary fibrosis." +MONDO_0008318,"Definition: Proteus syndrome is a highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Specific features include cerebriform connective tissue nevus, thin limbs, lipomas, and lung cysts. Some patients may have intellectual disability with dysmorphic facies. Deep venous thrombosis is common and constitutes a significant risk factor. Many features of Proteus syndrome overlap with other overgrowth syndromes (previous studies; review by previous studies). + +previous studies provided a detailed review of the clinical features, diagnosis, and management issues of Proteus syndrome. + +Some authors (previous studies; previous studies) have reported a 'Proteus-like' syndrome associated with germline and tissue-specific somatic mutations in the PTEN gene (previous studies), which is mutated in Cowden syndrome (CWS1); see previous studies for a discussion of these patients." +MONDO_0010038,"Definition: Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features." +MONDO_0013521,"Definition: Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, pulmonary and liver fibrosis, premature graying of the hair, immunodeficiency, and gastrointestinal disease (previous studies; previous studies). + +For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (previous studies)." +MONDO_0014404,"Definition: Webb-Dattani syndrome is an autosomal recessive disorder characterized by frontotemporal hypoplasia, globally delayed development, and pituitary and hypothalamic insufficiency due to hypoplastic development of these brain regions. Patients present soon after birth with multiple pituitary hormonal deficiencies and subsequently develop microcephaly, seizures, and spasticity. Other features include postretinal blindness and renal abnormalities (summary by previous studies)." +MONDO_0032572,Definition: CAFDADD is a multisystemic developmental disorder with variable cardiac and digital anomalies and facial dysmorphism. Some patients may have seizures and ocular/aural abnormalities (previous studies). +MONDO_0032895,"Definition: Developmental and epileptic encephalopathy-83 (DEE83) is a severe autosomal recessive neurodevelopmental disorder characterized by onset of frequent seizures in the first days to months of life that are usually refractory to medical treatment and are associated with significant EEG abnormalities. Affected individuals have profoundly impaired development, with no motor or language skill acquisition, poor or absent visual tracking, and poor oromotor function necessitating tube feeding. Many patients die in the first years of life (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +Orphanet_300547,"Definition: Infantile hypercalcemia is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypercalcemia, see HCINF1 (previous studies)." +Orphanet_3301,"Definition: Tetraamelia syndrome-1 is characterized by complete limb agenesis without defects of scapulae or clavicles. Other features include bilateral cleft lip/palate, diaphragmatic defect with bilobar right lung, renal and adrenal agenesis, pelvic hypoplasia, and urogenital defects (previous studies). + + Genetic Heterogeneity of tetraamelia syndrome + +Tetraamelia syndrome-2 (TETAMS2; previous studies) is caused by mutation in the RSPO2 gene (previous studies) on chromosome 8q23." +EFO_0009032,"Definition: Combined oxidative phosphorylation deficiency-21 (COXPD21) is an autosomal recessive disorder characterized either by onset within the first months of life of severe hypotonia, failure to thrive, epilepsy and early death or by onset after 6 months of life with a milder course and longer survival (summary by previous studies) + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +MONDO_0008939,"Definition: Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of hypotonia and developmental delay with subsequent impaired intellectual development and severe speech delay. In childhood, affected individuals show delayed walking and develop epilepsy that is usually controlled by medication. Brain imaging shows cerebellar hypoplasia/atrophy (summary by previous studies)." +MONDO_0009948,"Definition: Hereditary pyropoikilocytosis was originally described by previous studies as a distinct hemolytic anemia characterized by microspherocytosis, poikilocytosis, and an unusual thermal sensitivity of red cells. + +HPP is a subset of hereditary elliptocytosis (see previous studies) due to homozygous or compound heterozygous mutations in spectrin leading to severe disruption of spectrin self-association (review by previous studies)." +MONDO_0010171,"Definition: Usher syndrome type I is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually evident within the first decade), and constant vestibular dysfunction. Type I is distinguished from type II (previous studies) on the basis of severity of hearing loss and the extent of vestibular involvement. Type I patients are profoundly deaf, whereas type II patients are 'hard of hearing.' Vestibular function is defective in type I patients, whereas type II patients have normal vestibular function (previous studies). Patients with type III (USH3; previous studies) have progressive hearing loss. + +For a discussion of genetic heterogeneity of Usher syndrome type I, see USH1 (previous studies)." +MONDO_0011973,"Definition: Transient neonatal zinc deficiency occurs in breast-fed infants as a consequence of low milk zinc concentration in their nursing mothers, which cannot be corrected by maternal zinc supplementation. A large amount of zinc, an essential trace mineral, is required for normal growth particularly in infants, and breast milk normally contains adequate zinc to meet the requirement for infants up to 4 to 6 months of age. Zinc deficiency can lead to dermatitis, alopecia, decreased growth, and impaired immune function. The disorder shows autosomal dominant inheritance with incomplete penetrance (summary by previous studies). + +Some aspects of TNZD resemble the more severe disorder acrodermatitis enteropathica (AEZ; previous studies), an autosomal recessive disorder caused by mutation in the zinc transporter SLC39A4 (previous studies). However, infants with transient neonatal zinc deficiency do not require zinc supplementation following weaning and have normal zinc absorption, whereas those with AEZ require lifelong zinc supplementation (summary by previous studies)." +MONDO_0013595,"Definition: Hyperbiliverdinemia can manifest as green jaundice, which is a green discoloration of the skin, urine, serum, and other bodily fluids, due to increased biliverdin resulting from inefficient conversion to bilirubin. Although rarely reported, affected individuals appear to have symptoms only in the context of obstructive cholestasis and/or liver failure. In some cases, green jaundice can resolve after resolution of obstructive cholestasis. Green jaundice has also been associated with malnutrition, medication, and congenital biliary atresia (summary by previous studies)." +MONDO_0044721,"Definition: IMD52 is an autosomal recessive primary immunodeficiency with variable manifestations, including severe combined immunodeficiency, hematologic autoimmune disorders, progressive lymphopenia and hypogammaglobulinemia, and lymphoproliferation with splenomegaly. Patients develop severe recurrent infections from infancy, and most die without bone marrow transplantation. The variable clinical features result from a defect in T-cell receptor signaling (summary by previous studies and previous studies)." +MONDO_0859080,"Definition: X-linked syndromic intellectual developmental disorder with pigmentary mosaicism and coarse facies (MRXSPF) is characterized by a phenotypic triad of severe developmental delay, coarse facial dysmorphisms, and Blaschkoid pigmentary mosaicism. Additional clinical features may include epilepsy, orthopedic abnormalities, hypotonia, and growth abnormalities. The disorder affects both males and females (previous studies; previous studies)." +Orphanet_137667,"Definition: Capillary malformation-arteriovenous malformation-1 (CMAVM1) is an autosomal dominant disorder characterized by atypical capillary malformations (CMs), often in association with fast-flow vascular malformations, including arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs), and Parkes Weber syndrome (PKWS). The CMs are usually multifocal and are surrounded by a pale halo with a central red dot; they increase in number with age. The AVMs generally occur in the brain or on the face or extremities. Intracranial AVMs include vein of Galen aneurysmal malformations (VGAMs). Parkes Weber syndrome is a specific type of CMAVM that presents with limb overgrowth, more commonly affecting one of the lower extremities (previous studies; previous studies; previous studies). Parkes Weber syndrome is characterized by a cutaneous blush with underlying multiple micro-AVFs in association with soft-tissue and skeletal hypertrophy of the affected limb (previous studies). + + Genetic Heterogeneity of Capillary Malformation-Arteriovenous Malformation + +Also see CMAVM2 (previous studies), caused by mutation in the EPHB4 gene on chromosome 7q22." +Orphanet_1871,"Definition: Progressive cone dystrophy usually presents in childhood or early adult life, with many patients developing rod photoreceptor involvement in later life, thereby leading to considerable overlap between progressive cone dystrophy and cone-rod dystrophy. Both progressive cone dystrophy and cone-rod dystrophy have been associated with mutation in the GUCA1A gene (previous studies). + +Intrafamilial variability in GUCA1A-associated macular disease ranges from mild photoreceptor degeneration to central areolar choroidal dystrophy (CACD), a form of retinal degeneration that primarily involves the macula and is characterized by a well-defined atrophic region of retinal pigment epithelium and choriocapillaris in the latest stage (previous studies)." +MONDO_0011193,"Definition: Progressive cone dystrophy usually presents in childhood or early adult life, with many patients developing rod photoreceptor involvement in later life, thereby leading to considerable overlap between progressive cone dystrophy and cone-rod dystrophy. Both progressive cone dystrophy and cone-rod dystrophy have been associated with mutation in the GUCA1A gene (previous studies). + +Intrafamilial variability in GUCA1A-associated macular disease ranges from mild photoreceptor degeneration to central areolar choroidal dystrophy (CACD), a form of retinal degeneration that primarily involves the macula and is characterized by a well-defined atrophic region of retinal pigment epithelium and choriocapillaris in the latest stage (previous studies)." +EFO_0009023,"Definition: BBS12 is a clinically pleiotropic autosomal recessive ciliopathy. The patients with BBS12 studied by previous studies and previous studies met the diagnostic criteria of previous studies, which required the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features (e.g., developmental delay, ataxia, cataracts). + +For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +MONDO_0007809,"Definition: The Lambert type of ichthyosis hystrix (IHL) is characterized by normal skin at birth that develops striking spiny hyperkeratotic lesions within a few months. There is sparing of the face, palms, and soles, and affected individuals do not experience blistering. Marked improvement of lesions during the summer months has also been observed in some patients. Ultrastructurally, binuclear cells and tonofilament shells surrounding the nucleus in upper keratinocytes are observed (summary by previous studies; previous studies; previous studies). + +Another form of ichthyosis hystrix, the Curth-Macklin type (IHCM; previous studies), includes severe palmoplantar keratoderma among its features and is caused by mutation in the KRT1 (previous studies) gene." +MONDO_0007987,"Definition: Kniest dysplasia is characterized by skeletal and craniofacial anomalies. Skeletal anomalies include disproportionate dwarfism, a short trunk and small pelvis, kyphoscoliosis, short limbs, and prominent joints and premature osteoarthritis that restrict movement. Craniofacial manifestations include midface hypoplasia, cleft palate, early-onset myopia, retinal detachment, and hearing loss. The phenotype is severe in some patients and mild in others. There are distinct radiographic changes including coronal clefts of vertebrae and dumbbell-shaped femora. The chondrooseous morphology is pathognomonic with perilacunar 'foaminess' and sparse, aggregated collagen fibrils resulting in an interterritorial matrix with a 'Swiss-cheese' appearance (summary by previous studies)." +MONDO_0008151,"Definition: Gnathodiaphyseal dysplasia is an autosomal dominant generalized skeletal syndrome characterized by cementoosseous lesions of the jawbones, in conjunction with bone fragility, bowing/cortical thickening of tubular bones, and diaphyseal sclerosis of long bones (summary by previous studies)." +MONDO_0014190,"Definition: Combined oxidative phosphorylation deficiency-17 is an autosomal recessive disorder of mitochondrial dysfunction characterized by onset of severe hypertrophic cardiomyopathy in the first year of life. Other features include hypotonia, poor growth, lactic acidosis, and failure to thrive. The disorder may be fatal in early childhood (summary by previous studies)." +MONDO_0044724,"Definition: 3-Methylglutaconic aciduria type IX (MGCA9) is an autosomal recessive disorder characterized by early-onset seizures, severely delayed psychomotor development and intellectual disability. Patients have hypotonia or spasticity, and laboratory investigations show increased serum lactate and 3-methylglutaconic aciduria, suggestive of a mitochondrial defect (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (previous studies)." +MONDO_0100325,"Definition: Odontochondrodysplasia-1 (ODCD1) is characterized by mesomelic shortening of tubular bones, ligamentous laxity, and scoliosis, in association with dentinogenesis imperfecta involving both primary and secondary dentition. Affected individuals show variable severity. Radiologic features include trident pelvis, posteriorly flattened vertebrae, and brachydactyly with cone-shaped epiphyses (previous studies). Clinical variability and extraskeletal manifestations have been observed (previous studies). + + Genetic Heterogeneity of Odontochondrodysplasia + +Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2; previous studies) is caused by mutation in the TANGO1 gene (MIA3; previous studies) on chromosome 1q41." +EFO_0009037,"Definition: Combined oxidative phosphorylation deficiency-27 (COXPD27) is an autosomal recessive multisystem disorder characterized mainly by neurologic features, including delayed development, seizures, abnormal movements, and neurologic regression. Age at onset, ranging from infancy to late childhood, and severity are variable. Other features include hypotonia, myoclonus, brain imaging abnormalities, and evidence of mitochondrial dysfunction in skeletal muscle. Liver dysfunction has also been reported (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +EFO_0009300,"Definition: NDHMSD is a severe neurodevelopmental disorder characterized by profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, and a hyperkinetic movement disorder. Additional features may include cortical blindness, generalized cerebral atrophy, and seizures (summary by previous studies)." +MONDO_0013655,"Definition: NDHMSD is a severe neurodevelopmental disorder characterized by profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, and a hyperkinetic movement disorder. Additional features may include cortical blindness, generalized cerebral atrophy, and seizures (summary by previous studies)." +EFO_0009647,"Definition: Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB) is an autosomal recessive disorder characterized by severe neurologic impairment including impaired intellectual development, epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. Most affected individuals are nonambulatory, cannot sit unassisted, and have no speech development. More variable features include feeding difficulties, poor growth, cortical visual impairment, spasticity, scoliosis, immunodeficiency, and thrombocytopenia (previous studies)." +MONDO_0009305,"Definition: Immunodeficiency-59 is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocytopenia and B-cell and dentritic cell deficiency are present (previous studies)." +MONDO_0009345,"Definition: Histidinemia is a metabolic disorder characterized by increased levels of histidine in blood, urine, and cerebrospinal fluid, and decreased levels of the metabolite urocanic acid in blood, urine, and skin cells. Although histidinemia was originally associated with mental retardation and speech defects, it is generally considered to be a benign disorder (previous studies). However, it is possible that histidinemia may be a risk factor for developmental disorders in certain individuals under specific circumstances, such as perinatal events (previous studies)." +MONDO_0014031,"Definition: Alazami syndrome is an autosomal recessive disorder characterized by severe growth restriction present at birth, severely impaired intellectual development, and distinctive facial features. Some patients have been reported with skeletal and behavioral features (summary by previous studies)." +MONDO_0014816,"Definition: Split-foot malformation with mesoaxial polydactyly (SFMMP) is characterized by a split-foot defect and nail abnormalities of the hands, as well as hearing loss in some patients (previous studies)." +MONDO_0030916,"Definition: Autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50) is characterized by variable levels of impaired intellectual development, delayed speech and motor milestones, and behavioral abnormalities, most commonly autism spectrum disorder (ASD). Some patients may also have mild craniofacial dysmorphism, congenital cardiac anomalies, or seizures (summary by previous studies)." +MONDO_0008165,"Definition: Southeast Asian ovalocytosis is a hereditary red blood cell disorder that is widespread in certain ethnic groups of Malaysia, Papua New Guinea, the Philippines, and Indonesia. Ovalocytic erythrocytes are rigid and exhibit reduced expression of many erythrocyte antigens. The ovalocytes are resistant to invasion in vitro by several strains of malaria, including Plasmodium falciparum and Plasmodium knowlesi (summary by previous studies). The disorder is most often asymptomatic but has been reported to be associated with signs of mild hemolysis such as intermittent jaundice and gallstones (summary by previous studies)." +MONDO_0008925,"Definition: Juvenile-onset cataract-46 with or without arrhythmic cardiomyopathy (CRCT46) is characterized by onset of cataract in the first decades of life, associated with variable onset of a severe form of arrhythmic cardiomyopathy, with mild impairment of left ventricular systolic function but severe ventricular arrhythmias resulting in sudden cardiac death. Affected individuals are descendants of the Hutterite founder population (previous studies)." +MONDO_0009400,"Definition: previous studies noted that prospective studies of HPI probands identified through newborn screening as well as reports of several families have suggested that it is a metabolic disorder not clearly associated with clinical manifestations. previous studies concluded that HPI is a relatively benign condition in most individuals under most circumstances. However, other reports have suggested that some patients have a severe phenotype with neurologic manifestations, including epilepsy and mental retardation (previous studies). + + Genetic Heterogeneity of Hyperprolinemia + +See also hyperprolinemia type II (HYRPRO2; previous studies), which is caused by mutation in the gene encoding pyrroline-5-carboxylate dehydrogenase (P5CDH, ALDH4A1; previous studies) on chromosome 1p36." +MONDO_0009675,"Definition: Autosomal recessive limb-girdle muscular dystrophy-1 affects primarily the proximal muscles, resulting in difficulty walking. The age at onset varies, but most patients show onset in childhood, and the disorder is progressive. Other features may include scapular winging, calf pseudohypertrophy, and contractures (summary by previous studies). + + Genetic Heterogeneity of Autosomal Recessive Limb-Girdle Muscular Dystrophy + +Autosomal recessive LGMD is genetically heterogeneous. + +LGMDR2 (previous studies), previously symbolized LGMD2B, is caused by mutation in the dysferlin gene (DYSF; previous studies) on 2p13. LGMDR3 (previous studies), previously symbolized LGMD2D, is caused by mutation in the alpha-sarcoglycan gene (SGCA; previous studies) on 17q21. LGMDR4 (previous studies), previously symbolized LGMD2E, is caused by mutation in the beta-sarcoglycan gene (SGCB; previous studies) on 4q12. LGMDR5 (previous studies), previously symbolized LGMD2C, is caused by mutation in the gamma-sarcoglycan gene (SGCG; previous studies) on 13q12. LGMDR6 (previous studies), previously symbolized LGMD2F, is caused by mutation in the delta-sarcoglycan gene (SGCD; previous studies) on 5q33. LGMDR7 (previous studies), previously symbolized LGMD2G, is caused by mutation in the TCAP gene (previous studies) on 17q12. LGMDR8 (previous studies), previously symbolized LGMD2H, is caused by mutation in the TRIM32 gene (previous studies) on 9q33. LGMDR9 (previous studies), previously symbolized LGMD2I, is caused by mutation in the FKRP gene (previous studies) on 19q13. LGMDR10 (previous studies), previously symbolized LGMD2J, is caused by mutation in the titin gene (TTN; previous studies) on 2q31. LGMDR11 (previous studies), previously symbolized LGMD2K, is caused by mutation in the POMT1 gene (previous studies) on 9q34. LGMDR12 (previous studies), previously symbolized LGMD2L, is caused by mutation in the ANO5 gene (previous studies) on 11p14. LGMDR13 (previous studies), previously symbolized LGMD2M, is caused by mutation in the FKTN gene (previous studies) on 9q31. LGMDR14 (previous studies), previously symbolized LGMD2N, is caused by mutation in the POMT2 gene (previous studies) on 14q24. LGMDR15 (previous studies), previously symbolized LGMD2O, is caused by mutation in the POMGNT1 gene (previous studies) on 1p34. LGMDR16 (previous studies), previously symbolized LGMD2P, is caused by mutation in the DAG1 gene (previous studies) on 3p21. LGMDR17 (previous studies), previously symbolized LGMD2Q, is caused by mutation in the PLEC1 gene (previous studies) on 8q24. LGMDR18 (previous studies), previously symbolized LGMD2S, is caused by mutation in the TRAPPC11 gene (previous studies) on 4q35. LGMDR19 (previous studies), previously symbolized LGMD2T, is caused by mutation in the GMPPB gene (previous studies) on 3p21. LGMDR20 (previous studies), previously symbolized LGMD2U, is caused by mutation in the ISPD gene (CRPPA; previous studies) on 7p21. LGMDR21 (previous studies), previously symbolized LGMD2Z, is caused by mutation in the POGLUT1 gene (previous studies) on 3q13. LGMDR22 (previous studies), also known as Ullrich congenital muscular dystrophy, is caused by mutation in one of the collagen VI genes (previous studies, previous studies, previous studies). LGMDR23 (previous studies) is caused by mutation in the LAMA2 gene (previous studies) on 6q22. LGMDR24 (previous studies) is caused by mutation in the POMGNT2 gene (previous studies) on 3p22. LGMDR25 (previous studies), previously symbolized LGMD2X, is caused by mutation in the BVES gene (previous studies) on 6q21. LGMDR26 (previous studies) is caused by mutation in the POPDC3 gene (previous studies) on 6q21. LGMDR27 (previous studies) is caused by mutation in the JAG2 gene (previous studies) on 14q32. LGMDR28 (previous studies) is caused by mutation in the HMGCR gene (previous studies) on 5q13. + +Some forms of autosomal recessive LGMD were reclassified by previous studies. LGMD2R was reclassified as a form of myofibrillar myopathy (MFM1; previous studies). For forms previously designated LGMD2W and LGMD2Y, see previous studies and previous studies, respectively. + +For a discussion of autosomal dominant LGMD, see LGMDD1 (previous studies)." +MONDO_0010520,"Definition: Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (review by previous studies). + + Genetic Heterogeneity of Alport Syndrome + +Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type IV collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (ATS2; previous studies); autosomal dominant inheritance (ATS3; previous studies) is rare (previous studies). + +See also benign familial hematuria (BFH; previous studies), a phenotypically similar, but milder disorder. + +Alport syndrome is also a feature of 2 contiguous gene deletion syndromes involving the COL4A5 gene: Alport syndrome and diffuse leiomyomatosis (previous studies) and Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME; previous studies)." +MONDO_0011243,"Definition: Grange syndrome (GRNG) is a rare early-onset disease characterized by hypertension and multifocal stenoocclusive lesions of renal, cerebral, and abdominal arteries. Bone fragility, syndactyly, brachydactyly, congenital heart defects, and learning disabilities have been reported with variable expressivity and incomplete penetrance (summary by previous studies)." +Orphanet_773,"Definition: While most patients of PBD complementation group 11 manifest rhizomelic chondrodysplasia punctata (RCDP1; previous studies), a few have been reported with unusually mild phenotypes with longer survival, less neurologic involvement, normal or near-normal growth, and absence of rhizomelia (previous studies). In some cases this phenotype was indistinguishable from that of classic Refsum disease (previous studies) and patients carried this diagnosis. + +Individuals with PBDs of complementation group 11 (CG11, equivalent to CGR) have mutations in the PEX7 gene. For information on the history of PBD complementation groups, see previous studies." +EFO_0010739,"Definition: Early-onset epilepsy with or without developmental delay (EPEDD) is an autosomal dominant neurologic disorder characterized by the onset of generalized tonic-clonic seizures in the first days, months, or years of life. The severity is highly variable: some patients have normal psychomotor development and normal brain imaging, whereas others may show developmental delay associated with abnormalities on brain imaging (summary by previous studies)." +MONDO_0008892,"Definition: Progressive familial intrahepatic cholestasis is a heterogeneous group of autosomal recessive liver disorders characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood (previous studies; previous studies; previous studies). + + Genetic Heterogeneity of Progressive Familial Intrahepatic Cholestasis + +PFIC is a genetically heterogeneous disorder caused by defects in the transport of bile acids. See also PFIC2 (previous studies), caused by mutation in a liver-specific ATP-binding cassette transporter gene (ABCB11; previous studies) on chromosome 2q24; PFIC3 (previous studies), caused by mutation in the class III multidrug resistance P-glycoprotein gene (ABCB4; previous studies) on chromosome 7q21; PFIC4 (previous studies), caused by mutation in the TJP2 gene (previous studies) on chromosome 9q12; PFIC5 (previous studies), caused by mutation in the NR1H4 gene (previous studies) on chromosome 12q23; PFIC6 (previous studies), caused by mutation in the SLC51A gene (previous studies) on chromosome 3q29; PFIC7 (previous studies), caused by mutation in the USP53 gene (previous studies) on chromosome 4q26; PFIC8 (previous studies), caused by mutation in the KIF12 gene (previous studies) on chromosome 9q32; PFIC9 (previous studies), caused by mutation in the ZFYVE19 gene (previous studies) on chromosome 15q15; PFIC10 (previous studies), caused by mutation in the MYO5B gene (previous studies) on chromosome 18q21; PFIC11 (previous studies), caused by mutation in the SEMA7A gene (previous studies) on chromosome 15q24; and PFIC12 (previous studies), caused by mutation in the VPS33B gene (previous studies) on chromosome 15q26. + +PFIC1 and PFIC2 are associated with mildly elevated or normal serum levels of gamma-glutamyltransferase (GGT; see previous studies), whereas PFIC3 is associated with high serum GGT levels and liver histology that shows portal inflammation and ductular proliferation in an early stage (previous studies). PFIC4 is associated with normal or mildly increased GGT levels (previous studies). PFIC5 is associated with low to normal GGT levels. PFIC8 and PFIC9 are associated with high GGT levels. + +There are also several phenotypically similar liver disorders that result from congenital defects in bile acid synthesis. See CBAS1 (previous studies)." +MONDO_0009452,"Definition: Vici syndrome is a rare congenital multisystem disorder characterized by agenesis of the corpus callosum (ACC), cataracts, pigmentary defects, progressive cardiomyopathy, and variable immunodeficiency. Affected individuals also have profound psychomotor retardation and hypotonia due to a myopathy (summary by previous studies)." +MONDO_0009528,Definition: Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy (previous studies). +MONDO_0011156,"Definition: Progressive familial intrahepatic cholestasis-2 (PFIC2) is an autosomal recessive disorder characterized by progressive liver disease with impairment of bile flow, but without hepatobiliary structural abnormality. Patients have amorphous or finely filamentous bile and nonspecific giant cell hepatitis on presentation (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (previous studies)." +MONDO_0013904,"Definition: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (previous studies)." +MONDO_0014061,"Definition: Steel syndrome is characterized by characteristic facies, dislocated hips and radial heads, carpal coalition (fusion of carpal bones), short stature, scoliosis, and cervical spine anomalies. The dislocated hips are resistant to surgical intervention (summary by previous studies)." +MONDO_0014311,"Definition: Autosomal recessive spinocerebellar ataxia-15 (SCAR15) is characterized by early-onset ataxia, cognitive impairment, dysarthria, and developmental delay. Variable features include seizures, nystagmus, and abnormal reflexes (previous studies)." +MONDO_0014453,"Definition: Immunodeficiency-36 with lymphoproliferation (IMD36) is an autosomal dominant primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (previous studies)." +MONDO_0014810,"Definition: Common variable immunodeficiency-13 (CVID13) is an autosomal dominant primary immunodeficiency disorder characterized by recurrent bacterial infections, mainly affecting the respiratory tract, and associated with hypogammaglobulinemia and decreased numbers of B cells. The age at onset of clinical features can range from infancy to adulthood, and some patients may have a mild disorder or even remain clinically asymptomatic (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (previous studies)." +MONDO_0020840,"Definition: Immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100) is primarily a lung disorder characterized by onset of respiratory insufficiency due to pulmonary alveolar proteinosis (PAP) in the first months of life. Affected individuals may have normal respiratory function at birth. Development of the disorder appears to be influenced or triggered by viral infection, manifest as progressive respiratory insufficiency, confluent consolidations on lung imaging, and diffuse collection of periodic acid-Schiff (PAS)-positive material in pulmonary alveoli associated with small and nonfoamy alveolar macrophages. Patients also have hypogammaglobulinemia, leukocytosis, and splenomegaly. Many patients die of respiratory failure in infancy or early childhood; hematopoietic stem cell transplantation (HSCT) is curative. The pathogenesis may be related to abnormal function of alveolar macrophages, resulting in decreased catabolism of surfactant (summary by previous studies). previous studies determined that the disorder results from a gain-of-function effect that particularly affects B cells and monocytes." +MONDO_0029135,"Definition: MDDGC8 is an autosomal recessive muscular dystrophy with onset in childhood. The phenotype is highly variable: some patients may have gait difficulties and impaired intellectual development, whereas others may be clinically asymptomatic. Common features include calf hypertrophy and increased serum creatine kinase, and muscle biopsy often shows dystrophic features (summary by previous studies). The disorder is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (previous studies). + +For a discussion of genetic heterogeneity of muscular dystrophy- dystroglycanopathy type C, see MDDGC1 (previous studies)." +MONDO_0030990,"Definition: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. The phenotype is reminiscent of Kohlschutter-Tonz syndrome (KTZS; previous studies). More variable features of KTZSL include visual defects, behavioral abnormalities, and nonspecific involvement of other organ systems (summary by previous studies)." +MONDO_0859158,"Definition: Childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS) is a neurodevelopmental disorder characterized by delayed walking due to ataxia, intention tremor, and hypotonia apparent from early childhood. Affected individuals have global developmental delay with mildly impaired intellectual development and speech delay or learning disabilities. Eye movement abnormalities may also be present. Brain imaging shows cerebellar atrophy in some patients (summary by previous studies)." +Orphanet_168615,Definition: Hereditary persistence of alpha-fetoprotein (HPAFP) is a clinically benign autosomal dominant condition characterized by continued expression of alpha-fetoprotein in adult life (summary by previous studies). +MONDO_0007088,"Definition: Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions (previous studies). previous studies pointed out that the 'presenile' form, with onset before age 65, is identical to the most common form of late-onset or 'senile' dementia, and suggested the term 'senile dementia of the Alzheimer type' (SDAT). + +previous studies reviewed the genetics of AD. previous studies reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimer disease. previous studies reviewed the transcriptional regulation of the genes involved in Alzheimer disease. + + Genetic Heterogeneity of Alzheimer Disease + +Alzheimer disease is a genetically heterogeneous disorder. See also AD2 (previous studies), associated with the APOE*4 allele (previous studies) on chromosome 19; AD3 (previous studies), caused by mutation in the presenilin-1 gene (PSEN1; previous studies) on 14q; and AD4 (previous studies), caused by mutation in the PSEN2 gene (previous studies) on 1q31. + +There is evidence for additional AD loci on other chromosomes; see AD5 (previous studies) on 12p11; AD6 (previous studies) on 10q24; AD7 (previous studies) on 10p13; AD8 (previous studies) on 20p; AD9 (previous studies), associated with variation in the ABCA7 gene (previous studies) on 19p13; AD10 (previous studies) on 7q36; AD11 (previous studies) on 9q22; AD12 (previous studies) on 8p12-q22; AD13 (previous studies) on 1q21; AD14 (previous studies) on 1q25; AD15 (previous studies) on 3q22-q24; AD16 (previous studies) on Xq21.3; AD17 (previous studies) on 6p21.2; and AD18 (previous studies), associated with variation in the ADAM10 gene (previous studies) on 15q21. + +Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease (previous studies). + +Finally, there have been associations between AD and various polymorphisms in other genes, including alpha-2-macroglobulin (A2M; previous studies), low density lipoprotein-related protein-1 (LRP1; previous studies), the transferrin gene (TF; previous studies), the hemochromatosis gene (HFE; previous studies), the NOS3 gene (previous studies), the vascular endothelial growth factor gene (VEGF; previous studies), the ABCA2 gene (previous studies), and the TNF gene (previous studies) (see MOLECULAR GENETICS)." +MONDO_0007216,Definition: Brachydactyly type A2 is an autosomal dominant disorder characterized by malformations of the middle phalanx of the index finger and by anomalies of the second toe (summary by previous studies). +MONDO_0009061,"Definition: Cystic fibrosis (CF) is classically described as a triad of chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevation of sodium and chloride concentration in sweat. Almost all males with CF are infertile due to congenital bilateral absence of the vas deferens. The disorder is associated with decreased longevity (summary by previous studies). + +For discussion of a phenotype consisting of bronchiectasis with or without elevated sweat chloride caused by mutation in the genes encoding the 3 subunits of the epithelial sodium channel, see BESC1 (previous studies)." +MONDO_0010080,"Definition: Bilateral striatal necrosis (BSN) encompasses a heterogeneous group of neurologic disorders with different causation. Familial infantile striatal degeneration is rare and can be inherited as an autosomal recessive or mitochondrial (see previous studies) disorder. The familial form has an insidious onset and a slowly progressive course; the sporadic form is associated with acute systemic illness. Many features of BSN overlap with Leigh syndrome (see previous studies) and certain metabolic disorders, including glutaric acidemia I (previous studies) and methylmalonic aciduria (previous studies). See also Aicardi-Goutieres syndrome (previous studies) (previous studies; previous studies). + + Genetic Heterogeneity of Striatonigral Degeneration + +Childhood-onset striatonigral degeneration (previous studies) is caused by mutation in the VAC14 gene (previous studies) on chromosome 16q22. + +See also adult-onset autosomal dominant striatal degeneration (ADSD; previous studies), caused by mutation in the PDE8B gene (previous studies) on chromosome 5q13, and early-onset dystonia-37 with striatal lesions (DYT37; previous studies), caused by mutation in the NUP54 gene (previous studies) on chromosome 4q21." +MONDO_0012271,"Definition: Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) represents a distinctive combination of clinical features that includes mesoaxial osseous synostosis at a metacarpal level, reduction of one or more phalanges, hypoplasia of distal phalanges of preaxial and postaxial digits, clinodactyly of fifth fingers, and preaxial fusion of toes (previous studies)." +MONDO_0014162,Definition: Combined oxidative phosphorylation deficiency-16 (COXPD16) is an autosomal recessive multisystem disorder with hypertrophic cardiomyopathy as a major feature. +MONDO_0015270,"Definition: Individuals deficient in butyrylcholinesterase (BCHE) appear asymptomatic, apart from a heightened sensitivity to muscle relaxants such as suxamethonium (succinylcholine) and mivacurium, 2 BCHE carboxylester substrates. In individuals with usual BCHE levels, these drugs are rapidly hydrolyzed in plasma and their duration of action is short (less than 10 minutes). BCHE deficiency results in slower hydrolysis of these drugs and, consequently, a prolonged neuromuscular block, leading to apnea. Prolonged neuromuscular block occurs with BCHE deficiencies of marked severity (impairment over 70%). Although many acquired conditions may affect BCHE activity (e.g., liver or renal diseases, malnutrition, pregnancy, malignancy), BCHE deficiency is mainly due to mutations in the BCHE gene (summary by previous studies)." +MONDO_0018855,"Definition: Keratosis pilaris atrophicans (KPA) represents a group of rare genodermatoses characterized by perifollicular keratosis and inflammation that progresses to atrophy and scarring of the facial skin. Keratosis pilaris of extensor surfaces of limbs is a common associated finding. Affected individuals may present with features that overlap between 3 subtypes, keratosis pilaris atrophicans faciei (KPAF), keratosis follicularis spinulosa decalvans (KFSD), and atrophoderma vermiculata (AVA; see previous studies) (summary by previous studies)." +MONDO_0030006,"Definition: Combined oxidative phosphorylation deficiency-40 (COXPD40) is an autosomal recessive mitochondrial disorder with onset in utero or soon after birth. Affected individuals have severe hypertrophic cardiomyopathy, poor growth, and sensorineural hearing loss. Laboratory studies show evidence of mitochondrial dysfunction, such as lactic acidosis. Patient-derived tissues and cells show variably decreased activities of mitochondrial respiratory complexes I, III, IV, and V. The disorder is lethal, with no reported patients surviving past infancy (summary by previous studies). + +For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (previous studies)." +Orphanet_1766,"Definition: Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by previous studies). + +For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (previous studies)." +Orphanet_590,"Definition: Congenital myasthenic syndrome-13 (CMS13) is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by previous studies). + +For a discussion of genetic heterogeneity of CMS, see CMS1A (previous studies)." +Orphanet_98261,"Definition: Progressive myoclonic epilepsy-8 (EPM8) is a rare autosomal recessive form of progressive myoclonic epilepsy with phenotypic variability including ataxia and other movement disorders in addition to myoclonus (summary by previous studies). + +For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (previous studies)." +MONDO_0008907,"Definition: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs (see, e.g., CDG2A, previous studies) refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. CDG1A is the most common form of CDG and was the first to be characterized at the molecular level (reviews by previous studies; previous studies). + +previous studies noted that Jaeken syndrome (CDG1A) is a genetic multisystem disorder characterized by defective glycosylation of glycoconjugates. It usually presents as a severe disorder in the neonatal period. There is a severe encephalopathy with axial hypotonia, abnormal eye movement, and pronounced psychomotor retardation, as well as peripheral neuropathy, cerebellar hypoplasia, and retinitis pigmentosa. Patients show a peculiar distribution of subcutaneous fat, nipple retraction, and hypogonadism. There is a 20% lethality in the first year of life due to severe infections, liver insufficiency, or cardiomyopathy. + +previous studies noted that CDG1A is the most prevalent form of CDG, with more than 700 patients reported worldwide. + + Genetic Heterogeneity of Congenital Disorder of Glycosylation Type I + +Multiple forms of CDG type I have been identified; see CDG1B (previous studies) through CDG1Y (previous studies) and CDG1AA (previous studies) through CDG1CC (see previous studies). + +A congenital disorder of deglycosylation (CDDG; previous studies), formerly designated CDG1V, is caused by mutation in the NGLY1 gene (previous studies). + +A disorder formerly designated CDG1Z has been classified as a form of developmental and epileptic encephalopathy (DEE50; previous studies)." +MONDO_0009756,"Definition: Niemann-Pick disease types A and B are caused by an inherited deficiency of acid sphingomyelinase activity. The clinical phenotype ranges from a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age (type A) to a later-onset nonneurologic form (type B) that is compatible with survival into adulthood. Since intermediate cases also have been reported, the disease is best regarded as a single entity with a clinical spectrum (summary by previous studies). + +previous studies suggested that 3 types of the disorder can be distinguished: infantile cerebral, juvenile cerebral, and noncerebral. Later, 5 forms of Niemann-Pick disease were distinguished. Four were delineated by previous studies: the classical infantile form (type A), the visceral form (type B), the subacute or juvenile form (type C; previous studies), and the Nova Scotian variant (type D; see previous studies). The fifth, the adult form (type E; see previous studies), was described by previous studies and previous studies. previous studies used the designation type F (see previous studies) for a form characterized in 2 patients by a thermolabile enzyme. Most patients fall into Crocker's group A, with death before age 3 years. + +previous studies provided a detailed review of Niemann-Pick disease type A, including clinical management." +MONDO_0010537,"Definition: Borjeson-Forssman-Lehmann syndrome (BFLS) is an uncommon X-linked intellectual developmental disorder that evolves with age. Clinical manifestations in males are quite variable, with the most consistent features being initial hypotonia, mild to moderate impaired intellectual development, large fleshy ears, underdeveloped genitalia, gynecomastia, truncal obesity, tapering fingers, and shortening of the fourth and fifth toes. Heterozygous females may have a milder similar clinical phenotype, which can include hypothyroidism; however, many carrier females appear unaffected (summary by previous studies)." +MONDO_0010848,"Definition: For a general discussion of autosomal dominant spinocerebellar ataxia (SCA), see SCA1 (previous studies)." +MONDO_0010998,"Definition: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (previous studies). + +CDG1D is a type I CDG that generally presents with severe neurologic involvement associated with dysmorphism and visual impairment. Liver involvement is sometimes present (summary by previous studies). + +For a discussion of the classification of CDGs, see CDG1A (previous studies)." +MONDO_0012545,"Definition: Neutral lipid storage disease with myopathy is an autosomal recessive muscle disorder characterized by adult onset of slowly progressive proximal muscle weakness affecting the upper and lower limbs and associated with increased serum creatine kinase; distal muscle weakness may also occur. About half of patients develop cardiomyopathy later in the disease course. Other variable features include diabetes mellitus, hepatic steatosis, hypertriglyceridemia, and possibly sensorineural hearing loss. Leukocytes and muscle cells show cytoplasmic accumulation of triglycerides (summary by previous studies). + +Neutral lipid storage disease with myopathy belongs to a group of disorders termed neutral lipid storage disorders (NLSDs). These disorders are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Chanarin-Dorfman syndrome (CDS; previous studies) is defined as NLSD with ichthyosis (NLSDI). Patients with NLSDM present with myopathy but without ichthyosis (summary by previous studies)." +MONDO_0013564,"Definition: Anhaptoglobinemia refers to absence of the serum glycoprotein haptoglobin, a hemoglobin-binding acute-phase protein (summary by previous studies). Serum levels of haptoglobin vary among normal persons: levels are low in the neonatal period and in the elderly, differ by population, and can be influenced by environmental factors, such as infection. Secondary hypohaptoglobinemia can occur as a consequence of hemolysis, during which haptoglobin binds to free hemoglobin (summary by previous studies)." +MONDO_0014278,"Definition: Immunodeficiency-18 is an autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype, whereas T-cell development is not impaired in the mild form of IMD18 (summary by previous studies)." +MONDO_0014948,"Definition: The core features of short stature-micrognathia syndrome (SSMG) are intrauterine growth restriction (IUGR), postnatal short stature that is often rhizomelic, and micrognathia. Other common features include preterm birth, microcephaly, developmental delay, and genitourinary malformations in males. Transient liver dysfunction and glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, and cataracts have also been observed. Inter- and intrafamilial phenotypic severity varies greatly, from a relatively mild disorder to intrauterine death or stillbirth (previous studies)." +MONDO_0033658,"Definition: Neurodevelopmental disorder with seizures and brain atrophy (NEDSEBA) is an autosomal recessive disorder with highly variable manifestations and severity of these core features. The most severely affected individuals develop symptoms in utero, which may lead to spontaneous abortion or planned termination. Those that survive may present with severe seizures at birth, have poor overall growth with small head circumference, achieve no developmental progress, and show significant brain atrophy and other brain abnormalities. Patients at the mildest end of the phenotypic spectrum have onset of seizures later in childhood and show developmental delay with mildly impaired intellectual development and minimal brain atrophy (summary by previous studies)." +MONDO_0851095,"Definition: KINSSHIP syndrome (KINS) is an autosomal dominant disorder characterized by a recognizable pattern of anomalies including developmental delay, impaired intellectual development, seizures, mesomelic dysplasia, dysmorphic facial features, horseshoe or hypoplastic kidney, and failure to thrive (summary by previous studies)." +Orphanet_1334,"Definition: Immunodeficiency-51 (IMD51) is an autosomal recessive primary immune deficiency that is usually characterized by onset of chronic mucocutaneous candidiasis in the first years of life. Most patients also show recurrent Staphylococcal skin infections, and may show increased susceptibility to chronic bacterial respiratory infections. Patient cells show a lack of cellular responses to stimulation with certain IL17 isoforms, including IL17A (previous studies), IL17F (previous studies), IL17A/F, and IL17E (IL25; previous studies) (summary by previous studies)." +MONDO_0013500,"Definition: Immunodeficiency-51 (IMD51) is an autosomal recessive primary immune deficiency that is usually characterized by onset of chronic mucocutaneous candidiasis in the first years of life. Most patients also show recurrent Staphylococcal skin infections, and may show increased susceptibility to chronic bacterial respiratory infections. Patient cells show a lack of cellular responses to stimulation with certain IL17 isoforms, including IL17A (previous studies), IL17F (previous studies), IL17A/F, and IL17E (IL25; previous studies) (summary by previous studies)." +MONDO_0008483,"Definition: Stuttering is a disorder of the flow of speech characterized by involuntary repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks (summary by previous studies). Stuttering typically arises in young children, where it affects at least 15% of those in age range 4 to 6 years (previous studies). Stuttering usually resolves spontaneously before adolescence, leading to a population prevalence of 1 to 2% among adults. Stuttering beyond childhood is characterized by a significant bias towards males, with males outnumbering females by a ratio of 3:1 to 5:1 (previous studies). + + Genetic Heterogeneity of Familial Persistent Stuttering + +Also see STUT2 (previous studies), mapped to chromosome 12q24; STUT3 (previous studies), mapped to chromosome 3q; and STUT4 (previous studies) mapped to chromosome 16q." +MONDO_0009053,"Definition: De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see previous studies. + + Genetic Heterogeneity of de Barsy Syndrome + +Also see ARCL3B (previous studies), caused by mutation in the PYCR1 gene (previous studies) on chromosome 17q25." +MONDO_0010075,"Definition: Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) is characterized by vertebral abnormalities and ligamentous laxity that result in spinal misalignment and progressive severe kyphoscoliosis, thoracic asymmetry, and respiratory compromise resulting in early death. Nonaxial skeletal involvement includes elbow deformities with radial head dislocation, dislocated hips, clubfeet, and tapered fingers with spatulate distal phalanges. Many affected children have an oval face, flat midface, prominent eyes with blue sclerae, and a long philtrum. Palatal abnormalities and congenital heart disease are also observed (summary by previous studies). Patients with a similar phenotype and fractures have been described (previous studies). + + Genetic Heterogeneity of Spondyloepimetaphyseal Dysplasia with Joint Laxity + +Also see SEMDJL2 (previous studies), caused by mutation in the KIF22 gene (previous studies) on chromosome 16p11, and SEMDJL3 (previous studies), caused by mutation in the EXOC6B gene (previous studies) on chromosome 2p13." +MONDO_0010604,"Definition: Hemophilia B (HEMB), which results from factor IX deficiency, is phenotypically indistinguishable from hemophilia A (previous studies), which results from coagulation factor VIII (F8; previous studies) deficiency. The classic laboratory findings in hemophilia B include a prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT) (previous studies). + +Early studies made a distinction between cross-reactive-material (CRM)-negative and CRM-positive hemophilia B mutants. This classification referred to detection of the F9 antigen in plasma, even in the presence of decreased F9 activity. Detection of the antigen indicated the presence of a dysfunctional F9 protein. previous studies found that about 90% of patients with hemophilia B were CRM-negative, whereas about 10% were CRM-positive. However, previous studies found that a rather large proportion of the hemophilia B patients could be characterized as hemophilia B CRM+. They identified 14 cases of hemophilia B CRM+ from 11 families among a group of 33 patients. After immunologic and activity comparisons, they found at least 7 different factor IX variants. previous studies noted the high heterogeneity within this group. In an editorial on variants of vitamin K-dependent coagulation factors, previous studies stated that 9 defective variants of factor II, 5 variants of factor X, and many variants (about 180 pedigrees) of factor IX had been identified. At least one variant of factor VII (Padua) was also known." +MONDO_0010906,"Definition: Congenital 'healed' cleft lip (CHCL) is an unusual anomaly consisting of a paramedian 'scar' of the upper lip with an appearance suggesting that a typical cleft lip was corrected in utero. The CHCL is frequently associated with an ipsilateral notch in the vermilion border and a 'collapsed' nostril (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of nonsyndromic cleft lip with or without cleft palate, see OFC1 (previous studies)." +MONDO_0012407,Definition: PNPOD is an autosomal recessive inborn error of metabolism resulting in vitamin B6 deficiency that manifests as neonatal-onset severe seizures and subsequent encephalopathy. Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by previous studies). +MONDO_0030692,"Definition: Immunodeficiency-95 (IMD95) is an autosomal recessive disorder characterized predominantly by the onset of recurrent and severe viral respiratory infections in infancy or early childhood. Affected individuals often require hospitalization or respiratory support for these infections, which include human rhinovirus (HRV) and RSV. Immunologic workup is usually normal, although some mild abnormalities may be observed. The disorder results from a loss of ability of the innate immune system to sense viral genetic information, which causes a lack of interferon (IFN) production, poor response to viral and immunologic stimulation, and failure to control viral replication (summary by previous studies, previous studies, previous studies)." +MONDO_0031481,"Definition: Microcephaly, epilepsy, and diabetes syndrome-1 (MEDS1) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, simplified gyral pattern, severe epilepsy, and infantile diabetes (summary by previous studies). + + Genetic Heterogeneity of Microcephaly, Epilepsy, and Diabetes Syndrome + +MEDS2 (previous studies) is caused by mutation in the YIPF5 gene (previous studies) on chromosome 5q31." +MONDO_0800130,"Definition: Familial autoinflammatory syndrome with or without immunodeficiency (AISIMD) is characterized by onset of various autoimmune features usually in the first decades of life, although later onset has been reported. Typical features include autoimmune cytopenia, hemolytic anemia, thrombocytopenia, and lymphadenopathy. More variable features may include autoimmune thyroiditis, psoriasis or eczema, nephritis, hepatitis, and symptoms of systemic lupus erythematosus (SLE; see previous studies). Some patients may have recurrent infections or exacerbation of the disease with acute infection. Laboratory studies show variable findings, often decreased numbers of naive B cells, lymphopenia with skewed subsets, hypogammaglobulinemia, presence of autoantibodies, and a hyperinflammatory state. The disorder shows autosomal dominant inheritance with incomplete penetrance (summary by previous studies)." +Orphanet_2440,"Definition: Split-hand/foot malformation (SHFM) is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients with SHFM1 have been found to have mental retardation, ectodermal and craniofacial findings, orofacial clefting (previous studies), and neurosensory hearing loss (previous studies). + + Genetic Heterogeneity of Split-Hand/Foot Malformation + +Additional SHFM loci include SHFM2 (previous studies) on chromosome Xq26; SHFM3 (previous studies), caused by duplication of chromosome 10q24; SHFM4 (previous studies), caused by mutation in the TP63 gene (previous studies) on chromosome 3q28; SHFM5 (previous studies) on chromosome 2q31; and SHFM6 (previous studies), caused by mutation in the WNT10B gene (previous studies) on chromosome 12q13. + +Also see SHFM1D (previous studies) for a form of SHFM1 with deafness that may be caused by homozygous mutation in the DLX5 gene (previous studies). + + Associations Pending Confirmation + +For discussion of a possible association between split-hand/foot malformation and variation in the EPS15L1 gene, see previous studies." +EFO_0000558,"Definition: Kaposi sarcoma (KS) is an invasive angioproliferative inflammatory condition that occurs commonly in men infected with human immunodeficiency virus (HIV; see previous studies). In the early stages of KS, lesions appear reactive and are stimulated to grow by the actions of inflammatory cytokines and growth factors. In the late stages of KS, a malignant phenotype that appears to be monoclonal can develop. Infection with human herpesvirus-8 (HHV-8), also known as KS-associated herpesvirus (KSHV), is necessary but not sufficient for KS development. Coinfection with HIV markedly increases the likelihood of KS development, and additional environmental, hormonal, and genetic cofactors likely contribute to its pathogenesis (summary by previous studies). + +previous studies noted that HHV-8 is the etiologic agent not only of KS, but also of primary effusion lymphoma and plasma cell-type multicentric Castleman disease (MCD)." +MONDO_0009623,"Definition: The Nijmegen breakage syndrome and the phenotypically indistinguishable Berlin breakage syndrome are autosomal recessive chromosomal instability syndromes characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer. Ataxia-telangiectasia variant-1 is the designation applied to the Nijmegen breakage syndrome and AT variant-2 is the designation for the Berlin breakage syndrome, which differ only in complementation studies. Cells from NBS/BBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from those of ataxia-telangiectasia (AT; previous studies), but NBS/BBS patients have a distinct clinical phenotype. + +The clinical features of LIG4 syndrome (previous studies), caused by mutation in the LIG4 gene (previous studies), resemble those of NBS." +MONDO_0011273,"Definition: The histiocytosis-lymphadenopathy plus syndrome comprises features of 4 histiocytic disorders previously thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID). FHC described an autosomal recessive disease involving joint deformities, sensorineural hearing loss, and subsequent development of generalized lymphadenopathy and swellings in the eyelids that contain histiocytes (summary by previous studies). SHML, or familial Rosai-Dorfman disease, was described as a rare cause of lymph node enlargement in children, consisting of chronic massive enlargement of cervical lymph nodes frequently accompanied by fever, leukocytosis, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal sites were involved in approximately 25% of patients, including salivary glands, orbit, eyelid, spleen, and testes. The involvement of retropharyngeal lymphoid tissue sometimes caused snoring and sleep apnea (summary by previous studies). H syndrome was characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism; hearing loss was also found in about half of patients, and many had short stature. PHID was characterized by predominantly antibody-negative insulin-dependent diabetes mellitus associated with pigmented hypertrichosis and variable occurrence of other features of H syndrome, with hepatosplenomegaly occurring in about half of patients (previous studies). previous studies noted that mutations in the SLC29A3 gene (previous studies) had been implicated in H syndrome, PHID, FHC, and SHML, and that some patients presented a combination of features from 2 or more of these syndromes, leading to the suggestion that these phenotypes should be grouped together as 'SLC29A3 disorder.' previous studies suggested that the histologic features of the lesions seemed to be the most uniform phenotype in these patients. In addition, the immunophenotype of infiltrating cells in H syndrome patients was shown to be the same as that seen in patients with the familial form of Rosai-Dorfman disease, further supporting the relationship between these disorders (previous studies; previous studies)." +MONDO_0014131,"Definition: Shaheen syndrome is an autosomal recessive form of syndromic mental retardation. Affected individuals show severe intellectual disability, hypohidrosis, dental enamel hypoplasia, and hyperkeratosis of the palms and soles. Some may develop mild microcephaly (summary by previous studies)." +MONDO_0014431,"Definition: Familial partial lipodystrophy-6 (FPLD6) is characterized by abnormal subcutaneous fat distribution, with variable excess accumulation of fat in the face, neck, shoulders, axillae, back, abdomen, and pubic region, and reduction in subcutaneous fat of the lower extremities. Progressive adult-onset myopathy is seen in some patients, and there is variable association with diabetes, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and hepatic steatosis (previous studies)." +MONDO_0033549,"Definition: Optic atrophy-12 (OPA12) is an autosomal dominant neurologic disorder characterized by slowly progressive visual impairment with onset usually in the first decade, although later onset has been reported. Affected individuals have impaired color vision, photophobia, pale optic discs, optic nerve atrophy, and decreased thickness of the retinal nerve fiber layer. Some patients may exhibit additional neurologic features, including impaired intellectual development, dystonia, movement disorders, or ataxia (summary by previous studies). + +For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (previous studies)." +MONDO_0033551,"Definition: Immunodeficiency-72 with autoinflammation and lymphoproliferation (IMD72) is an autosomal recessive immunologic disorder characterized by onset of recurrent infections or systemic inflammation in the first year of life. Affected individuals develop bacterial and viral infections that can be severe, including bacteremia, recurrent pneumonia, and meningitis, consistent with an immunodeficiency. There is also an autoimmune and hyperinflammatory aspect to the disorder, manifest as atopy or allergies, hepatosplenomegaly, and lymphoproliferation, including hemophagocytic lymphohistiocytosis (HLH). Immunologic workup shows variable abnormalities, including low or high Ig subsets, increased B cells, irregular T-cell activation and cytokine response, impaired immune synapse formation, and defective cellular migration. At the cellular level, these defects are related to abnormal F-actin polymerization and altered intracellular signaling (summary by previous studies)." +MONDO_0044322,"Definition: Intellectual developmental disorder with neuropsychiatric features is an autosomal recessive disorder characterized by moderate intellectual disability, relatively mild seizures, and neuropsychiatric abnormalities, such as anxiety, obsessive-compulsive behavior, and autistic features. Mild facial dysmorphic features may also be present (summary by previous studies)." +MONDO_0044701,"Definition: CONDBA is a severe progressive neurodegenerative disorder characterized by loss of motor and cognitive skills between ages 2 and 7 years. Affected individuals may have normal development or mild developmental delay, but all eventually lose all motor skills, resulting in inability to walk, absence of language, and profound intellectual disability. Brain imaging shows progressive cerebral and cerebellar atrophy (summary by previous studies)." +EFO_0004268,"Definition: Neonatal sclerosing cholangitis (NSC) is a rare autosomal recessive form of severe liver disease with onset in infancy. Affected infants have jaundice, cholestasis, acholic stools, and progressive liver dysfunction resulting in fibrosis and cirrhosis; most require liver transplantation in the first few decades of life. Cholangiography shows patent biliary ducts, but there are bile duct irregularities (summary by previous studies; previous studies)." +EFO_0008493,"Definition: Brain small vessel disease-3 (BSVD3) is an autosomal recessive disorder resulting from fragility of cerebral vessels causing an increased risk of intracranial bleeding. The resultant phenotype is highly variable depending on timing and location of the intracranial bleed. Some patients may have onset in utero or early infancy, with subsequent global developmental delay, spasticity, and porencephaly on brain imaging. Other patients may have normal or mildly delayed development with sudden onset of intracranial hemorrhage causing acute neurologic deterioration (summary by previous studies). + +For a discussion of genetic heterogeneity of brain small vessel disease, see BSVD1 (previous studies)." +MONDO_0009058,"Definition: Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (previous studies)." +MONDO_0010283,"Definition: X-linked Lubs-type syndromic intellectual developmental disorder (MRXSL) is a neurodevelopmental disorder characterized by severely to profoundly impaired intellectual development, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity, and recurrent infections. Only males are affected, although female carriers may have some mild neuropsychiatric features, such as anxiety. Submicroscopic Xq28 duplications encompassing MECP2 are considered nonrecurrent events, because the breakpoint locations and rearrangement sizes vary among affected individuals (summary by previous studies)." +MONDO_0012160,"Definition: Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by previous studies). + +previous studies reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence." +Orphanet_85167,"Definition: Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by previous studies). + +previous studies reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence." +MONDO_0012438,"Definition: Pontocerebellar hypoplasia (PCH) refers to a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of pontocerebellar hypoplasia, see PCH1 (previous studies)." +MONDO_0014141,"Definition: MDDGB14 is an autosomal recessive congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and impaired intellectual development. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; previous studies), collectively known as 'dystroglycanopathies' (summary by previous studies). + +For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (previous studies)." +MONDO_0030847,"Definition: Distal arthrogryposis type 1C (DA1C) is characterized by multiple congenital contractures, scoliosis, and short stature. Contractures involving the proximal joints appear to be more common in MYLPF-associated DA than in other forms of DA, and segmental amyoplasia has been observed (previous studies)." +EFO_0010266,"Definition: Charcot-Marie-Tooth disease type 1G is an autosomal dominant progressive peripheral sensorimotor neuropathy characterized by distal muscle weakness and atrophy with onset in the first or second decade. Affected individuals have difficulty walking, distal sensory impairment with decreased or absent reflexes, and often have foot deformities. Median motor nerve conduction velocities (NCV) are decreased (less than 38 m/s) and sural nerve biopsy shows myelin defects and onion bulb formation (summary by previous studies and previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (previous studies)." +EFO_0010740,Definition: Diets-Jongmans syndrome (DIJOS) is an autosomal dominant disorder characterized by mild to moderately impaired intellectual development with a recognizable facial gestalt (summary by previous studies). +MONDO_0007221,"Definition: The brachydactyly type C (BDC) phenotype includes brachymesophalangy of fingers 2, 3, and 5. The fourth finger is usually unaffected and thus appears as the longest finger of the hand. Shortening of metacarpal 1 and hyperphalangy in fingers 2 and 3 may occur and can be considered relatively characteristic signs. BDC can be highly variable, ranging from severely affected hands with very short fingers to mildly affected cases with only moderate brachydactyly, most often affecting the middle and proximal phalanges of fingers 2 and 3 (summary by previous studies)." +MONDO_0009557,"Definition: Mandibuloacral dysplasia with type A lipodystrophy (MADA) is an autosomal recessive disorder characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. The lipodystrophy is characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue in the neck and trunk. Some patients may show progeroid features. Metabolic complications can arise due to insulin resistance and diabetes (previous studies; previous studies; summary by previous studies). + +See also MAD type B (MADB; previous studies), which is caused by mutation in the ZMPSTE24 gene (previous studies)." +MONDO_0011789,"Definition: Meningiomas are, in general, slowly growing benign tumors derived from the arachnoidal cap cells of the leptomeninges, the soft coverings of the brain and spinal cord. Meningiomas are believed to be the most common primary tumors of the central nervous system in man. The vast majority of meningiomas are sporadic; familial occurrence of meningioma is rare (previous studies). + +Familial or multiple meningiomas may also be seen in tumor predisposition syndromes. Some patients with schwannomatosis (previous studies), caused by mutation in the SMARCB1 gene, may develop meningiomas. One patient with malignant gliomas (GLM2; previous studies) associated with a mutation in the PTEN gene (previous studies) developed a meningioma (previous studies)." +MONDO_0011831,"Definition: ARVD8 is characterized by progressive degeneration of the right ventricular myocardium. Patients may experience life-threatening cardiac arrhythmias and show depolarization, conduction, and repolarization defects on electrocardiography (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of ARVD, see previous studies." +MONDO_0012163,"Definition: Immunodeficiency-104 (IMD104) is an autosomal recessive disorder characterized by the onset of recurrent infections in early infancy. Manifestations may include oral thrush, fever, and failure to thrive. Some patients have lymphadenopathy and hepatosplenomegaly, whereas others have absence of lymph nodes and lack a thymic shadow. Laboratory studies show decreased or absent numbers of nonfunctional T cells, normal or increased levels of B cells, variable hypogammaglobulinemia, and normal NK cells. The disorder is caused by a defect in IL7 (previous studies) signaling due to a mutant IL7 receptor. Hematopoietic stem cell transplantation may be curative (previous studies and previous studies). + +previous studies provided a detailed review of IL7R deficiency, including discussion of the IL7R gene and its function in the immune system, clinical features of the disorder, and experiences with hematopoietic stem cell transplant as treatment. + +For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see previous studies." +MONDO_0014252,"Definition: Hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL; previous studies) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy, and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein B-containing particles. Obligate heterozygous parents of FHBL patients typically have half normal levels of apoB-containing lipoproteins consistent with autosomal codominant inheritance, whereas obligate heterozygous parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance (summary by previous studies). + + Genetic Heterogeneity of Familial Hypobetalipoproteinemia + +Familial hypobetalipoproteinemia-2 (FHBL2; previous studies) is caused by mutation in the ANGPTL3 gene (previous studies) on chromosome 1p31." +MONDO_0014507,"Definition: Catel-Manzke syndrome is characterized by the Pierre Robin anomaly, which comprises cleft palate, glossoptosis, and micrognathia, and a unique form of bilateral hyperphalangy in which there is an accessory bone inserted between the second metacarpal and its corresponding proximal phalanx, resulting in radial deviation of the index finger (summary by previous studies)." +MONDO_0014644,"Definition: Spastic paraplegia-74 (SPG74) is an autosomal recessive neurologic disorder characterized by onset of slowly progressive lower limb spasticity, optic atrophy, and peripheral neuropathy in the first decade (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0014701,"Definition: Spondyloepiphyseal dysplasia with accumulation of glycoprotein in chondrocytes has been designated the 'Stanescu type.' Clinical hallmarks include progressive joint contracture with premature degenerative joint disease, particularly in the knee, hip, and finger joints. Interphalangeal joints of the hands are swollen due to osseous distention of the metaphyseal ends of the phalanges. Affected individuals may be relatively tall despite the presence of a short trunk. Radiologically, there is generalized platyspondyly with mild modification of the endplates, hypoplastic pelvis, epiphyseal flattening with metaphyseal splaying of the long bones, and enlarged phalangeal epimetaphyses of the hands. In addition, the proximal femora are characteristically broad and elongated with striking coxa valga (summary by previous studies)." +MONDO_0030375,"Definition: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2) is an autosomal recessive multisystemic disorder characterized by cholestatic hepatitis, poor feeding associated with poor overall growth, and hypoglycemia apparent from infancy. Most, but not all, patients have variable global developmental delay. Additional common features include sensorineural deafness, retinal abnormalities with visual defects, and hypotonia. Some patients have endocrine abnormalities, including hyperinsulinemic hypoglycemia, pancreatic dysfunction, hypothyroidism, and primary amenorrhea. Additional features may include hypertriglyceridemia, anemia, proteinuria, increased lactate, and recurrent infections. Brain imaging often shows dysmyelination, thin corpus callosum, cerebral atrophy, and white matter abnormalities. Although the clinical manifestations and severity of the disorder are highly variable, death in early childhood may occur (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of IMNEPD, see IMNEPD1 (previous studies)." +MONDO_0032928,"Definition: Infantile T-cell lymphopenia with or without nail dystrophy (TLIND) is an autosomal dominant disorder characterized by decreased numbers of T cells, particularly cytotoxic CD8+ T cells, usually apparent from infancy. Patients are often identified through newborn screening with the finding of low levels of T-cell receptor excision circles (TRECs). Affected individuals tend to be more susceptible to recurrent infections, mainly respiratory viral infections. However, the severity is highly variable, and patients usually improve with age later in childhood and as adults, even if CD8+ T cells remain decreased compared to normal. Additional features may include a small thymic shadow, indicative of impaired thymic development, skin abnormalities, such as atopic dermatitis, and nail dystrophy. As rare patients may develop more serious infections, affected individuals should be monitored. Bone marrow transplantation is not curative (summary by previous studies)." +MONDO_0033665,"Definition: Autosomal dominant deafness-78 (DFNA78) is characterized by profound congenital bilateral sensorineural hearing loss affecting all frequencies. Some patients may have mild motor delay early in life due to vestibular dysfunction, although the motor skills catch up with age. Affected individuals do not have systemic or other neurologic manifestations (summary by previous studies)." +Orphanet_2087,"Definition: Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome is an autosomal dominant disorder characterized by these 4 features, which begin in early childhood and are progressive (summary by previous studies)." +Orphanet_79499,"Definition: The DDOD syndrome is characterized by autosomal dominant inheritance of congenital deafness and onychodystrophy. Conical, hypoplastic teeth is also a feature (previous studies). + +See also DOOR syndrome (previous studies), an autosomal recessive disorder, which includes congenital deafness, onychodystrophy, osteodystrophy, and mental retardation." +MONDO_0007420,"Definition: The DDOD syndrome is characterized by autosomal dominant inheritance of congenital deafness and onychodystrophy. Conical, hypoplastic teeth is also a feature (previous studies). + +See also DOOR syndrome (previous studies), an autosomal recessive disorder, which includes congenital deafness, onychodystrophy, osteodystrophy, and mental retardation." +MONDO_0007810,"Definition: The phenotypic characteristics of ichthyosis vulgaris include palmar hyperlinearity, keratosis pilaris, and a fine scale that is most prominent over the lower abdomen, arms, and legs. Marked presentation includes prominent scaling, whereas mild presentation consists of palmar hyperlinearity, keratosis pilaris, and, in some cases, fine scaling (summary by previous studies)." +MONDO_0008630,"Definition: Autonomic bladder dysfunction with impaired pupillary reflex and secondary CAKUT (congenital anomalies of the kidney and urinary tract) is an autosomal recessive neurogenic disorder with onset in utero or early childhood. Affected individuals have impaired neuronal bladder and ureteral innervation causing coordination defects that result in secondary structural defects of the renal system, including hydronephrosis, vesicoureteral reflux (VUR), and small kidneys, that may result in chronic kidney disease as well as recurrent urinary tract infections (UTIs). Surgical treatment of VUR is not effective. Most individuals also have additional autonomic features, most commonly impaired pupillary reflex and sometimes orthostatic hypotension (summary by previous studies)." +MONDO_0009747,"Definition: Mitochondrial DNA depletion syndrome-6 is an autosomal recessive disorder characterized by infantile onset of progressive liver failure, often leading to death in the first year of life. Those that survive develop progressive neurologic involvement, including ataxia, hypotonia, dystonia, and psychomotor regression (previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +MONDO_0011018,"Definition: Dental anomalies and short stature (DASS) is characterized by significant short stature with brachyolmia as well as hypoplastic amelogenesis imperfecta with almost absent enamel (previous studies). Some patients exhibit valvular and/or vascular defects, including mitral valve prolapse, aortic root dilation, and aortic as well as other arterial aneurysms (previous studies; previous studies). Inter- and intrafamilial variability has been reported." +MONDO_0011227,"Definition: Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is an autosomal recessive multiple congenital anomaly syndrome with features of a first and second branchial arch syndrome. Craniofacial abnormalities can lead to conductive hearing loss, respiratory insufficiency, and feeding difficulties. Additional features include rhizomelic skeletal anomalies as well as abnormalities of the shoulder and pelvic joints. Affected individuals may also have some features of a neurocristopathy or abnormal mesoderm development, such as urogenital anomalies, that are distinct from other branchial arch syndromes (summary by previous studies)." +MONDO_0013533,"Definition: Hepatic lipase deficiency is characterized by premature atherosclerosis, elevated total cholesterol, triglycerides (TG), and very low density lipoprotein (VLDL), as well as TG-rich low density lipoprotein (LDL) and HDL subfractions (summary by previous studies)." +MONDO_0013898,Definition: Karyomegalic tubulointerstitial nephritis (KMIN) is a rare kidney disease characterized clinically by onset in the third decade of progressive renal failure. Renal biopsy shows chronic tubulointerstitial nephritis and interstitial fibrosis associated with enlarged and atypical tubular epithelial cell nuclei (summary by previous studies). +MONDO_0014511,"Definition: Charcot-Marie-Tooth disease type 2S is a relatively pure form of autosomal recessive axonal neuropathy characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy affecting the lower and upper limbs. Patients have decreased reflexes and variable distal sensory impairment (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0021569,"Definition: EDMD is characterized by myopathic changes in certain skeletal muscles and early contractures at the neck, elbows, and Achilles tendons, as well as cardiac conduction defects. 'Classic' Emery-Dreifuss muscular dystrophy (EDMD1; previous studies) is an X-linked disorder caused by mutation in the emerin gene (EMD; previous studies) on Xq28 (previous studies). + +For a discussion of genetic heterogeneity of EDMD, see previous studies." +MONDO_0026777,"Definition: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) is an adult-onset inflammatory disease that primarily affects males and is caused by somatic, not germline, mutations. The disorder is characterized by adult onset of rheumatologic symptoms at a mean age of 64 years. Features include recurrent fevers, pulmonary and dermatologic inflammatory manifestations, vasculitis, deep vein thrombosis, arthralgias, and ear and nose chondritis. Laboratory studies indicate hematologic abnormalities, including macrocytic anemia, as well as increased levels of acute-phase reactants; about half of patients have positive autoantibodies. Bone marrow biopsy shows degenerative vacuolization restricted to myeloid and erythroid precursor cells, as well as variable hematopoietic dyspoiesis and dysplasias. The condition does not respond to rheumatologic medications and the features may result in premature death (summary by previous studies)." +MONDO_0032940,"Definition: Retinitis pigmentosa-88 (RP88) is characterized by night blindness and constriction of peripheral visual fields, with mildly reduced visual acuity. Examination shows typical findings of RP, including attenuated retinal vessels, pale optic discs, and pigment deposits in the peripheral retinal pigment epithelium (previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of RP, see previous studies." +MONDO_0033864,"Definition: Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder characterized by infantile hypotonia, ophthalmic abnormalities, moderate to profound global developmental delay, poor or absent speech, behavioral abnormalities, hyperkinetic movements, and EEG abnormalities in the absence of overt seizures (summary by previous studies)." +EFO_0009020,"Definition: Ayme-Gripp syndrome is a clinically homogeneous phenotype characterized by congenital cataracts, sensorineural hearing loss, intellectual disability, seizures, brachycephaly, a distinctive flat facial appearance, and reduced growth (previous studies)." +MONDO_0007740,"Definition: Wagner vitreoretinopathy is a rare vitreoretinal degeneration inherited as an autosomal dominant trait, first described in a large Swiss pedigree (previous studies) and subsequently identified in other families. Penetrance in Wagner syndrome is complete, and the disease manifests in childhood or adolescence with a progressive course. Affected individuals usually present with an 'empty' vitreous cavity with fibrillary condensation or avascular strands and veils. Additional features, which are variable and age-dependent, include chorioretinal atrophy with loss of the retinal pigment epithelium (RPE), lattice degeneration of the retina, complicated cataracts, mild myopia, and peripheral traction retinal detachment. Rod and cone electroretinography shows reduced b-wave amplitude and correlates with severe chorioretinal pathology. It is believed that liquefaction of vitreous initiates a degenerative cascade that results in the complex eye phenotype of Wagner syndrome (summary by previous studies). Patients with additional ocular features such as progressive nyctalopia (night blindness), visual field constriction, and chorioretinal atrophy, with loss of RPE and choriocapillaries on fluorescein angiography and rod-cone abnormalities on electroretinography, were initially believed to have a distinct clinical entity, which was designated 'erosive vitreoretinopathy' (ERVR). Extraocular abnormalities are not present in patients diagnosed with Wagner or erosive vitreoretinopathy (summary by previous studies)." +MONDO_0009367,"Definition: McKusick-Kaufman syndrome is an autosomal recessive disorder characterized by genitourinary malformations, especially hydrometrocolpos, polydactyly, and, more rarely, heart or gastrointestinal malformations (summary by previous studies)." +MONDO_0009560,"Definition: Manitoba oculotrichoanal syndrome (MOTA) is a rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance was assumed because of consanguinity in the Oji-Cree population of Manitoba in which the syndrome was first described (summary by previous studies)." +MONDO_0011010,"Definition: Syndromic microphthalmia-9, also referred to as pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect, is characterized by bilateral clinical anophthalmia, pulmonary hypoplasia/aplasia, cardiac malformations, and diaphragmatic defects. The phenotype is variable, ranging from isolated clinical anophthalmia or microphthalmia to complex presentations involving the cardiac, pulmonary, diaphragmatic, and renal systems. At its most severe, infants are born without pulmonary structures and die soon after birth (previous studies)." +MONDO_0014115,"Definition: Hypomyelination with brainstem and spinal cord involvement and leg spasticity is an autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation. Affected individuals show delayed motor development and nystagmus; some may have mild mental retardation. Brain MRI shows hypomyelination and white matter lesions in the cerebrum, brainstem, cerebellum, and spinal cord (summary by previous studies)." +MONDO_0014606,"Definition: White-Sutton syndrome (WHSUS) is a neurodevelopmental disorder characterized by delayed psychomotor development apparent in infancy and a characteristic constellation of dysmorphic facial features. Additional features may include hypotonia, sensorineural hearing impairment, visual defects, joint laxity, and gastrointestinal difficulties, such as poor feeding (summary by previous studies). A significant number of patients have autism or autistic features (summary by previous studies)." +MONDO_0018346,"Definition: Neurodevelopmental disorder with epilepsy and hemochromatosis (NEDEPH) is an X-linked recessive disorder characterized by global developmental delay, early-onset seizures, and progressive systemic iron deposition particularly affecting the liver and resulting in juvenile-onset hemochromatosis. Variable additional features may include joint contractures, visual or hearing impairment, and skin abnormalities (summary by previous studies and previous studies)." +MONDO_0033667,"Definition: Delpire-McNeill syndrome (DELMNES) is a neurodevelopmental disorder with highly variable manifestations. Patients present in infancy with global developmental delay, including motor, speech, and impaired intellectual development. The most severely affected patients have hypotonia, inability to hold their head or walk, bilateral sensorineural deafness, and absent language, whereas others have delayed walking and mild to moderate intellectual disability, often with speech delay and autistic features. More variable features may include spasticity or minor involvement of other organ systems, such as hip dislocation or ventricular septal defect (summary by previous studies)." +EFO_0004698,"Definition: Delayed sleep phase syndrome is a circadian rhythm sleep disorder characterized by sleep-onset insomnia and difficulty in awakening at the desired time. Patients with DSPD have chronic difficulty in adjusting their sleep-onset and wake-up times to occupational, school, and social activities. Although psychosocial and environmental factors sometimes induce this kind of disorder, most patients with DSPD appear to have an abnormal circadian pacemaker and/or an abnormal entrainment system (summary by previous studies)." +MONDO_0007856,"Definition: Palmoplantar keratoderma (PPK) is a complex group of hereditary syndromes that have been classified into diffuse, punctate, and focal forms according to the pattern of hyperkeratosis on the palms and soles (previous studies). + +For a discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (previous studies)." +MONDO_0010083,"Definition: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. The clinical features include developmental delay, hypotonia, mental retardation, ataxia, seizures, hyperkinetic behavior, aggression, and sleep disturbances (summary by previous studies)." +MONDO_0010631,"Definition: Familial incontinentia pigmenti (IP) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males (previous studies). In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes, and central nervous system. The prominent skin signs occur in 4 classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation, and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. + +Also see hypomelanosis of Ito (previous studies), which was formerly designated incontinentia pigmenti type I (IP1)." +MONDO_0011475,"Definition: Autosomal recessive Charcot-Marie-Tooth disease type 4B is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. CMT4B1 (previous studies) is a clinically similar disorder caused by mutation in the MTMR2 gene (previous studies) on 11q22. + +For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating CMT, see CMT4A (previous studies)." +MONDO_0025699,"Definition: Coffin-Siris syndrome-12 (CSS12) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, speech and language delay, and behavioral abnormalities, such as autism or hyperactivity. Affected individuals may have hypotonia and poor feeding in infancy. There are variable dysmorphic facial features, although most patients do not have the classic hypoplastic fifth digit/nail abnormalities that are often observed in other forms of CSS (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (previous studies)." +MONDO_0030330,"Definition: Familial restrictive cardiomyopathy-6 (RCM6) is characterized by prenatal onset of severe restrictive cardiomyopathy predominantly involving the right ventricle, resulting in irreversible heart failure and early death (previous studies). + +For a general phenotypic description and discussion of genetic heterogeneity of familial restrictive cardiomyopathy, see RCM1 (previous studies)." +MONDO_0044720,"Definition: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive adult-onset, slowly progressive neurologic disorder characterized by imbalance due to cerebellar gait and limb ataxia, impaired vestibular function bilaterally, and non-length-dependent sensory neuropathy (summary by previous studies)." +MONDO_0060510,"Definition: Cohen-Gibson syndrome (COGIS) is an overgrowth disorder characterized by increased somatic parameters apparent from birth and associated with variable intellectual disability. Affected individuals have dysmorphic facial features, advanced bone age, and skeletal abnormalities, including flaring of the metaphyses of the long bones, large hands with long fingers and camptodactyly, and often scoliosis or cervical spine anomalies. Other features may include hypotonia, difficulty walking due to skeletal anomalies, and umbilical hernia (summary by previous studies)." +MONDO_0008094,"Definition: Capillary malformations are a form of vascular malformation that are present from birth, tend to grow with the individual, do not regress spontaneously, and show normal rates of endothelial cell turnover. Capillary malformations are distinct from capillary hemangiomas (previous studies), which are highly proliferative lesions that appear shortly after birth and show rapid growth, slow involution, and endothelial hypercellularity (previous studies; previous studies)." +MONDO_0011202,"Definition: RHYNS syndrome is characterized by gaze palsy, retinitis pigmentosa, sensorineural hearing loss, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (previous studies)." +MONDO_0011584,"Definition: Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +MONDO_0011601,"Definition: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive metabolic disorder characterized by poor growth, intrahepatic cholestasis, and increased serum citrulline. Most patients show spontaneous improvement by 1 year of age. However, some patients may have a progressive course with continued failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and some may develop chronic or fatal liver disease (summary by previous studies)." +MONDO_0012683,"Definition: Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (previous studies)." +MONDO_0012714,"Definition: Congenital myopathy-5 with cardiomyopathy (CMYP5) is an autosomal recessive disorder characterized by the onset of muscle weakness in infancy manifest as neonatal hypotonia, delayed motor development, and often distal contractures. Affected individuals may have congenital heart defects and most develop severe cardiomyopathy in childhood or adolescence that may lead to death or require heart transplant. Skeletal muscle biopsy shows multiminicore myopathy, centrally located nuclei, and type 1 fiber predominance (previous studies; previous studies). + +For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (previous studies)." +MONDO_0014523,"Definition: Combined cerebellar and peripheral ataxia with hearing loss and diabetes mellitus (ACPHD) is an autosomal recessive multisystem disorder including defects in glucose metabolism, diffuse neurodegeneration, multiple hormone deficiencies, severe growth retardation with possible growth hormone deficiencies, and subtle osseous changes suggesting early-onset bone dysplasia (summary by previous studies)." +MONDO_0030047,"Definition: Microcephaly, developmental delay, and brittle hair syndrome (MDBH) is a multisystem disorder with clinical variability. Affected individuals show cognitive and motor disabilities, as well as some degree of fine, brittle hair with microscopic shaft abnormalities. Other shared features include failure to thrive in early childhood and short stature, with some patients exhibiting feeding difficulties and hepatic steatosis (previous studies)." +MONDO_0030967,"Definition: Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE) is an autosomal recessive complex neurodegenerative disorder characterized by congenital neurosensory deafness followed by onset of neurodegenerative symptoms, including pyramidal signs and cognitive decline, in young adulthood. Some patients may have mild developmental delay or learning difficulties in childhood, but most can function independently. The onset of motor and cognitive decline in adulthood can be rapid and may result in early death. Brain imaging shows diffuse white matter abnormalities affecting various brain regions, consistent with a progressive leukoencephalopathy. More variable additional features may include visual impairment and axonal peripheral neuropathy (summary by previous studies)." +MONDO_0032645,"Definition: Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (previous studies)." +MONDO_0007042,"Definition: Saethre-Chotzen syndrome is characterized by craniosynostosis, facial dysmorphism, and hand and foot abnormalities. Coronal synostosis resulting in brachycephaly is the most frequent cranial abnormality observed, and the most common facial features are asymmetry, hypertelorism, and maxillary hypoplasia. Other features include high forehead, low frontal hairline, late-closing fontanel, strabismus, ptosis, lacrimal duct stenosis, deviated nasal septum, small low-set posteriorly rotated ears with prominent crus, and hearing loss. The limb anomalies consist of radioulnar synostosis, brachydactyly, cutaneous syndactyly, and hallux valgus. Patients also exhibit short stature and vertebral fusion, and mild to moderate mental retardation has been noted in some cases. Inter- and intrafamilial variability is significant, with some patients having fusion of other sutures, or no apparent craniosynostosis but abnormal skull morphology. The degree of syndactyly is also variable, and digital abnormalities can be absent (previous studies)." +MONDO_0009104,"Definition: The faciooculoacousticorenal (FOAR) syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. Facial features include prominent brow, short nose, and hypertelorism, and ocular anomalies include myopia, iris hypoplasia, and/or retinal detachment (previous studies). Donnai-Barrow syndrome (DBS) was first described as a distinct disorder characterized by diaphragmatic hernia, exomphalos, absent corpus callosum, myopia, and sensorineural deafness. The classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR (previous studies). However, early reports noted that the 2 disorders shared many phenotypic features and may be identical (e.g., previous studies). Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), the disorders are now considered to represent the same entity (previous studies)." +MONDO_0011569,"Definition: Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a motor median nerve conduction velocity less than 38 m/s (see CMT1B; previous studies); and type 2, the axonal form, with a normal or slightly reduced nerve conduction velocity. + +For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A1 (previous studies)." +MONDO_0013164,"Definition: Beta-ureidopropionase deficiency is a rare autosomal recessive inborn error of metabolism due to a defect in pyrimidine degradation. Less than 10 patients have been reported, and the phenotype can range from severe neurologic involvement with mental retardation and seizures to normal neurologic development (previous studies)." +MONDO_0013931,"Definition: Peroxisome biogenesis disorder-4B (PBD4B) includes the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by previous studies). + +For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see previous studies. + +Individuals with mutations in the PEX6 gene have cells of complementation group 4 (CG4, equivalent to CG6 and CGC). For information on the history of PBD complementation groups, see previous studies." +MONDO_0014793,"Definition: Microcephaly, congenital cataract, and psoriasiform dermatitis (MCCPD) represents an inborn error of cholesterol metabolism that is characterized by accumulation of a large amount of methylsterols, particularly dimethylsterols, in affected patients. The associated features of immune dysregulation, skin disease, and growth delay can be at least partially corrected with cholesterol and statin supplements (previous studies)." +MONDO_0030514,"Definition: Hypomyelinating leukodystrophy-23 with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy (HLD23) is an autosomal recessive neurodegenerative disorder with systemic manifestations. Affected individuals show delayed motor development and ataxic gait in early childhood that progresses to spastic paraplegia with loss of ambulation in the first decades of life. Additional features include progressive sensorineural hearing loss resulting in deafness, hepatic dysfunction with elevated liver enzymes, and dilated cardiomyopathy that ultimately results in death in the first or second decades. Brain imaging shows hypomyelination, diffuse white matter abnormalities consistent with leukodystrophy, and thin corpus callosum (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see previous studies." +Orphanet_254898,"Definition: CoQ10 deficiency-2 (COQ10D2) is an autosomal recessive disorder characterized by sensorineural deafness, optic atrophy, mildly impaired intellectual development, muscular weakness, and cardiac involvement (summary by previous studies)." +MONDO_0013837,"Definition: CoQ10 deficiency-2 (COQ10D2) is an autosomal recessive disorder characterized by sensorineural deafness, optic atrophy, mildly impaired intellectual development, muscular weakness, and cardiac involvement (summary by previous studies)." +MONDO_0007160,"Definition: Stickler syndrome is a clinically variable and genetically heterogeneous disorder characterized by ocular, auditory, skeletal, and orofacial abnormalities. Most forms of Stickler syndrome are characterized by the eye findings of high myopia, vitreoretinal degeneration, retinal detachment, and cataracts. Additional findings may include midline clefting (cleft palate or bifid uvula), Pierre Robin sequence, flat midface, sensorineural or conductive hearing loss, mild spondyloepiphyseal dysplasia, and early-onset osteoarthritis (summary by previous studies). + + Genetic Heterogeneity of Stickler Syndrome + +See previous studies for a form of Stickler syndrome type I that is solely or predominantly ocular and is also caused by mutation in the COL2A1 gene. Stickler syndrome type II (STL2; previous studies), sometimes called the beaded vitreous type, is caused by mutation in the COL11A1 gene (previous studies) on chromosome 1p21. These forms of Stickler syndrome are autosomal dominant. + +Autosomal recessive forms of Stickler syndrome include Stickler syndrome type IV (STL4; previous studies), caused by mutation in the COL9A1 gene (previous studies) on chromosome 6q13,; Stickler syndrome type V (STL5; previous studies), caused by mutation in the COL9A2 gene (previous studies) on chromosome 1p34; and Stickler syndrome type VI (STL6; previous studies), caused by mutation in the COL9A3 gene (previous studies) on chromosome 20q13. + +A disorder previously designated Stickler syndrome type III (STL3), or 'nonocular Stickler syndrome,' has been reclassified as a form of otospondylomegaepiphyseal dysplasia (OSMEDA; previous studies)." +MONDO_0008269,"Definition: Preaxial polydactyly, i.e., polydactyly on the radial side of the hand, is a heterogeneous category. Four types are: (1) thumb polydactyly, (2) polydactyly of triphalangeal thumb, (3) polydactyly of index finger, and (4) polysyndactyly. Preaxial polydactyly I, 'thumb polydactyly,' involves duplication of 1 or more of the skeletal components of a biphalangeal thumb. Severity varies from mere broadening of the distal phalanx with slight bifurcation at the tip to full duplication of the thumb including the metacarpals. This type is the most frequent form of polydactyly in many populations (previous studies)." +MONDO_0008340,"Definition: Hereditary congenital ptosis occurs in 3 main forms: simple; with external ophthalmoplegia; and with blepharophimosis. + +See PTOS2 (previous studies) for description of an X-linked form of congenital bilateral isolated ptosis." +MONDO_0008893,"Definition: The C syndrome, also known as Opitz trigonocephaly syndrome, is a malformation syndrome characterized by trigonocephaly, severe mental retardation, hypotonia, variable cardiac defects, redundant skin, and dysmorphic facial features, including upslanted palpebral fissures, epicanthal folds, depressed nasal bridge, and low-set, posteriorly rotated ears (summary by previous studies). + +C syndrome shows phenotypic overlap with Bohring-Opitz syndrome, or C-like syndrome (previous studies), a disorder with more severe features than C syndrome, caused by heterozygous mutation in the ASXL1 gene (previous studies) on chromosome 20q11." +MONDO_0010959,"Definition: Van den Ende-Gupta syndrome is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (summary by previous studies)." +MONDO_0011830,"Definition: Lissencephaly (LIS), literally meaning smooth brain, is characterized by smooth or nearly smooth cerebral surface and a paucity of gyral and sulcal development, encompassing a spectrum of brain surface malformations ranging from complete agyria to subcortical band heterotopia (SBH). Classic lissencephaly is associated with an abnormally thick cortex, reduced or abnormal lamination, and diffuse neuronal heterotopia. SBH consists of circumferential bands of heterotopic neurons located just beneath the cortex and separated from it by a thin band of white matter. SBH represents the less severe end of the lissencephaly spectrum of malformations (previous studies, summary by previous studies). Agyria, i.e., brain without convolutions or gyri, was considered a rare malformation until recent progress in neuroradiology (previous studies). With this technical advantage, a number of lissencephaly syndromes have been distinguished. + +Classic lissencephaly (formerly type I) is a brain malformation caused by abnormal neuronal migration at 9 to 13 weeks' gestation, resulting in a spectrum of agyria, mixed agyria/pachygyria, and pachygyria. It is characterized by an abnormally thick and poorly organized cortex with 4 primitive layers, diffuse neuronal heterotopia, enlarged and dysmorphic ventricles, and often hypoplasia of the corpus callosum (previous studies). + +previous studies presented a classification system for neuronal migration disorders based on brain imaging findings and molecular analysis. The authors also reviewed the contributions and interactions of the 5 genes then known to cause human lissencephaly: LIS1 (PAFAH1B1), 14-3-3-epsilon (YWHAE), DCX, RELN, and ARX. + + Genetic Heterogeneity of Lissencephaly + +Lissencephaly is a genetically heterogeneous disorder. See also LIS2 (previous studies), caused by mutation in the RELN gene (previous studies) on chromosome 7q22; LIS3 (previous studies), caused by mutation in the TUBA1A gene (previous studies) on chromosome 12q13; LIS4 (previous studies), caused by mutation in the NDE1 gene (previous studies) on chromosome 16p13; LIS5 (previous studies), caused by mutation in the LAMB1 gene (previous studies) on chromosome 7q31; LIS6 (previous studies), caused by mutation in the KATNB1 gene (previous studies) on chromosome 16q21; LIS7 (previous studies), caused by mutation in the CDK5 gene (previous studies) on chromosome 7q36; LIS8 (previous studies), caused by mutation in the TMTC3 gene (previous studies) on chromosome 12q21; LIS9 (previous studies), caused by mutation in the MACF1 gene (previous studies) on chromosome 1p34; and LIS10 (previous studies), caused by mutation in the CEP85L gene (previous studies) on chromosome 6q22. + +X-linked forms include LISX1 (previous studies), caused by mutation in the DCX gene (previous studies) on chromosome Xq23, and LISX2 (previous studies), caused by mutation in the ARX gene (previous studies) on chromosome Xp21. + +See also Miller-Dieker lissencephaly syndrome (MDLS; previous studies), a contiguous gene microdeletion syndrome involving chromosome 17p13 and including the PAFAH1B1 and YWHAE (previous studies) genes. Lissencephaly caused by mutations in the PAFAH1B1 gene is also called 'isolated' lissencephaly to distinguish it from the accompanying features of MDLS." +MONDO_0012719,"Definition: Combined saposin deficiency (PSAPD), a deficiency of prosaposin and saposins A, B, C, and D, is a fatal infantile storage disorder with hepatosplenomegaly and severe neurologic disease (summary by previous studies)." +MONDO_0013583,"Definition: Occipital cortical malformations (OCCM) is an autosomal recessive condition in which affected individuals develop seizures, sometimes associated with transient visual changes. Brain MRI shows both pachygyria and polymicrogyria restricted to the lateral occipital lobes (summary by previous studies)." +MONDO_0014791,"Definition: Luscan-Lumish syndrome (LLS) is characterized by macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures (previous studies; previous studies)" +MONDO_0030458,"Definition: Axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH) is an autosomal dominant peripheral neuropathy characterized predominantly by onset of vocal cord weakness resulting in stridor in infancy or early childhood. The vocal cord paresis remains throughout life and may be severe enough to require tracheostomy. Additional features of the disorder usually include pes cavus and scoliosis. Some patients have mild distal muscle weakness and atrophy primarily affecting the lower limbs, although the upper limbs may also be involved, and distal sensory impairment, often with hyporeflexia (previous studies). + +For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (previous studies)." +MONDO_0030535,"Definition: Autosomal recessive generalized intermediate or severe epidermolysis bullosa simplex 2D (EBS2D) is characterized by widespread intraepidermal skin blistering and erosions from birth (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies)." +MONDO_0031003,"Definition: Familial hypercholanemia-2 (FHCA2) is an autosomal recessive inborn error of metabolism characterized by persistently increased plasma levels of conjugated bile salts apparent from infancy. Most patients are asymptomatic and have no liver dysfunction, although some neonates may have transient jaundice or transiently elevated liver enzymes. These abnormalities improve with age. The bile acid defect can result in impaired absorption of fat-soluble vitamins, including D and K, causing decreased bone mineral density or prolonged prothrobin time (PT) (summary by previous studies and previous studies). + +For a discussion of genetic heterogeneity of FHCA, see FHCA1 (previous studies)." +MONDO_0054748,"Definition: Fanconi anemia complementation group S is an autosomal recessive disorder characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic features. Laboratory studies show defective DNA repair and increased chromosomal breakage during stress. Some patients may have radial ray anomalies, anemia, and increased risk of cancer; patients often have a family history of cancer in family members who have heterozygous mutations (summary by previous studies). + +For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see previous studies." +Orphanet_1454,"Definition: COACH syndrome is an autosomal recessive disorder characterized by impaired intellectual development, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Other features, such as coloboma and renal cysts, may be variable. COACH syndrome is considered by some to be a subtype of Joubert syndrome (JBTS; see previous studies) with congenital hepatic fibrosis. Identification of liver disease in these patients is critical because some may develop complications such as portal hypertension with fatal variceal bleeding (previous studies; previous studies). + + Genetic Heterogeneity of COACH Syndrome + +Also see COACH syndrome-2 (COACH2; previous studies), caused by mutation in in the CC2D2A gene (previous studies), and COACH syndrome-3 (COACH3; previous studies), caused by mutation in the RPGRIP1L gene (previous studies). + +Most cases of COACH syndrome are caused by mutation in the TMEM67 gene." +Orphanet_2963,"Definition: Fontaine progeroid syndrome (FPS) is characterized by prenatal and postnatal growth retardation, decreased subcutaneous fat tissue, sparse hair, triangular face, widely open anterior fontanel, convex and broad nasal ridge, micrognathia, craniosynostosis in some patients, and early death in many (summary by previous studies)." +EFO_0009015,"Definition: Xia-Gibbs syndrome (XIGIS) is characterized by impaired intellectual development with absent or poor expressive language, obstructive sleep apnea, mild dysmorphic features, and brain abnormalities (previous studies). Patients with XIGIS can have a broad clinical spectrum with multisystemic involvement in addition to neurologic manifestation (previous studies)." +EFO_0010633,"Definition: Siddiqi syndrome (SIDDIS) is an autosomal recessive disorder characterized by global developmental delay, early-onset progressive sensorineural hearing impairment, regression of motor skills, dystonia, poor overall growth, and low body mass index (BMI). More variable features may include ichthyosis-like skin abnormalities or sensory neuropathy (summary by previous studies)." +EFO_1000478,"Definition: Somatic mutations in the GNAS gene have been found predominantly in GH-secreting pituitary adenomas but also in ACTH-secreting adenomas. + +Mutations in the GNAS gene have been found in about 40% of sporadic somatotrophin adenomas (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of pituitary adenomas, see PITA1 (previous studies)." +MONDO_0005148,"Definition: Type 2 diabetes mellitus is distinct from maturity-onset diabetes of the young (see previous studies) in that it is polygenic, characterized by gene-gene and gene-environment interactions with onset in adulthood, usually at age 40 to 60 but occasionally in adolescence if a person is obese. The pedigrees are rarely multigenerational. The penetrance is variable, possibly 10 to 40% (previous studies). Persons with type 2 diabetes usually have an obese body habitus and manifestations of the so-called metabolic syndrome (see previous studies), which is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia. + + Genetic Heterogeneity of Susceptibility to Type 2 Diabetes + +Susceptibility to T2D1 (previous studies) is conferred by variation in the calpain-10 gene (CAPN10; previous studies) on chromosome 2q37. The T2D2 locus (previous studies) on chromosome 12q was found in a Finnish population. The T2D3 locus (previous studies) maps to chromosome 20. The T2D4 locus (previous studies) maps to chromosome 5q34-q35. Susceptibility to T2D5 (previous studies) is conferred by variation in the TBC1D4 gene (previous studies) on chromosome 13q22. + +A mutation has been observed in hepatocyte nuclear factor-4-alpha (HNF4A; previous studies) in a French family with NIDDM of late onset. Mutations in the NEUROD1 gene (previous studies) on chromosome 2q32 were found to cause type II diabetes mellitus in 2 families. Mutation in the GLUT2 glucose transporter was associated with NIDDM in 1 patient (previous studies). Mutation in the MAPK8IP1 gene, which encodes the islet-brain-1 protein, was found in a family with type II diabetes in individuals in 4 successive generations (previous studies). Polymorphism in the KCNJ11 gene (previous studies) confers susceptibility. In French white families, previous studies found evidence for a susceptibility locus for type II diabetes on 3q27-qter. They confirmed the diabetes susceptibility locus on 1q21-q24 reported by previous studies in whites and by previous studies in Pima Indians. A mutation in the GPD2 gene (previous studies) on chromosome 2q24.1, encoding mitochondrial glycerophosphate dehydrogenase, was found in a patient with type II diabetes mellitus and in his glucose-intolerant half sister. Mutations in the PAX4 gene (previous studies) have been identified in patients with type II diabetes. previous studies stated that in the Oji-Cree, a gly319-to-ser change in HNF1-alpha (previous studies) behaves as a susceptibility allele for type II diabetes. Mutation in the HNF1B gene (previous studies) was found in 2 Japanese patients with typical late-onset type II diabetes. Mutations in the IRS1 gene (previous studies) have been found in patients with type II diabetes. A missense mutation in the AKT2 gene (previous studies) caused autosomal dominant type II diabetes in 1 family. A (single-nucleotide polymorphism) SNP in the 3-prime untranslated region of the resistin gene (previous studies) was associated with susceptibility to diabetes and to insulin resistance-related hypertension in Chinese subjects. Susceptibility to insulin resistance has been associated with polymorphism in the TCF1 (previous studies), PPP1R3A (previous studies), PTPN1 (previous studies), ENPP1 (previous studies), IRS1 (previous studies), and EPHX2 (previous studies) genes. The K121Q polymorphism of ENPP1 (previous studies) is associated with susceptibility to type II diabetes; a haplotype defined by 3 SNPs of this gene, including K121Q, is associated with obesity, glucose intolerance, and type II diabetes. A SNP in the promoter region of the hepatic lipase gene (previous studies) predicts conversion from impaired glucose tolerance to type II diabetes. Variants of transcription factor 7-like-2 (TCF7L2; previous studies), located on 10q, have also been found to confer risk of type II diabetes. A common sequence variant, previous studies, on chromosome 9p21 near the CDKN2A (previous studies) and CDKN2B (previous studies) genes has been associated with risk of type II diabetes. Variation in the PPARG gene (previous studies) has been associated with risk of type 2 diabetes. A promoter polymorphism in the IL6 gene (previous studies) is associated with susceptibility to NIDDM. Variation in the KCNJ15 gene (previous studies) has been associated with T2DM in lean Asians. Variation in the SLC30A8 gene (previous studies) has been associated with susceptibility to T2D. Variation in the HMGA1 gene (previous studies) is associated with an increased risk of type II diabetes. Mutation in the MTNR1B gene (previous studies) is associated with susceptibility to type 2 diabetes. + + Protection Against Type 2 Diabetes Mellitus + +Protein-truncating variants in the SLC30A8 (previous studies) have been associated with a reduced risk for T2D." +MONDO_0007812,"Definition: Autosomal dominant lamellar ichthyosis (ADLI) is characterized by onset at birth or in the early neonatal period. Patients have large dark scales over the entire body, which are more prominent on the extremities, and palmoplantar keratoderma is present. Some patients experience mild erythema and/or moderate itching. Absence of sweating in severely affected areas has been reported (previous studies). + +previous studies reported a large family of German descent (East Prussia) in which 5 individuals over 3 generations exhibited congenital lamellar ichthyosis that was evident at birth. The 8-year-old proband, her 27-year-old mother, and 52-year-old maternal grandfather exhibited large dark-brown scales over most of the body, including the palms and soles, with relative sparing of the face, anterior chest, and abdomen. The hyperkeratotic skin appeared lichenified on the back of the hands and feet as well as on the wrists, knees, and ankles. There was no history of erythema or blistering. The proband's teeth showed severe caries, but hair was normal. Her 13-month-old brother showed large translucent scales over the entire body, with relative sparing of the diaper area, especially the buttocks. He had 2 circumscribed erythematous patches on his legs, and experienced severe itching. The mother's deceased sister was also reported to have been affected. Histopathologic analysis of severely affected skin from the proband and her mother showed both orthokeratosis and parakeratosis, associated with a marked increase in the granular layer. The authors designated the disorder 'autosomal dominant lamellar ichthyosis (ADLI).' + +previous studies described the ultrastructural characteristics of affected skin from the mother and daughter originally reported by previous studies. There were slightly enlarged nuclei that sometimes showed prominent nucleoli, an increased number of mitochondria, and numerous free ribosomes in the cells of the malpighian layer. The widened granular layer also contained numerous mitochondria, and nucleated keratinocytes were found even in the uppermost transforming keratinocytes. previous studies noted that in contrast to other ichthyoses, there was a prominent transformation zone between the stratum granulosum and corneum, consisting of up to 6 cell layers that reflected the structural and biochemical conversion of fully developed granular cells into horny cells. The authors suggested that ADLI might serve as a model for the study of cornification in humans. + +previous studies concurred that the family described by previous studies with affected members in 3 generations had an autosomal dominant form of 'lamellar' ichthyosis and mentioned a similar family of their own. + +previous studies briefly described one 3-generation family and five 2-generation families with lamellar ichthyosis. The disorder was severe in these families and was accompanied by a collodion membrane at birth. previous studies concluded that the pattern of lipids in the scales, as demonstrated by sequential high-performance thin-layer chromatography, differs from that of the erythrodermic and nonerythrodermic variants of autosomal recessive lamellar ichthyosis. + +previous studies studied 13 patients in 4 families segregating autosomal dominant lamellar ichthyosis and mutations in the ASPRV1 gene, including the 3-generation German family (kindred 630) originally reported by previous studies. The affected individuals exhibited a consistent phenotype, with all presenting at birth or within the first months of life with scaling involving the entire body, including the flexures, palms, and soles. None had collodion membrane. Scales were large and plate-like, and most prominent on the arms and legs. Erythema was absent or mild. Scaling improved, but did not completely resolve, during warmer weather. Affected individuals reported an inability to perspire when scaling was severe. Palmoplantar keratoderma was present, with prominent scaling and accentuation of creases. Some patients reported moderate itch. Histology showed acanthosis, compact orthohyperkeratosis, and a slightly expanded granular layer." +MONDO_0009007,"Definition: Jalili syndrome is an autosomal recessive disorder consisting of cone-rod dystrophy and amelogenesis imperfecta. Significant visual impairment with nystagmus and photophobia is present from infancy or early childhood and progresses with age. Enamel of primary and secondary dentitions is grossly abnormal and prone to rapid posteruptive failure, in part reflecting hypomineralization (summary by previous studies)." +MONDO_0009168,"Definition: The proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is a rare, autosomal recessive, usually prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. It is usually diagnosed by ultrasound between 26 and 33 weeks' gestation (summary by previous studies). Rarely, affected individuals may survive, but are severely impaired with almost no neurologic development (previous studies)." +MONDO_0011334,"Definition: Limb-mammary syndrome (LMS) is an autosomal dominant disorder characterized by variable expressivity of severe hand and/or foot anomalies (deficiencies, duplications, and fusion/separation defects) and hypoplasia/aplasia of the mammary gland and nipple. Less frequent findings include lacrimal duct atresia, nail dysplasia hypohidrosis, hypodontia, and cleft palate with or without bifid uvula (previous studies)." +MONDO_0007080,"Definition: Glucocorticoid-remediable aldosteronism is an autosomal dominant disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol (previous studies). There is significant phenotypic heterogeneity, and some individuals never develop hypertension (previous studies). + + Genetic Heterogeneity of Familial Hyperaldosteronism + +Familial hyperaldosteronism type II (HALD2; previous studies) is caused by mutation in the CLCN2 gene (previous studies) on chromosome 3q27. Familial hyperaldosteronism type III (HALD3; previous studies) is caused by mutation in the KCNJ5 gene (previous studies) on chromosome 11q24. Familial hyperaldosteronism type IV (HALD4; previous studies) is caused by mutation in the CACNA1H gene (previous studies) on chromosome 16p13." +MONDO_0007220,"Definition: Type B1 brachydactyly (BDB1) is the most severe type of human brachydactyly, and shows high penetrance and variable expressivity. Hypoplastic or absent distal phalanges and nails of digits 2 through 5 in the hands and feet are cardinal phenotypic features of BDB1. The middle phalanges of digits 2 through 5 are usually short and may form a bony fusion with the corresponding hypoplastic distal phalanges. The deformed thumbs are often flat, broad, or bifid. A rarer feature of BDB1 is cutaneous syndactyly affecting both fingers and toes (summary by previous studies)." +MONDO_0008057,"Definition: Carney complex is an autosomal dominant multiple neoplasia syndrome characterized by cardiac, endocrine, cutaneous, and neural myxomatous tumors, as well as a variety of pigmented lesions of the skin and mucosae. Carney complex may simultaneously involve multiple endocrine glands, similar to classic MEN syndromes (MEN1; previous studies and MEN2; previous studies). Carney complex shows some similarities to McCune-Albright syndrome (MAS; previous studies), a sporadic condition that is also characterized by multiple endocrine and nonendocrine tumors, and shares skin abnormalities and some nonendocrine tumors with the lentiginoses and certain of the hamartomatoses, particularly Peutz-Jeghers syndrome (PJS; previous studies). Carney complex is often associated with the unusual large-cell calcifying Sertoli cell tumor and psammomatous melanotic schwannomas (previous studies; previous studies). + + Genetic Heterogeneity of Carney Complex + +Carney complex type 2 (CNC2; previous studies) has been mapped to chromosome 2p16, indicating genetic heterogeneity. + +See also isolated primary pigmented nodular adrenocortical disease (PPNAD1; previous studies) and isolated cardiac myxoma (previous studies), both of which are manifestations of the Carney complex that can be seen in isolation. + +A family with features of the Carney complex and distal arthrogryposis (previous studies) associated with a mutation in the MYH8 gene (previous studies) has also been reported." +MONDO_0008111,"Definition: Oculodentodigital syndrome is characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding (summary by previous studies). + +Neurologic abnormalities are sometimes associated (previous studies), and lymphedema has been reported in some patients with ODDD (previous studies). See review by previous studies. + + Genetic Heterogeneity of Oculodentodigital Syndrome + +An autosomal recessive form of ODDD (previous studies) is also caused by mutation in the GJA1 gene, but the majority of cases are autosomal dominant." +MONDO_0009704,"Definition: Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. The myopathic form presents most frequently in children or young adults with muscle pain with or, in most cases, without myoglobinuria with elevation of serum creatine kinase precipitated by strenuous exercise, cold, fever, or prolonged fasting. Severity of attacks is highly variable. Myoglobinuria can cause kidney failure and death (summary by previous studies and previous studies). + +See also the lethal neonatal (previous studies) and infantile (previous studies) forms of the disorder, which are also caused by mutation in the CPT2 gene." +MONDO_0011002,"Definition: Hereditary motor and sensory neuropathy type VI is an autosomal dominant neurologic disorder characterized by peripheral neuropathy and optic atrophy (summary by previous studies). + + Genetic Heterogeneity of Hereditary Motor and Sensory Neuropathy Type VI + +See also HMSN6B (previous studies), caused by mutation in the SLC25A46 gene (previous studies) on chromosome 5q22, and HMSN6C (previous studies), caused by mutation in the PDXK gene (previous studies) on chromosome 21q22. + +For a general phenotypic description and a discussion of genetic heterogeneity of CMT, see CMT1B (previous studies)." +MONDO_0014942,"Definition: Developmental and epileptic encephalopathy-45 (DEE45) is a neurologic disorder characterized by global developmental delay apparent in infancy or early childhood and onset of seizures within the first 12 months of life. Affected individuals have severely impaired intellectual development, hypotonia, and other persistent neurologic deficits (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0018582,"Definition: Mahvash disease (MVAH) is an autosomal recessive disorder caused by inactivating mutations in the glucagon receptor, leading to alpha-cell hyperplasia of the pancreas, hyperglucagonemia without glucagonoma syndrome, and occasional hypoglycemia. The disease may lead to glucagonomas and/or primitive neuroectodermal tumors (PNETs)." +MONDO_0030750,"Definition: Intermediate junctional epidermolysis bullosa-4 (JEB4) is an autosomal recessive, nonlethal skin disorder characterized by blistering and erosions at birth or shortly afterward. The plane of cleavage of blistering is through the lamina lucida of the cutaneous basement zone. Blisters may heal with atrophic scarring and variable hypo- or hyperpigmentation. Oral mucosa may be involved. Nails may be lost or dystrophic, and dental enamel defects are present (summary by previous studies). A previous designation, GABEB (generalized atrophic benign epidermolysis bullosa), was used to classify patients whose phenotype included alopecia; see NOMENCLATURE. + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies)." +MONDO_0859211,"Definition: Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD) is an autosomal recessive complex neurologic disorder characterized by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders (summary by previous studies and previous studies)." +Orphanet_391417,"Definition: HSD10 mitochondrial disease (HSD10MD) most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (summary by previous studies; previous studies). + +In a review of this disorder, previous studies noted that although it was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity (see PATHOGENESIS)." +MONDO_0009776,"Definition: Spermatogenic arrest during meiosis is a cause of infertility. The histologic picture of meiotic arrest is rather constant. Meiotic arrest is characterized by germ cells that enter meiosis and undergo the first chromosomal reduction from 4n to 2n but are then unable to proceed further. This results in tubules containing spermatocytes as the latest developmental stage of germ cells. Meiotically arrested spermatocytes accumulate in the tubules, degenerate, and are easily distinguishable from normal spermatocytes by their partially condensed chromosomes. Although the cause of infertility in patients with meiotic arrest often remains unidentified, this histologic picture can be observed in patients with nonidiopathic infertility as well, such as in the case of microdeletions of the Y chromosome, chromosomal abnormalities, and cryptorchidism, suggesting that different causal factors can result in the same effect (summary by previous studies). + + Genetic Heterogeneity of Spermatogenic Failure + +See SPGF2 (previous studies), caused by mutation in the MSH4 gene (previous studies) on chromosome 1p31; SPGF3 (previous studies), caused by mutation in the SLC26A8 gene (previous studies) on chromosome 6p21; SPGF4 (previous studies), caused by mutation in the SYCP3 gene (previous studies) on chromosome 12q23; SPGF5 (previous studies), caused by mutation in the AURKC gene (previous studies) on chromosome 19q13; SPGF6 (previous studies), caused by mutation in the SPATA16 gene (previous studies) on chromosome 3q26; SPGF7 (previous studies), caused by mutation in the CATSPER gene (previous studies) on chromosome 11q13; SPGF8 (previous studies), caused by mutation in the NR5A1 gene (previous studies) on chromosome 9q33; SPGF9 (previous studies), caused by mutation in the DPY19L2 gene (previous studies) on chromosome 12q14; SPGF10 (previous studies), caused by mutation in the SEPT12 gene (previous studies) on chromosome 16p13; SPGF11 (previous studies), caused by mutation in the KLHL10 gene (previous studies) on chromosome 17p21; SPGF12 (previous studies), caused by mutation in the NANOS1 gene (previous studies) on chromosome 10q26; SPGF13 (previous studies), caused by mutation in the TAF4B gene (previous studies) on chromosome 18q11; SPGF14 (previous studies), caused by mutation in the ZMYND15 gene (previous studies) on chromosome 17p13; SPGF15 (previous studies), caused by mutation in the SYCE1 gene (previous studies) on chromosome 10q26; SPGF16 (previous studies), caused by mutation in the SUN5 gene (previous studies) on chromosome 20q11; SPGF17 (previous studies), caused by mutation in the PLCZ1 gene (previous studies) on chromosome 12p12; SPGF18 (previous studies), caused by mutation in the DNAH1 gene (previous studies) on chromosome 3p21; SPGF19 (previous studies), caused by mutation in the CFAP43 gene (previous studies) on chromosome 10q25; SPGF20 (previous studies), caused by mutation in the CFAP44 gene (previous studies) on chromosome 3q13; SPGF21 (previous studies), caused by mutation in the BRDT gene (previous studies) on chromosome 1p22; SPGF22 (previous studies), caused by mutation in the MEIOB gene (previous studies) on chromosome 16p13; SPGF23 (previous studies), caused by mutation in the TEX14 gene (previous studies) on chromosome 17q22; SPGF24 (previous studies), caused by mutation in the CFAP69 gene (previous studies) on chromosome 7q21; SPGF25 (previous studies), caused by mutation in the TEX15 gene (previous studies) on chromosome 8p12; SPGF26 (previous studies), caused by mutation in the TSGA10 gene (previous studies) on chromosome 2q11; SPGF27 (previous studies), caused by mutation in the AK7 gene (previous studies) on chromosome 14q32; SPGF28 (previous studies), caused by mutation in the FANCM gene (previous studies) on chromosome 14q21; SPGF29 (previous studies), caused by mutation in the SPINK2 gene (previous studies) on chromosome 4q12; SPGF30 (previous studies), caused by mutation in the TDRD9 gene (previous studies) on chromosome 14q32; SPGF31 (previous studies), caused by mutation in the PMFBP1 gene (previous studies) on chromosome 16q22; SPGF32 (previous studies), caused by mutation in the SOHLH1 gene (previous studies) on chromosome 9q34; SPGF33 (previous studies), caused by mutation in the WDR66 gene (previous studies) on chromosome 12q24; SPGF34 (previous studies), caused by mutation in the FSIP2 gene (previous studies) on chromosome 2q32; SPGF35, caused by mutation in the QRICH2 gene (previous studies) on chromosome 17q25; SPGF36 (previous studies), caused by mutation in the PPP2R3C gene (previous studies) on chromosome 14q13; SPGF37 (previous studies), caused by mutation in the TTC21A gene (previous studies) on chromosome 3p22; SPGF38 (previous studies), caused by mutation in the ARMC2 gene (previous studies) on chromosome 6q21; SPGF39 (previous studies), caused by mutation in the DNAH17 gene (previous studies) on chromosome 17q25; SPGF40 (previous studies), caused by mutation in the CFAP65 gene (previous studies) on chromosome 2q35; SPGF41 (previous studies), caused by mutation in the CFAP70 gene (previous studies) on chromosome 10q22; SPGF42 (previous studies), caused by mutation in the TTC29 gene (previous studies) on chromosome 4q31; SPGF43 (previous studies), caused by mutation in the SPEF2 gene (previous studies) on chromosome 5p13; SPGF44 (previous studies), caused by mutation in the CEP112 gene (previous studies) on chromosome 17q24; SPGF45 (previous studies), caused by mutation in the DNAH2 gene (previous studies) on chromosome 17p13; SPGF46 (previous studies), caused by mutation in the DNAH8 gene (previous studies) on chromosome 6p21; SPGF47 (previous studies), caused by mutation in the DZIP1 gene (previous studies) on chromosome 13q32; SPGF48 (previous studies), caused by mutation in the M1AP gene (previous studies) on chromosome 2p13; SPGF49 (previous studies), caused by mutation in the CFAP58 gene (previous studies) on chromosome 10q25; SPGF50 (previous studies), caused by mutation in the XRCC2 gene (previous studies) on chromosome 7q36; SPGF51 (previous studies), caused by mutation in the CFAP91 gene (previous studies) on chromosome 3q13; SPGF52 (previous studies), caused by mutation in the C14ORF39 gene (previous studies) on chromosome 14q23; SPGF53 (previous studies), caused by mutation in the ACTL9 gene (previous studies) on chromosome 19p13; SPGF54 (previous studies), caused by mutation in the CATIP gene (previous studies) on chromosome 2q35; SPGF55 (previous studies), caused by mutation in the SPAG17 gene (previous studies) on chromosome 1p12; SPGF56 (previous studies), caused by mutation in the DNAH10 gene (previous studies) on chromosome 12q24; SPGF57 (previous studies), caused by mutation in the PNLDC1 gene (previous studies) on chromosome 6q25; SPGF58 (previous studies), caused by mutation in the IFT74 gene (previous studies) on chromosome 9p21; SPGF59 (previous studies), caused by mutation in the TERB2 gene (previous studies) on chromosome 15q21; SPGF60 (previous studies), caused by mutation in the TERB1 gene (previous studies) on chromosome 16q22; SPGF61 (previous studies), caused by mutation in the STAG3 gene (previous studies) on chromosome 7q22; SPGF62 (previous studies), caused by mutation in the RNF212 gene (previous studies) on chromosome 4p16; SPGF63 (previous studies), caused by mutation in the RPL10L gene (previous studies) on chromosome 14q21; SPGF64 (previous studies), caused by mutation in the FBXO43 gene (previous studies) on chromosome 8q22; SPGF65 (previous studies), caused by mutation in the DNHD1 gene (previous studies) on chromosome 11p15; SPGF66 (previous studies), caused by mutation in the ZPBP gene (previous studies) on chromosome 7p12; SPGF67 (previous studies), caused by mutation in the CCDC62 gene (previous studies) on chromosome 12q24; SPGF68 (previous studies), caused by mutation in the C2CD6 gene (previous studies) on chromosome 2q33; SPGF69 (previous studies), caused by mutation in the GGN gene (previous studies) on chromosome 19q13; SPGF70 (previous studies), caused by mutation in the PDHA2 gene (previous studies) on chromosome 4q22; SPGF71 (previous studies), caused by mutation in the ZSWIM7 gene (previous studies) on chromosome 17p12; SPGF72 (previous studies), caused by mutation in the WDR19 gene (previous studies) on chromosome 4p14; SPGF73 (previous studies), caused by mutation in the MOV10L1 gene (previous studies) on chromosome 22q13; SPGF74 (previous studies), caused by mutation in the MSH5 gene (previous studies) on chromosome 6p21; SPGF75 (previous studies), caused by mutation in the SHOC1 gene (previous studies) on chromosome 9q31; SPGF76 (previous studies), caused by mutation in the CCDC34 gene (previous studies) on chromosome 11p14; SPGF77 (previous studies), caused by mutation in the FKBP6 gene (previous studies) on chromosome 7q11; SPGF78 (previous studies), caused by mutation in the IQCN gene (previous studies) on chromosome 19p13; SPGF79 (previous studies), caused by mutation in the KCNU1 gene (previous studies) on chromosome 8p11; SPGF80 (previous studies), caused by mutation in the DRC1 gene (previous studies) on chromosome 2p23; SPGF81 (previous studies), caused by mutation in the TEKT3 gene (previous studies) on chromosome 17p12; SPGF82 (previous studies), caused by mutation in the AKAP3 gene (previous studies) on chromosome 12p13; SPGF83 (previous studies), caused by mutation in the DNALI1 gene (previous studies) on chromosome 1p34; and SPGF84 (previous studies), caused by mutation in the CFAP61 gene (previous studies) on chromosome 20p11. + +X-linked forms of spermatogenic failure include SPGFX1 (previous studies), SPGFX2 (previous studies), SPGFX3 (previous studies), SPGFX4 (previous studies), SPGFX5 (previous studies), and SPGFX6 (previous studies). + +Y-linked forms of spermatogenic failure include SPGFY1 (previous studies) and SPGFY2 (previous studies). + +Spermatogenic failure can also result from underlying endocrinologic disorders (see, e.g., hypogonadotropic hypogonadism, previous studies) or ciliary dyskinesias (see, e.g., CILD1, previous studies)." +MONDO_0009928,"Definition: Pulmonary alveolar microlithiasis (PULAM) is a rare disease characterized by the deposition of calcium phosphate microliths throughout the lungs. Most patients are asymptomatic for several years or even for decades, and, generally, the diagnosis is incidental to clinical investigations unrelated to the specific disorder. Cases with early onset or rapid progression are rare. A 'sandstorm-appearing' chest roentgenogram is a typical diagnostic finding. The onset of this potentially lethal disease varies from the neonatal period to old age, and the disease follows a long-term progressive course, resulting in a slow deterioration of lung functions. About one-third of the reported cases are said to be familial (summary by previous studies)." +MONDO_0010850,"Definition: Oblique facial clefts are a rare form of orofacial clefting, comprising about 0.25% of all facial clefts. Two major types have been described classically: nasoocular and oroocular, the latter of which can be subdivided into oromedial-canthal and orolateral-canthal (summary by previous studies)." +MONDO_0011215,"Definition: Gracile bone dysplasia is a perinatally lethal condition characterized by gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia (summary by previous studies)." +MONDO_0012803,"Definition: Trehalose is a disaccharide found in mushrooms, algae, and insect hemolymph; mushrooms and products containing baker's yeast are thus the only sources of trehalose in the human diet. The high concentration of trehalose in cryptobiotic plants is responsible for their remarkable ability to go through cycles of desiccation and rehydration without injury. This led to interest by the food industry in the addition of trehalose to foodstuffs to improve the longevity and quality of dried food. However, ingestion of a disaccharide in an individual who cannot digest it results in osmotic diarrhea, abdominal pain, and increased rectal flatulence (summary by previous studies). Isolated trehalose intolerance due to deficiency of trehalase (TREH; previous studies) is probably rare in adult white Americans (previous studies), but has been estimated at 8% in Greenlanders (previous studies)." +MONDO_0013136,"Definition: Hypotrichosis and recurrent skin vesicles (HYPTSV) is characterized by sparse to absent scalp hair, eyebrows, eyelashes, and body hair, as well as recurrent vesicles of scalp and skin. Some patients also exhibit trauma-induced blistering, and anomalies of dental enamel and of nails may be observed (previous studies; previous studies)." +MONDO_0014028,"Definition: This autosomal recessive form of distal arthrogryposis, designated DA5D by previous studies, is characterized by severe camptodactyly of the hands, including adducted thumbs and wrists; mild camptodactyly of the toes; clubfoot and/or a calcaneovalgus deformity; extension contractures of the knee; unilateral ptosis or ptosis that is more severe on one side; a round-shaped face; arched eyebrows; a bulbous, upturned nose; and micrognathia. Notably, these patients do not have ophthalmoplegia. + +For a general phenotypic description and discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (previous studies). + +For discussion of genetic heterogeneity of distal arthrogryposis type 5, see DA5 (previous studies)." +MONDO_0014717,"Definition: Progressive myoclonic epilepsy-10 is an autosomal recessive neurodegenerative disorder characterized by onset of progressive myoclonus, ataxia, spasticity, dysarthria, and cognitive decline in the first decade of life. The severity is variable, but some patients may become mute and bedridden with psychosis (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (previous studies)." +MONDO_0030029,"Definition: CSGALNACT1 deficiency is characterized by mild skeletal dysplasia, joint hypermobility, and advanced bone age. Shortness of long bones is evident prenatally, and patients exhibit short stature and relative macrocephaly. Advanced carpotarsal bone age and monkey-wrench appearance of the femur observed in infancy may disappear with age (previous studies)." +MONDO_0030900,"Definition: Intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS) is an autosomal recessive complex neurologic disorder characterized by global developmental delay with impaired intellectual development and language delay. In addition, most patients develop a paroxysmal hyperkinetic movement disorder in the first months or years of life manifest as sudden falls or backward propulsion, eye or head deviation, and dystonic limb posturing followed by chorea and dyskinetic movements. The episodes are pharmacoresistant to anticonvulsant medication. EEG may show interictal abnormalities, but are usually not consistent with epilepsy. However, some patients may also develop epileptic seizures or only have seizures without a movement disorder (summary by previous studies)." +MONDO_0032780,"Definition: Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay, poor or absent speech, hypotonia, variable ocular movement and visual abnormalities, and respiratory difficulties, including hypoventilation, and sleep apnea. Patients may have significant breathing problems during respiratory infections that may lead to early death (summary by previous studies)." +MONDO_0032927,"Definition: Triokinase and FMN cyclase deficiency syndrome (TKFCD) is a multisystem disease with marked clinical variability, even intrafamilially. In addition to cataract and developmental delay of variable severity, other features may include liver dysfunction, microcytic anemia, and cerebellar hypoplasia. Fatal cardiomyopathy with lactic acidosis has been observed (previous studies)." +MONDO_0033558,"Definition: Autoinflammation, immune dysregulation, and eosinophilia (AIIDE) is an autosomal dominant disorder characterized by onset of severe atopic dermatitis and chronic gastrointestinal inflammation, mainly involving the colon, in infancy or early childhood. Affected individuals tend to have asthma and food or environmental allergies, as well as poor overall growth with short stature. Severe liver involvement has also been reported (previous studies). Laboratory studies show increased eosinophils with normal or increased IgE levels, as well as evidence of a hyperactive immune state, including increased erythrocyte sedimentation rate and C-reactive protein. Treatment with JAK inhibitors, such as ruxolitinib and tofacitinib, results in dramatic clinical improvement (summary by previous studies)." +MONDO_0859143,"Definition: Radio-Tartaglia syndrome (RATARS) is a neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, speech delay, and variable behavioral abnormalities. Affected individuals show hypotonia, mild motor difficulties, and craniofacial dysmorphism. Brain imaging may show nonspecific defects; rare patients have seizures or pyramidal signs. A subset of individuals may have congenital heart defects, precocious puberty, and obesity in females. Some of the features are similar to those observed in patients with chromosome 1p36 deletion syndrome (previous studies) (summary by previous studies)." +Orphanet_306504,"Definition: Junctional epidermolysis bullosa-7 with interstitial lung disease and nephrotic syndrome (JEB7), also known as ILNEB, is an autosomal recessive multiorgan disorder that includes congenital interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa. The respiratory and renal features predominate, and lung involvement accounts for the lethal course of the disease (summary by previous studies)." +MONDO_0013881,"Definition: Junctional epidermolysis bullosa-7 with interstitial lung disease and nephrotic syndrome (JEB7), also known as ILNEB, is an autosomal recessive multiorgan disorder that includes congenital interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa. The respiratory and renal features predominate, and lung involvement accounts for the lethal course of the disease (summary by previous studies)." +MONDO_0007549,"Definition: Epidermolysis bullosa dystrophica is a clinically heterogeneous disorder characterized by blistering and scarring of the skin and mucous membranes in response to mechanical force. Microscopic examination of the skin shows cleavage below the basement membrane within the papillary dermis. All forms are caused by mutation in the COL7A1 gene. previous studies proposed that the Cockayne-Touraine and Pasini subtypes of dystrophic epidermolysis bullosa be combined into 1 category known as 'dominant dystrophic epidermolysis bullosa' (DDEB), since both are caused by mutations in the COL7A1 gene and show overlapping clinical features. + +Epidermolysis bullosa simplex (see, e.g., previous studies) and epidermolysis bullosa junctional (see, e.g., previous studies) are clinically and genetically distinct disorders characterized by tissue separation at the levels of the basal keratinocyte layer and lamina lucida, respectively." +MONDO_0008199,"Definition: Parkinson disease was first described by James Parkinson in 1817. It is the second most common neurodegenerative disorder after Alzheimer disease (AD; previous studies), affecting approximately 1% of the population over age 50 (previous studies). + + Reviews + +previous studies reviewed the genetic and environmental causes of Parkinson disease. previous studies reviewed the genetics of Parkinson disease and provided a speculative model of interactions among proteins implicated in PD. previous studies provided a review of Parkinson disease, with emphasis on diagnosis, neuropathology, and treatment. + + Genetic Heterogeneity of Parkinson Disease + +Several loci for autosomal dominant Parkinson disease have been identified, including PARK1 (previous studies) and PARK4, caused by mutation in or triplication of the alpha-synuclein gene (SNCA; previous studies), respectively, on 4q22; PARK5 (previous studies), caused by mutation in the UCHL1 gene on 4p13; PARK8 (previous studies), caused by mutation in the LRRK2 gene (previous studies) on 12q12; PARK11 (previous studies), caused by mutation in the GIGYF2 gene (previous studies) on 2q37; PARK13 (previous studies), caused by mutation in the HTRA2 gene (previous studies) on 2p13; PARK17 (previous studies), caused by mutation in the VPS35 gene (previous studies) on 16q11; PARK18 (previous studies), caused by mutation in the EIF4G1 gene (previous studies) on 3q27; PARK22 (previous studies), caused by mutation in the CHCHD2 gene (previous studies) on chromosome 7p11.2; and PARK24 (previous studies), caused by mutation in the PSAP gene (previous studies) on chromosome 10q22. + +Several loci for autosomal recessive early-onset Parkinson disease have been identified: PARK2 (previous studies), caused by mutation in the gene encoding parkin (PARK2; previous studies) on 6q26; PARK6 (previous studies), caused by mutation in the PINK1 gene (previous studies) on 1p36; PARK7 (previous studies), caused by mutation in the DJ1 gene (PARK7; previous studies) on 1p36; PARK14 (previous studies), caused by mutation in the PLA2G6 gene (previous studies) on 22q13; PARK15 (previous studies), caused by mutation in the FBXO7 gene (previous studies) on 22q12-q13; PARK19A (previous studies) and PARK19B (see previous studies), caused by mutation in the DNAJC6 gene (previous studies) on 1p32; PARK20 (previous studies), caused by mutation in the SYNJ1 gene (previous studies) on 21q22; and PARK23 (previous studies), caused by mutation in the VPS13C gene (previous studies) on chromosome 15q22. + +PARK3 (previous studies) has been mapped to chromosome 2p13; PARK10 (previous studies) has been mapped to chromosome 1p34-p32; PARK16 (previous studies) has been mapped to chromosome 1q32. See also PARK21 (previous studies). A locus on the X chromosome has been identified (PARK12; previous studies). There is also evidence that mitochondrial mutations may cause or contribute to Parkinson disease (see previous studies). Susceptibility to the development of the more common late-onset form of Parkinson disease has been associated with polymorphisms or mutations in several genes, including GBA (previous studies), MAPT (previous studies), MC1R (previous studies), ADH1C (previous studies), and genes at the HLA locus (see, e.g., HLA-DRA, previous studies). Each of these risk factors independently may have a modest effect on disease development, but together may have a substantial cumulative effect (previous studies). + +Susceptibility to PD may also be conferred by expanded trinucleotide repeats in several genes causing other neurologic disorders usually characterized by spinocerebellar ataxia (SCA), including the ATXN2 (previous studies), ATXN3 (previous studies), TBP (previous studies), and ATXN8OS (previous studies) genes." +MONDO_0030903,"Definition: Hermansky-Pudlak syndrome-11 (HPS11) is characterized by mild oculocutaneous albinism in association with a moderate bleeding diathesis. Patients lack detectable platelet dense granules, and show mildly impaired activation-induced ATP release and platelet aggregation in vitro (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (previous studies)." +MONDO_0032925,"Definition: Congenital juvenile respiratory papillomatosis (JRRP) is an autosomal recessive disorder characterized by the development of recurrent growth of papillomas (warts) on respiratory epithelial cells in the upper airway, particularly the larynx. Patients present in early childhood with hoarse voice and, in severe cases, respiratory stridor due to airway obstruction. Affected individuals may also have mild dermatologic abnormalities similar to those observed in AIADK. While JRRP is a genetic disorder resulting from abnormal activation of the immune system, RRP in general is usually associated with acquired HPV infection, commonly with HPV types 6 and 11 (summary by previous studies)." +MONDO_0033006,"Definition: Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most patients have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Most patients die in the first years of life (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (previous studies)." +MONDO_0007732,"Definition: Holt-Oram syndrome is an autosomal dominant disorder characterized by abnormalities of the upper limbs and shoulder girdle, associated with a congenital heart lesion. The typical combination is considered to be a triphalangeal thumb with a secundum atrial septal defect (ASD), but there is a great range in the severity of both the heart and skeletal lesions (summary by previous studies)." +MONDO_0008858,"Definition: 'Behr syndrome' is a clinical term that refers to the constellation of early-onset optic atrophy accompanied by neurologic features, including ataxia, pyramidal signs, spasticity, and mental retardation (previous studies; previous studies). + +Patients with mutations in genes other than OPA1 can present with clinical features reminiscent of Behr syndrome. Mutations in one of these genes, OPA3 (previous studies), result in type III 3-methylglutaconic aciduria (MGCA3; previous studies). previous studies noted that the abnormal urinary pattern in MGCA3 may not be picked up by routine organic acid analysis, suggesting that early reports of Behr syndrome with normal metabolic features may actually have been 3-methylglutaconic aciduria type III." +MONDO_0011959,"Definition: Acute febrile neutrophilic dermatosis (AFND) is an autosomal dominant autoinflammatory disorder characterized by onset of recurrent fever and dermatologic abnormalities in childhood. Laboratory studies show elevated acute-phase reactants and activation of the inflammatory response, particularly IL1B (previous studies). Additional more variable features may include myalgia and arthralgia (summary by previous studies)." +MONDO_0011988,"Definition: Immunodeficiency-73A with defective neutrophil chemotaxis and leukocytosis (IMD73A) is an immunologic disorder characterized by onset of recurrent infections in early infancy. Affected infants have periumbilical erythema and later develop skin abscesses and invasive infections. Laboratory studies show leukocytosis, neutrophilia, decreased TRECs, and T-cell abnormalities. Neutrophils showed decreased chemotaxis associated with actin polymerization abnormalities, as well as variably impaired oxidative responses. Hematopoietic stem cell transplant may be curative (summary by previous studies; review by previous studies). + +In a review of autosomal forms of chronic granulomatous disease (see previous studies for genetic heterogeneity of CGD), previous studies noted that patients with RAC2 mutations may manifest CGD-like symptoms due to defects in neutrophil NADPH oxidase activity." +MONDO_0013226,"Definition: Roifman-Chitayat syndrome (ROCHIS) is an autosomal recessive digenic disorder characterized by global developmental delay, variable neurologic features such as seizures, ataxia, and optic atrophy, dysmorphic facial features, distal skeletal anomalies, and combined immunodeficiency manifest as recurrent infections (summary by previous studies)." +Orphanet_221139,"Definition: Roifman-Chitayat syndrome (ROCHIS) is an autosomal recessive digenic disorder characterized by global developmental delay, variable neurologic features such as seizures, ataxia, and optic atrophy, dysmorphic facial features, distal skeletal anomalies, and combined immunodeficiency manifest as recurrent infections (summary by previous studies)." +MONDO_0013934,"Definition: Immunodeficiency-110 (IMD110) is an autosomal recessive primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, and autoimmune manifestations. Patients are at risk for developing lymphoproliferative disorders or lymphoma, particularly associated with EBV. Some patients may show cardiac malformations, including atrial septal defect (previous studies; previous studies)." +MONDO_0014247,"Definition: Familial episodic pain syndrome-3 (FEPS3) is an autosomal dominant disorder characterized by early childhood onset of intense episodic pain mainly affecting the distal lower extremities, but sometimes affecting the upper extremities as well. The pain comes in cycles lasting several days, is exacerbated by fatigue, may be accompanied by sweating, and can be relieved by antiinflammatory medication. Severe episodic pain tends to diminish with age (summary by previous studies). + +For a discussion of the genetic heterogeneity of familial episodic pain syndrome, see FEPS1 (previous studies)." +MONDO_0014883,"Definition: Familial cardiomyopathy caused by mutation in the FLNC gene has been described as hypertrophic, restrictive, dilated, or arrhythmogenic right ventricular cardiomyopathy. Affected individuals, especially those with dilated cardiomyopathy, are at risk for arrhythmias and sudden death. Arrhythmias without cardiomyopathy, and left ventricular noncompaction, have also been reported (previous studies; previous studies)." +MONDO_0032943,"Definition: Nabais Sa-de Vries syndrome type 2 (NSDVS2) is characterized by global developmental delay apparent from birth and distinctive dysmorphic facial features. Most patients have additional anomalies, including congenital heart defects, sleep disturbances, hypotonia, and variable endocrine abnormalities, such as hypothyroidism (summary by previous studies)." +MONDO_0060533,"Definition: MISSLA is an autosomal recessive disorder characterized by intrauterine growth retardation, microcephaly, variable short stature, and limb abnormalities mainly affecting the upper limb and radial ray. Affected individuals typically have mild intellectual disability, but may have normal development (summary by previous studies)." +Orphanet_98985,"Definition: Mutations in the MIP gene have been found to cause multiple types of cataract, which have been described as 'polymorphic,' progressive punctate lamellar, cortical, anterior and posterior polar, nonprogressive lamellar with sutural opacities, embryonic nuclear, and pulverulent cortical." +MONDO_0014420,"Definition: Acid-labile subunit deficiency is characterized by severely reduced serum insulin-like growth factor I (IGF1; previous studies) and IGF-binding protein-3 (IGFBP3; previous studies) concentrations that are incongruent with an associated mild growth retardation (height, -2 to -3 SD before and during puberty). Pubertal delay in boys and insulin insensitivity are common findings (summary by previous studies)." +MONDO_0024772,"Definition: The Pilorge type of X-linked syndromic intellectual developmental disorder (MRXSP) is characterized by global developmental delay with variably impaired intellectual development, speech delay, and behavioral abnormalities, including autism spectrum disorder (ASD). More variable features include motor incoordination, seizures, and ocular abnormalities (summary by previous studies)." +MONDO_0030525,"Definition: Generalized intermediate epidermolysis bullosa simplex-2B (EBS2B) is an autosomal dominant disorder of skin in which intraepidermal blistering occurs after minor mechanical trauma. Skin blistering is generalized, begins at birth, and is worsened by heat, humidity, and sweating. The tendency to blistering diminishes in adolescence, when it may become localized to hands and feet. Intermediate EBS has previously been known as the Koebner type (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (previous studies). + + Reviews + +previous studies reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility." +MONDO_0054837,"Definition: MRD57 is an autosomal dominant neurodevelopmental disorder with a highly variable phenotype. Most affected individuals have delayed psychomotor development apparent in infancy or early childhood, language delay, and behavioral abnormalities. Additional features may include hypotonia, feeding problems, gastrointestinal issues, and dysmorphic facial features (summary by previous studies)." +EFO_0010276,"Definition: Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements (NEDNEH) is an autosomal recessive severe neurologic disorder characterized by delayed psychomotor development with inability to walk or speak, early-onset refractory seizures, and nonepileptic hyperkinetic movement disorders, including myoclonus dystonia and dyskinesias. Patients require tube feeding and may die of respiratory failure in childhood or in the second decade (summary by previous studies)." +MONDO_0014788,"Definition: Autosomal recessive muscular dystrophy with cardiomyopathy and triangular tongue (MDRCMTT) is an autosomal recessive muscle disorder characterized by onset of severe and progressive muscle weakness and atrophy in childhood, resulting in loss of independent ambulation. Patients may also have dilated cardiomyopathy and have macroglossia with a small tip, resulting in a triangular appearance of the tongue (summary by previous studies)." +MONDO_0030953,"Definition: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies-2 (SSFSC2) is characterized by thin and short long bones, distinctive facial dysmorphism, and dental and skeletal abnormalities, in the absence of developmental delay or intellectual disability. Cardiac anomalies have been reported in some patients (previous studies). + +For a discussion of genetic heterogeneity of SSFSC, see SSFSC1 (previous studies)." +MONDO_0031006,"Definition: Neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA) is an autosomal dominant disorder with somewhat variable manifestations. Most affected individuals present in mid-adulthood with slowly progressive cerebellar and gait ataxia, optic atrophy, and myopathy or myalgia. Some patients may have a childhood history of neurologic features, including limited extraocular movements. Additional features can include cardiomyopathy, psychiatric disturbances, and peripheral sensory impairment (summary by previous studies and previous studies)." +MONDO_0032758,"Definition: Early-onset neurodegeneration with choreoathetoid movements and microcytic anemia (NDCAMA) is an autosomal recessive disorder characterized by severe psychomotor developmental abnormalities, abnormal movements, and functional iron deficiency (previous studies)." +Orphanet_2510,"Definition: Warburg Micro syndrome-1 (WARBM1) is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by previous studies). + + Genetic Heterogeneity of Warburg Micro Syndrome + +Warburg Micro syndrome-2 (WARBM2; previous studies) is caused by mutation in the RAB3GAP2 gene (previous studies) on chromosome 1q41. WARBM3 (previous studies) is caused by mutation in the RAB18 gene (previous studies) on chromosome 10p12. WARBM4 (previous studies) is caused by mutation in the TBC1D20 gene (previous studies) on chromosome 20p13. + +previous studies provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, previous studies stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap." +Orphanet_2697,"Definition: Arthrogryposis, renal dysfunction, and cholestasis-1 (ARCS1) is characterized by congenital joint contractures, renal tubular dysfunction, cholestasis with low GGT (previous studies) activity, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. Most patients with ARC do not survive past the first year of life (previous studies; previous studies). + +Another form of arthrogryposis, renal dysfunction, and cholestasis, ARCS2 (previous studies), is caused by mutation in the VIPAR gene on chromosome 14q24 (previous studies)." +MONDO_0013254,"Definition: Microcephaly, seizures, and developmental delay (MCSZ) is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients develop refractory seizures in infancy, consistent with a developmental and epileptic encephalopathy (DEE), whereas others have more well-controlled seizures and a more protracted course associated with cerebellar atrophy and peripheral neuropathy (previous studies and previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0014310,"Definition: Poikiloderma, characterized by mottled pigmentation, telangiectasia, and epidermal atrophy, can be accompanied by tendon contractures, myopathy, and progressive pulmonary fibrosis. Clinical manifestations include poikiloderma from early childhood with telangiectasia and pigmentary anomalies on sun-exposed areas, tendon contractures that tend to involve the ankles and feet with gait disturbances, and development of pulmonary fibrosis during the second decade of life resulting in progressive dyspnea and restrictive impairment of lung function. Additional features include heat intolerance, reduced sweating, and thin hair (summary by previous studies)." +MONDO_0020853,"Definition: MMERV is an episodic acute reversible encephalopathy that occurs in children and is frequently associated with a trigger, such as a febrile illness. Affected individuals have impaired consciousness, delirious behavior, and/or seizures with lip smacking or eye deviation. These changes are associated with white matter lesions in the brain that often occur in the splenium of the corpus callosum, but may occur in surrounding areas. The acute phase of the disorder can be treated with steroids, and most patients make a full neurologic recovery between episodes with no sequelae (summary by previous studies)." +MONDO_0030472,"Definition: Developmental and epileptic encephalopathy-98 (DEE98) is characterized by onset of seizures in the first decade (range infancy to late childhood) associated with variable global developmental delay. Other features may include hypotonia, spasticity, and quadriparesis. Brain imaging may be normal or show nonspecific and variable abnormalities, including polymicrogyria. The severity is variable; some patients may die of refractory status epilepticus (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see previous studies." +MONDO_0054817,"Definition: Hypomyelinating leukodystrophy-17 is an autosomal recessive neurodevelopmental disorder characterized by poor, if any, development apparent from infancy. Affected individuals never learn to walk or speak, and have early-onset multifocal seizures, spasticity, poor overall growth, and microcephaly (up to -10 SD). Brain imaging shows multiple abnormalities, including cerebral and cerebellar atrophy, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination. Some patients may die in childhood (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see previous studies." +EFO_0000239,"Definition: Pheochromocytomas are catecholamine-secreting tumors that usually arise within the adrenal medulla. Approximately 10% arise in extraadrenal sympathetic ganglia, and are referred to as 'paragangliomas.' Approximately 10% are malignant, and approximately 10% are hereditary (previous studies; previous studies). + +previous studies introduced the concept and designation of the neurocristopathies, and identified 'simple,' including pheochromocytoma and medullary carcinoma of the thyroid, and 'complex' neurocristopathies and neurocristopathic syndromes, including NF1 and MEN2. + +previous studies applied Knudson's 2-mutation theory to pheochromocytoma (see discussion in previous studies) and concluded that it fits. + +previous studies reviewed the clinical entities and genes associated with pheochromocytoma." +MONDO_0009274,Definition: Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive disorder characterized by increased bone density with predominant diaphyseal involvement and aregenerative corticosteroid-sensitive anemia (summary by previous studies). +MONDO_0010961,"Definition: Proprotein convertase-1/3 deficiency is an autosomal recessive disorder characterized by neonatal severe generalized malabsorptive diarrhea and failure to thrive. As the disease progresses, additional endocrine abnormalities develop, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism (summary by previous studies)." +MONDO_0011539,"Definition: Autosomal recessive severe infantile nemaline myopathy-5A (NEM5A) is a skeletal muscle disorder characterized by symptom onset soon after birth or in early infancy. Affected infants show axial hypotonia, stiffness, rigid spine with progressive kyphosis, pectus deformities, and contractures or limited movement of the large joints. Some patients show transient tremors. There is muscle atrophy and poor gross motor development. Respiratory insufficiency develops in the first years of life, often leading to death. Muscle biopsy shows nemaline rods (previous studies; previous studies). + +For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (previous studies)." +MONDO_0012088,"Definition: Primary ciliary dyskinesia-5 (CILD5) is an autosomal recessive disorder characterized by early onset of a progressive decline in lung function due to an inability to clear mucus and particles from the airways. Affected individuals have recurrent infections of the sinuses, ears, airways, and lungs. Sperm motility is also decreased. Individuals with CILD5 do not have situs inversus (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (previous studies)." +MONDO_0013748,"Definition: Ventricular septal defect (VSD) is the most common form of congenital cardiovascular anomaly, occurring in nearly 50% of all infants with a congenital heart defect and accounting for 14% to 16% of cardiac defects that require invasive treatment within the first year of life. Congenital VSDs may occur alone or in combination with other cardiac malformations. Large VSDs that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death (summary by previous studies). + +For a discussion of genetic heterogeneity of ventricular septal defect, see VSD1 (previous studies)." +MONDO_0029133,"Definition: Autosomal dominant limb-girdle muscular dystrophy-4 (LGMDD4) is characterized by onset of proximal muscle weakness in young adulthood. Affected individuals often have gait difficulties; some may have upper limb involvement. Other features include variably increased serum creatine kinase, myalgia, and back pain. The severity and expressivity of the disorder is highly variable, even within families (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see previous studies." +MONDO_0033650,"Definition: Mitochondrial complex IV deficiency nuclear type 15 (MC4DN15) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show global developmental delay, poor feeding, short stature with microcephaly, proximal muscle weakness, and distal spasticity. Other manifestations include scoliosis, primary pulmonary hypertension, childhood-onset refractory seizures, and inability to walk. Brain imaging shows features consistent with Leigh syndrome (see previous studies) and enlarged ventricles. Laboratory studies show increased serum and CSF lactate, as well as decreased levels and activity of mitochondrial respiratory complex IV (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +Orphanet_71289,"Definition: Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is characterized by thrombocytopenia that progresses to pancytopenia, in association with congenital proximal fusion of the radius and ulna that results in extremely limited pronation and supination of the forearm (summary by previous studies). + +For a discussion of genetic heterogeneity of radioulnar synostosis with amegakaryocytic thrombocytopenia, see RUSAT1 (previous studies)." +EFO_0001365,"Definition: Age-related macular degeneration (ARMD) is a common complex disorder that affects the central region of the retina (macula) and is the leading cause of legal blindness in white Americans over age 65. Contributions of environmental factors and genetic susceptibility have been identified. The strongest nongenetic risk factor for ARMD is cigarette smoking. + +For a general phenotypic description and a discussion of genetic heterogeneity of ARMD, see previous studies." +EFO_0700023,"Definition: Susceptibility to platelet-type bleeding disorder-13 is due to a defective thromboxane A2 receptor on platelets. The susceptibility is inherited in an autosomal dominant pattern, but clinical features, including mild mucocutaneous bleeding, occur only in the presence of a 'second hit' affecting platelet function; this second hit may be either in the TBXA2R gene or in another gene affecting the coagulation cascade (summary by previous studies)." +MONDO_0007380,"Definition: Lattice corneal dystrophy type I (CDL1) is an autosomal dominant condition characterized by deposition of amyloid in the corneal stroma. Onset occurs in the first or second decade of life and progresses over time. The anterior stroma has rod-like or linear opacities. Recurrent erosions are common and central anterior stromal haze may develop with age. The lesions usually affect the anterior and central corneas, leaving a relatively normal periphery (summary by previous studies)." +MONDO_0009561,"Definition: Alpha-mannosidosis is an autosomal recessive lysosomal storage disease characterized by mental retardation, coarse facial features, skeletal abnormalities, hearing impairment, neurologic motor problems, and immune deficiency. Expression of the disease varies considerably, and there is a wide spectrum of clinical findings and severity. Affected children are often normal at birth and during early development. They present in early childhood with delayed psychomotor development, delayed speech, and hearing loss. Additional features include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, dysostosis multiplex, and motor impairment (summary by previous studies). + + Classification Systems + +Two classification systems have been used to describe the clinical presentation of alpha-mannosidosis. The earlier system delineated a more severe 'type I,' which shows infantile onset, rapid mental deterioration, hypotonia, splenomegaly, severe dysostosis multiplex, and severe recurrent infections, often resulting in death by age 8 years. Individuals with the less severe 'type II' show normal early development with later childhood development of mental retardation, hearing loss, coarse facies, neurologic deterioration, and survival well into adulthood (summary by previous studies and previous studies). A later classification system delineated 3 clinical types. Type 1 is the mildest form, with onset after age 10 years, without skeletal abnormalities and very slow progression. Type 2 is a moderate form, with onset before age 10 years, presence of skeletal abnormalities, and slow progression with development of ataxia by age 20 to 30 years. Type 3 is the severe form, with onset in early infancy, skeletal abnormalities, and obvious progression leading to early death from primary central nervous system involvement or myopathy. Most patients belong to clinical type 2 (summary by previous studies). Despite the clinical heterogeneity of the disorder, there are no apparent genotype/phenotype correlations (previous studies; previous studies)." +MONDO_0009876,"Definition: Isolated growth hormone deficiency type IA is an autosomal recessive disorder characterized by severe growth failure (SDS less than -4.5) by 6 months of age, undetectable growth hormone (GH) concentrations, and a tendency to develop antibodies despite an initial good response to rhGH treatment (summary by previous studies). + + Genetic Heterogeneity of Isolated Growth Hormone Deficiency + +See IGHD1B (previous studies) and IGHD2 (previous studies), both caused by mutation in the GH1 gene; IGHD3 (previous studies), caused by mutation in the BTK gene (previous studies); and IGHD4 (previous studies), caused by mutation in the GHRHR gene (previous studies). + +Isolated growth hormone deficiency-5 (IGHD5) has been reclassified as combined pituitary hormone deficiency-7 (CPHD7; previous studies)." +MONDO_0011283,"Definition: Mitochondrial DNA depletion syndrome-1 (MTDPS1) is an autosomal recessive progressive multisystem disorder clinically characterized by onset between the second and fifth decades of life of ptosis, progressive external ophthalmoplegia (PEO), gastrointestinal dysmotility (often pseudoobstruction), cachexia, diffuse leukoencephalopathy, peripheral neuropathy, and mitochondrial dysfunction. Mitochondrial DNA abnormalities can include depletion, deletion, and point mutations (previous studies). + + Genetic Heterogeneity of Mitochondrial DNA Depletion Syndromes + +Mitochondrial DNA depletion syndromes are clinically and genetically heterogeneous, and most are autosomal recessive disorders. See also MTDPS2 (previous studies), caused by mutation in the TK2 gene (previous studies); MTDPS3 (previous studies), caused by mutation in the DGUOK gene (previous studies); MTDPS4A (previous studies) and MTDPS4B (previous studies), both caused by mutation in the POLG gene (previous studies); MTDPS5 (previous studies), caused by mutation in the SUCLA2 gene (previous studies); MTDPS6 (previous studies), caused by mutation in the MPV17 gene (previous studies); MTDPS7 (previous studies), caused by mutation in the C10ORF2 gene (previous studies); MTDPS8A (previous studies) and MTDPS8B (see previous studies), both caused by mutation in the RRM2B gene (previous studies); MTDPS9 (previous studies), caused by mutation in the SUCLG1 gene (previous studies); MTDPS10 (previous studies), caused by mutation in the AGK gene (previous studies); MTDPS11 (previous studies), caused by mutation in the MGME1 gene (previous studies); MTDPS12A (previous studies) and MTDPS12B (previous studies), both caused by mutation in the SLC25A4 gene (previous studies); MTDPS13 (previous studies), caused by mutation in the FBXL4 gene (previous studies); MTDPS14 (previous studies), caused by mutation in the OPA1 gene (previous studies); MTDPS15 (previous studies), caused by mutation in the TFAM gene (previous studies); MTDPS16 (previous studies), caused by mutation in the POLG2 gene (previous studies); MTDPS17 (previous studies), caused by mutation in the MRM2 gene (previous studies); MTDPS18 (previous studies), caused by mutation in the SLC25A21 gene (previous studies); MTDPS19 (previous studies), caused by mutation in the SLC25A10 gene (previous studies); and MTDPS20 (previous studies), caused by mutation in the LIG3 gene (previous studies)." +MONDO_0011724,"Definition: GLUT1 deficiency syndrome-1 is a neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation. Hypoglycorrhachia (low CSF glucose, less than 40 mg/dl) and low CSF lactate are essentially diagnostic for the disorder. As more cases with GLUT1 deficiency syndrome were described, the phenotype was broadened to include individuals with ataxia and mental retardation but without seizures, individuals with dystonia and choreoathetosis, and rare individuals with absence seizures and no movement disorder. The disorder, which results from a defect in the GLUT1 glucose transporter causing decreased glucose concentration in the central nervous system, is part of a spectrum of neurologic phenotypes resulting from GLUT1 deficiency. GLUT deficiency syndrome-2 (previous studies) represents the less severe end of the phenotypic spectrum and is associated with paroxysmal exercise-induced dystonia with or without seizures. Correct diagnosis of GLUT1 deficiency is important because a ketogenic diet often results in marked clinical improvement of the motor and seizure symptoms (reviews by previous studies and previous studies)." +MONDO_0014957,"Definition: LADCI is an autosomal recessive neurodevelopmental disorder characterized by severe expressive and receptive language delay apparent from early childhood. Affected individuals have additional developmental or behavioral abnormalities, including attention deficit, hyperactivity, or mild intellectual disability. Some patients develop cardiac arrhythmias reminiscent of sick sinus syndrome (summary by previous studies and previous studies)." +MONDO_0030072,"Definition: Developmental and epileptic encephalopathy-88 (DEE88) is an autosomal recessive severe neurologic disorder characterized by global developmental delay, early-onset epilepsy, and progressive microcephaly. Brain MRI findings may include corpus callosum abnormalities, prominent ventricles, and mild hypoplasia of the inferior vermis and pons (previous studies). + +For a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see previous studies." +MONDO_0030512,"Definition: Autosomal recessive spastic paraplegia-85 (SPG85) is a neurologic disorder characterized by the onset of motor symptoms in the first few years of life. Affected individuals have spasticity and hyperreflexia of the lower limbs resulting in gait abnormalities. Older patients may have upper limb involvement and demonstrate axonal polyneuropathy. Additional features include optic atrophy, dysarthria, dysphagia, ataxia, and urinary incontinence. Brain imaging may show cerebellar atrophy (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (previous studies)." +MONDO_0032648,"Definition: MCCCHCM is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, and characteristic brain abnormalities on brain imaging. Affected individuals have enlargement of the corpus callosum, enlarged ventricles, and cerebellar and brainstem hypoplasia. Other features may include lack of speech development, gait instability, and seizures. Some patients with MAST1 mutations may have impaired intellectual development and/or autism spectrum disorder without significant findings on brain imaging (summary by previous studies)." +MONDO_0032932,"Definition: Mitochondrial DNA depletion syndrome-18 (MTDPS18) is an autosomal recessive neuromuscular disorder characterized by early-onset progressive weakness and atrophy of the distal limb muscles, resulting in loss of ambulation as well as atrophy of the intrinsic hand muscles with clawed hands. Affected individuals may also develop scoliosis and have hypo- or hyperreflexia and decreased pulmonary vital capacity. Examination of skeletal muscle shows neurogenic atrophy and combined mitochondrial oxidative phosphorylation deficiency associated with mtDNA depletion. The clinical phenotype is reminiscent of spinal muscular atrophy (see SMA, previous studies) and the metabolic profile is reminiscent of 2-aminoadipic 2-oxoadipic aciduria (AMOXAD; previous studies), which is caused by mutation in the DHTKD1 gene (previous studies) (summary by previous studies). + +For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (previous studies)." +Orphanet_98676,"Definition: Optic atrophy-9 (OPA9) is characterized by onset of decreased visual acuity and optic disc pallor in the first decade of life, with severely reduced visual acuity and color vision deficits observed in the third decade. Although initially described as an autosomal recessive disease (previous studies; previous studies; previous studies), autosomal dominant cases of OPA9 have also been reported (previous studies). + +Mutation in the ACO2 gene also causes a neurodegenerative disorder, infantile cerebellar-retinal degeneration (ICRD; previous studies), of which optic atrophy is a feature. + + Dominant and Recessive OPA9 + +From a cohort of approximately 1,000 patients with optic atrophy, previous studies identified 50 probands with dominant mutations in the ACO2 gene, and 11 patients with biallelic variants. There was no significant difference in distribution of mutation type, with two-thirds of all variants being missense mutations in both groups, and nonsense, frameshift, and splice site mutations comprising the remaining third. Age at onset of symptoms occurred during the first 2 decades, without significant difference between dominant and recessive cases. Visual acuity was significantly more affected in recessive cases than in dominant ones, with more than 60% of eyes from the recessive group having a visual acuity lower than 20/200, whereas more than 80% of eyes from the dominant group had a visual acuity above 20/200. Analysis of the optic disc as well as retinal nerve fiber layer thickness measurements indicated a preferential involvement of the temporal quadrant in both patient groups. Assessment of color vision revealed highly variable alterations, including protan, deutan, and tritan types of dyschromatopsia. Some patients had additional retinal changes, including macular microcysts as well as macular dystrophy in 1 case. Extraocular symptoms were observed in 6 (12%) of the dominant cases and in 3 (27%) of the recessive cases, including hearing impairment in 2 dominant cases, and late-onset cerebellar ataxia in 1 dominant case and in 1 recessive case." +EFO_0010661,"Definition: Neurodevelopmental disorder with nonspecific brain abnormalities is a highly variable syndrome characterized by impaired intellectual development and behavioral abnormalities associated with structural changes on brain imaging. Some patients have seizures, hypotonia, and scoliosis/kyphosis. Cognitive function ranges from severely impaired to the ability to attend schools with special assistance (summary by previous studies)." +MONDO_0007113,"Definition: Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, movement or balance disorder, typical abnormal behaviors, and severe limitations in speech and language. Most cases are caused by absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Prader-Willi syndrome (PWS; previous studies) is a clinically distinct disorder resulting from paternal deletion of the same 15q11-q13 region. In addition, the chromosome 15q11-q13 duplication syndrome (previous studies) shows overlapping clinical features. + +previous studies provided a review of Angelman syndrome. previous studies reviewed the molecular and clinical aspects of both Prader-Willi syndrome and Angelman syndrome. previous studies provided a detailed review of the mechanisms of imprinting of the Prader-Willi/Angelman syndrome region. + +previous studies provided a review of Angelman syndrome and discussed genetic counseling of the disorder, which can show a recurrence risk of up to 50%, depending on the underlying genetic mechanism." +MONDO_0007705,"Definition: This is a form of nonspherocytic hemolytic anemia of Dacie type I (in vitro autohemolysis is not corrected by added glucose). After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. + +Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies; previous studies)." +MONDO_0009019,"Definition: Corneal endothelial dystrophy is characterized by thickening and opacification of the cornea, altered morphology of the endothelium, and secretion of an abnormal collagenous layer at the Descemet membrane (summary by previous studies)." +MONDO_0012665,"Definition: Mutations in the BFSP1 gene have been found to cause multiple types of cataract, which have been described as cortical, nuclear, and progressive punctate lamellar. Both autosomal dominant and autosomal recessive modes of inheritance have been reported." +MONDO_0013968,"Definition: Congenital disorder of glycosylation type It (CDG1T) is an autosomal recessive disorder characterized by a wide range of clinical manifestations and severity. The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism (summary by previous studies). + +For a discussion of the classification of CDGs, see CDG1A (previous studies)." +MONDO_0014410,"Definition: Spinocerebellar ataxia-37 (SCA37) is an autosomal dominant neurologic disorder characterized by adult onset of slowly progressive gait instability, frequent falls, and dysarthria associated with cerebellar atrophy on brain imaging (summary by previous studies). + +For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (previous studies)." +MONDO_0030061,"Definition: Periventricular nodular heterotopia-9 (PVNH9) is an autosomal dominant neurologic disorder characterized as a malformation of cortical development. Anterior predominant PVNH, thin corpus callosum, and decreased white matter volume are found on brain imaging, but the clinical effects are variable. Most patients have impaired intellectual development and cognitive defects associated with low IQ (range 50 to 80), learning disabilities, and behavior abnormalities. Some patients develop seizures that tend to have a focal origin. However, some mutation carriers may be less severely affected with borderline or even normal IQ, suggesting incomplete penetrance of the phenotype (summary by previous studies, previous studies). + +For a discussion of genetic heterogeneity of periventricular nodular heterotopia, see previous studies." +MONDO_0030988,"Definition: Developmental delay with dysmorphic facies and dental anomalies (DEFDA) is characterized by generally mild global developmental delay with variably impaired intellectual development, walking by 2 to 3 years, and slow language acquisition. The severity of the disorder ranges from moderate cognitive deficits to mild learning difficulties or behavioral abnormalities. Most patients have dysmorphic facial features, often with abnormal dentition and nonspecific visual defects, such as myopia, astigmatism, and strabismus. Although rare, involvement of other systems, such as skeletal, cardiac, and gastrointestinal, may be present (summary by previous studies)." +Orphanet_98915,"Definition: Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction. Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE inhibitors and amifampridine should be avoided (summary by previous studies). + +For a discussion of genetic heterogeneity of CMS, see CMS1A (previous studies)." +MONDO_0008116,"Definition: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular disease characterized by proximal muscle weakness, ptosis, and swallowing difficulty (summary by previous studies)." +MONDO_0009660,"Definition: Mucopolysaccharidosis type IVB (MPS4B) is an autosomal recessive disorder characterized by skeletal dysplasia and corneal clouding. There is no central nervous system involvement and intelligence is normal. There is increased urinary keratan sulfate excretion (previous studies). + +See mucopolysaccharidosis type IVA (MPS4A; previous studies), also known as Morquio syndrome A, a genetically distinct disorder with overlapping clinical features caused by mutation in the GALNS gene (previous studies) on chromosome 16q24. + +There may also be a nonkeratan sulfate-excreting form of Morquio syndrome, so-called type C (previous studies)." +MONDO_0010547,"Definition: SCAX1 is an X-linked recessive neurologic disorder characterized by hypotonia at birth, delayed motor development, gait ataxia, difficulty standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar ataxia (summary by previous studies). + + Genetic Heterogeneity of X-linked Spinocerebellar Ataxia + +X-linked recessive spinocerebellar ataxia (SCAX) is a clinically and genetically heterogeneous disorder. See also SCAX2 (previous studies), SCAX3 (previous studies), SCAX4 (previous studies), and SCAX5 (previous studies)." +MONDO_0014968,"Definition: PEAMO is a severe autosomal recessive neurodegenerative disorder characterized by delayed development with hypotonia apparent in infancy and subsequent motor regression. Most affected individuals are unable to or lose the ability to sit and show distal amyotrophy and weakness of all 4 limbs. The patients are cognitively impaired and unable to speak or have severe dysarthria. Additional features include optic atrophy, thin corpus callosum, and cerebellar atrophy (summary by previous studies)." +MONDO_0020798,"Definition: Patients with familial isolated hypoparathyroidism-2 (FIH2) usually present with seizures, caused by hypocalcemia, in early life. Serum parathyroid hormone (PTH; previous studies) levels are low to undetectable. Hyperphosphatemia is present, and levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D may be within the normal range. Development can be normal if hypocalcemia is treated with calcium and vitamin D supplementation (previous studies). Some patients have been found to lack parathyroid glands (previous studies). + +For a discussion of genetic heterogeneity of familial isolated hypoparathyroidism, see FIH1 (previous studies)." +MONDO_0032591,"Definition: Transient neonatal hyperparathyroidism is characterized by interference with placental maternal-fetal calcium transport, causing fetal calcium deficiency resulting in hyperparathyroidism and metabolic bone disease. Because 80% of calcium is transferred during the third trimester, abnormalities may not be detected on second-trimester ultrasounds. Affected infants present at birth with prenatal fractures, shortened ribs, and bowing of long bones, as well as respiratory and feeding difficulties. Postnatal recovery or improvement is observed once calcium is provided orally, with most patients showing complete resolution of skeletal abnormalities by 2 years of age (previous studies)." +MONDO_0033638,"Definition: Mitochondrial complex IV deficiency nuclear type 8 (MC4DN8) is an autosomal recessive metabolic disorder characterized by the onset of neuromuscular symptoms in the first decade of life after normal early development. Affected individuals develop a slowly progressive decline in neurologic function with gait difficulties, spasticity, dysarthria, hypotonia, and variable intellectual disability. Other features may include facial hypotonia, optic atrophy with visual impairment, nystagmus, muscle rigidity, and loss of ambulation. Rare patients may have renal tubulopathy. Brain imaging shows T2-weighted hyperintensities in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see previous studies). Serum lactate is often increased, and patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +Orphanet_2616,"Definition: 3M syndrome is characterized by poor postnatal growth and distinctive facial features, including triangular facies, frontal bossing, fleshy tipped nose, and fleshy lips. Other features may include skeletal anomalies and prominent heels (summary by previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of 3M syndrome, see 3M1 (previous studies)." +MONDO_0005147,"Definition: Type 1 diabetes mellitus (T1D), also designated insulin-dependent diabetes mellitus (IDDM), is a disorder of glucose homeostasis characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (previous studies). Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. + +The classic phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels." +MONDO_0008115,"Definition: Feingold syndrome is an autosomal dominant disorder characterized by variable combinations of microcephaly, limb malformations, esophageal and duodenal atresias, and learning disability/mental retardation. Hand and foot abnormalities may include hypoplastic thumbs, clinodactyly of second and fifth fingers, syndactyly (characteristically between second and third and fourth and fifth toes), and shortened or absent middle phalanges. Cardiac and renal malformations, vertebral anomalies, and deafness have also been described in a minority of patients (summary by previous studies). + + Genetic Heterogeneity of Feingold Syndrome + +Feingold syndrome-2 (FGLDS2; previous studies) is caused by hemizygous deletion of the MIR17HG gene (previous studies) on chromosome 13q31.3." +MONDO_0008134,"Definition: Autosomal dominant optic atrophy is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disc pallor, color vision deficits, and centrocecal scotoma of variable density (previous studies). + +Some patients with mutations in the OPA1 gene may also develop extraocular neurologic features, such as deafness, progressive external ophthalmoplegia, muscle cramps, hyperreflexia, and ataxia; see previous studies. There appears to be a wide range of intermediate phenotypes (previous studies). + +previous studies provided a detailed review of autosomal dominant optic atrophy and Leber hereditary optic neuropathy (LHON; previous studies), with emphasis on the selective vulnerability of retinal ganglion cells to mitochondrial dysfunction in both disorders. + + Genetic Heterogeneity of Optic Atrophy + +Also see optic atrophy-2 (OPA2; previous studies), mapped to chromosome Xp11.4-p11.21; OPA3 (previous studies), caused by mutation in the OPA3 gene (previous studies) on chromosome 19q13; OPA4 (previous studies), mapped to chromosome 18q12.2-q12.3; OPA5 (previous studies), caused by mutation in the DNM1L gene (previous studies) on chromosome 12p11; OPA6 (previous studies), mapped to chromosome 8q21-q22; OPA7 (previous studies), caused by mutation in the TMEM126A gene (previous studies) on chromosome 11q14; OPA8 (previous studies), mapped to chromosome 16q21-q22; OPA9 (previous studies), caused by mutation in the ACO2 gene (previous studies) on chromosome 22q13; OPA10 (previous studies), caused by mutation in the RTN4IP1 gene (previous studies) on chromosome 6q21; OPA11 (previous studies), caused by mutation in the YME1L1 gene (previous studies) on chromosome 10p12; OPA12 (previous studies), caused by mutation in the AFG3L2 gene (previous studies) on chromosome 18p11; and OPA13 (previous studies), caused by mutation in the SSBP1 gene (previous studies) on chromosome 7q34." +MONDO_0009276,"Definition: Bernard-Soulier syndrome is an autosomal recessive bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor (VWF; previous studies) receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5 (previous studies). + + Genetic Heterogeneity of Platelet-Type Bleeding Disorders + +Inherited platelet disorders are a heterogeneous group of bleeding disorders affecting platelet number, function, or both. Functional defects can involve platelet receptors, signaling pathways, cytoskeletal proteins, granule contents, activation, or aggregation (review by previous studies and previous studies). + +Platelet-type bleeding disorders include Bernard-Soulier syndrome (BDPLT1); Glanzmann thrombasthenia (BDPLT2; previous studies), caused by mutation in the ITGA2B (previous studies) or ITGB3 (previous studies) gene; pseudo-von Willebrand disease (BDPLT3; previous studies), caused by mutation in the GP1BA gene (previous studies); gray platelet syndrome (BDPLT4; previous studies), caused by mutation in the NBEAL2 gene (previous studies); Quebec platelet disorder (BDPLT5; previous studies), caused by tandem duplication of the PLAU gene (previous studies); May-Hegglin anomaly (BDPLT6; previous studies), caused by mutation in the MYH9 gene (previous studies); Scott syndrome (BDPLT7; previous studies), caused by mutation in the TMEM16F gene (previous studies); BDPLT8 (previous studies), caused by mutation in the P2RY12 gene (previous studies); BDPLT9 (previous studies), associated with deficiency of the glycoprotein Ia/IIa receptor (see ITGA2; previous studies); glycoprotein IV deficiency (BDPLT10; previous studies), caused by mutation in the CD36 gene (previous studies); BDPLT11 (previous studies), caused by mutation in the GP6 gene (previous studies); BDPLT12 (previous studies), associated with a deficiency of platelet COX1 (previous studies); susceptibility to BDPLT13 (previous studies), caused by mutation in the TBXA2R gene (previous studies); BDPLT14 (previous studies), associated with deficiency of thromboxane synthetase (TBXAS1; previous studies); BDPLT15 (previous studies), caused by mutation in the ACTN1 gene (previous studies); BDPLT16 (previous studies), caused by mutation in the ITGA2B (previous studies) or ITGB3 (previous studies) gene; BDPLT17 (previous studies), caused by mutation in the GFI1B gene (previous studies); BDPLT18 (previous studies), caused by mutation in the RASGRP2 gene (previous studies); BDPLT19 (previous studies), caused by mutation in the PRKACG gene (previous studies); BDPLT20 (previous studies), caused by mutation in the SLFN14 gene (previous studies); BDPLT21 (previous studies), caused by mutation in the FLI1 gene (previous studies); and BDPLT22 (previous studies), caused by mutation in the EPHB2 gene (previous studies). + +See reviews by previous studies, previous studies, and previous studies. + +For a discussion of the genetic heterogeneity of hereditary thrombocytopenia, see THC1 (previous studies)." +MONDO_0010170,"Definition: Usher syndrome type III is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life (previous studies; previous studies). + +For a discussion of phenotypic heterogeneity of Usher syndrome, see USH1 (previous studies). + + Genetic Heterogeneity of Usher syndrome Type III + +Usher syndrome type IIIB (previous studies) is caused by mutation in the HARS gene (previous studies) on chromosome 5q31.3." +MONDO_0011663,"Definition: Although primary lateral sclerosis is similar to amyotrophic lateral sclerosis (ALS; previous studies), they are considered to be clinically distinct progressive paralytic neurodegenerative disorders. Following a period of diagnostic confusion, the clinical distinction between ALS and PLS became clear and diagnostic criteria established (previous studies). PLS is characterized by degeneration of the upper motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a more severe disorder characterized by degeneration of both the upper and lower motor neurons. A diagnosis of PLS is essentially one of exclusion (previous studies; previous studies; previous studies)." +MONDO_0012206,"Definition: Czech dysplasia is an autosomal dominant skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes (previous studies; previous studies)." +MONDO_0014025,"Definition: The Jokela type of spinal muscular atrophy (SMAJ) is an autosomal dominant lower motor neuron disorder characterized by adult-onset of muscle cramps and fasciculations affecting the proximal and distal muscles of the upper and lower limbs. The disorder is slowly progressive, resulting in weakness and mild muscle atrophy later in life (summary by previous studies)." +MONDO_0030031,"Definition: Lissencephaly-10 (LIS10) is a neurologic disorder characterized by variably delayed development with mildly to moderately impaired intellectual development and language delay, as well as seizures, which are often intractable. There is a spectrum of severity, with some patients having normal early development and only borderline to mild cognitive impairment. Brain imaging shows features consistent with neuronal migration defects, including posterior-predominant lissencephaly, pachygyria, agyria, and subcortical band heterotopia (summary by previous studies). + +For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (previous studies)." +MONDO_0030899,"Definition: Oculocutaneous albinism type VIII (OCA8) is characterized by mild hair and skin hypopigmentation, associated with ocular features including nystagmus, reduced visual acuity, iris transillumination, and hypopigmentation of the retina (previous studies)." +MONDO_0032898,"Definition: Spermatogenic failure-43 (SPGF43) is characterized by infertility and spermatozoa lacking progressive motility due to multiple morphologic abnormalities of the flagella (MMAF), including short, absent, coiled, irregular-caliber, and/or bent flagella. Most flagella lack the central pair (9+0 configuration) on ultrastructural analysis (previous studies; previous studies; previous studies). + +For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (previous studies)." +MONDO_0033630,"Definition: Neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID) is characterized by developmental delay associated with mild to moderately impaired intellectual development or learning difficulties, behavioral or psychiatric abnormalities, and delayed speech and language acquisition. Additional features include dysmorphic facies, distal limb anomalies, gastrointestinal problems or feeding difficulties, and hypotonia. The phenotypic features and severity of the disorder are variable (summary by previous studies)." +Orphanet_79211,"Definition: Familial combined hyperlipidemia (FCHL) is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B (APOB; previous studies). Patients with FCHL are at increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, nonalcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome (summary by previous studies). + +previous studies gave the designation 'familial combined hyperlipidemia' to the most common genetic form of hyperlipidemia identified in a study of survivors of myocardial infarction. Affected persons characteristically showed elevation of both cholesterol and triglycerides in the blood. The combined disorder was shown to be distinct from familial hypercholesterolemia (previous studies) and from familial hypertriglyceridemia (previous studies) for the following reasons: (1) lipid distributions in relatives were unique; (2) unlike familial hypercholesterolemia, children of affected persons did not express hypercholesterolemia; and (3) informative matings suggested that variable expression of a single gene rather than segregation for 2 separate genes was responsible. This disorder leads to elevated levels of VLDL, LDL, or both in plasma. From time to time the pattern can change in a given person. Unlike familial hypercholesterolemia, hyperlipidemia appears in only 10 to 20% of patients in childhood, usually in the form of hypertriglyceridemia. Xanthomas are rare. Increased production of VLDL may be a common underlying metabolic characteristic in this disorder, which may be heterogeneous. The disorder may be 5 times as frequent as familial hypercholesterolemia, occurring in 1% of the U.S. population. + + Genetic Heterogeneity of Susceptibility to Familial Combined Hyperlipidemia + +Also see FCHL1 (previous studies), associated with variation in the USF1 gene (previous studies) on chromosome 1q23, and FCHL2 (previous studies), mapped to chromosome 11." +Orphanet_84064,"Definition: Trichohepatoenteric syndrome-2 (THES2) is a rare and severe disease characterized by intrauterine growth retardation, facial dysmorphism, hair abnormalities, intractable diarrhea, and immunodeficiency (summary by previous studies). + +For a discussion of genetic heterogeneity of trichohepatoenteric syndrome, see THES1 (previous studies)." +Orphanet_98994,"Definition: Mutations in the CRYBB2 gene have been found to cause several types of cataract, which have been described as congenital cerulean, 'blue dot,' Coppock-like, sutural with punctate and cerulean opacities, pulverulent embryonal, pulverulent with cortical opacities, dense posterior star-shaped subcapsular with pulverulent opacities in the cortical and embryonal regions, and dense embryonal. + +Before it was known that mutations in the CRYBB2 gene cause several types of cataract, the preferred title of this entry was 'Cataract, Congenital, Cerulean Type 2,' with the symbol CCA2." +EFO_0009024,"Definition: BBS4 is a rare multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction that accounts for less than 3% of BBS (previous studies). Anosmia has been described in patients with BBS4 (previous studies), as well as polydactyly confined to the hands (previous studies). + +For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (previous studies)." +MONDO_0007251,"Definition: Campomelic dysplasia (CMPD) is an autosomal dominant skeletal dysplasia characterized by congenital shortness and bowing of long tubular bones, especially in the lower extremities, as well as by hypoplastic scapulae, narrow iliac wings, and nonmineralized thoracic pedicles. CMPD is often lethal in the first year of life, due to respiratory insufficiency related to small chest size and tracheobronchial hypoplasia (summary by previous studies). + +SOX9 mutations causing campomelic dysplasia have also been associated with 46,XY sex reversal, with marked variability in the degree of gonadal dysgenesis among patients carrying the same mutation (previous studies)." +MONDO_0008535,"Definition: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain. The most frequent form of hereditary hemorrhagic telangiectasia maps to the long arm of chromosome 9. + + Genetic Heterogeneity of Hereditary Hemorrhagic Telangiectasia + +See also HHT2 (previous studies), caused by mutation in the ALK1 gene (ACVRL1; previous studies) on chromosome 12q13; HHT3 (previous studies), mapped to chromosome 5q31; HHT4 (previous studies), mapped to chromosome 7p14; and HHT5 (previous studies), caused by mutation in the GDF2 gene (previous studies) on chromosome 10q11. + +See also juvenile polyposis/HHT syndrome (previous studies), caused by mutation in the SMAD4 gene (previous studies)." +MONDO_0009562,"Definition: Beta-mannosidosis is an autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of lysosomal beta-mannosidase activity. The most severely affected patients show developmental delay and mental retardation, but there are differing levels of severity and some patients may have comparatively mild disease (previous studies) The disorder was first described in goats (previous studies), who have a more severe neurodegenerative disorder than that seen in humans." +MONDO_0009563,"Definition: The major clinical features of maple syrup urine disease are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. There are 5 clinical subtypes of MSUD: the 'classic' neonatal severe form, an 'intermediate' form, an 'intermittent' form, a 'thiamine-responsive' form, and an 'E3-deficient with lactic acidosis' form (previous studies). All of these subtypes can be caused by mutations in any of the 4 genes mentioned above, except for the E3-deficient form, which is caused only by mutation in the E3 gene (previous studies)." +MONDO_0009923,"Definition: Pseudovaginal perineoscrotal hypospadias is a form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum." +MONDO_0010561,"Definition: Coffin-Lowry syndrome is a rare form of X-linked mental retardation characterized by skeletal malformations, growth retardation, hearing deficit, paroxysmal movement disorders, and cognitive impairment in affected males and some carrier females (previous studies). + +previous studies reviewed human disorders which share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (previous studies), ICF syndrome (previous studies), Rett syndrome (previous studies), Rubinstein-Taybi syndrome (previous studies), and Coffin-Lowry syndrome. + +previous studies provided a review of Coffin-Lowry syndrome. + +Mutation in the RPS6KA3 gene can also cause nonsyndromic X-linked mental retardation-19 (MRX19; previous studies), a milder disorder without skeletal anomalies." +MONDO_0011790,"Definition: Amish-type microcephaly is a severe autosomal recessive metabolic disorder characterized by severe microcephaly apparent at birth, profoundly delayed psychomotor development, brain malformations, and episodic encephalopathy associated with lactic acidosis and alpha-ketoglutaric aciduria (summary by previous studies). + +For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (previous studies)." +MONDO_0012548,"Definition: Severe congenital neutropenia-3 is an autosomal recessive bone marrow failure disorder characterized by low numbers of neutrophils, increased susceptibility to bacterial and fungal infections, and increased risk of developing myelodysplastic syndrome or acute myeloid leukemia. In addition, patients with HAX1 mutations affecting both isoform A and B of the gene develop neurologic abnormalities (summary by previous studies). + +The Swedish physician Rolf previous studies described an autosomal recessive hematologic disorder, termed infantile agranulocytosis, with severe neutropenia with an absolute neutrophil count below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disorder was later termed Kostmann syndrome (previous studies). previous studies discussed severe congenital neutropenia in a review of immunodeficiencies caused by defects in phagocytes. + +In addition to Kostmann agranulocytosis, recessively inherited neutropenic syndromes include congenital neutropenia with eosinophilia (previous studies), Chediak-Higashi syndrome (previous studies), and Fanconi pancytopenic syndrome (see previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (previous studies)." +MONDO_0013781,"Definition: Familial hyperkalemic hypertension, also known as type II pseudohypoaldosteronism (PHAII) or Gordon syndrome, is a rare autosomal dominant disease in which a net positive sodium ion balance is associated with renal potassium ion retention, resulting in hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (summary by previous studies). + + Genetic Heterogeneity of Type II Pseudohypoaldosteronism + +For a discussion of genetic heterogeneity of type II pseudohypoaldosteronism, see PHA2A (previous studies)." +MONDO_0025708,"Definition: Megacystis-microcolon-intestinal hypoperistalsis syndrome-2 (MMIHS2) is characterized by prenatal bladder enlargement, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition and urinary catheterization. The majority of cases have a fatal outcome due to malnutrition and sepsis, followed by multiorgan failure (summary by previous studies). + +For a discussion of genetic heterogeneity of MMIHS, see previous studies." +MONDO_0032922,"Definition: Beck-Fahrner syndrome (BEFAHRS) is a developmental disorder characterized by global developmental delay with variably impaired intellectual development. Affected individuals often have behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD), as well as learning disabilities. Most patients have hypotonia and dysmorphic facies. Some may have growth abnormalities, including overgrowth or poor growth, poor feeding, and rarely, seizures. Although both monoallelic and biallelic mutations have been reported, some heterozygous carriers in autosomal recessive families may have milder symptoms; thus, both groups are included in this entry (summary by previous studies)." +MONDO_0033646,"Definition: Mitochondrial complex IV deficiency nuclear type 12 (MC4DN12) is an autosomal recessive metabolic disorder characterized by the onset of neurologic dysfunction in early infancy. Affected individuals demonstrate hypotonia with poor head control, profoundly delayed global development with inability to fix and follow, poor overall growth, abnormal spasms or myoclonus, and seizures. Most patients die in the first years of life; those that survive have spastic quadriplegia, feeding difficulties necessitating tube feeding, and profoundly impaired intellectual development with poor or absent communication. More variable features include cortical blindness, nystagmus, scoliosis, and hearing impairment. Brain imaging shows abnormalities consistent with Leigh syndrome (see previous studies), as well as cystic cavitation. Laboratory studies show lactic acidosis, increased serum creatine kinase, and decreased levels and activity of mitochondrial respiratory complex IV (summary by previous studies). + +For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see previous studies." +Orphanet_169142,"Definition: Specific granule deficiency-1 (SGD1) is an immunologic disorder characterized by onset of recurrent bacterial infections in infancy or early childhood. Both autosomal recessive and autosomal dominant inheritance have been reported. Affected individuals usually develop skin infections due to Staphylococcus aureus which may progress to more invasive infections. Otitis media and other upper respiratory infections are frequently observed. Neutrophils from patients with the disorder display atypical hyposegmented or bilobed nuclei and show decreased or absent expression of secondary and tertiary granule proteins due to a defect in myeloid maturation. Neutrophils may also demonstrate defects in chemotaxis or bactericidal activity; some patients show neutropenia and lack of eosinophils. Treatment consists mainly of prophylactic antibiotics, although at least 1 patient has been cured with hematopoietic stem cell transplantation (summary by previous studies and previous studies). + + Genetic Heterogeneity of Specific Granule Deficiency + +See also SGD2 (previous studies), caused by mutation in the SMARCD2 gene (previous studies) on chromosome 17q23." +Orphanet_182050,"Definition: Macrothrombocytopenia with or without granulocyte inclusions, nephritis, or sensorineural hearing loss was previously thought to comprise 4 distinct entities with overlapping features: Fechtner syndrome, May-Hegglin anomaly, Epstein syndrome, and Sebastian syndrome. Fechtner syndrome was characterized by the triad of thrombocytopenia, giant platelets, and Dohle body-like inclusions in peripheral blood leukocytes, with the additional Alport syndrome (previous studies)-like features of nephritis, hearing loss, and eye abnormalities, predominantly cataracts (previous studies). May-Hegglin anomaly was characterized by the triad of thrombocytopenia, giant platelets, and Dohle body-like inclusions in peripheral blood leukocytes. Epstein syndrome was characterized by thrombocytopenia, deafness, and nephritis, and lacked leukocyte inclusion bodies on classic staining of peripheral blood smears. Sebastian syndrome was similar to May-Hegglin anomaly, but had a different ultrastructural appearance of the leukocyte inclusions. previous studies suggested that these 4 disorders were not distinct entities, but rather represented a single disorder with a continuous clinical spectrum because variable phenotypic expression is observed not only between families but also within families having the same MYH9 mutation. In addition, previous studies noted that all patients present leukocyte inclusion bodies, although of variable size. previous studies proposed the term 'MYH9-related disease' for the disorder; however, an isolated form of nonsyndromic deafness (DFNA17; previous studies) is also caused by mutation in the MYH9 gene." +MONDO_0008059,"Definition: Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is a rare autosomal dominant disorder of skin, hair, and teeth. It is characterized by complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation that tends to disappear with age, thickening of the palms and soles (palmoplantar keratoderma), and decreased sweating. Dental anomalies including enamel defects, skin blistering, and nail dystrophy have been reported in some patients. It can be distinguished from dermatopathia pigmentosa reticularis (DPR) by the latter's features of lifelong persistence of the skin hyperpigmentation, partial alopecia, and absence of dental anomalies (summary by previous studies)." +MONDO_0009259,"Definition: Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases involving enzymes in the gamma-glutamyl cycle (previous studies). The other 3 disorders are glutathione synthetase deficiency (previous studies), 5-oxoprolinuria, which is a severe or generalized form of glutathione synthetase deficiency (previous studies), and gamma-glutamyl transpeptidase deficiency (previous studies). All except gamma-glutamyl transpeptidase deficiency are accompanied by hemolytic anemia (previous studies)." +MONDO_0010572,"Definition: Occipital horn syndrome (OHS) is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by previous studies)." +MONDO_0013640,"Definition: Retinal arterial macroaneurysm is an autosomal recessive condition characterized by the bilateral appearance of 'beading' along the major retinal arterial trunks, with the subsequent formation of macroaneurysms. Affected individuals also have supravalvular pulmonic stenosis, often requiring surgical correction (summary by previous studies)." +MONDO_0014263,"Definition: Verheij syndrome is characterized by growth retardation, delayed psychomotor development, dysmorphic facial features, and skeletal, mainly vertebral, abnormalities. Additional variable features may include coloboma, renal defects, and cardiac defects (summary by previous studies and previous studies)." +MONDO_0014326,"Definition: Nemaline myopathy-9 is an autosomal recessive muscle disorder characterized by onset of muscle weakness in early infancy. The phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. Muscle biopsy shows typical rod-like structure in myofibers (summary by previous studies). + +For a discussion of genetic heterogeneity of nemaline myopathy, see previous studies." +MONDO_0014512,"Definition: Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF) is characterized by severe hypotonia at birth associated with respiratory difficulties, including apnea and hypoventilation, and feeding difficulties. Many infants require ventilatory support or feeding tubes. Affected patients have global developmental delay, often never achieving walking or speech, although the severity can be variable. Additional common features may include seizures, exaggerated startle reflex, abnormal movements, and dysmorphic facial features. Brain imaging often shows hypomyelination and parenchymal atrophy. A subset of patients may have systemic features, such as cardiac defects, scoliosis, endocrine anomalies, constipation, or cryptorchidism (summary by previous studies)." +MONDO_0032885,"Definition: The Isidor-Toutain type of spondyloepimetaphyseal dysplasia (SEMDIST) is characterized by normal birth length, early postnatal growth deficiency, severe short stature, and genu varum. Skeletal radiographs show platyspondyly and severe epiphyseal and metaphyseal changes in the lower limbs (previous studies)." +MONDO_0033201,"Definition: Autosomal recessive deafness-57 is characterized by symmetric bilateral moderate to severe hearing loss, represented by gently downward-sloping audiograms. The hearing loss may be mildly progressive (previous studies)." +MONDO_0009919,"Definition: Peroxisomal acyl-CoA oxidase deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also D-bifunctional protein deficiency (previous studies), caused by mutation in the HSD17B4 gene (previous studies) on chromosome 5q2. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including Zellweger cerebrohepatorenal syndrome (see previous studies) and neonatal adrenoleukodystrophy (see previous studies) (previous studies)." +MONDO_0010435,"Definition: Classic congenital or infantile nystagmus presents as conjugate, horizontal oscillations of the eyes, in primary or eccentric gaze, often with a preferred head turn or tilt. Other associated features may include mildly decreased visual acuity, strabismus, astigmatism, and occasionally head nodding. Eye movement recordings reveal that infantile nystagmus is predominantly a horizontal jerk waveform, with a diagnostic accelerating velocity slow phase. However, pendular and triangular waveforms may also be present. The nystagmus may rarely be vertical. As these patients often have normal visual acuity, it is presumed that the nystagmus represents a primary defect in the parts of the brain responsible for ocular motor control; thus the disorder has sometimes been termed 'congenital motor nystagmus' (previous studies; previous studies). + +For a discussion of genetic heterogeneity of congenital nystagmus, see NYS1 (previous studies)." +MONDO_0011346,"Definition: Xanthinuria type II is an autosomal recessive inborn error of metabolism resulting from a defect in the synthesis of the molybdenum cofactor, which is necessary for the 2 enzymes that degrade xanthine: XDH (previous studies) and AOX1 (previous studies). Most individuals with type II xanthinuria are asymptomatic, but some develop urinary tract calculi, acute renal failure, or myositis due to tissue deposition of xanthine. Laboratory studies show increased serum and urinary hypoxanthine and xanthine and decreased serum and urinary uric acid (summary by previous studies). + +Two clinically similar but distinct forms of xanthinuria are recognized. In type I xanthinuria (XAN1; previous studies), there is an isolated deficiency of xanthine dehydrogenase resulting from mutation in the XDH gene; in type II, there is a dual deficiency of xanthine dehydrogenase and aldehyde oxidase. Type I patients can metabolize allopurinol, whereas type II patients cannot (previous studies)." +MONDO_0011906,"Definition: Congenital defects of bile acid synthesis are autosomal recessive disorders characterized by neonatal onset of progressive liver disease with cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract resulting from a primary failure to synthesize bile acids. Affected infants show failure to thrive and secondary coagulopathy. In most forms of the disorder, there is a favorable response to oral bile acid therapy (summary by previous studies). + + Genetic Heterogeneity of Congenital Defects in Bile Acid Synthesis + +There are several disorders that result from defects in bile acid synthesis. See CBAS2 (previous studies), caused by mutation in the delta(4)-3-oxosteroid 5-beta-reductase gene (AKR1D1; previous studies) on chromosome 7q33; CBAS3 (previous studies), caused by mutation in the 7-alpha hydroxylase gene (CYP7B1; previous studies) on chromosome 8q12; CBAS4 (previous studies), caused by mutation in the AMACR gene (previous studies) on chromosome 5p13; CBAS5 (previous studies), caused by mutation in the ABCD3 gene (previous studies) on chromosome 1p21; and CBAS6 (previous studies), caused by mutation in the ACOX2 gene (previous studies) on chromosome 3p14. + +See also progressive familial intrahepatic cholestasis (PFIC1; previous studies), which has a similar phenotype." +MONDO_0012858,"Definition: CD59-mediated hemolytic anemia with immune-mediated polyneuropathy is an autosomal recessive disorder characterized by infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Immunosuppressive treatment may result in some clinical improvement (summary by previous studies)." +MONDO_0030749,"Definition: Severe junctional epidermolysis bullosa 3B (JEB3B) is an autosomal recessive skin blistering disorder characterized by extreme fragility of the skin and epithelia of various extracutaneous tissues. Skin blisters and erosions are present at birth. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Patients die in infancy to early adulthood (summary by previous studies). + +For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (previous studies). + + Reviews + +previous studies reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa." +MONDO_0030927,"Definition: Myofibrillar myopathy-11 (MFM11) is an autosomal recessive skeletal muscle disorder characterized by onset of slowly progressive proximal muscle weakness in the first decade of life. Some patients may present at birth with hypotonia and feeding difficulties, whereas others present later in mid-childhood. Although most patients show delayed walking at 2 to 3 years, all remain ambulatory into adulthood. More variable features may include decreased respiratory forced vital capacity, variable cardiac features, and calf hypertrophy. Skeletal muscle biopsy shows myopathic changes with variation in fiber size, type 1 fiber predominance, centralized nuclei, eccentrically placed core-like lesions, and distortion of the myofibrillary pattern with Z-line streaming and abnormal myofibrillar aggregates or inclusions (summary by previous studies). + +For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (previous studies)." +MONDO_0032892,"Definition: Patients with BAIDCS have small head circumference with abnormalities in brain anatomy including variable deficiency of the corpus callosum (including agenesis), abnormal conformation of the ventricles and posterior fossa, hypoplasia of both cerebellar hemispheres, colpocephaly, and partial rhombencephalosynapsis (absence of the cerebellar vermis with fusion of the cerebellar hemispheres). Intellectual development is moderately to severely impaired. Bicoronal synostosis, scoliosis, and tethered cord may be present (previous studies; previous studies). + +Craniosynostosis-6 (CRS6; previous studies) is an allelic disorder."