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whs	whs	[ "4p- Syndrome", "Monosomy 4p", "4p- Syndrome", "Monosomy 4p", "Pitt-Rogers-Danks Syndrome", "Complexin-1", "C-terminal-binding protein 1", "Fibroblast growth factor receptor-like 1", "GPI ethanolamine phosphate transferase 2", "Histone-lysine N-methyltransferase NSD2", "Mitochondrial proton/calcium exchanger protein", "Negative elongation factor A", "Not applicable", "CPLX1", "CTBP1", "FGFRL1", "LETM1", "NELFA", "Not applicable", "NSD2", "PIGG", "Wolf-Hirschhorn Syndrome" ]	Wolf-Hirschhorn Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Agatino Battaglia, John C Carey, Sarah T South	Summary Wolf-Hirschhorn syndrome (WHS) is characterized by typical craniofacial features in infancy consisting of "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead), microcephaly, high anterior hairline with prominent glabella, widely spaced eyes, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle underdevelopment. Developmental delay/intellectual disability of variable degree is present in all. Seizures occur in 90% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%). The diagnosis of WHS is established by the finding of a heterozygous deletion of the Wolf-Hirschhorn syndrome critical region (WHSCR) on chromosome 4p16.3 by chromosomal microarray (CMA), conventional G-banded cytogenetic analysis, or fluorescence in situ hybridization (FISH). WHS is caused by deletion of the WHSCR of chromosome 4p16.3 by one of several genetic mechanisms. About 50%-60% of individuals with WHS have a	## Diagnosis Wolf-Hirschhorn syndrome (WHS) "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead) Microcephaly High anterior hairline with prominent glabella Widely spaced eyes Epicanthus Highly arched eyebrows Short philtrum Downturned corners of the mouth Micrognathia Poorly formed ears with pits/tags The diagnosis of Wolf-Hirschhorn syndrome The WHSCR on 4p16.3 is defined as the presence of a deletion at the approximate position of chr4: 419,224-2,010,962 in the reference genome (NCBI BuildGRCh37/hg19). Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the WHS (see Note: CMA testing may be appropriate in a proband who previously had a normal conventional G-band cytogenetic study. Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ Genomic Testing Used in Wolf-Hirschhorn syndrome See Standardized clinical annotation and interpretation for genomic variants from the See Molecular Genetics, Chromosome microarray analysis (CMA) using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the WHSCR. A combination of CMA, FISH, and/or G-banded cytogenetic studies may be necessary for complete characterization of the chromosome rearrangement. This number applies only to the situation in which the deletion can be detected by cytogenetic analysis in the proband. FISH is not appropriate for an individual in whom a WHSCR deletion was not detected by CMA designed to target 4p16.3. • "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead) • Microcephaly • High anterior hairline with prominent glabella • Widely spaced eyes • Epicanthus • Highly arched eyebrows • Short philtrum • Downturned corners of the mouth • Micrognathia • Poorly formed ears with pits/tags • Note: CMA testing may be appropriate in a proband who previously had a normal conventional G-band cytogenetic study. • Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). • About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. • The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ • Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). • About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. • The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ • Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). • About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. • The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ ## Suggestive Findings Wolf-Hirschhorn syndrome (WHS) "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead) Microcephaly High anterior hairline with prominent glabella Widely spaced eyes Epicanthus Highly arched eyebrows Short philtrum Downturned corners of the mouth Micrognathia Poorly formed ears with pits/tags • "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead) • Microcephaly • High anterior hairline with prominent glabella • Widely spaced eyes • Epicanthus • Highly arched eyebrows • Short philtrum • Downturned corners of the mouth • Micrognathia • Poorly formed ears with pits/tags ## Establishing the Diagnosis The diagnosis of Wolf-Hirschhorn syndrome The WHSCR on 4p16.3 is defined as the presence of a deletion at the approximate position of chr4: 419,224-2,010,962 in the reference genome (NCBI BuildGRCh37/hg19). Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the WHS (see Note: CMA testing may be appropriate in a proband who previously had a normal conventional G-band cytogenetic study. Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ Genomic Testing Used in Wolf-Hirschhorn syndrome See Standardized clinical annotation and interpretation for genomic variants from the See Molecular Genetics, Chromosome microarray analysis (CMA) using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the WHSCR. A combination of CMA, FISH, and/or G-banded cytogenetic studies may be necessary for complete characterization of the chromosome rearrangement. This number applies only to the situation in which the deletion can be detected by cytogenetic analysis in the proband. FISH is not appropriate for an individual in whom a WHSCR deletion was not detected by CMA designed to target 4p16.3. • Note: CMA testing may be appropriate in a proband who previously had a normal conventional G-band cytogenetic study. • Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). • About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. • The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ • Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). • About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. • The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ • Many individuals (~55%) have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"). • About 40%-45% of affected individuals have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. • The remaining individuals have other complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4) [ ## Clinical Characteristics Frequency of Clinical Findings in Wolf-Hirschhorn Syndrome Hypotonia Decreased muscle bulk Feeding difficulties Skin changes (hemangioma; marble/dry skin) Skeletal anomalies Craniofacial asymmetry Ptosis Abnormal teeth Antibody deficiency Hearing loss Heart defects Eye/optic nerve anomalies Cleft lip/palate Genitourinary tract anomalies Structural brain anomalies Stereotypies (hand washing/flapping, rocking) Liver Gallbladder Gut Diaphragm Esophagus Lung Aorta From About 10% of affected individuals achieve sphincter control by day, usually between ages eight and 14 years. By age two to 12 years, approximately 45% of affected individuals walk, either independently (25%) or with support (20%) [ Other seizure types described in a few individuals include tonic spasms, myoclonic seizures, and complex partial seizures [ Seizures can be difficult to control in some individuals during the early years, but if properly treated tend to disappear with age. Seizures stop by age two to 13 years in up to 55% of individuals [ Distinctive electroencephalographic (EEG) abnormalities have been found in 90% of individuals with WHS, including diffuse ill-defined sharp element spike/wave complexes at 2-3.5 Hz, occurring in long bursts, activated by sleep; and high amplitude spikes-polyspike/wave complexes at 4-6 Hz, over the posterior third of the head, often triggered by eye closure [ Hypospadias and cryptorchidism are seen in 50% of males [ Absent uterus, streak gonads, and clitoral aplasia/hyperplasia have been reported in females [ In order to explain the wide phenotypic variability of WHS, investigators have searched for correlations between the size of the 4p deletion and the severity of the clinical manifestations. Although The classic phenotype may include less typical anomalies in persons with WHS and partial trisomy of another chromosome resulting from an unbalanced translocation. It has been shown that double cryptic chromosome imbalances, initially mistaken as microdeletions, but caused by large deletions associated with an unbalanced translocation, can be an important factor in explaining phenotypic variability in Wolf-Hirschhorn syndrome [ Previously thought to be separate disorders, WHS and Pitt-Rogers-Danks syndrome (PRDS) are now recognized as the clinical spectrum associated with a single syndrome due to heterozygous deletion of the WHSCR on 4p16.3 [ The prevalence of WHS is estimated at approximately 1:50,000 births, with a 2:1 female/male ratio. However, this is likely an underestimate because of misdiagnosis and under-recognition of affected individuals [ • Hypotonia • Decreased muscle bulk • Feeding difficulties • Skin changes (hemangioma; marble/dry skin) • Skeletal anomalies • Craniofacial asymmetry • Ptosis • Abnormal teeth • Antibody deficiency • Hearing loss • Heart defects • Eye/optic nerve anomalies • Cleft lip/palate • Genitourinary tract anomalies • Structural brain anomalies • Stereotypies (hand washing/flapping, rocking) • Liver • Gallbladder • Gut • Diaphragm • Esophagus • Lung • Aorta ## Clinical Description Frequency of Clinical Findings in Wolf-Hirschhorn Syndrome Hypotonia Decreased muscle bulk Feeding difficulties Skin changes (hemangioma; marble/dry skin) Skeletal anomalies Craniofacial asymmetry Ptosis Abnormal teeth Antibody deficiency Hearing loss Heart defects Eye/optic nerve anomalies Cleft lip/palate Genitourinary tract anomalies Structural brain anomalies Stereotypies (hand washing/flapping, rocking) Liver Gallbladder Gut Diaphragm Esophagus Lung Aorta From About 10% of affected individuals achieve sphincter control by day, usually between ages eight and 14 years. By age two to 12 years, approximately 45% of affected individuals walk, either independently (25%) or with support (20%) [ Other seizure types described in a few individuals include tonic spasms, myoclonic seizures, and complex partial seizures [ Seizures can be difficult to control in some individuals during the early years, but if properly treated tend to disappear with age. Seizures stop by age two to 13 years in up to 55% of individuals [ Distinctive electroencephalographic (EEG) abnormalities have been found in 90% of individuals with WHS, including diffuse ill-defined sharp element spike/wave complexes at 2-3.5 Hz, occurring in long bursts, activated by sleep; and high amplitude spikes-polyspike/wave complexes at 4-6 Hz, over the posterior third of the head, often triggered by eye closure [ Hypospadias and cryptorchidism are seen in 50% of males [ Absent uterus, streak gonads, and clitoral aplasia/hyperplasia have been reported in females [ • Hypotonia • Decreased muscle bulk • Feeding difficulties • Skin changes (hemangioma; marble/dry skin) • Skeletal anomalies • Craniofacial asymmetry • Ptosis • Abnormal teeth • Antibody deficiency • Hearing loss • Heart defects • Eye/optic nerve anomalies • Cleft lip/palate • Genitourinary tract anomalies • Structural brain anomalies • Stereotypies (hand washing/flapping, rocking) • Liver • Gallbladder • Gut • Diaphragm • Esophagus • Lung • Aorta ## Genotype-Phenotype Correlations In order to explain the wide phenotypic variability of WHS, investigators have searched for correlations between the size of the 4p deletion and the severity of the clinical manifestations. Although The classic phenotype may include less typical anomalies in persons with WHS and partial trisomy of another chromosome resulting from an unbalanced translocation. It has been shown that double cryptic chromosome imbalances, initially mistaken as microdeletions, but caused by large deletions associated with an unbalanced translocation, can be an important factor in explaining phenotypic variability in Wolf-Hirschhorn syndrome [ ## Nomenclature Previously thought to be separate disorders, WHS and Pitt-Rogers-Danks syndrome (PRDS) are now recognized as the clinical spectrum associated with a single syndrome due to heterozygous deletion of the WHSCR on 4p16.3 [ ## Prevalence The prevalence of WHS is estimated at approximately 1:50,000 births, with a 2:1 female/male ratio. However, this is likely an underestimate because of misdiagnosis and under-recognition of affected individuals [ ## Genetically Related (Allelic) Disorders Deletions from the 4p terminus larger than 22 to 25 Mb in length are associated with a severe phenotype that is said to differ from the spectrum observed in WHS [ Deletions within just the distal portion of the WHSCR may be either benign or associated with mild developmental delay, growth delay, and possible seizures, but without the diagnostic features of WHS [ ## Differential Diagnosis ## Management To establish the extent of disease and needs in an individual diagnosed with Wolf-Hirschhorn syndrome, the following evaluations are recommended: Measurement of growth parameters and plotting on growth charts Evaluation of cognitive, language, and motor development and social skills Waking/sleeping video-EEG-polygraphic studies in childhood (mainly ages 1-6 years) to detect atypical absence seizures that may be subtle [ Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team Physical examination for skeletal anomalies (e.g., clubfoot, scoliosis, kyphosis); if anomalies are present, referral for orthopedic and physical therapy evaluation (including full biomechanical assessment) Ophthalmology consultation in infancy even in the absence of overt anomalies Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy Testing for immunodeficiency (particularly plasma Ig levels, lymphocyte subsets, and polysaccharide responsiveness); although limited data on immunodeficiency in individuals with WHS are available, such testing should be considered when clinically appropriate. Complete blood count to evaluate for hematopoietic dysfunction Comprehensive evaluation by an otolaryngologist and comprehensive audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies and/or vesicoureteral reflux [ Baseline liver ultrasound to evaluate for hepatic adenoma Consultation with a clinical geneticist and/or genetic counselor Sodium bromide has recently been proposed as the initial treatment for the prevention of the development of status epilepticus [ Clonic, tonic-clonic, absence, or myoclonic status epilepticus can be well controlled by intravenous benzodiazepines (Diazepam) [ Because individuals with WHS have distinctive EEG abnormalities not necessarily associated with seizures [ Gavage feeding may be indicated in individuals with poorly coordinated swallow. Gastroesophageal reflux should be addressed in a standard manner. In one study, almost 44% of individuals with WHS were managed with gastrostomy and, occasionally, gastroesophageal fundoplication [ Antibiotic prophylaxis is indicated for vesicoureteral reflux. Intravenous Ig infusions or continuous antibiotics may be indicated for those with antibody deficiencies. Systematic follow up allows for adjustment of rehabilitation and treatment as skills improve or deteriorate and medical needs change [ Complete blood count annually to evaluate for hematopoietic dysfunction Annual renal function testing, including serum BUN, creatinine, and cystatin C; urinalysis; and creatinine clearance test Consideration of routine liver ultrasonography to evaluate for liver adenomas Carbamazepine may worsen atypical absence seizures [ See Search • Measurement of growth parameters and plotting on growth charts • Evaluation of cognitive, language, and motor development and social skills • Waking/sleeping video-EEG-polygraphic studies in childhood (mainly ages 1-6 years) to detect atypical absence seizures that may be subtle [ • Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team • Physical examination for skeletal anomalies (e.g., clubfoot, scoliosis, kyphosis); if anomalies are present, referral for orthopedic and physical therapy evaluation (including full biomechanical assessment) • Ophthalmology consultation in infancy even in the absence of overt anomalies • Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy • Testing for immunodeficiency (particularly plasma Ig levels, lymphocyte subsets, and polysaccharide responsiveness); although limited data on immunodeficiency in individuals with WHS are available, such testing should be considered when clinically appropriate. • Complete blood count to evaluate for hematopoietic dysfunction • Comprehensive evaluation by an otolaryngologist and comprehensive audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions • Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies and/or vesicoureteral reflux [ • Baseline liver ultrasound to evaluate for hepatic adenoma • Consultation with a clinical geneticist and/or genetic counselor • Complete blood count annually to evaluate for hematopoietic dysfunction • Annual renal function testing, including serum BUN, creatinine, and cystatin C; urinalysis; and creatinine clearance test • Consideration of routine liver ultrasonography to evaluate for liver adenomas ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Wolf-Hirschhorn syndrome, the following evaluations are recommended: Measurement of growth parameters and plotting on growth charts Evaluation of cognitive, language, and motor development and social skills Waking/sleeping video-EEG-polygraphic studies in childhood (mainly ages 1-6 years) to detect atypical absence seizures that may be subtle [ Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team Physical examination for skeletal anomalies (e.g., clubfoot, scoliosis, kyphosis); if anomalies are present, referral for orthopedic and physical therapy evaluation (including full biomechanical assessment) Ophthalmology consultation in infancy even in the absence of overt anomalies Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy Testing for immunodeficiency (particularly plasma Ig levels, lymphocyte subsets, and polysaccharide responsiveness); although limited data on immunodeficiency in individuals with WHS are available, such testing should be considered when clinically appropriate. Complete blood count to evaluate for hematopoietic dysfunction Comprehensive evaluation by an otolaryngologist and comprehensive audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies and/or vesicoureteral reflux [ Baseline liver ultrasound to evaluate for hepatic adenoma Consultation with a clinical geneticist and/or genetic counselor • Measurement of growth parameters and plotting on growth charts • Evaluation of cognitive, language, and motor development and social skills • Waking/sleeping video-EEG-polygraphic studies in childhood (mainly ages 1-6 years) to detect atypical absence seizures that may be subtle [ • Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team • Physical examination for skeletal anomalies (e.g., clubfoot, scoliosis, kyphosis); if anomalies are present, referral for orthopedic and physical therapy evaluation (including full biomechanical assessment) • Ophthalmology consultation in infancy even in the absence of overt anomalies • Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy • Testing for immunodeficiency (particularly plasma Ig levels, lymphocyte subsets, and polysaccharide responsiveness); although limited data on immunodeficiency in individuals with WHS are available, such testing should be considered when clinically appropriate. • Complete blood count to evaluate for hematopoietic dysfunction • Comprehensive evaluation by an otolaryngologist and comprehensive audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions • Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies and/or vesicoureteral reflux [ • Baseline liver ultrasound to evaluate for hepatic adenoma • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Sodium bromide has recently been proposed as the initial treatment for the prevention of the development of status epilepticus [ Clonic, tonic-clonic, absence, or myoclonic status epilepticus can be well controlled by intravenous benzodiazepines (Diazepam) [ Because individuals with WHS have distinctive EEG abnormalities not necessarily associated with seizures [ Gavage feeding may be indicated in individuals with poorly coordinated swallow. Gastroesophageal reflux should be addressed in a standard manner. In one study, almost 44% of individuals with WHS were managed with gastrostomy and, occasionally, gastroesophageal fundoplication [ ## Prevention of Secondary Complications Antibiotic prophylaxis is indicated for vesicoureteral reflux. Intravenous Ig infusions or continuous antibiotics may be indicated for those with antibody deficiencies. ## Surveillance Systematic follow up allows for adjustment of rehabilitation and treatment as skills improve or deteriorate and medical needs change [ Complete blood count annually to evaluate for hematopoietic dysfunction Annual renal function testing, including serum BUN, creatinine, and cystatin C; urinalysis; and creatinine clearance test Consideration of routine liver ultrasonography to evaluate for liver adenomas • Complete blood count annually to evaluate for hematopoietic dysfunction • Annual renal function testing, including serum BUN, creatinine, and cystatin C; urinalysis; and creatinine clearance test • Consideration of routine liver ultrasonography to evaluate for liver adenomas ## Agents/Circumstances to Avoid Carbamazepine may worsen atypical absence seizures [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Wolf-Hirschhorn syndrome (WHS) is caused by deletion of the Wolf-Hirschhorn critical region (WHSCR) within chromosome 4p16.3 by one of several genetic mechanisms. Risk to family members depends on the mechanism of origin of the deletion. The parents of a proband are unaffected. About 55% of individuals with WHS have a About 40%-45% of individuals with WHS have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be Parental testing for a balanced rearrangement involving 4p16.3 is always recommended. The risk to the sibs of a proband depends on the genetic status of the parents. If the deletion in the proband is If a parent is a balanced translocation carrier, the risk to sibs of being affected with 4p monosomy (i.e., WHS) or 4p trisomy is increased. Asymptomatic sibs may inherit a balanced translocation from a parent and have reproductive risks themselves. Specific empiric risks for translocations involving 4p and another chromosome are unavailable. However, 4p subtelomere FISH analysis of both parents may be considered to rule out this possibility. Genetic counseling is appropriate for families interested in risk of recurrence. Studies suggest that terminal deletions may vary in size between generations. This has been described for both 4p and 18q [ The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The parents of a proband are unaffected. • About 55% of individuals with WHS have a • About 40%-45% of individuals with WHS have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be • Parental testing for a balanced rearrangement involving 4p16.3 is always recommended. • The risk to the sibs of a proband depends on the genetic status of the parents. • If the deletion in the proband is • If a parent is a balanced translocation carrier, the risk to sibs of being affected with 4p monosomy (i.e., WHS) or 4p trisomy is increased. • Asymptomatic sibs may inherit a balanced translocation from a parent and have reproductive risks themselves. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance Wolf-Hirschhorn syndrome (WHS) is caused by deletion of the Wolf-Hirschhorn critical region (WHSCR) within chromosome 4p16.3 by one of several genetic mechanisms. ## Risk to Family Members Risk to family members depends on the mechanism of origin of the deletion. The parents of a proband are unaffected. About 55% of individuals with WHS have a About 40%-45% of individuals with WHS have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be Parental testing for a balanced rearrangement involving 4p16.3 is always recommended. The risk to the sibs of a proband depends on the genetic status of the parents. If the deletion in the proband is If a parent is a balanced translocation carrier, the risk to sibs of being affected with 4p monosomy (i.e., WHS) or 4p trisomy is increased. Asymptomatic sibs may inherit a balanced translocation from a parent and have reproductive risks themselves. • The parents of a proband are unaffected. • About 55% of individuals with WHS have a • About 40%-45% of individuals with WHS have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be • Parental testing for a balanced rearrangement involving 4p16.3 is always recommended. • The risk to the sibs of a proband depends on the genetic status of the parents. • If the deletion in the proband is • If a parent is a balanced translocation carrier, the risk to sibs of being affected with 4p monosomy (i.e., WHS) or 4p trisomy is increased. • Asymptomatic sibs may inherit a balanced translocation from a parent and have reproductive risks themselves. ## Related Genetic Counseling Issues Specific empiric risks for translocations involving 4p and another chromosome are unavailable. However, 4p subtelomere FISH analysis of both parents may be considered to rule out this possibility. Genetic counseling is appropriate for families interested in risk of recurrence. Studies suggest that terminal deletions may vary in size between generations. This has been described for both 4p and 18q [ The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Diagnosis ## Resources 2159 128th Street New Richmond WI 54017 Via Bologna 65 Montecosaro 62010 Italy United Kingdom PO Box 724 Boca Raton FL 33429-0724 • • 2159 128th Street • New Richmond WI 54017 • • • Via Bologna 65 • Montecosaro 62010 • Italy • • • • • United Kingdom • • • PO Box 724 • Boca Raton FL 33429-0724 • ## Molecular Genetics Wolf-Hirschhorn Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Wolf-Hirschhorn Syndrome ( The proximal boundary of the WHSCR was defined by the identification of two individuals with the WHS phenotype and a 1.9-Mb terminal deletion of 4p16.3 that includes the candidate genes Much work is still needed to identify the function of ## Molecular Pathogenesis The proximal boundary of the WHSCR was defined by the identification of two individuals with the WHS phenotype and a 1.9-Mb terminal deletion of 4p16.3 that includes the candidate genes Much work is still needed to identify the function of ## References ## Literature Cited ## Chapter Notes Agatino Battaglia, MD (2001-present)John C Carey, MD (2001-present)Sarah T South, PhD (2001-present)Tracy J Wright, PhD; Hunter Animal Hospital (2001-2015) 18 April 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population 20 August 2015 (me) Comprehensive update posted live 17 June 2010 (me) Comprehensive update posted live 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically 25 September 2006 (me) Comprehensive update posted live 6 April 2004 (me) Comprehensive update posted live 29 April 2002 (me) Review posted live 2 February 2001 (ab) Original submission • 18 April 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population • 20 August 2015 (me) Comprehensive update posted live • 17 June 2010 (me) Comprehensive update posted live • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically • 25 September 2006 (me) Comprehensive update posted live • 6 April 2004 (me) Comprehensive update posted live • 29 April 2002 (me) Review posted live • 2 February 2001 (ab) Original submission ## Author History Agatino Battaglia, MD (2001-present)John C Carey, MD (2001-present)Sarah T South, PhD (2001-present)Tracy J Wright, PhD; Hunter Animal Hospital (2001-2015) ## Revision History 18 April 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population 20 August 2015 (me) Comprehensive update posted live 17 June 2010 (me) Comprehensive update posted live 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically 25 September 2006 (me) Comprehensive update posted live 6 April 2004 (me) Comprehensive update posted live 29 April 2002 (me) Review posted live 2 February 2001 (ab) Original submission • 18 April 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population • 20 August 2015 (me) Comprehensive update posted live • 17 June 2010 (me) Comprehensive update posted live • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically • 25 September 2006 (me) Comprehensive update posted live • 6 April 2004 (me) Comprehensive update posted live • 29 April 2002 (me) Review posted live • 2 February 2001 (ab) Original submission Facial appearance of 16 individuals with WHS at different ages Reprinted from	[ "EF Andersen, JC Carey, DL Earl, D Corzo, M Suttie, P Hammond, ST South. Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome.. Eur J Hum Genet. 2014;22:464-70", "T Antonius, J Draaisma, E Levichenko, N Knoers, W Renier, C van Ravenswaaij. Growth charts for Wolf-Hirschhorn (4p-) syndrome (0-4 years of age).. Eur J Pediatr 2008;167:807-10", "NG Bailey, ST South, M Hummel, SL Wenger. Case report: cytogenetic and molecular analysis of proximal iInterstitial deletion of 4p, review of the literature and comparison with Wolf-Hirschhorn syndrome.. J Assoc Genet Technol 2010;36:5-10", "A Battaglia, JC Carey. Update on the clinical features and natural history of Wolf Hirschhorn syndrome (WHS): experience with 48 cases.. Am J Hum Genet 2000;67:127", "A Battaglia, JC Carey. Seizure and EEG patterns in Wolf-Hirschhorn (4p-) syndrome.. Brain Dev 2005;27:362-4", "A Battaglia, JC Carey, P Cederholm, DH Viskochil, AR Brothman, C Galasso. Natural history of Wolf-Hirschhorn syndrome: experience with 15 cases.. Pediatrics 1999a;103:830-6", "A Battaglia, JC Carey, P Cederholm, DH Viskochil, AR Brothman, C Galasso. Storia naturale della sindrome di Wolf-Hirschhorn: esperienza con 15 casi.. Pediatrics 1999b;11:236-42", "A Battaglia, JC Carey, DH Viskochil, P Cederholm, JM Opitz. Wolf-Hirschhorn syndrome (WHS): a history in pictures.. Clin Dysmorphol 2000;9:25-30", "A Battaglia, JC Carey, TJ Wright. Wolf-Hirschhorn (4p-) syndrome.. Adv Pediatr 2001;48:75-113", "A Battaglia, T Filippi, JC Carey. Update on the clinical features and natural history of Wolf-Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision.. Am J Med Genet Part C Semin Med Genet 2008;148C:246-51", "A Battaglia, T Filippi, ST South, JC Carey. Spectrum of epilepsy and EEG patterns in Wolf-Hirschhorn syndrome: experience with 87 patients.. Dev Med Child Neurol 2009;51:373-80", "B Bayindir, E Piazza, E Della Mina, I Limongelli, F Brustia, R Ciccone, P Veggiotti, O Zuffardi, MR Dehghani. Dravet phenotype in a subject with a der(4)t(4;8)(p16.3;p23.3) without the involvement of the LETM1 gene.. Eur J Med Genet. 2013;56:551-5", "AD Bergemann, F Cole, K Hirschhorn. The etiology of Wolf-Hirschhorn syndrome.. Trends Genet 2005;21:188-95", "C Catela, D Bilbao-Cortes, E Slonimsky, P Kratsios, N Rosenthal, P te Welscher. Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated in Fgfrl1 null mice.. Dis Model Mech 2009;2:283-94", "CP Chen, CY Hsu, CC Lee, WL Chen, LF Chen, W Wang. Prenatal diagnosis of de novo pure partial monosomy 4p (4p15.1-->pter) in a growth-restricted fetus with a Greek warrior helmet face and unilateral facial cleft on three-dimensional ultrasound.. Prenat Diagn 2004;24:934-6", "LM Curfs, R Didden, SP Sikkema, CE De Die-Smulders. Management of sleeping problems in Wolf-Hirschhorn syndrome: a case study.. Genet Couns 1999;10:345-50", "KS Dimmer, F Navoni, A Casarin, E Trevisson, S Endele, A Winterpacht, L Salviati, L Scorrano. LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability.. Hum Mol Genet 2008;17:201-14", "H Engbers, JJ van der Smagt, R van ‘t Slot, JR Vermeesch, R Hochstenbach, M Poot. Wolf-Hirschhorn syndrome facial dysmorphic features in a patient with a terminal 4p16.3 deletion telomeric to the WHSCR and WHSCR 2 regions.. Eur J Hum Genet 2009;17:129-32", "F Faravelli, M Murdolo, G Marangi, FD Bricarelli, M Di Rocco, M Zollino. Mother to son amplification of a small subtelomeric deletion: a new mechanism of familial recurrence in microdeletion syndromes.. Am J Med Genet A. 2007;143A:1169-73", "A Ferrarini, G Selicorni, M Cagnoli, M Zollino, R Lecce, C Chines, A Battaglia. Distinct facial dysmorphism, pre and postnatal growth retardation, microcephaly, seizures. Mental retardation and hypotonia.. Ital J Pediatr 2003;29:393-7", "GS Fisch, P Grossfeld, R Falk, A Battaglia, J Youngblom, R Simensen. Cognitive-behavioral features of Wolf-Hirschhorn syndrome and other subtelomeric microdeletions.. Am J Med Genet 2010;154C:417-26", "S Grisaru, IJ Ramage, ND Rosenblum. Vesicoureteric reflux associated with renal dysplasia in the Wolf-Hirschhorn syndrome.. Pediatr Nephrol 2000;14:146-8", "P Hammond, F Hannes, M Suttie, K Devriendt, JR Vermeesch, F Faravelli, F Forzano, S Parekh, S Williams, D McMullan, ST South, JC Carey, O Quarrell. Fine-grained facial phenotype-genotype analysis in Wolf-Hirschhorn syndrome. European journal of human genetics. EJHG 2012;20:33-40", "J Hanley-Lopez, LL Estabrooks, R Stiehm. Antibody deficiency in Wolf-Hirschhorn syndrome.. J Pediatr 1998;133:141-3", "A Hasegawa, AM van der Bliek. Inverse correlation between expression of the Wolfs Hirschhorn candidate gene Letm1 and mitochondrial volume in C. elegans and in mammalian cells.. Hum Mol Genet 2007;16:2061-71", "D Jiang, L Zhao, DE Clapham. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter.. Science 2009;326:144-7", "K Kagitani-Shimono, K Imai, K Otani, N Kamio, T Okinaga, Y Toribe, Y Suzuki, K Ozono. Epilepsy in Wolf-Hirschhorn syndrome (4p-).. Epilepsia 2005;46:150-5", "C Kerzendorfer, F Hannes, R Colnaghi, I Abramowicz, G Carpenter, JR Vermeesch, M O'Driscoll. Characterizing the functional consequences of haploinsufficiency of NELF-A (WHSC2) and SLBP identifies novel cellular phenotypes in Wolf-Hirschhorn syndrome.. Hum Mol Genet 2012;21:2181-93", "M Kuum, V Veksler, J Liiv, R Ventura-Clapier, A Kaasik. Endoplasmic reticulum potassium-hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes.. Journal of cell science 2012;125:625-33", "NM Maas, G Van Buggenhout, F Hannes, B Thienpont, D Sanlaville, K Kok, A Midro, J Andrieux, BM Anderlid, J Schoumans, R Hordijk, K Devriendt, JP Fryns, JR Vermeesch. Genotype-phenotype correlation in 21 patients with Wolf-Hirschhorn syndrome using high resolution array comparative genome hybridisation (CGH).. J Med Genet. 2008;45:71-80", "A Meloni, RR Shepard, A Battaglia, TJ Wright, JC Carey. Wolf-Hirschhorn syndrome: correlation between cytogenetics, FISH, and severity of disease.. Am J Hum Genet 2000;67:149", "D Misceo, T Barøy, JR Helle, O Braaten, M Fannemel, E Frengen. 1.5Mb deletion of chromosome 4p16.3 associated with postnatal growth delay, psychomotor impairment, epilepsy, impulsive behavior and asynchronous skeletal development.. Gene. 2012;507:85-91", "K Nowikovsky, EM Froschauer, G Zsurka, J Samaj, S Reipert, M Kolisek, G Wiesenberger, RJ Schweyen. The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome.. J Biol Chem 2004;279:30307-15", "G Prunotto, P Cianci, A Cereda, A Scatigno, C Fossati, S Maitz, A Biondi, A Selicorni. Two cases of hepatic adenomas in patients with Wolf-Hirschhorn syndrome: a new rare complication?. Am J Med Genet A. 2013;161A:1759-62", "L Rodríguez, M Zollino, S Climent, E Mansilla, F López-Grondona, ML Martínez-Fernández, M Murdolo, ML Martínez-Frías. The new Wolf-Hirschhorn syndrome critical region (WHSCR-2): a description of a second case.. Am J Med Genet A. 2005;136:175-8", "S Schlickum, A Moghekar, JC Simpson, C Steglich, RJ O'Brien, A Winterpacht, SU Endele. LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein.. Genomics 2004;83:254-61", "AL Shanske, N Yachelevich, L Ala-Kokko, J Leonard, B Levy. Wolf-Hirschhorn syndrome and ectrodactyly: new findings and a review of the literature.. Am J Med Genet Part A 2010;152A:203-8", "A Sharathkumar, M Kirby, M Freedman, M Abdelhaleem, D Chitayat, IE Teshima, Y Dror. Malignant hematological disorders in children with Wolf-Hirschhorn syndrome.. Am J Med Genet A 2003;119A:194-9", "ST South, SB Bleyl, JC Carey. Two unique patients with novel microdeletions in 4p16.3 that exclude the WHS critical regions: implications for critical region designation.. Am J Med Genet A. 2007;143A:2137-42", "ST South, F Hannes, GS Fisch, JR Vermeesch, M Zollino. Pathogenic significance of deletions distal to the currently described Wolf-Hirschhorn syndrome critical regions on 4p16.3.. Am J Med Genet C Semin Med Genet. 2008a;148C:270-4", "ST South, AF Rope, AN Lamb, E Aston, N Glaus, H Whitby, T Maxwell, XL Zhu, AR Brothman. Expansion in size of a terminal deletion: a paradigm shift for parental follow-up studies.. J Med Genet. 2008b;45:391-5", "ST South, H Whitby, A Battaglia, JC Carey, AR Brothman. Comprehensive analysis of Wolf-Hirschhorn syndrome using array CGH indicates a high prevalence of translocations.. Eur J Hum Genet. 2008c;16:45-52", "SO Ulualp, CG Wright, KS Pawlowski, PS Roland. Histopathological basis of hearing impairment in Wolf-Hirschhorn syndrome.. Laryngoscope 2004;114:1426-30", "G Van Buggenhout, C Melotte, B Dutta, G Froyen, P Van Hummelen, P Marynen, G Matthijs, T de Ravel, K Devriendt, JP Fryns, JR Vermeesch. Mild Wolf-Hirschhorn syndrome: micro-array CGH analysis of atypical 4p16.3 deletions enables refinement of the genotype-phenotype map.. J Med Genet. 2004;41:691-8", "D Wieczorek, M Krause, F Majewski, B Albrecht, D Horn, O Riess, G Gillessen-Kaesbach. Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion.. Eur J Hum Genet 2000;8:519-26", "TJ Wright, DO Ricke, K Denison, S Abmayr, PD Cotter, K Hirschhorn, M Keinanen, D McDonald-McGinn, M Somer, N Spinner, T Yang-Feng, E Zackai, MR Altherr. A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region.. Hum Mol Genet 1997;6:317-24", "WY Wu-Chen, SP Christiansen, SA Berry, WK Engel, KJ Fray, CG Summers. Ophthalmic manifestations of Wolf-Hirschhorn syndrome.. J AAPOS 2004;8:345-8", "M Zollino, C Di Stefano, G Zampino, P Mastroiacovo, TJ Wright, G Sorge, A Selicorni, R Tenconi, A Zappala, A Battaglia, M Di Rocco, G Palka, R Pallotta, MR Altherr, G Neri. Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome.. Am J Med Genet 2000;94:254-61", "M Zollino, R Lecce, R Fischetto, M Murdolo, F Faravelli, A Selicorni, C Butte, L Memo, G Capovilla, G Neri. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2.. Am J Hum Genet 2003;72:590-7", "M Zollino, R Lecce, A Selicorni, M Murdolo, I Mancuso, G Marangi, G Zampino, L Garavelli, A Ferrarini, M Rocchi, JM Opitz, G Neri. A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome.. Eur J Hum Genet 2004;12:797-804", "M Zollino, M Murdolo, G Marangi, V Pecile, C Galasso, L Mazzanti, G Neri. On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review.. Am J Med Genet C Semin Med Genet 2008;148C:257-69", "M Zollino, D Orteschi, M Ruiter, R Pfundt, K Steindl, C Cafiero, S Ricciardi, I Contaldo, D Chieffo, D Ranalli, C Acquafondata, M Murdolo, G Marangi, A Asaro, D. Battaglia. Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder.. Epilepsia. 2014;55:849-57" ]	29/4/2002	20/8/2015	24/3/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
wiedemann-steiner	wiedemann-steiner	[ "KMT2A-Related Neurodevelopmental Disorder", "KMT2A-Related Neurodevelopmental Disorder", "Histone-lysine N-methyltransferase 2A", "KMT2A", "Wiedemann-Steiner Syndrome" ]	Wiedemann-Steiner Syndrome	Sarah E Sheppard, Fabiola Quintero-Rivera	Summary Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. The facial features include thick eyebrows with lateral flare, vertically narrow and downslanted palpebral fissures, widely spaced eyes, long eyelashes, wide nasal bridge, broad nasal tip, thin vermilion of the upper lip, and thick scalp hair. About 60% of affected individuals have hypertrichosis cubiti ("hairy elbows"), which was once thought to be pathognomic for the syndrome, with a majority having hypertrichosis of other body parts. Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical spine), renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies. The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a	## Diagnosis No consensus clinical diagnostic criteria for Wiedemann-Steiner syndrome (WSS) have been published. Wiedemann-Steiner syndrome Distinctive facial features ( Hypertrichosis cubiti ("hairy elbows"), hypertrichosis of the back, and/or hypertrichosis of the lower limbs Sacral dimple Developmental delay / intellectual disability Hypotonia Feeding difficulties Failure to thrive Short stature Constipation Abnormal brain MRI, most commonly demonstrating abnormalities of the corpus callosum or abnormal myelination Congenital heart disease Genitourinary anomalies, most commonly vesiculouretal reflux with hydronephrosis, cryptorchidism in males, or absent uterus in females Vertebral anomalies, especially fusion anomalies in the cervical spine The diagnosis of WSS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of WSS, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability, comprehensive genomic testing may be considered. If testing for single-nucleotide pathogenic variants is normal but the suspicion for WSS remains high, methylation testing, including epigenetic signature, can be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Wiedemann-Steiner Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. • Distinctive facial features ( • Hypertrichosis cubiti ("hairy elbows"), hypertrichosis of the back, and/or hypertrichosis of the lower limbs • Sacral dimple • Developmental delay / intellectual disability • Hypotonia • Feeding difficulties • Failure to thrive • Short stature • Constipation • Abnormal brain MRI, most commonly demonstrating abnormalities of the corpus callosum or abnormal myelination • Congenital heart disease • Genitourinary anomalies, most commonly vesiculouretal reflux with hydronephrosis, cryptorchidism in males, or absent uterus in females • Vertebral anomalies, especially fusion anomalies in the cervical spine • For an introduction to multigene panels click ## Suggestive Findings Wiedemann-Steiner syndrome Distinctive facial features ( Hypertrichosis cubiti ("hairy elbows"), hypertrichosis of the back, and/or hypertrichosis of the lower limbs Sacral dimple Developmental delay / intellectual disability Hypotonia Feeding difficulties Failure to thrive Short stature Constipation Abnormal brain MRI, most commonly demonstrating abnormalities of the corpus callosum or abnormal myelination Congenital heart disease Genitourinary anomalies, most commonly vesiculouretal reflux with hydronephrosis, cryptorchidism in males, or absent uterus in females Vertebral anomalies, especially fusion anomalies in the cervical spine • Distinctive facial features ( • Hypertrichosis cubiti ("hairy elbows"), hypertrichosis of the back, and/or hypertrichosis of the lower limbs • Sacral dimple • Developmental delay / intellectual disability • Hypotonia • Feeding difficulties • Failure to thrive • Short stature • Constipation • Abnormal brain MRI, most commonly demonstrating abnormalities of the corpus callosum or abnormal myelination • Congenital heart disease • Genitourinary anomalies, most commonly vesiculouretal reflux with hydronephrosis, cryptorchidism in males, or absent uterus in females • Vertebral anomalies, especially fusion anomalies in the cervical spine ## Establishing the Diagnosis The diagnosis of WSS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of WSS, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability, comprehensive genomic testing may be considered. If testing for single-nucleotide pathogenic variants is normal but the suspicion for WSS remains high, methylation testing, including epigenetic signature, can be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Wiedemann-Steiner Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of WSS, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability, comprehensive genomic testing may be considered. If testing for single-nucleotide pathogenic variants is normal but the suspicion for WSS remains high, methylation testing, including epigenetic signature, can be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Wiedemann-Steiner Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. ## Clinical Characteristics Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. To date, more than 200 individuals have been reported in the medical literature with a pathogenic variant in Wiedemann-Steiner Syndrome: Frequency of Select Features ASD = autism spectrum disorder; ENT = ears, nose, throat Defined as length/height that is more than two standard deviations below the mean for age and sex or less than the fifth centile, or postnatal growth failure Thick eyebrows Long eyelashes Vertically narrow palpebral fissures Widely spaced eyes Wide nasal bridge with broad or bulbous tip Lateral (or other) flare to the eyebrow Downslanted palpebral fissures Blepharoptosis Exaggerated Cupid's bow Thin vermilion border to the upper lip Posteriorly rotated ears Some affected individuals are able to maintain jobs as adults. IQ in those tested ranges from 40 to 85 (median 65). For more detailed information on developmental and learning issues, see Weight remains below the fifth centile for age in about one third of affected individuals. Almost 60% of affected individuals have short stature (defined as height <5th centile for age and sex OR 2 SD below the mean for age and sex OR "postnatal growth failure"). Bone age radiographs were abnormal (delayed, advanced, or disharmonic – i.e., different levels of maturation) in almost 65%. About one third of affected individuals have microcephaly (head circumference >5th centile for age OR 2 SD below the mean for age). Sacral anomaly, most commonly a sacral dimple, was seen in about 45% of affected individuals. Other sacral anomalies include spina bifida occulta and tethered cord requiring surgery. Hypotonia is present in about two thirds of affected individuals. Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. Some individuals continue to require supplemental nutrition through their gastrostomy tube. Hypotonia appears to improve over time in some. Seizures are present in almost one fifth of affected individuals. Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ Epileptic encephalopathy has also been reported. Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ Central apnea has also been reported. Abnormalities of the corpus callosum Abnormal myelination White matter changes, such as punctate foci of hyperintensity within the white matter, evidence of white matter volume loss, and paucity of white matter Chiari 1 malformation spectrum, which may include relatively narrow foramen magnum and platybasia Periventricular nodular heterotopia Choroid plexus cysts Abnormalities involving the pituitary gland, such as absent pituitary neurohypophysis, abnormal shape of the sella turcica, ectopic posterior bright spot with hypoplasia of hypothalamic pituitary axis, and pituitary hypoplasia (see Cortical malformations, including bilateral frontal polymicrogyria [ Hypoplastic optic nerves [ Cerebrospinal fluid anomalies including aqueductal stenosis and third ventricle dilatation [ Cerebral atrophy Vermis hypoplasia [ Cerebellar atrophy [ Eyebrows Long eyelashes Thick hair on the scalp Hypertrichosis of the back Hypertrichosis cubiti Hypertrichosis of the lower limbs Rib anomalies (e.g., reduced number of rib pairs, hypoplastic appearance of ribs, cervical ribs) are found in about one third of affected individuals. Broad first digits and/or tapering fingers are present in about one quarter of affected individuals, with some individuals having persistent fetal fingertip pads [ Fewer than one fifth of affected individuals have scoliosis, which in rare cases can be severe enough to require surgery. Pectus excavatum has been described in a small number of affected individuals. Hip dysplasia has also been seen in a small number of affected individuals, although none of those with hip dysplasia were breech at birth. Several individuals required surgery and one required a Pavlik harness. One individual had scaphocephaly and another had metopic craniosynostosis [ Structural cardiac anomalies (patent ductus arteriosus, patent foramen ovale, right aortic arch, aortic insufficiency, bicuspid aortic valve, atrial septal defect, ventricular septal defect, tetralogy of Fallot, aberrant right subclavian artery, mitral valve prolapse, dextrocardia, mitral regurgitation, tricuspid regurgitation, overriding aorta, and thickened aortic valve) Arrhythmia (one affected individual required a pacemaker), including third-degree AV block [ Pulmonary hypertension Syncopal episodes Renal anomaly was seen in about one quarter and included vesiculouretal reflux with hydronephrosis. Uterine or testicular anomalies were seen in almost 20%, including absent uterus in females and cryptorchidism in males. About 10% have an external genital anomaly, including prominent clitoris, underdeveloped scrotum, and hypospadias. Strabismus Astigmatism Hyperopia Myopia Amblyopia Lacrimal duct abnormalities Ptosis Rarely, cataract, coloboma, or glaucoma Short stature (see Premature adrenarche Menorrhagia, polycystic ovary syndrome, and/or irregular menses Abnormality of the pituitary gland seen on brain MRI (see Growth hormone (GH) deficiency, defined by low serum GH, IGF-1 or GH stimulation test Osteopenia Hypothyroidism (including congenital hypothyroidism and Hashimoto thyroiditis) Hypoparathyroidism Immunodeficiency, including common variable immunodeficiency Insufficient response to vaccinations History of recurrent infections Recurrent fevers of unknown origin Eosinophilia [ One boy had recurrent pulmonary infections and died of sepsis [ Some genotype-phenotype correlations have been established. Individuals with loss-of-function variants in In contrast, participants with non-loss-of-function variants are more likely to have seizures [ Missense variants in the CXXC DNA-binding domain (amino acids 1147-1195) may be associated with more significant neurodevelopmental issues [ In 1970, Dr P Beighton described a father and two of his children with familial hypertrichosis cubiti or "hairy elbows" syndrome [ The prevalence of WSS is not known. Almost 250 individuals have been reported in the literature. Multiple adults were diagnosed as part of their child's evaluation, so it is possible that WSS could be underdiagnosed [ • Thick eyebrows • Long eyelashes • Vertically narrow palpebral fissures • Widely spaced eyes • Wide nasal bridge with broad or bulbous tip • Lateral (or other) flare to the eyebrow • Downslanted palpebral fissures • Blepharoptosis • Exaggerated Cupid's bow • Thin vermilion border to the upper lip • Posteriorly rotated ears • Some affected individuals are able to maintain jobs as adults. • IQ in those tested ranges from 40 to 85 (median 65). • For more detailed information on developmental and learning issues, see • Weight remains below the fifth centile for age in about one third of affected individuals. • Almost 60% of affected individuals have short stature (defined as height <5th centile for age and sex OR 2 SD below the mean for age and sex OR "postnatal growth failure"). • Bone age radiographs were abnormal (delayed, advanced, or disharmonic – i.e., different levels of maturation) in almost 65%. • About one third of affected individuals have microcephaly (head circumference >5th centile for age OR 2 SD below the mean for age). • Sacral anomaly, most commonly a sacral dimple, was seen in about 45% of affected individuals. Other sacral anomalies include spina bifida occulta and tethered cord requiring surgery. • Hypotonia is present in about two thirds of affected individuals. • Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. • Some individuals continue to require supplemental nutrition through their gastrostomy tube. • Hypotonia appears to improve over time in some. • Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. • Some individuals continue to require supplemental nutrition through their gastrostomy tube. • Hypotonia appears to improve over time in some. • Seizures are present in almost one fifth of affected individuals. • Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ • Epileptic encephalopathy has also been reported. • Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ • Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ • Epileptic encephalopathy has also been reported. • Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ • Central apnea has also been reported. • Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. • Some individuals continue to require supplemental nutrition through their gastrostomy tube. • Hypotonia appears to improve over time in some. • Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ • Epileptic encephalopathy has also been reported. • Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ • Abnormalities of the corpus callosum • Abnormal myelination • White matter changes, such as punctate foci of hyperintensity within the white matter, evidence of white matter volume loss, and paucity of white matter • Chiari 1 malformation spectrum, which may include relatively narrow foramen magnum and platybasia • Periventricular nodular heterotopia • Choroid plexus cysts • Abnormalities involving the pituitary gland, such as absent pituitary neurohypophysis, abnormal shape of the sella turcica, ectopic posterior bright spot with hypoplasia of hypothalamic pituitary axis, and pituitary hypoplasia (see • Cortical malformations, including bilateral frontal polymicrogyria [ • Hypoplastic optic nerves [ • Cerebrospinal fluid anomalies including aqueductal stenosis and third ventricle dilatation [ • Cerebral atrophy • Vermis hypoplasia [ • Cerebellar atrophy [ • Eyebrows • Long eyelashes • Thick hair on the scalp • Hypertrichosis of the back • Hypertrichosis cubiti • Hypertrichosis of the lower limbs • Rib anomalies (e.g., reduced number of rib pairs, hypoplastic appearance of ribs, cervical ribs) are found in about one third of affected individuals. • Broad first digits and/or tapering fingers are present in about one quarter of affected individuals, with some individuals having persistent fetal fingertip pads [ • Fewer than one fifth of affected individuals have scoliosis, which in rare cases can be severe enough to require surgery. • Pectus excavatum has been described in a small number of affected individuals. • Hip dysplasia has also been seen in a small number of affected individuals, although none of those with hip dysplasia were breech at birth. • Several individuals required surgery and one required a Pavlik harness. • One individual had scaphocephaly and another had metopic craniosynostosis [ • Structural cardiac anomalies (patent ductus arteriosus, patent foramen ovale, right aortic arch, aortic insufficiency, bicuspid aortic valve, atrial septal defect, ventricular septal defect, tetralogy of Fallot, aberrant right subclavian artery, mitral valve prolapse, dextrocardia, mitral regurgitation, tricuspid regurgitation, overriding aorta, and thickened aortic valve) • Arrhythmia (one affected individual required a pacemaker), including third-degree AV block [ • Pulmonary hypertension • Syncopal episodes • Renal anomaly was seen in about one quarter and included vesiculouretal reflux with hydronephrosis. • Uterine or testicular anomalies were seen in almost 20%, including absent uterus in females and cryptorchidism in males. • About 10% have an external genital anomaly, including prominent clitoris, underdeveloped scrotum, and hypospadias. • Strabismus • Astigmatism • Hyperopia • Myopia • Amblyopia • Lacrimal duct abnormalities • Ptosis • Rarely, cataract, coloboma, or glaucoma • Short stature (see • Premature adrenarche • Menorrhagia, polycystic ovary syndrome, and/or irregular menses • Abnormality of the pituitary gland seen on brain MRI (see • Growth hormone (GH) deficiency, defined by low serum GH, IGF-1 or GH stimulation test • Osteopenia • Hypothyroidism (including congenital hypothyroidism and Hashimoto thyroiditis) • Hypoparathyroidism • Immunodeficiency, including common variable immunodeficiency • Insufficient response to vaccinations • History of recurrent infections • Recurrent fevers of unknown origin • Eosinophilia [ • Individuals with loss-of-function variants in • In contrast, participants with non-loss-of-function variants are more likely to have seizures [ • Missense variants in the CXXC DNA-binding domain (amino acids 1147-1195) may be associated with more significant neurodevelopmental issues [ ## Clinical Description Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. To date, more than 200 individuals have been reported in the medical literature with a pathogenic variant in Wiedemann-Steiner Syndrome: Frequency of Select Features ASD = autism spectrum disorder; ENT = ears, nose, throat Defined as length/height that is more than two standard deviations below the mean for age and sex or less than the fifth centile, or postnatal growth failure Thick eyebrows Long eyelashes Vertically narrow palpebral fissures Widely spaced eyes Wide nasal bridge with broad or bulbous tip Lateral (or other) flare to the eyebrow Downslanted palpebral fissures Blepharoptosis Exaggerated Cupid's bow Thin vermilion border to the upper lip Posteriorly rotated ears Some affected individuals are able to maintain jobs as adults. IQ in those tested ranges from 40 to 85 (median 65). For more detailed information on developmental and learning issues, see Weight remains below the fifth centile for age in about one third of affected individuals. Almost 60% of affected individuals have short stature (defined as height <5th centile for age and sex OR 2 SD below the mean for age and sex OR "postnatal growth failure"). Bone age radiographs were abnormal (delayed, advanced, or disharmonic – i.e., different levels of maturation) in almost 65%. About one third of affected individuals have microcephaly (head circumference >5th centile for age OR 2 SD below the mean for age). Sacral anomaly, most commonly a sacral dimple, was seen in about 45% of affected individuals. Other sacral anomalies include spina bifida occulta and tethered cord requiring surgery. Hypotonia is present in about two thirds of affected individuals. Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. Some individuals continue to require supplemental nutrition through their gastrostomy tube. Hypotonia appears to improve over time in some. Seizures are present in almost one fifth of affected individuals. Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ Epileptic encephalopathy has also been reported. Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ Central apnea has also been reported. Abnormalities of the corpus callosum Abnormal myelination White matter changes, such as punctate foci of hyperintensity within the white matter, evidence of white matter volume loss, and paucity of white matter Chiari 1 malformation spectrum, which may include relatively narrow foramen magnum and platybasia Periventricular nodular heterotopia Choroid plexus cysts Abnormalities involving the pituitary gland, such as absent pituitary neurohypophysis, abnormal shape of the sella turcica, ectopic posterior bright spot with hypoplasia of hypothalamic pituitary axis, and pituitary hypoplasia (see Cortical malformations, including bilateral frontal polymicrogyria [ Hypoplastic optic nerves [ Cerebrospinal fluid anomalies including aqueductal stenosis and third ventricle dilatation [ Cerebral atrophy Vermis hypoplasia [ Cerebellar atrophy [ Eyebrows Long eyelashes Thick hair on the scalp Hypertrichosis of the back Hypertrichosis cubiti Hypertrichosis of the lower limbs Rib anomalies (e.g., reduced number of rib pairs, hypoplastic appearance of ribs, cervical ribs) are found in about one third of affected individuals. Broad first digits and/or tapering fingers are present in about one quarter of affected individuals, with some individuals having persistent fetal fingertip pads [ Fewer than one fifth of affected individuals have scoliosis, which in rare cases can be severe enough to require surgery. Pectus excavatum has been described in a small number of affected individuals. Hip dysplasia has also been seen in a small number of affected individuals, although none of those with hip dysplasia were breech at birth. Several individuals required surgery and one required a Pavlik harness. One individual had scaphocephaly and another had metopic craniosynostosis [ Structural cardiac anomalies (patent ductus arteriosus, patent foramen ovale, right aortic arch, aortic insufficiency, bicuspid aortic valve, atrial septal defect, ventricular septal defect, tetralogy of Fallot, aberrant right subclavian artery, mitral valve prolapse, dextrocardia, mitral regurgitation, tricuspid regurgitation, overriding aorta, and thickened aortic valve) Arrhythmia (one affected individual required a pacemaker), including third-degree AV block [ Pulmonary hypertension Syncopal episodes Renal anomaly was seen in about one quarter and included vesiculouretal reflux with hydronephrosis. Uterine or testicular anomalies were seen in almost 20%, including absent uterus in females and cryptorchidism in males. About 10% have an external genital anomaly, including prominent clitoris, underdeveloped scrotum, and hypospadias. Strabismus Astigmatism Hyperopia Myopia Amblyopia Lacrimal duct abnormalities Ptosis Rarely, cataract, coloboma, or glaucoma Short stature (see Premature adrenarche Menorrhagia, polycystic ovary syndrome, and/or irregular menses Abnormality of the pituitary gland seen on brain MRI (see Growth hormone (GH) deficiency, defined by low serum GH, IGF-1 or GH stimulation test Osteopenia Hypothyroidism (including congenital hypothyroidism and Hashimoto thyroiditis) Hypoparathyroidism Immunodeficiency, including common variable immunodeficiency Insufficient response to vaccinations History of recurrent infections Recurrent fevers of unknown origin Eosinophilia [ One boy had recurrent pulmonary infections and died of sepsis [ • Thick eyebrows • Long eyelashes • Vertically narrow palpebral fissures • Widely spaced eyes • Wide nasal bridge with broad or bulbous tip • Lateral (or other) flare to the eyebrow • Downslanted palpebral fissures • Blepharoptosis • Exaggerated Cupid's bow • Thin vermilion border to the upper lip • Posteriorly rotated ears • Some affected individuals are able to maintain jobs as adults. • IQ in those tested ranges from 40 to 85 (median 65). • For more detailed information on developmental and learning issues, see • Weight remains below the fifth centile for age in about one third of affected individuals. • Almost 60% of affected individuals have short stature (defined as height <5th centile for age and sex OR 2 SD below the mean for age and sex OR "postnatal growth failure"). • Bone age radiographs were abnormal (delayed, advanced, or disharmonic – i.e., different levels of maturation) in almost 65%. • About one third of affected individuals have microcephaly (head circumference >5th centile for age OR 2 SD below the mean for age). • Sacral anomaly, most commonly a sacral dimple, was seen in about 45% of affected individuals. Other sacral anomalies include spina bifida occulta and tethered cord requiring surgery. • Hypotonia is present in about two thirds of affected individuals. • Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. • Some individuals continue to require supplemental nutrition through their gastrostomy tube. • Hypotonia appears to improve over time in some. • Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. • Some individuals continue to require supplemental nutrition through their gastrostomy tube. • Hypotonia appears to improve over time in some. • Seizures are present in almost one fifth of affected individuals. • Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ • Epileptic encephalopathy has also been reported. • Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ • Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ • Epileptic encephalopathy has also been reported. • Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ • Central apnea has also been reported. • Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube. • Some individuals continue to require supplemental nutrition through their gastrostomy tube. • Hypotonia appears to improve over time in some. • Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [ • Epileptic encephalopathy has also been reported. • Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [ • Abnormalities of the corpus callosum • Abnormal myelination • White matter changes, such as punctate foci of hyperintensity within the white matter, evidence of white matter volume loss, and paucity of white matter • Chiari 1 malformation spectrum, which may include relatively narrow foramen magnum and platybasia • Periventricular nodular heterotopia • Choroid plexus cysts • Abnormalities involving the pituitary gland, such as absent pituitary neurohypophysis, abnormal shape of the sella turcica, ectopic posterior bright spot with hypoplasia of hypothalamic pituitary axis, and pituitary hypoplasia (see • Cortical malformations, including bilateral frontal polymicrogyria [ • Hypoplastic optic nerves [ • Cerebrospinal fluid anomalies including aqueductal stenosis and third ventricle dilatation [ • Cerebral atrophy • Vermis hypoplasia [ • Cerebellar atrophy [ • Eyebrows • Long eyelashes • Thick hair on the scalp • Hypertrichosis of the back • Hypertrichosis cubiti • Hypertrichosis of the lower limbs • Rib anomalies (e.g., reduced number of rib pairs, hypoplastic appearance of ribs, cervical ribs) are found in about one third of affected individuals. • Broad first digits and/or tapering fingers are present in about one quarter of affected individuals, with some individuals having persistent fetal fingertip pads [ • Fewer than one fifth of affected individuals have scoliosis, which in rare cases can be severe enough to require surgery. • Pectus excavatum has been described in a small number of affected individuals. • Hip dysplasia has also been seen in a small number of affected individuals, although none of those with hip dysplasia were breech at birth. • Several individuals required surgery and one required a Pavlik harness. • One individual had scaphocephaly and another had metopic craniosynostosis [ • Structural cardiac anomalies (patent ductus arteriosus, patent foramen ovale, right aortic arch, aortic insufficiency, bicuspid aortic valve, atrial septal defect, ventricular septal defect, tetralogy of Fallot, aberrant right subclavian artery, mitral valve prolapse, dextrocardia, mitral regurgitation, tricuspid regurgitation, overriding aorta, and thickened aortic valve) • Arrhythmia (one affected individual required a pacemaker), including third-degree AV block [ • Pulmonary hypertension • Syncopal episodes • Renal anomaly was seen in about one quarter and included vesiculouretal reflux with hydronephrosis. • Uterine or testicular anomalies were seen in almost 20%, including absent uterus in females and cryptorchidism in males. • About 10% have an external genital anomaly, including prominent clitoris, underdeveloped scrotum, and hypospadias. • Strabismus • Astigmatism • Hyperopia • Myopia • Amblyopia • Lacrimal duct abnormalities • Ptosis • Rarely, cataract, coloboma, or glaucoma • Short stature (see • Premature adrenarche • Menorrhagia, polycystic ovary syndrome, and/or irregular menses • Abnormality of the pituitary gland seen on brain MRI (see • Growth hormone (GH) deficiency, defined by low serum GH, IGF-1 or GH stimulation test • Osteopenia • Hypothyroidism (including congenital hypothyroidism and Hashimoto thyroiditis) • Hypoparathyroidism • Immunodeficiency, including common variable immunodeficiency • Insufficient response to vaccinations • History of recurrent infections • Recurrent fevers of unknown origin • Eosinophilia [ ## Genotype-Phenotype Correlations Some genotype-phenotype correlations have been established. Individuals with loss-of-function variants in In contrast, participants with non-loss-of-function variants are more likely to have seizures [ Missense variants in the CXXC DNA-binding domain (amino acids 1147-1195) may be associated with more significant neurodevelopmental issues [ • Individuals with loss-of-function variants in • In contrast, participants with non-loss-of-function variants are more likely to have seizures [ • Missense variants in the CXXC DNA-binding domain (amino acids 1147-1195) may be associated with more significant neurodevelopmental issues [ ## Nomenclature In 1970, Dr P Beighton described a father and two of his children with familial hypertrichosis cubiti or "hairy elbows" syndrome [ ## Prevalence The prevalence of WSS is not known. Almost 250 individuals have been reported in the literature. Multiple adults were diagnosed as part of their child's evaluation, so it is possible that WSS could be underdiagnosed [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The features associated with Wiedemann-Steiner syndrome (WSS) overlap those of a wide range of disorders. Key Disorders in the Differential Diagnosis of Wiedemann-Steiner Syndrome AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; FTT = failure to thrive; ID = intellectual disability, MOI = mode of inheritance; WSS = Wiedemann-Steiner syndrome; XL = X-linked Noonan syndrome (NS) is most often inherited in an autosomal dominant manner. ## Management Suggested clinical practice guidelines for Wiedemann-Steiner syndrome (WSS) have been published. See To establish the extent of disease and needs in an individual diagnosed with WSS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Wiedemann-Steiner Syndrome To incl brain MRI, as clinically indicated Consider EEG if seizures are a concern & in those who have a loss-of-function pathogenic To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Signs/symptoms suggestive of vertebral anomalies & hip dysplasia Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of nutritional status Consider eval for gastrostomy tube placement in those w/FTT. To assess for short stature, growth hormone deficiency, hypothyroidism, & metabolic bone disease May consist of blood tests as well as radiographs (e.g., bone age x-rays) depending on clinical context To assess for immunodeficiency & vaccine response May incl quantitative immunoglobulins, vaccine titers, lymphocyte profile Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; ASD = autism spectrum disorder; EEG = electroencephalogram; EKG = electrocardiogram; FTT = failure to thrive; MOI = mode of inheritance; MRI = magnetic resonance imaging; OT = occupational therapy; PT = physical therapy Pelvic ultrasound and even pelvic MRI in females who have not experienced recent estrogen may not be able to identify a uterus. Neither of these imaging modalities is sufficient in this scenario to confirm absence of a uterus. Referral to a gynecologist for evaluation could be considered. Medical geneticist, certified genetic counselor, certified advanced genetic nurse WSS parent-specific resources may include the WSS Foundation (see Treatment of Manifestations in Individuals with Wiedemann-Steiner Syndrome Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Nasogastric or gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; IVIG = intravenous immunoglobulin; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation) [ Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Wiedemann-Steiner Syndrome Measure growth parameters & evaluate growth velocity. Evaluate nutritional status. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures. Assess for clinical signs of medullar compression, esp in those w/vertebral anomalies. May include EEG follow up, as indicated Visit frequency may vary based on individual needs, but generally visits may be every six months in early childhood and transition to annual visits around school age. The authors are aware of one individual with WSS who developed hyperammonemia with the use of the anti-seizure medication valproate. While this is not specific to individuals with WSS, valproate should be used with caution. See Some women with WSS have a seizure disorder that is treated with an anti-seizure medication. In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ Cervical spine anomalies may lead to immobility or instability, which may complicate airway management. Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia. Affected fetuses may be at risk for late prematurity, with average gestation ranging from 36 to 38 weeks [ See Search • To incl brain MRI, as clinically indicated • Consider EEG if seizures are a concern & in those who have a loss-of-function pathogenic • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Signs/symptoms suggestive of vertebral anomalies & hip dysplasia • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of nutritional status • Consider eval for gastrostomy tube placement in those w/FTT. • To assess for short stature, growth hormone deficiency, hypothyroidism, & metabolic bone disease • May consist of blood tests as well as radiographs (e.g., bone age x-rays) depending on clinical context • To assess for immunodeficiency & vaccine response • May incl quantitative immunoglobulins, vaccine titers, lymphocyte profile • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Nasogastric or gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation) [ • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Measure growth parameters & evaluate growth velocity. • Evaluate nutritional status. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures. • Assess for clinical signs of medullar compression, esp in those w/vertebral anomalies. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with WSS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Wiedemann-Steiner Syndrome To incl brain MRI, as clinically indicated Consider EEG if seizures are a concern & in those who have a loss-of-function pathogenic To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Signs/symptoms suggestive of vertebral anomalies & hip dysplasia Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of nutritional status Consider eval for gastrostomy tube placement in those w/FTT. To assess for short stature, growth hormone deficiency, hypothyroidism, & metabolic bone disease May consist of blood tests as well as radiographs (e.g., bone age x-rays) depending on clinical context To assess for immunodeficiency & vaccine response May incl quantitative immunoglobulins, vaccine titers, lymphocyte profile Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; ASD = autism spectrum disorder; EEG = electroencephalogram; EKG = electrocardiogram; FTT = failure to thrive; MOI = mode of inheritance; MRI = magnetic resonance imaging; OT = occupational therapy; PT = physical therapy Pelvic ultrasound and even pelvic MRI in females who have not experienced recent estrogen may not be able to identify a uterus. Neither of these imaging modalities is sufficient in this scenario to confirm absence of a uterus. Referral to a gynecologist for evaluation could be considered. Medical geneticist, certified genetic counselor, certified advanced genetic nurse WSS parent-specific resources may include the WSS Foundation (see • To incl brain MRI, as clinically indicated • Consider EEG if seizures are a concern & in those who have a loss-of-function pathogenic • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Signs/symptoms suggestive of vertebral anomalies & hip dysplasia • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of nutritional status • Consider eval for gastrostomy tube placement in those w/FTT. • To assess for short stature, growth hormone deficiency, hypothyroidism, & metabolic bone disease • May consist of blood tests as well as radiographs (e.g., bone age x-rays) depending on clinical context • To assess for immunodeficiency & vaccine response • May incl quantitative immunoglobulins, vaccine titers, lymphocyte profile • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Wiedemann-Steiner Syndrome Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Nasogastric or gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; IVIG = intravenous immunoglobulin; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation) [ Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Nasogastric or gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation) [ • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation) [ Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation) [ • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Wiedemann-Steiner Syndrome Measure growth parameters & evaluate growth velocity. Evaluate nutritional status. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures. Assess for clinical signs of medullar compression, esp in those w/vertebral anomalies. May include EEG follow up, as indicated Visit frequency may vary based on individual needs, but generally visits may be every six months in early childhood and transition to annual visits around school age. • Measure growth parameters & evaluate growth velocity. • Evaluate nutritional status. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures. • Assess for clinical signs of medullar compression, esp in those w/vertebral anomalies. ## Agents/Circumstances to Avoid The authors are aware of one individual with WSS who developed hyperammonemia with the use of the anti-seizure medication valproate. While this is not specific to individuals with WSS, valproate should be used with caution. ## Evaluation of Relatives at Risk See ## Pregnancy Management Some women with WSS have a seizure disorder that is treated with an anti-seizure medication. In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ Cervical spine anomalies may lead to immobility or instability, which may complicate airway management. Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia. Affected fetuses may be at risk for late prematurity, with average gestation ranging from 36 to 38 weeks [ See ## Therapies Under Investigation Search ## Genetic Counseling Wiedemann-Steiner syndrome (WSS) is inherited in an autosomal dominant manner. Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a Rarely, individuals diagnosed with WSS have an affected parent [ If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either apparently asymptomatic parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with WSS may appear to be negative because of failure to recognize the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Clinical variability among affected sibs with the same pathogenic variant has been observed. In a family with six sibs with WSS, all had failure to thrive and feeding difficulties, there was a range of developmental delay, and some had structural malformations whereas others did not [ If the proband has a known If the parents are clinically unaffected after a thorough evaluation for subtle findings but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a • Rarely, individuals diagnosed with WSS have an affected parent [ • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either apparently asymptomatic parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with WSS may appear to be negative because of failure to recognize the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • Clinical variability among affected sibs with the same pathogenic variant has been observed. In a family with six sibs with WSS, all had failure to thrive and feeding difficulties, there was a range of developmental delay, and some had structural malformations whereas others did not [ • If the proband has a known • If the parents are clinically unaffected after a thorough evaluation for subtle findings but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance Wiedemann-Steiner syndrome (WSS) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a Rarely, individuals diagnosed with WSS have an affected parent [ If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either apparently asymptomatic parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with WSS may appear to be negative because of failure to recognize the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Clinical variability among affected sibs with the same pathogenic variant has been observed. In a family with six sibs with WSS, all had failure to thrive and feeding difficulties, there was a range of developmental delay, and some had structural malformations whereas others did not [ If the proband has a known If the parents are clinically unaffected after a thorough evaluation for subtle findings but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. • Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a • Rarely, individuals diagnosed with WSS have an affected parent [ • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either apparently asymptomatic parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with WSS may appear to be negative because of failure to recognize the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • Clinical variability among affected sibs with the same pathogenic variant has been observed. In a family with six sibs with WSS, all had failure to thrive and feeding difficulties, there was a range of developmental delay, and some had structural malformations whereas others did not [ • If the proband has a known • If the parents are clinically unaffected after a thorough evaluation for subtle findings but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 1314 44th Street Sacramento 95819 United Kingdom Sanford Research • • 1314 44th Street • Sacramento 95819 • • • • • United Kingdom • • • • • Sanford Research • ## Molecular Genetics Wiedemann-Steiner Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Wiedemann-Steiner Syndrome ( The KMT2A is the mammalian homolog of About 10% of all pediatric and adult leukemias are caused by more than 90 different fusions involving There is a single report of a family including three sibs with primary mediastinal large B-cell lymphoma and their cousin with diffuse large B-cell lymphoma, both subtypes of non-Hodgkin lymphoma, with a variant in ## Molecular Pathogenesis The KMT2A is the mammalian homolog of ## Cancer and Benign Tumors About 10% of all pediatric and adult leukemias are caused by more than 90 different fusions involving There is a single report of a family including three sibs with primary mediastinal large B-cell lymphoma and their cousin with diffuse large B-cell lymphoma, both subtypes of non-Hodgkin lymphoma, with a variant in ## Chapter Notes We thank the participants and their families and our co-authors [ 26 May 2022 (ma) Review posted live 3 August 2021 (fqr) Original submission • 26 May 2022 (ma) Review posted live • 3 August 2021 (fqr) Original submission ## Acknowledgments We thank the participants and their families and our co-authors [ ## Revision History 26 May 2022 (ma) Review posted live 3 August 2021 (fqr) Original submission • 26 May 2022 (ma) Review posted live • 3 August 2021 (fqr) Original submission ## References ## Literature Cited Individuals with characteristic facial features of Wiedemann-Steiner syndrome; first 15 are shown in front and side views. Modified from Individuals with characteristic facial features of Wiedemann-Steiner syndrome: family groups A. 3 sibs shown in front and side views B. Father and son C. Mother and daughter D. Father and daughter Modified from Eight individuals with Wiedemann-Steiner syndrome shown as they age Modified from	[ "A Aggarwal, DF Rodriguez-Buritica, H Northrup. Wiedemann-Steiner syndrome: novel pathogenic variant and review of literature.. Eur J Med Genet. 2017;60:285-8", "V Arora, RD Puri, S Bijarnia-Mahay, IC Verma. Expanding the phenotypic and genotypic spectrum of Wiedemann-Steiner syndrome: first patient from India.. 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williams	williams	[ "Williams-Beuren Syndrome", "Williams-Beuren Syndrome", "Elastin", "General transcription factor II-I", "General transcription factor II-I repeat domain-containing protein 1", "LIM domain kinase 1", "Neutrophil cytosol factor 1", "Not applicable", "ELN", "GTF2I", "GTF2IRD1", "LIMK1", "NCF1", "Not applicable", "Williams Syndrome" ]	Williams Syndrome	Colleen A Morris	Summary Williams syndrome (WS) is characterized by developmental delay, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, cardiovascular disease (supravalvar aortic stenosis, peripheral pulmonary stenosis, hypertension), connective tissue abnormalities, growth deficiency, endocrine abnormalities (early puberty, hypercalcemia, hypercalciuria, hypothyroidism), and distinctive facies. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. Feeding difficulties often lead to poor weight gain in infancy. The diagnosis of WS is established by identification of a heterozygous 1.5- to 1.8-Mb deletion of the Williams-Beuren syndrome critical region (WBSCR) on chromosome 7q11.23. WS is an autosomal dominant disorder. Most individuals diagnosed with WS have the disorder as the result of a	## Diagnosis Williams syndrome (WS) Note: See the National Human Genome Research Institute (NHGRI) The diagnosis of WS Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from WS (see Although several genes of interest (e.g., Note: (1) Most individuals with WS are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorders. (2) The recurrent deletion was detected by early arrays (e.g., BAC arrays). Note: (1) Targeted deletion testing by FISH is not appropriate for the relative of an individual suspected of having WS in whom a deletion was not detected by FISH or by CMA designed to target 7q11.23. By definition, such individuals do not have WS. (2) It is not possible to routinely size the deletion by use of FISH. Genomic Testing Used in Williams Syndrome See Standardized ISCN annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 7q11.23 region. FISH is not appropriate as a diagnostic method for the relative of an affected individual in whom Williams syndrome was not detected by FISH or by CMA designed to target this region. • Note: (1) Most individuals with WS are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorders. (2) The recurrent deletion was detected by early arrays (e.g., BAC arrays). • Note: (1) Targeted deletion testing by FISH is not appropriate for the relative of an individual suspected of having WS in whom a deletion was not detected by FISH or by CMA designed to target 7q11.23. By definition, such individuals do not have WS. (2) It is not possible to routinely size the deletion by use of FISH. ## Suggestive Findings Williams syndrome (WS) Note: See the National Human Genome Research Institute (NHGRI) ## Establishing the Diagnosis The diagnosis of WS Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from WS (see Although several genes of interest (e.g., Note: (1) Most individuals with WS are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorders. (2) The recurrent deletion was detected by early arrays (e.g., BAC arrays). Note: (1) Targeted deletion testing by FISH is not appropriate for the relative of an individual suspected of having WS in whom a deletion was not detected by FISH or by CMA designed to target 7q11.23. By definition, such individuals do not have WS. (2) It is not possible to routinely size the deletion by use of FISH. Genomic Testing Used in Williams Syndrome See Standardized ISCN annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 7q11.23 region. FISH is not appropriate as a diagnostic method for the relative of an affected individual in whom Williams syndrome was not detected by FISH or by CMA designed to target this region. • Note: (1) Most individuals with WS are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorders. (2) The recurrent deletion was detected by early arrays (e.g., BAC arrays). • Note: (1) Targeted deletion testing by FISH is not appropriate for the relative of an individual suspected of having WS in whom a deletion was not detected by FISH or by CMA designed to target 7q11.23. By definition, such individuals do not have WS. (2) It is not possible to routinely size the deletion by use of FISH. ## Clinical Characteristics Williams syndrome (WS) is a multisystem disorder characterized by cardiovascular disease (elastin arteriopathy, most often manifesting as supravalvar aortic stenosis), developmental delay, usually mild intellectual disability, a specific cognitive profile, unique personality characteristics, connective tissue abnormalities, growth abnormalities, other endocrine manifestations, and distinctive facies. Additional manifestations can include sleep problems, ocular issues, hearing loss, dental problems, gastrointestinal difficulties, urinary tract abnormalities, and musculoskeletal issues. Williams Syndrome: Frequency of Select Features ADHD = attention-deficit/hyperactivity disorder; PPS = peripheral pulmonic stenosis; SVAS = supravalvar aortic stenosis Academically, individuals with WS perform relatively well in reading, and adults may read at a high school level, though the range of achievement is wide. Reading skills correlate with method of reading instruction rather than IQ, with the highest reading skills following systemic phonics instruction [ Adaptive behavior is less than expected for IQ in both children and adults [ Peripheral pulmonic stenosis (PPS) is common in infancy but usually improves over time without intervention. However, individuals with combined SVAS and PPS (biventricular outflow tract obstruction) may develop biventricular hypertrophy and hypertension, increasing the risk for myocardial ischemia, dysrhythmias, and sudden death [ Coronary artery stenosis has been implicated as a cause of sudden death in individuals with WS [ The prevalence of hypertension in individuals with WS is 40%-50%. Hypertension may present at any age [ Mitral valve prolapse and aortic insufficiency have been reported in adults [ Prolonged QTc has been reported in 13.6% of individuals with WS; screening for repolarization abnormalities is recommended [ Anesthesia and sedation are associated with an increased risk for adverse events, including cardiac arrest, in individuals with WS [ Stenosis of additional arteries has been reported. Neurovascular abnormalities are rarely reported but may result in stroke [ Progressive sensorineural hearing loss has been observed; mild-to-moderate hearing loss is detected in 63% of children and 92% of adults [ Chronic abdominal pain is common in children and adults with WS; possible causes include gastroesophageal reflux, hiatal hernia, peptic ulcer disease, cholelithiasis, diverticulitis, ischemic bowel disease, chronic constipation, and somatization of anxiety. The prevalence of diverticulitis is increased in adolescents [ Hypercalcemia may contribute to irritability, vomiting, constipation, and muscle cramps. Hypercalcemia is more common in infancy but may recur in adults [ Puberty may occur early, and central precocious puberty is present in 18% of individuals with WS [ The 7q11.23 recurrent deletions of the Williams-Beuren syndrome critical region (WBSCR) comprise either 1.55 Mb (90%-95% of individuals with WS) or 1.84 Mb (5%-10% of individuals with WS) [ Hypertension is less prevalent in individuals with WS whose deletion includes A more severe phenotype with lower cognitive ability is observed in individuals with very large deletions (>2-4 Mb) that include the WBSCR than in individuals with a typical 1.5- to 1.8-Mb WBSCR deletion [ Deletions within the WBSCR smaller than the recurrent deletions associated with WS are rare and are associated with a variable phenotype. Genotype-phenotype correlations are limited for genes other than Individuals with partial WBSCR deletions that include the usual telomeric breakpoint (including Individuals with partial deletions that include Individuals with partial WBSCR deletions that include Deletions within the WBSCR may be of maternal or paternal origin [ Penetrance is 100%. The first descriptions of WS were incomplete in that they reflected the chief complaint of the individual or the medical specialty of the observer. Thus, nephrologists and endocrinologists described "idiopathic infantile hypercalcemia" and cardiologists reported "supravalvular aortic stenosis syndrome." Early reports also noted dysmorphic facial features that were thought to resemble elves of legend: for a time, the term "Williams elfin facies syndrome" was used. After the reports of A study of WS in Norway reported a prevalence of 1:7,500 [ • Hypertension is less prevalent in individuals with WS whose deletion includes • A more severe phenotype with lower cognitive ability is observed in individuals with very large deletions (>2-4 Mb) that include the WBSCR than in individuals with a typical 1.5- to 1.8-Mb WBSCR deletion [ • Individuals with partial WBSCR deletions that include the usual telomeric breakpoint (including • Individuals with partial deletions that include • Individuals with partial WBSCR deletions that include ## Clinical Description Williams syndrome (WS) is a multisystem disorder characterized by cardiovascular disease (elastin arteriopathy, most often manifesting as supravalvar aortic stenosis), developmental delay, usually mild intellectual disability, a specific cognitive profile, unique personality characteristics, connective tissue abnormalities, growth abnormalities, other endocrine manifestations, and distinctive facies. Additional manifestations can include sleep problems, ocular issues, hearing loss, dental problems, gastrointestinal difficulties, urinary tract abnormalities, and musculoskeletal issues. Williams Syndrome: Frequency of Select Features ADHD = attention-deficit/hyperactivity disorder; PPS = peripheral pulmonic stenosis; SVAS = supravalvar aortic stenosis Academically, individuals with WS perform relatively well in reading, and adults may read at a high school level, though the range of achievement is wide. Reading skills correlate with method of reading instruction rather than IQ, with the highest reading skills following systemic phonics instruction [ Adaptive behavior is less than expected for IQ in both children and adults [ Peripheral pulmonic stenosis (PPS) is common in infancy but usually improves over time without intervention. However, individuals with combined SVAS and PPS (biventricular outflow tract obstruction) may develop biventricular hypertrophy and hypertension, increasing the risk for myocardial ischemia, dysrhythmias, and sudden death [ Coronary artery stenosis has been implicated as a cause of sudden death in individuals with WS [ The prevalence of hypertension in individuals with WS is 40%-50%. Hypertension may present at any age [ Mitral valve prolapse and aortic insufficiency have been reported in adults [ Prolonged QTc has been reported in 13.6% of individuals with WS; screening for repolarization abnormalities is recommended [ Anesthesia and sedation are associated with an increased risk for adverse events, including cardiac arrest, in individuals with WS [ Stenosis of additional arteries has been reported. Neurovascular abnormalities are rarely reported but may result in stroke [ Progressive sensorineural hearing loss has been observed; mild-to-moderate hearing loss is detected in 63% of children and 92% of adults [ Chronic abdominal pain is common in children and adults with WS; possible causes include gastroesophageal reflux, hiatal hernia, peptic ulcer disease, cholelithiasis, diverticulitis, ischemic bowel disease, chronic constipation, and somatization of anxiety. The prevalence of diverticulitis is increased in adolescents [ Hypercalcemia may contribute to irritability, vomiting, constipation, and muscle cramps. Hypercalcemia is more common in infancy but may recur in adults [ Puberty may occur early, and central precocious puberty is present in 18% of individuals with WS [ ## Genotype-Phenotype Correlations The 7q11.23 recurrent deletions of the Williams-Beuren syndrome critical region (WBSCR) comprise either 1.55 Mb (90%-95% of individuals with WS) or 1.84 Mb (5%-10% of individuals with WS) [ Hypertension is less prevalent in individuals with WS whose deletion includes A more severe phenotype with lower cognitive ability is observed in individuals with very large deletions (>2-4 Mb) that include the WBSCR than in individuals with a typical 1.5- to 1.8-Mb WBSCR deletion [ Deletions within the WBSCR smaller than the recurrent deletions associated with WS are rare and are associated with a variable phenotype. Genotype-phenotype correlations are limited for genes other than Individuals with partial WBSCR deletions that include the usual telomeric breakpoint (including Individuals with partial deletions that include Individuals with partial WBSCR deletions that include Deletions within the WBSCR may be of maternal or paternal origin [ • Hypertension is less prevalent in individuals with WS whose deletion includes • A more severe phenotype with lower cognitive ability is observed in individuals with very large deletions (>2-4 Mb) that include the WBSCR than in individuals with a typical 1.5- to 1.8-Mb WBSCR deletion [ • Individuals with partial WBSCR deletions that include the usual telomeric breakpoint (including • Individuals with partial deletions that include • Individuals with partial WBSCR deletions that include ## Penetrance Penetrance is 100%. ## Nomenclature The first descriptions of WS were incomplete in that they reflected the chief complaint of the individual or the medical specialty of the observer. Thus, nephrologists and endocrinologists described "idiopathic infantile hypercalcemia" and cardiologists reported "supravalvular aortic stenosis syndrome." Early reports also noted dysmorphic facial features that were thought to resemble elves of legend: for a time, the term "Williams elfin facies syndrome" was used. After the reports of ## Prevalence A study of WS in Norway reported a prevalence of 1:7,500 [ ## Genetically Related (Allelic) Disorders Disorders associated with germline intragenic Disorders Associated with Germline Intragenic WS = Williams syndrome ## Differential Diagnosis Williams syndrome (WS) should be distinguished from other chromosomal (see Selected Chromosomal Disorders in the Differential Diagnosis of Williams Syndrome CHD = congenital heart disease; DD = developmental delay; ID = intellectual disability; SVAS = supravalvar aortic stenosis Selected Single-Gene Disorders with Short Stature and Congenital Heart Disease in the Differential Diagnosis of Williams Syndrome AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; SVAS = supravalvar aortic stenosis; WS = Williams syndrome; XL = X-linked Noonan syndrome (NS) is most often inherited in an autosomal dominant manner. NS caused by pathogenic variants in ## Management Clinical practice guidelines for Williams syndrome (WS) have been published [ To establish the extent of disease and needs in an individual diagnosed with WS, and to guide medical management, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Williams Syndrome Plotting of growth parameters on WS growth charts Complete physical & neurologic exam To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Eval by cardiologist w/experience in WS Measurement of blood pressure in all four limbs Echocardiogram, incl doppler flow studies Electrocardiogram Ultrasound exam of bladder & kidneys Serum concentration of BUN & creatinine Urinalysis Gross motor & fine motor skills Contractures & kyphoscoliosis Mobility, ADL Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Serum concentration of calcium or ionized calcium Urine calcium-to-creatinine on spot urine sample Community or Social work involvement for parental support; Home nursing referral. = activities of daily living; BUN = blood urea nitrogen; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; WS = Williams syndrome Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Williams Syndrome Developmental disabilities should be addressed by early intervention programs, special education programs, & vocational training. Recommended therapies include speech-language therapy, PT, & OT. Consider hippotherapy (use of equine movement during speech-language therapy, PT, &/or OT). Verbal strengths can be used to assist in learning spatial tasks. Phonics methods are recommended to teach reading. Mastery of ADL contributes to adult well-being & should be encouraged. Treatment per psychologist &/or psychiatrist Behavior in young children may be addressed using techniques based on applied behavior analysis. Behavioral counseling & psychotropic medication are often used to manage behavior issues, esp ADHD & anxiety, which require pharmacologic treatment in ~50%. Self-calming techniques can help manage anxiety. Surgical correction of SVAS is performed in 30%. Surgical treatment of mitral valve insufficiency or renal artery stenosis may be required. Anesthesia consultation for surgical procedures Electrocardiogram prior to surgery Use of a center equipped for cardiopulmonary resuscitation Guidelines for sedation & anesthesia risk assessment & anesthetic mgmt for WS have been published. There is ↑ risk for myocardial insufficiency & cardiac arrest in persons w/biventricular outflow tract obstruction, esp during induction of anesthesia. Hyperopia is treated w/corrective lenses. Strabismus is treated w/patching of 1 eye or surgery. Standard treatments for lacrimal duct abnormalities Recurrent otitis media may be treated w/tympanotomy tubes. Hypersensitivity to sounds may be treated w/ear protection when ↑ noise levels can be predicted. Hearing aids may be helpful per otolaryngologist. Dental care may require assistance w/daily brushing & flossing. Dental cleaning frequency should be ↑ to every 4 mos in adolescents & adults. Orthodontic referral for treatment of malocclusion. Investigation of lower urinary tract (voiding cystourethrogram) in those w/febrile urinary tract infections to direct treatment Mgmt of nephrocalcinosis, persistent hypercalcemia, &/or hypercalciuria per nephrologist Range of motion exercises to prevent or ameliorate joint contractures Orthopedics / physical medicine & rehab / PT & OT as needed for contractures & kyphoscoliosis Avoid vitamin supplements w/vitamin D, esp in young children. Assess hydration status & ↑ water intake as indicated. Adjust diet w/nutritionist to maintain calcium intake no higher than 100% of RDI. Parents should be counseled not to restrict dietary intake of calcium w/o medical supervision. Refractory hypercalcemia may be treated w/oral steroids. Referral to endocrinologist &/or nephrologist for treatment of persistent hypercalcemia, hypercalciuria, &/or nephrocalcinosis If vitamin D deficiency is suspected, check vitamin D levels prior to initiating therapy, & monitor calcium levels during treatment. Absorption of calcium from the gut is ↑ in WS (cause unknown) & vitamin D promotes calcium absorption. Intravenous pamidronate has been used successfully to treat infants w/severe symptomatic hypercalcemia. Exercise & balanced diet Mgmt per endocrinologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; OT = occupational therapy; PT = physical therapy; RDI = recommended daily intake; SVAS = supravalvar aortic stenosis See For discussion of antihypertensive therapy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis). Consider hippotherapy (use of equine movement during speech-language therapy, physical therapy, and/or occupational therapy). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder or anxiety. Surveillance for Williams Syndrome Serum calcium measurement every 4-6 mos until age 2 yrs Thyroid function test annually until age 3 yrs Medical eval Vision screening to monitor for refractive errors & strabismus (& cataracts in adults) Hearing eval Assessment of blood pressure in both arms Measurement of calcium-to-creatinine ratio in random spot urine & urinalysis Cardiology eval at least annually until age 5 yrs, every 2-3 yrs thereafter for life Serum concentration of calcium Thyroid function & TSH level Renal & bladder ultrasound Oral glucose tolerance test starting at age 20 yrs to evaluate for diabetes mellitus Eval for mitral valve prolapse, aortic insufficiency, hypertension, long QT interval, arterial stenoses TSH = thyroid-stimulating hormone Except as noted If normal, oral glucose tolerance test should be repeated every five years. Children with WS should not be given multivitamins because all pediatric multivitamin preparations contain vitamin D. See Pregnancies in women with WS are high risk. They should be monitored for the development of pregnancy-induced hypertension, arrhythmias, and heart failure. Regular urinalyses should be performed in late gestation due to the increased risk for urinary tract infection. Ultrasound monitoring of the fetus is suggested [ Search • Plotting of growth parameters on WS growth charts • Complete physical & neurologic exam • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Eval by cardiologist w/experience in WS • Measurement of blood pressure in all four limbs • Echocardiogram, incl doppler flow studies • Electrocardiogram • Ultrasound exam of bladder & kidneys • Serum concentration of BUN & creatinine • Urinalysis • Gross motor & fine motor skills • Contractures & kyphoscoliosis • Mobility, ADL • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Serum concentration of calcium or ionized calcium • Urine calcium-to-creatinine on spot urine sample • Community or • Social work involvement for parental support; • Home nursing referral. • Developmental disabilities should be addressed by early intervention programs, special education programs, & vocational training. • Recommended therapies include speech-language therapy, PT, & OT. • Consider hippotherapy (use of equine movement during speech-language therapy, PT, &/or OT). • Verbal strengths can be used to assist in learning spatial tasks. • Phonics methods are recommended to teach reading. • Mastery of ADL contributes to adult well-being & should be encouraged. • Treatment per psychologist &/or psychiatrist • Behavior in young children may be addressed using techniques based on applied behavior analysis. • Behavioral counseling & psychotropic medication are often used to manage behavior issues, esp ADHD & anxiety, which require pharmacologic treatment in ~50%. • Self-calming techniques can help manage anxiety. • Surgical correction of SVAS is performed in 30%. • Surgical treatment of mitral valve insufficiency or renal artery stenosis may be required. • Anesthesia consultation for surgical procedures • Electrocardiogram prior to surgery • Use of a center equipped for cardiopulmonary resuscitation • Guidelines for sedation & anesthesia risk assessment & anesthetic mgmt for WS have been published. • There is ↑ risk for myocardial insufficiency & cardiac arrest in persons w/biventricular outflow tract obstruction, esp during induction of anesthesia. • Hyperopia is treated w/corrective lenses. • Strabismus is treated w/patching of 1 eye or surgery. • Standard treatments for lacrimal duct abnormalities • Recurrent otitis media may be treated w/tympanotomy tubes. • Hypersensitivity to sounds may be treated w/ear protection when ↑ noise levels can be predicted. • Hearing aids may be helpful per otolaryngologist. • Dental care may require assistance w/daily brushing & flossing. • Dental cleaning frequency should be ↑ to every 4 mos in adolescents & adults. • Orthodontic referral for treatment of malocclusion. • Investigation of lower urinary tract (voiding cystourethrogram) in those w/febrile urinary tract infections to direct treatment • Mgmt of nephrocalcinosis, persistent hypercalcemia, &/or hypercalciuria per nephrologist • Range of motion exercises to prevent or ameliorate joint contractures • Orthopedics / physical medicine & rehab / PT & OT as needed for contractures & kyphoscoliosis • Avoid vitamin supplements w/vitamin D, esp in young children. • Assess hydration status & ↑ water intake as indicated. • Adjust diet w/nutritionist to maintain calcium intake no higher than 100% of RDI. • Parents should be counseled not to restrict dietary intake of calcium w/o medical supervision. • Refractory hypercalcemia may be treated w/oral steroids. • Referral to endocrinologist &/or nephrologist for treatment of persistent hypercalcemia, hypercalciuria, &/or nephrocalcinosis • If vitamin D deficiency is suspected, check vitamin D levels prior to initiating therapy, & monitor calcium levels during treatment. Absorption of calcium from the gut is ↑ in WS (cause unknown) & vitamin D promotes calcium absorption. • Intravenous pamidronate has been used successfully to treat infants w/severe symptomatic hypercalcemia. • Exercise & balanced diet • Mgmt per endocrinologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis). • Consider hippotherapy (use of equine movement during speech-language therapy, physical therapy, and/or occupational therapy). • Serum calcium measurement every 4-6 mos until age 2 yrs • Thyroid function test annually until age 3 yrs • Medical eval • Vision screening to monitor for refractive errors & strabismus (& cataracts in adults) • Hearing eval • Assessment of blood pressure in both arms • Measurement of calcium-to-creatinine ratio in random spot urine & urinalysis • Cardiology eval at least annually until age 5 yrs, every 2-3 yrs thereafter for life • Serum concentration of calcium • Thyroid function & TSH level • Renal & bladder ultrasound • Oral glucose tolerance test starting at age 20 yrs to evaluate for diabetes mellitus • Eval for mitral valve prolapse, aortic insufficiency, hypertension, long QT interval, arterial stenoses ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with WS, and to guide medical management, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Williams Syndrome Plotting of growth parameters on WS growth charts Complete physical & neurologic exam To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Eval by cardiologist w/experience in WS Measurement of blood pressure in all four limbs Echocardiogram, incl doppler flow studies Electrocardiogram Ultrasound exam of bladder & kidneys Serum concentration of BUN & creatinine Urinalysis Gross motor & fine motor skills Contractures & kyphoscoliosis Mobility, ADL Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Serum concentration of calcium or ionized calcium Urine calcium-to-creatinine on spot urine sample Community or Social work involvement for parental support; Home nursing referral. = activities of daily living; BUN = blood urea nitrogen; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; WS = Williams syndrome Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Plotting of growth parameters on WS growth charts • Complete physical & neurologic exam • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Eval by cardiologist w/experience in WS • Measurement of blood pressure in all four limbs • Echocardiogram, incl doppler flow studies • Electrocardiogram • Ultrasound exam of bladder & kidneys • Serum concentration of BUN & creatinine • Urinalysis • Gross motor & fine motor skills • Contractures & kyphoscoliosis • Mobility, ADL • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Serum concentration of calcium or ionized calcium • Urine calcium-to-creatinine on spot urine sample • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Williams Syndrome Developmental disabilities should be addressed by early intervention programs, special education programs, & vocational training. Recommended therapies include speech-language therapy, PT, & OT. Consider hippotherapy (use of equine movement during speech-language therapy, PT, &/or OT). Verbal strengths can be used to assist in learning spatial tasks. Phonics methods are recommended to teach reading. Mastery of ADL contributes to adult well-being & should be encouraged. Treatment per psychologist &/or psychiatrist Behavior in young children may be addressed using techniques based on applied behavior analysis. Behavioral counseling & psychotropic medication are often used to manage behavior issues, esp ADHD & anxiety, which require pharmacologic treatment in ~50%. Self-calming techniques can help manage anxiety. Surgical correction of SVAS is performed in 30%. Surgical treatment of mitral valve insufficiency or renal artery stenosis may be required. Anesthesia consultation for surgical procedures Electrocardiogram prior to surgery Use of a center equipped for cardiopulmonary resuscitation Guidelines for sedation & anesthesia risk assessment & anesthetic mgmt for WS have been published. There is ↑ risk for myocardial insufficiency & cardiac arrest in persons w/biventricular outflow tract obstruction, esp during induction of anesthesia. Hyperopia is treated w/corrective lenses. Strabismus is treated w/patching of 1 eye or surgery. Standard treatments for lacrimal duct abnormalities Recurrent otitis media may be treated w/tympanotomy tubes. Hypersensitivity to sounds may be treated w/ear protection when ↑ noise levels can be predicted. Hearing aids may be helpful per otolaryngologist. Dental care may require assistance w/daily brushing & flossing. Dental cleaning frequency should be ↑ to every 4 mos in adolescents & adults. Orthodontic referral for treatment of malocclusion. Investigation of lower urinary tract (voiding cystourethrogram) in those w/febrile urinary tract infections to direct treatment Mgmt of nephrocalcinosis, persistent hypercalcemia, &/or hypercalciuria per nephrologist Range of motion exercises to prevent or ameliorate joint contractures Orthopedics / physical medicine & rehab / PT & OT as needed for contractures & kyphoscoliosis Avoid vitamin supplements w/vitamin D, esp in young children. Assess hydration status & ↑ water intake as indicated. Adjust diet w/nutritionist to maintain calcium intake no higher than 100% of RDI. Parents should be counseled not to restrict dietary intake of calcium w/o medical supervision. Refractory hypercalcemia may be treated w/oral steroids. Referral to endocrinologist &/or nephrologist for treatment of persistent hypercalcemia, hypercalciuria, &/or nephrocalcinosis If vitamin D deficiency is suspected, check vitamin D levels prior to initiating therapy, & monitor calcium levels during treatment. Absorption of calcium from the gut is ↑ in WS (cause unknown) & vitamin D promotes calcium absorption. Intravenous pamidronate has been used successfully to treat infants w/severe symptomatic hypercalcemia. Exercise & balanced diet Mgmt per endocrinologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; OT = occupational therapy; PT = physical therapy; RDI = recommended daily intake; SVAS = supravalvar aortic stenosis See For discussion of antihypertensive therapy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis). Consider hippotherapy (use of equine movement during speech-language therapy, physical therapy, and/or occupational therapy). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder or anxiety. • Developmental disabilities should be addressed by early intervention programs, special education programs, & vocational training. • Recommended therapies include speech-language therapy, PT, & OT. • Consider hippotherapy (use of equine movement during speech-language therapy, PT, &/or OT). • Verbal strengths can be used to assist in learning spatial tasks. • Phonics methods are recommended to teach reading. • Mastery of ADL contributes to adult well-being & should be encouraged. • Treatment per psychologist &/or psychiatrist • Behavior in young children may be addressed using techniques based on applied behavior analysis. • Behavioral counseling & psychotropic medication are often used to manage behavior issues, esp ADHD & anxiety, which require pharmacologic treatment in ~50%. • Self-calming techniques can help manage anxiety. • Surgical correction of SVAS is performed in 30%. • Surgical treatment of mitral valve insufficiency or renal artery stenosis may be required. • Anesthesia consultation for surgical procedures • Electrocardiogram prior to surgery • Use of a center equipped for cardiopulmonary resuscitation • Guidelines for sedation & anesthesia risk assessment & anesthetic mgmt for WS have been published. • There is ↑ risk for myocardial insufficiency & cardiac arrest in persons w/biventricular outflow tract obstruction, esp during induction of anesthesia. • Hyperopia is treated w/corrective lenses. • Strabismus is treated w/patching of 1 eye or surgery. • Standard treatments for lacrimal duct abnormalities • Recurrent otitis media may be treated w/tympanotomy tubes. • Hypersensitivity to sounds may be treated w/ear protection when ↑ noise levels can be predicted. • Hearing aids may be helpful per otolaryngologist. • Dental care may require assistance w/daily brushing & flossing. • Dental cleaning frequency should be ↑ to every 4 mos in adolescents & adults. • Orthodontic referral for treatment of malocclusion. • Investigation of lower urinary tract (voiding cystourethrogram) in those w/febrile urinary tract infections to direct treatment • Mgmt of nephrocalcinosis, persistent hypercalcemia, &/or hypercalciuria per nephrologist • Range of motion exercises to prevent or ameliorate joint contractures • Orthopedics / physical medicine & rehab / PT & OT as needed for contractures & kyphoscoliosis • Avoid vitamin supplements w/vitamin D, esp in young children. • Assess hydration status & ↑ water intake as indicated. • Adjust diet w/nutritionist to maintain calcium intake no higher than 100% of RDI. • Parents should be counseled not to restrict dietary intake of calcium w/o medical supervision. • Refractory hypercalcemia may be treated w/oral steroids. • Referral to endocrinologist &/or nephrologist for treatment of persistent hypercalcemia, hypercalciuria, &/or nephrocalcinosis • If vitamin D deficiency is suspected, check vitamin D levels prior to initiating therapy, & monitor calcium levels during treatment. Absorption of calcium from the gut is ↑ in WS (cause unknown) & vitamin D promotes calcium absorption. • Intravenous pamidronate has been used successfully to treat infants w/severe symptomatic hypercalcemia. • Exercise & balanced diet • Mgmt per endocrinologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis). • Consider hippotherapy (use of equine movement during speech-language therapy, physical therapy, and/or occupational therapy). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis). Consider hippotherapy (use of equine movement during speech-language therapy, physical therapy, and/or occupational therapy). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis). • Consider hippotherapy (use of equine movement during speech-language therapy, physical therapy, and/or occupational therapy). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder or anxiety. ## Surveillance Surveillance for Williams Syndrome Serum calcium measurement every 4-6 mos until age 2 yrs Thyroid function test annually until age 3 yrs Medical eval Vision screening to monitor for refractive errors & strabismus (& cataracts in adults) Hearing eval Assessment of blood pressure in both arms Measurement of calcium-to-creatinine ratio in random spot urine & urinalysis Cardiology eval at least annually until age 5 yrs, every 2-3 yrs thereafter for life Serum concentration of calcium Thyroid function & TSH level Renal & bladder ultrasound Oral glucose tolerance test starting at age 20 yrs to evaluate for diabetes mellitus Eval for mitral valve prolapse, aortic insufficiency, hypertension, long QT interval, arterial stenoses TSH = thyroid-stimulating hormone Except as noted If normal, oral glucose tolerance test should be repeated every five years. • Serum calcium measurement every 4-6 mos until age 2 yrs • Thyroid function test annually until age 3 yrs • Medical eval • Vision screening to monitor for refractive errors & strabismus (& cataracts in adults) • Hearing eval • Assessment of blood pressure in both arms • Measurement of calcium-to-creatinine ratio in random spot urine & urinalysis • Cardiology eval at least annually until age 5 yrs, every 2-3 yrs thereafter for life • Serum concentration of calcium • Thyroid function & TSH level • Renal & bladder ultrasound • Oral glucose tolerance test starting at age 20 yrs to evaluate for diabetes mellitus • Eval for mitral valve prolapse, aortic insufficiency, hypertension, long QT interval, arterial stenoses ## Agents/Circumstances to Avoid Children with WS should not be given multivitamins because all pediatric multivitamin preparations contain vitamin D. ## Evaluation of Relatives at Risk See ## Pregnancy Management Pregnancies in women with WS are high risk. They should be monitored for the development of pregnancy-induced hypertension, arrhythmias, and heart failure. Regular urinalyses should be performed in late gestation due to the increased risk for urinary tract infection. Ultrasound monitoring of the fetus is suggested [ ## Therapies Under Investigation Search ## Genetic Counseling Williams syndrome (WS) is an autosomal dominant disorder typically caused by a Most individuals diagnosed with WS have the disorder as the result of a Rarely, an individual with WS has an affected parent [ Studies have shown that, in approximately 25% of families, the unaffected parent in whom the deletion originated has an inversion on chromosome 7 involving 7q11.23 [ Recommendations for the parents of a proband with WS include obtaining a medical history to determine if signs or symptoms of WS are present. In the absence of clinical findings of WS in the parents, testing of the parents for the 7q11.23 deletion identified in the proband is not warranted. If one of the parents has the 7q11.23 deletion identified in the proband, the risk to each sib of inheriting the deletion and being affected is 50%. It is not possible to reliably predict the phenotype in a sib who inherits a 7q11.23 deletion because manifestations of WS may vary in affected family members. There have been two reports of sib recurrence: in one family, the deletions occurred on the paternal chromosome that had an inversion involving 7q11.23; in the other, the deletions were likely the result of maternal germline mosaicism because no inversion involving 7q11.23 was found [ When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%) because few familial cases have been reported. However, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism or an inversion polymorphism in a parent. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with WS. Once the WS-causing 1.5- to 1.8-Mb 7q11.23 deletion has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Prenatal test results cannot reliably predict phenotype. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with WS have the disorder as the result of a • Rarely, an individual with WS has an affected parent [ • Studies have shown that, in approximately 25% of families, the unaffected parent in whom the deletion originated has an inversion on chromosome 7 involving 7q11.23 [ • Recommendations for the parents of a proband with WS include obtaining a medical history to determine if signs or symptoms of WS are present. In the absence of clinical findings of WS in the parents, testing of the parents for the 7q11.23 deletion identified in the proband is not warranted. • If one of the parents has the 7q11.23 deletion identified in the proband, the risk to each sib of inheriting the deletion and being affected is 50%. It is not possible to reliably predict the phenotype in a sib who inherits a 7q11.23 deletion because manifestations of WS may vary in affected family members. • There have been two reports of sib recurrence: in one family, the deletions occurred on the paternal chromosome that had an inversion involving 7q11.23; in the other, the deletions were likely the result of maternal germline mosaicism because no inversion involving 7q11.23 was found [ • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%) because few familial cases have been reported. However, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism or an inversion polymorphism in a parent. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with WS. ## Mode of Inheritance Williams syndrome (WS) is an autosomal dominant disorder typically caused by a ## Risk to Family Members Most individuals diagnosed with WS have the disorder as the result of a Rarely, an individual with WS has an affected parent [ Studies have shown that, in approximately 25% of families, the unaffected parent in whom the deletion originated has an inversion on chromosome 7 involving 7q11.23 [ Recommendations for the parents of a proband with WS include obtaining a medical history to determine if signs or symptoms of WS are present. In the absence of clinical findings of WS in the parents, testing of the parents for the 7q11.23 deletion identified in the proband is not warranted. If one of the parents has the 7q11.23 deletion identified in the proband, the risk to each sib of inheriting the deletion and being affected is 50%. It is not possible to reliably predict the phenotype in a sib who inherits a 7q11.23 deletion because manifestations of WS may vary in affected family members. There have been two reports of sib recurrence: in one family, the deletions occurred on the paternal chromosome that had an inversion involving 7q11.23; in the other, the deletions were likely the result of maternal germline mosaicism because no inversion involving 7q11.23 was found [ When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%) because few familial cases have been reported. However, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism or an inversion polymorphism in a parent. • Most individuals diagnosed with WS have the disorder as the result of a • Rarely, an individual with WS has an affected parent [ • Studies have shown that, in approximately 25% of families, the unaffected parent in whom the deletion originated has an inversion on chromosome 7 involving 7q11.23 [ • Recommendations for the parents of a proband with WS include obtaining a medical history to determine if signs or symptoms of WS are present. In the absence of clinical findings of WS in the parents, testing of the parents for the 7q11.23 deletion identified in the proband is not warranted. • If one of the parents has the 7q11.23 deletion identified in the proband, the risk to each sib of inheriting the deletion and being affected is 50%. It is not possible to reliably predict the phenotype in a sib who inherits a 7q11.23 deletion because manifestations of WS may vary in affected family members. • There have been two reports of sib recurrence: in one family, the deletions occurred on the paternal chromosome that had an inversion involving 7q11.23; in the other, the deletions were likely the result of maternal germline mosaicism because no inversion involving 7q11.23 was found [ • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%) because few familial cases have been reported. However, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism or an inversion polymorphism in a parent. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with WS. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with WS. ## Prenatal Testing and Preimplantation Genetic Testing Once the WS-causing 1.5- to 1.8-Mb 7q11.23 deletion has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Prenatal test results cannot reliably predict phenotype. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada United Kingdom • • Canada • • • • • • • • • United Kingdom • • • ## Molecular Genetics Williams Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Williams Syndrome ( Both the 7q11.23 deletion that causes Williams syndrome (WS) and the reciprocal Three genes that encode transcription factors, The following genes may be involved in the WS phenotype, but to date the contribution of each these genes has not been confirmed. For the remaining genes in the 7q11.23 deletion, the relationship to the WS phenotype is unknown. ## Molecular Pathogenesis Both the 7q11.23 deletion that causes Williams syndrome (WS) and the reciprocal Three genes that encode transcription factors, The following genes may be involved in the WS phenotype, but to date the contribution of each these genes has not been confirmed. For the remaining genes in the 7q11.23 deletion, the relationship to the WS phenotype is unknown. ## Chapter Notes The author's research was supported by grant NS35102 from the National Institute of Neurological Disorders and Stroke, the Williams Syndrome Association, and the Las Vegas Pediatric Research Fund of the University of Nevada. The research has advanced thanks to the work of multiple talented scientist-collaborators over the past 30 years. Current co-investigators include Dr Carolyn B Mervis of the University of Louisville, Department of Psychology, and Dr Lucy Osborne of the University of Toronto, Department of Molecular Genetics. Thanks must also be given to the individuals who have participated in Williams syndrome research for their commitment to the research as well as giving generously of their time. 13 April 2023 (sw) Comprehensive update posted live 23 March 2017 (ha) Comprehensive update posted live 13 June 2013 (me) Comprehensive update posted live 21 April 2006 (me) Comprehensive update posted live 22 August 2003 (me) Comprehensive update posted live 9 April 1999 (me) Review posted live 7 January 1999 (cm) Original submission • 13 April 2023 (sw) Comprehensive update posted live • 23 March 2017 (ha) Comprehensive update posted live • 13 June 2013 (me) Comprehensive update posted live • 21 April 2006 (me) Comprehensive update posted live • 22 August 2003 (me) Comprehensive update posted live • 9 April 1999 (me) Review posted live • 7 January 1999 (cm) Original submission ## Acknowledgments The author's research was supported by grant NS35102 from the National Institute of Neurological Disorders and Stroke, the Williams Syndrome Association, and the Las Vegas Pediatric Research Fund of the University of Nevada. The research has advanced thanks to the work of multiple talented scientist-collaborators over the past 30 years. Current co-investigators include Dr Carolyn B Mervis of the University of Louisville, Department of Psychology, and Dr Lucy Osborne of the University of Toronto, Department of Molecular Genetics. Thanks must also be given to the individuals who have participated in Williams syndrome research for their commitment to the research as well as giving generously of their time. ## Revision History 13 April 2023 (sw) Comprehensive update posted live 23 March 2017 (ha) Comprehensive update posted live 13 June 2013 (me) Comprehensive update posted live 21 April 2006 (me) Comprehensive update posted live 22 August 2003 (me) Comprehensive update posted live 9 April 1999 (me) Review posted live 7 January 1999 (cm) Original submission • 13 April 2023 (sw) Comprehensive update posted live • 23 March 2017 (ha) Comprehensive update posted live • 13 June 2013 (me) Comprehensive update posted live • 21 April 2006 (me) Comprehensive update posted live • 22 August 2003 (me) Comprehensive update posted live • 9 April 1999 (me) Review posted live • 7 January 1999 (cm) Original submission ## References Morris CA, Braddock SR, et al. Health care supervision for children with Williams syndrome. Pediatrics. 2020;145:e20193761. Available • Morris CA, Braddock SR, et al. Health care supervision for children with Williams syndrome. Pediatrics. 2020;145:e20193761. Available ## Published Guidelines / Consensus Statements Morris CA, Braddock SR, et al. Health care supervision for children with Williams syndrome. Pediatrics. 2020;145:e20193761. Available • Morris CA, Braddock SR, et al. Health care supervision for children with Williams syndrome. Pediatrics. 2020;145:e20193761. Available ## Literature Cited Note the stellate iris pattern in an individual with Williams syndrome A broad forehead, bitemporal narrowing, periorbital fullness, strabismus, short nose, broad nasal tip, malar flattening, long philtrum, thick vermilion of the upper and lower lips, wide mouth, malocclusion, small jaw, and large earlobes are observed at all ages and in all ethnic groups. The ages of the children shown here are as follows: A and B. 3 years C. 4 years D. 7 years E. 8 years F, G, and H. 12 years I and J. 16 years Young children with Williams syndrome typically have epicanthal folds, full cheeks, and small, widely spaced teeth, as seen in these children at the following ages: A. Newborn B. 10 months C and D. 21 months Adults typically have a long face and neck, accentuated by sloping shoulders, resulting in a gaunt appearance, as seen in this affected individual, age 43 years.	[]	9/4/1999	13/4/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
wilms-ov	wilms-ov	[ "Breast cancer type 2 susceptibility protein", "Cellular tumor antigen p53", "DIS3-like exonuclease 2", "Endoribonuclease Dicer", "Glypican-3", "Glypican-4", "Histone-lysine N-methyltransferase, H3 lysine-36 specific", "Parafibromin", "RE1-silencing transcription factor", "RecQ-like DNA helicase BLM", "Transcription intermediary factor 1-beta", "Wilms tumor protein", "BLM", "BRCA2", "CDC73", "DICER1", "DIS3L2", "GPC3", "GPC4", "NSD1", "REST", "TP53", "TRIM28", "WT1", "Wilms Tumor Predisposition", "Overview" ]	Wilms Tumor Predisposition	Joyce T Turner, Jack Brzezinski, Jeffrey S Dome	Summary The purpose of this Briefly describe the Review the Provide an Review Review	## Clinical Characteristics of Wilms Tumor Wilms tumor (nephroblastoma), an embryonal malignancy of the kidney, is the most common renal tumor of childhood [ Approximately 5%-10% of individuals with Wilms tumor have bilateral or multicentric tumors. The prevalence of bilateral involvement is higher in individuals with a predisposition to Wilms tumor than in those without a genetic predisposition (see A definitive diagnosis of Wilms tumor can be made only on histologic assessment of the tumor. There are two main histologic subtypes: favorable and anaplastic. Tumors with anaplastic histology usually have somatic mutation of Nephrogenic rests, benign foci of embryonal kidney cells that persist abnormally into postnatal life, are considered to be Wilms tumor precursors. Pathogenic variants may predispose to nephrogenic rests. Additional pathogenic variants transform nephrogenic rests into a Wilms tumor [ Treatment includes surgery, chemotherapy, and radiation therapy for individuals with incomplete resection or metastatic disease. Outcomes are generally outstanding with survival estimates of approximately 90%. Anaplastic histology, bilateral disease, distant metastasis, and recurrent disease are associated with less favorable outcome [ ## Mechanisms of Predisposition to Wilms Tumor In 10%-15% of individuals with Wilms tumor, the cause is considered to be a germline pathogenic variant or an epigenetic alteration occurring early during embryogenesis [ Bilateral Wilms tumor Unilateral multicentric Wilms tumor Early onset Wilms tumor (age <2 years) Multiple nephrogenic rests (both unilateral and bilateral) Clinical features of Wilms tumor predisposition syndromes (See More Common Genes, Loci, and Syndromes Associated with Wilms Tumor Predisposition Highest risk: truncating variants 70%-80%: exon 8/9 missense variants <2%: intron 9 variants Other variants have intermediate risk. AD = autosomal dominant; ESKD = end-stage kidney disease; GU = genitourinary; ID = intellectual disability; MOI = mode of inheritance Germline In the absence of genitourinary anomalies, renal mesangial sclerosis, nephrogenic rests, or bilateral tumors, the likelihood that a child with Wilms tumor has a germline Isolated Wilms tumor has been associated with constitutional alterations of chromosome 11p15 most commonly hypermethylation at IC1 and paternal uniparental disomy of 11p15. Loss of methylation at IC2 and genomic abnormalities of 11p15 may be associated with Wilms tumor but reports are rare and the evidence is still emerging. Molecular alterations at 11p15 including loss of methylation at IC2, gain of methylation at IC1, and 11p15 paternal uniparental disomy have been reported in individuals who have apparently isolated hemihyperplasia (see 85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission. Less Common Genes and Syndromes Associated with Wilms Tumor Predisposition AD = autosomal dominant; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AR = autosomal recessive; DD = developmental delay; FSGS = Focal segmental glomerular sclerosis; GI = gastrointestinal; GLOW = One large family with multiple individuals with Somatic mosaic pathogenic variants affecting the RNase IIIb domain have been identified in several individuals with GLOW syndrome [ Wilms tumor has been reported in individuals with Trisomy 13 and trisomy 18 (both characterized by multiple congenital anomalies and intellectual disability) are associated with an estimated <1% risk of Wilms tumor. A non-recurrent deletion at chromosome 9q22.3 encompassing a 352-kb critical region including One individual with Wilms tumor and a germline pathogenic variant of • Bilateral Wilms tumor • Unilateral multicentric Wilms tumor • Early onset Wilms tumor (age <2 years) • Multiple nephrogenic rests (both unilateral and bilateral) • Clinical features of Wilms tumor predisposition syndromes (See • Highest risk: truncating variants • 70%-80%: exon 8/9 missense variants • <2%: intron 9 variants • Other variants have intermediate risk. ## Suggestive Features of a Predisposition to Wilms Tumor Bilateral Wilms tumor Unilateral multicentric Wilms tumor Early onset Wilms tumor (age <2 years) Multiple nephrogenic rests (both unilateral and bilateral) Clinical features of Wilms tumor predisposition syndromes (See • Bilateral Wilms tumor • Unilateral multicentric Wilms tumor • Early onset Wilms tumor (age <2 years) • Multiple nephrogenic rests (both unilateral and bilateral) • Clinical features of Wilms tumor predisposition syndromes (See ## Common Genes, Loci, and Syndromes Associated with Wilms Tumor Predisposition More Common Genes, Loci, and Syndromes Associated with Wilms Tumor Predisposition Highest risk: truncating variants 70%-80%: exon 8/9 missense variants <2%: intron 9 variants Other variants have intermediate risk. AD = autosomal dominant; ESKD = end-stage kidney disease; GU = genitourinary; ID = intellectual disability; MOI = mode of inheritance Germline In the absence of genitourinary anomalies, renal mesangial sclerosis, nephrogenic rests, or bilateral tumors, the likelihood that a child with Wilms tumor has a germline Isolated Wilms tumor has been associated with constitutional alterations of chromosome 11p15 most commonly hypermethylation at IC1 and paternal uniparental disomy of 11p15. Loss of methylation at IC2 and genomic abnormalities of 11p15 may be associated with Wilms tumor but reports are rare and the evidence is still emerging. Molecular alterations at 11p15 including loss of methylation at IC2, gain of methylation at IC1, and 11p15 paternal uniparental disomy have been reported in individuals who have apparently isolated hemihyperplasia (see 85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission. Less Common Genes and Syndromes Associated with Wilms Tumor Predisposition AD = autosomal dominant; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AR = autosomal recessive; DD = developmental delay; FSGS = Focal segmental glomerular sclerosis; GI = gastrointestinal; GLOW = One large family with multiple individuals with Somatic mosaic pathogenic variants affecting the RNase IIIb domain have been identified in several individuals with GLOW syndrome [ Wilms tumor has been reported in individuals with • Highest risk: truncating variants • 70%-80%: exon 8/9 missense variants • <2%: intron 9 variants • Other variants have intermediate risk. ## Other Syndromes That May Be Associated with Wilms Tumor Trisomy 13 and trisomy 18 (both characterized by multiple congenital anomalies and intellectual disability) are associated with an estimated <1% risk of Wilms tumor. A non-recurrent deletion at chromosome 9q22.3 encompassing a 352-kb critical region including One individual with Wilms tumor and a germline pathogenic variant of ## Evaluation Strategy to Identify the Genetic Cause of Wilms Tumor in a Proband Can aid in discussions regarding risks for additional medical complications; Can aid in discussion regarding appropriate cancer surveillance; Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, family history, and molecular genetic testing. Histologic features can suggest a specific genetic cause including fetal rhabdomyomatous nephroblastoma or stromal ( Molecular genetic testing approaches can include a combination of a The risk for genetic predisposition is low in those with unilateral unifocal Wilms tumor and no apparent risk factors, although germline variants have been identified in some individuals. Parents and/or affected individuals should be counseled regarding the small chance of the presence of an underlying genetic predisposition for Wilms tumor and given the option of further evaluation. Note: Some centers recommend molecular testing for all individuals with Wilms tumor. • Can aid in discussions regarding risks for additional medical complications; • Can aid in discussion regarding appropriate cancer surveillance; • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, family history, and molecular genetic testing. ## Individuals with Wilms Tumor and Additional Clinical Features and/or Family History of Other Cancers ## Individuals with Isolated Bilateral and/or Multifocal, Early-Onset (age <2 years), and/or Familial Wilms Tumor ## Individuals with Unilateral Wilms Tumor without Features Suggestive of Genetic Predisposition The risk for genetic predisposition is low in those with unilateral unifocal Wilms tumor and no apparent risk factors, although germline variants have been identified in some individuals. Parents and/or affected individuals should be counseled regarding the small chance of the presence of an underlying genetic predisposition for Wilms tumor and given the option of further evaluation. Note: Some centers recommend molecular testing for all individuals with Wilms tumor. ## Management Most guidelines recommend continuing surveillance until the age at which 90%-95% of Wilms tumors will have occurred. One method to determine how long to continue Wilms tumor surveillance in an individual with a specific syndrome is to calculate the residual risk of Wilms tumor using the overall and age-related risk of Wilms tumor. For example, in WAGR syndrome, the overall Wilms tumor risk is ~50%, 90% of tumors occur by age four years, and 98% of tumors occur by age seven years, the residual Wilms tumor risk for an individual age four years is 5% (0.5 x 0.1) and for an individual by age seven years is 1% (0.5 x 0.02). Therefore, surveillance would continue until age five to eight years depending on the risk tolerance of the provider, affected individual, and family. For In families with more than one individual with Wilms tumor and families with one individual with Evaluations may include molecular genetic testing if the causative genetic alteration has been identified in an affected family member. Surveillance with ultrasound may be pursued if the Wilms tumor risk associated with the causative variant is sufficiently high. If the causative genetic alteration has not been identified in an affected family member: Offspring of the affected individual should be screened with abdominal ultrasound examination every three months until age eight years. Note: The risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown. Some bilateral Wilms tumors arise from somatic or epigenetic alterations that occur early during embryogenesis before lateralization and affect both kidneys, but are not present in the germline. Such variants are not heritable [ The benefit of surveillance of sibs of the affected individual is unclear. A National Wilms Tumor Study on familial Wilms tumor showed that 15 of 456 individuals (3.3%) with bilateral Wilms tumor had a family member with Wilms tumor and six of those individuals clustered within three families [ • Offspring of the affected individual should be screened with abdominal ultrasound examination every three months until age eight years. Note: The risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown. Some bilateral Wilms tumors arise from somatic or epigenetic alterations that occur early during embryogenesis before lateralization and affect both kidneys, but are not present in the germline. Such variants are not heritable [ • The benefit of surveillance of sibs of the affected individual is unclear. A National Wilms Tumor Study on familial Wilms tumor showed that 15 of 456 individuals (3.3%) with bilateral Wilms tumor had a family member with Wilms tumor and six of those individuals clustered within three families [ ## Surveillance of Children with a Germline Pathogenic Variant or with Wilms Tumor-Associated Syndromes Most guidelines recommend continuing surveillance until the age at which 90%-95% of Wilms tumors will have occurred. One method to determine how long to continue Wilms tumor surveillance in an individual with a specific syndrome is to calculate the residual risk of Wilms tumor using the overall and age-related risk of Wilms tumor. For example, in WAGR syndrome, the overall Wilms tumor risk is ~50%, 90% of tumors occur by age four years, and 98% of tumors occur by age seven years, the residual Wilms tumor risk for an individual age four years is 5% (0.5 x 0.1) and for an individual by age seven years is 1% (0.5 x 0.02). Therefore, surveillance would continue until age five to eight years depending on the risk tolerance of the provider, affected individual, and family. For ## Surveillance for Relatives at Risk for Wilms Tumor Predisposition In families with more than one individual with Wilms tumor and families with one individual with Evaluations may include molecular genetic testing if the causative genetic alteration has been identified in an affected family member. Surveillance with ultrasound may be pursued if the Wilms tumor risk associated with the causative variant is sufficiently high. If the causative genetic alteration has not been identified in an affected family member: Offspring of the affected individual should be screened with abdominal ultrasound examination every three months until age eight years. Note: The risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown. Some bilateral Wilms tumors arise from somatic or epigenetic alterations that occur early during embryogenesis before lateralization and affect both kidneys, but are not present in the germline. Such variants are not heritable [ The benefit of surveillance of sibs of the affected individual is unclear. A National Wilms Tumor Study on familial Wilms tumor showed that 15 of 456 individuals (3.3%) with bilateral Wilms tumor had a family member with Wilms tumor and six of those individuals clustered within three families [ • Offspring of the affected individual should be screened with abdominal ultrasound examination every three months until age eight years. Note: The risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown. Some bilateral Wilms tumors arise from somatic or epigenetic alterations that occur early during embryogenesis before lateralization and affect both kidneys, but are not present in the germline. Such variants are not heritable [ • The benefit of surveillance of sibs of the affected individual is unclear. A National Wilms Tumor Study on familial Wilms tumor showed that 15 of 456 individuals (3.3%) with bilateral Wilms tumor had a family member with Wilms tumor and six of those individuals clustered within three families [ ## Genetic Counseling If an individual has a specific disorder associated with Wilms tumor (e.g., Recent studies have shown that some bilateral Wilms tumors arise from somatic genetic or epigenetic alterations that occur early during nephrogenesis before lateralization, affecting both kidneys but not the entire germline. Predisposition caused by somatic genetic or epigenetic alterations is not heritable if the underlying pathogenic variant is isolated to the kidney tissue and not present in germ cells [ Features suggestive of a predisposition to Wilms tumor (e.g., bilateral or multifocal Wilms tumor and/or a family history of Wilms tumor) the empiric risk to offspring is estimated to be higher than the population risk and ultrasound surveillance is recommended for their offspring. The benefit of surveillance of sibs of the proband is unclear; the chance of detecting Wilms tumor in a sib of a proband with bilateral Wilms tumor in the absence of known familial disease is less than 1%. (See Unilateral, unifocal Wilms tumor without features suggestive of genetic predisposition (i.e., no physical, radiologic, histologic, or family history features suggestive of a genetic predisposition following a detailed, targeted evaluation), the risk to sibs of the proband and offspring of the proband is less than 1%. No Wilms tumor was observed in the 179 offspring of 96 long-term survivors who had been diagnosed with unilateral, nonfamilial Wilms tumor [ See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a Wilms tumor-related genetic alteration. Once a Wilms tumor-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Features suggestive of a predisposition to Wilms tumor (e.g., bilateral or multifocal Wilms tumor and/or a family history of Wilms tumor) the empiric risk to offspring is estimated to be higher than the population risk and ultrasound surveillance is recommended for their offspring. The benefit of surveillance of sibs of the proband is unclear; the chance of detecting Wilms tumor in a sib of a proband with bilateral Wilms tumor in the absence of known familial disease is less than 1%. (See • Unilateral, unifocal Wilms tumor without features suggestive of genetic predisposition (i.e., no physical, radiologic, histologic, or family history features suggestive of a genetic predisposition following a detailed, targeted evaluation), the risk to sibs of the proband and offspring of the proband is less than 1%. No Wilms tumor was observed in the 179 offspring of 96 long-term survivors who had been diagnosed with unilateral, nonfamilial Wilms tumor [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a Wilms tumor-related genetic alteration. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a Wilms tumor-related genetic alteration. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a Wilms tumor-related genetic alteration. ## Prenatal Testing and Preimplantation Genetic Testing Once a Wilms tumor-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Chapter Notes Jack Brzezinski, MD, PhD (2022-present)Jeffrey S Dome, MD, PhD (2003-present)Vicki Huff, PhD; University of Texas MD Anderson Cancer Center (2003-2022)Joyce T Turner, MS (2022-present) 24 March 2022 (sw) Comprehensive update posted live 20 October 2016 (sw) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 14 June 2011 (me) Comprehensive update posted live 10 April 2006 (me) Comprehensive update posted live 19 December 2003 (me) Overview posted live 14 July 2003 (jsd) Original submission • 24 March 2022 (sw) Comprehensive update posted live • 20 October 2016 (sw) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 14 June 2011 (me) Comprehensive update posted live • 10 April 2006 (me) Comprehensive update posted live • 19 December 2003 (me) Overview posted live • 14 July 2003 (jsd) Original submission ## Author History Jack Brzezinski, MD, PhD (2022-present)Jeffrey S Dome, MD, PhD (2003-present)Vicki Huff, PhD; University of Texas MD Anderson Cancer Center (2003-2022)Joyce T Turner, MS (2022-present) ## Revision History 24 March 2022 (sw) Comprehensive update posted live 20 October 2016 (sw) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 14 June 2011 (me) Comprehensive update posted live 10 April 2006 (me) Comprehensive update posted live 19 December 2003 (me) Overview posted live 14 July 2003 (jsd) Original submission • 24 March 2022 (sw) Comprehensive update posted live • 20 October 2016 (sw) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 14 June 2011 (me) Comprehensive update posted live • 10 April 2006 (me) Comprehensive update posted live • 19 December 2003 (me) Overview posted live • 14 July 2003 (jsd) Original submission ## References ## Literature Cited	[]	19/12/2003	24/3/2022	24/5/2004	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
wilson	wilson	[ "Hepatolenticular Degeneration", "Hepatolenticular Degeneration", "Copper-transporting ATPase 2", "ATP7B", "Wilson Disease" ]	Wilson Disease	Karl Heinz Weiss, Michael Schilsky	Summary Wilson disease is a disorder of copper metabolism that, when untreated, can present with hepatic, neurologic, or psychiatric disturbances – or a combination of these – in individuals ages three years to older than 70 years. Manifestations in untreated individuals vary among and within families. Liver disease can include recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease. Neurologic presentations can include dysarthria, movement disorders (tremors, involuntary movements, chorea, choreoathetosis), dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement), dysautonomia, seizures, sleep disorders, or insomnia. Psychiatric disturbances can include depression, bipolar disorder / bipolar spectrum disorder, neurotic behaviors, personality changes, or psychosis. Other multisystem involvement can include the eye (Kayser-Fleischer rings), hemolytic anemia, the kidneys, the endocrine glands, and the heart. The diagnosis of Wilson disease is established in most instances by a combination of biochemical findings (low serum ceruloplasmin concentration, low serum concentration of total copper, and increased urinary copper excretion) and/or detection of biallelic pathogenic (or likely pathogenic) variants in The goals of supportive treatment for extrahepatic manifestations of individuals with symptomatic Wilson disease are individualized to maximize function and reduce complications. Depending on their clinical manifestations, symptomatic individuals may require specialists in neurology, occupational therapy, physical therapy, physiatry, orthopedics, nutrition, speech-language pathology, social work, and psychology/psychiatry. At least twice annually: assessment of serum copper and ceruloplasmin levels, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment At least once annually: measurement of 24-hour urinary excretion of copper Monitoring the individual's response to supportive treatment for extrahepatic manifestations and the emergence of new manifestations is per the recommendations of the treating clinical specialists. In case of biochemical abnormalities in liver function tests or transaminases, alcohol consumption is strongly discouraged. Wilson disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis The diagnostic algorithm for Wilson disease in the European Association for Study of Liver (EASL) Clinical Practice Guidelines [ Wilson disease Note: Specific instances when Wilson disease should be considered is ALF with nonimmune hemolytic anemia or autoimmune hepatitis. Dysarthria Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) Dysautonomia Seizures Sleep disorders / insomnia Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see Self-limited hemolytic anemia, with or without acute liver failure Kidney abnormalities: aminoaciduria and nephrolithiasis Hypoparathyroidism, pancreatitis Cardiomyopathy, arrhythmias Premature osteoporosis and arthritis Infertility, recurrent miscarriages Modalities such as magnetic resonance imaging (MRI) are of limited value in determining the extent of clinical neurologic disease but may help initially in supporting a diagnosis of Wilson disease and excluding other neurologic disorders. Brain MRI findings consistent with Wilson disease include signal changes in the basal ganglia, thalami, pons, and white matter, as well as atrophy. Although the "face of the giant panda" sign (see Suggestive biochemical findings in a symptomatic individual relies on a combination of the following findings: Low serum ceruloplasmin concentration Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ Note: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration (100-250 µg/g dry weight), which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease. Family history is consistent with autosomal recessive inheritance. The family history may include affected sibs (e.g., sibs with liver disease, neurologic manifestations, and/or psychiatric disturbance) and/or parental consanguinity. Absence of a known family history does not preclude the diagnosis. The diagnosis of Wilson disease, using clinical, biochemical, and molecular genetic findings, is based on the diagnostic scoring system developed at the 8th International Meeting on Wilson Disease, Leipzig 2001 [ Diagnostic Scoring System for Wilson disease Adapted with permission from ULN = upper limit of normal Or typical abnormalities on brain MRI If no quantitative liver copper available Per the diagnostic scoring system (see Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis can be performed first in individuals from populations with known founder variants (e.g., Ashkenazi Jewish, Canary Islands, Druze, Sardinia; see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Wilson Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions and duplications, encompassing one or more exons, are rare. Exon and multiexon deletions have been reported (see, e.g., • Note: Specific instances when Wilson disease should be considered is ALF with nonimmune hemolytic anemia or autoimmune hepatitis. • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Low serum ceruloplasmin concentration • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ • Note: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration (100-250 µg/g dry weight), which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease. • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ ## Suggestive Findings Wilson disease Note: Specific instances when Wilson disease should be considered is ALF with nonimmune hemolytic anemia or autoimmune hepatitis. Dysarthria Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) Dysautonomia Seizures Sleep disorders / insomnia Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see Self-limited hemolytic anemia, with or without acute liver failure Kidney abnormalities: aminoaciduria and nephrolithiasis Hypoparathyroidism, pancreatitis Cardiomyopathy, arrhythmias Premature osteoporosis and arthritis Infertility, recurrent miscarriages Modalities such as magnetic resonance imaging (MRI) are of limited value in determining the extent of clinical neurologic disease but may help initially in supporting a diagnosis of Wilson disease and excluding other neurologic disorders. Brain MRI findings consistent with Wilson disease include signal changes in the basal ganglia, thalami, pons, and white matter, as well as atrophy. Although the "face of the giant panda" sign (see Suggestive biochemical findings in a symptomatic individual relies on a combination of the following findings: Low serum ceruloplasmin concentration Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ Note: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration (100-250 µg/g dry weight), which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease. Family history is consistent with autosomal recessive inheritance. The family history may include affected sibs (e.g., sibs with liver disease, neurologic manifestations, and/or psychiatric disturbance) and/or parental consanguinity. Absence of a known family history does not preclude the diagnosis. • Note: Specific instances when Wilson disease should be considered is ALF with nonimmune hemolytic anemia or autoimmune hepatitis. • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Low serum ceruloplasmin concentration • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ • Note: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration (100-250 µg/g dry weight), which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease. • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ ## Clinical Findings Note: Specific instances when Wilson disease should be considered is ALF with nonimmune hemolytic anemia or autoimmune hepatitis. Dysarthria Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) Dysautonomia Seizures Sleep disorders / insomnia Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see Self-limited hemolytic anemia, with or without acute liver failure Kidney abnormalities: aminoaciduria and nephrolithiasis Hypoparathyroidism, pancreatitis Cardiomyopathy, arrhythmias Premature osteoporosis and arthritis Infertility, recurrent miscarriages • Note: Specific instances when Wilson disease should be considered is ALF with nonimmune hemolytic anemia or autoimmune hepatitis. • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages • Dysarthria • Movement disorders (tremors, involuntary movements, chorea, choreoathetosis) • Dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement) • Dysautonomia • Seizures • Sleep disorders / insomnia • Eye: Kayser-Fleisher rings, copper deposits in the periphery of the cornea, are observed by slit lamp examination and anterior segment optical coherence tomography (see • Self-limited hemolytic anemia, with or without acute liver failure • Kidney abnormalities: aminoaciduria and nephrolithiasis • Hypoparathyroidism, pancreatitis • Cardiomyopathy, arrhythmias • Premature osteoporosis and arthritis • Infertility, recurrent miscarriages ## Brain Imaging Modalities such as magnetic resonance imaging (MRI) are of limited value in determining the extent of clinical neurologic disease but may help initially in supporting a diagnosis of Wilson disease and excluding other neurologic disorders. Brain MRI findings consistent with Wilson disease include signal changes in the basal ganglia, thalami, pons, and white matter, as well as atrophy. Although the "face of the giant panda" sign (see ## Biochemical Findings Suggestive biochemical findings in a symptomatic individual relies on a combination of the following findings: Low serum ceruloplasmin concentration Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ Note: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration (100-250 µg/g dry weight), which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease. • Low serum ceruloplasmin concentration • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ • Note: Serum copper is low in healthy newborns. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: (1) In later stages of Wilson disease, copper is distributed unevenly in the liver and measurement of hepatic copper concentration is less reliable. (2) Some individuals have only a moderately elevated hepatic copper concentration (100-250 µg/g dry weight), which overlaps with values occasionally found in heterozygotes. Thus, hepatic copper concentration in this range does not exclude the diagnosis of Wilson disease. • Note: Healthy newborns have low serum ceruloplasmin concentrations. The concentrations increase during the first six months of life and peak by age two to three years at a concentration that may exceed the healthy adult reference range. • Note: A normal serum ceruloplasmin concentration is found in at least 5% of individuals with Wilson disease with neurologic manifestations and up to 40% of individuals with hepatic findings [ ## Family History Family history is consistent with autosomal recessive inheritance. The family history may include affected sibs (e.g., sibs with liver disease, neurologic manifestations, and/or psychiatric disturbance) and/or parental consanguinity. Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of Wilson disease, using clinical, biochemical, and molecular genetic findings, is based on the diagnostic scoring system developed at the 8th International Meeting on Wilson Disease, Leipzig 2001 [ Diagnostic Scoring System for Wilson disease Adapted with permission from ULN = upper limit of normal Or typical abnormalities on brain MRI If no quantitative liver copper available Per the diagnostic scoring system (see Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis can be performed first in individuals from populations with known founder variants (e.g., Ashkenazi Jewish, Canary Islands, Druze, Sardinia; see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Wilson Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions and duplications, encompassing one or more exons, are rare. Exon and multiexon deletions have been reported (see, e.g., ## Option 1 Note: Targeted analysis can be performed first in individuals from populations with known founder variants (e.g., Ashkenazi Jewish, Canary Islands, Druze, Sardinia; see For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Wilson Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions and duplications, encompassing one or more exons, are rare. Exon and multiexon deletions have been reported (see, e.g., ## Clinical Characteristics Untreated symptomatic Wilson disease can manifest in individuals ages three years to older than 70 years as hepatic, neurologic, psychiatric, or hematologic disturbances, or a combination of these. Phenotypic expression varies even within families. The understanding of the phenotypic spectrum has further expanded through the widespread use of molecular genetic testing, which has confirmed the diagnosis in individuals with atypical clinical and biochemical findings. Clinical Findings in Individuals with Untreated Symptomatic Wilson Disease by Presenting Finding Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis. Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [ Pseudobulbar involvement such as dysarthria, drooling, and difficulty swallowing is more common in older individuals, but also occurs in children and adolescents. In contrast to the neurologic findings in individuals with a frank neurologic presentation, the neurologic findings in individuals with a hepatic presentation may be subtle. Mood disturbance (mainly depression; occasionally poor impulse control), changes in school performance, and/or difficulty with fine motor skills (especially handwriting) or gross motor skills may be observed. In individuals with a neurologic presentation, extensive changes on brain imaging (such as evidence of tissue cavitation) suggest structural, irreversible brain damage. These individuals are less likely to improve with treatment [ Intellectual deterioration may also occur with poor memory, difficulty in abstract thinking, and shortened attention span. Kayser-Fleischer rings result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body. They do not affect vision and are reduced or disappear with effective decoppering treatment (see Kidney involvement: low molecular weight proteinuria, microscopic hematuria, Fanconi syndrome, aminoaciduria, and nephrolithiasis Arthritis: involvement of large joints from synovial copper accumulation Reduced bone mineral density with an increased prevalence of osteoporosis (in approximately 10% of affected individuals) Pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders Sunflower cataracts: observed occasionally on slit lamp examination Hepatocellular carcinoma rarely develops in Wilson disease; the estimated incidence is below 1% [ Successful pregnancies of women with Wilson disease who received treatment have been reported [ The mainstay of treatment for Wilson disease remains lifelong oral pharmacotherapy and dietary copper restriction [ No genotype-phenotype correlations for The neurologic form of Wilson disease has also been known as Westphal-Strumpell pseudosclerosis. The prevalence of Wilson disease is estimated at one in 30,000 in most populations, with a corresponding carrier frequency in the general population of one in 90 [ In some population-based studies, the genetic prevalence was three to four times higher than clinically based estimates [ Recent studies suggest a prevalence as high as one in 10,000, especially in isolated populations such as Sardinia [ Founder variants have been identified in persons of Ashkenazi Jewish and Druze ancestry, as well as individuals from the Canary Islands and Sardinia (see • Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis. • Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [ • Kayser-Fleischer rings result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body. They do not affect vision and are reduced or disappear with effective decoppering treatment (see • Kidney involvement: low molecular weight proteinuria, microscopic hematuria, Fanconi syndrome, aminoaciduria, and nephrolithiasis • Arthritis: involvement of large joints from synovial copper accumulation • Reduced bone mineral density with an increased prevalence of osteoporosis (in approximately 10% of affected individuals) • Pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders • Sunflower cataracts: observed occasionally on slit lamp examination ## Clinical Description Untreated symptomatic Wilson disease can manifest in individuals ages three years to older than 70 years as hepatic, neurologic, psychiatric, or hematologic disturbances, or a combination of these. Phenotypic expression varies even within families. The understanding of the phenotypic spectrum has further expanded through the widespread use of molecular genetic testing, which has confirmed the diagnosis in individuals with atypical clinical and biochemical findings. Clinical Findings in Individuals with Untreated Symptomatic Wilson Disease by Presenting Finding Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis. Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [ Pseudobulbar involvement such as dysarthria, drooling, and difficulty swallowing is more common in older individuals, but also occurs in children and adolescents. In contrast to the neurologic findings in individuals with a frank neurologic presentation, the neurologic findings in individuals with a hepatic presentation may be subtle. Mood disturbance (mainly depression; occasionally poor impulse control), changes in school performance, and/or difficulty with fine motor skills (especially handwriting) or gross motor skills may be observed. In individuals with a neurologic presentation, extensive changes on brain imaging (such as evidence of tissue cavitation) suggest structural, irreversible brain damage. These individuals are less likely to improve with treatment [ Intellectual deterioration may also occur with poor memory, difficulty in abstract thinking, and shortened attention span. Kayser-Fleischer rings result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body. They do not affect vision and are reduced or disappear with effective decoppering treatment (see Kidney involvement: low molecular weight proteinuria, microscopic hematuria, Fanconi syndrome, aminoaciduria, and nephrolithiasis Arthritis: involvement of large joints from synovial copper accumulation Reduced bone mineral density with an increased prevalence of osteoporosis (in approximately 10% of affected individuals) Pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders Sunflower cataracts: observed occasionally on slit lamp examination Hepatocellular carcinoma rarely develops in Wilson disease; the estimated incidence is below 1% [ Successful pregnancies of women with Wilson disease who received treatment have been reported [ The mainstay of treatment for Wilson disease remains lifelong oral pharmacotherapy and dietary copper restriction [ • Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis. • Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [ • Kayser-Fleischer rings result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body. They do not affect vision and are reduced or disappear with effective decoppering treatment (see • Kidney involvement: low molecular weight proteinuria, microscopic hematuria, Fanconi syndrome, aminoaciduria, and nephrolithiasis • Arthritis: involvement of large joints from synovial copper accumulation • Reduced bone mineral density with an increased prevalence of osteoporosis (in approximately 10% of affected individuals) • Pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders • Sunflower cataracts: observed occasionally on slit lamp examination ## Untreated Symptomatic Wilson Disease Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis. Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [ Pseudobulbar involvement such as dysarthria, drooling, and difficulty swallowing is more common in older individuals, but also occurs in children and adolescents. In contrast to the neurologic findings in individuals with a frank neurologic presentation, the neurologic findings in individuals with a hepatic presentation may be subtle. Mood disturbance (mainly depression; occasionally poor impulse control), changes in school performance, and/or difficulty with fine motor skills (especially handwriting) or gross motor skills may be observed. In individuals with a neurologic presentation, extensive changes on brain imaging (such as evidence of tissue cavitation) suggest structural, irreversible brain damage. These individuals are less likely to improve with treatment [ Intellectual deterioration may also occur with poor memory, difficulty in abstract thinking, and shortened attention span. Kayser-Fleischer rings result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body. They do not affect vision and are reduced or disappear with effective decoppering treatment (see Kidney involvement: low molecular weight proteinuria, microscopic hematuria, Fanconi syndrome, aminoaciduria, and nephrolithiasis Arthritis: involvement of large joints from synovial copper accumulation Reduced bone mineral density with an increased prevalence of osteoporosis (in approximately 10% of affected individuals) Pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders Sunflower cataracts: observed occasionally on slit lamp examination Hepatocellular carcinoma rarely develops in Wilson disease; the estimated incidence is below 1% [ Successful pregnancies of women with Wilson disease who received treatment have been reported [ • Movement disorders tend to occur earlier and include tremors, poor coordination, loss of fine motor control, micrographia (abnormally small, cramped handwriting), chorea, and/or choreoathetosis. • Spastic dystonia disorders manifest as mask-like facies, rigidity, and gait disturbance [ • Kayser-Fleischer rings result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body. They do not affect vision and are reduced or disappear with effective decoppering treatment (see • Kidney involvement: low molecular weight proteinuria, microscopic hematuria, Fanconi syndrome, aminoaciduria, and nephrolithiasis • Arthritis: involvement of large joints from synovial copper accumulation • Reduced bone mineral density with an increased prevalence of osteoporosis (in approximately 10% of affected individuals) • Pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, and various endocrine disorders • Sunflower cataracts: observed occasionally on slit lamp examination ## Treated Wilson Disease The mainstay of treatment for Wilson disease remains lifelong oral pharmacotherapy and dietary copper restriction [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Nomenclature The neurologic form of Wilson disease has also been known as Westphal-Strumpell pseudosclerosis. ## Prevalence The prevalence of Wilson disease is estimated at one in 30,000 in most populations, with a corresponding carrier frequency in the general population of one in 90 [ In some population-based studies, the genetic prevalence was three to four times higher than clinically based estimates [ Recent studies suggest a prevalence as high as one in 10,000, especially in isolated populations such as Sardinia [ Founder variants have been identified in persons of Ashkenazi Jewish and Druze ancestry, as well as individuals from the Canary Islands and Sardinia (see ## Genetically Related Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The complete differential diagnosis of Wilson disease is extensive and includes: Copper metabolism disorders; Hereditary disorders involving the liver; Hereditary disorders involving the nervous system; and Acquired conditions such as viral hepatitis, severe drug toxicity, and nonalcoholic steatohepatitis (NASH). Note: Wilson disease must be specifically excluded in individuals thought to have NASH, or the opportunity for life-saving treatment will be missed. Hereditary Disorders of Known Genetic Cause in the Differential Diagnosis of Wilson Disease AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; PFIC = progressive familial intrahepatic cholestasis; XL = X-linked Onset during infancy Iron overload due to lack of oxidase activity of ceruloplasmin Characterized by cataract, sensorineural deafness, and severe developmental delay Primary sclerosing cholangitis (OMIM Presents with abnormal liver biochemistries with or without hepatomegaly Alpha-1 antitrypsin deficiency is inherited in an autosomal codominant manner. See Hereditary Ataxia Overview, The mode of inheritance depends on the genetic etiology of ataxia. • Copper metabolism disorders; • Hereditary disorders involving the liver; • Hereditary disorders involving the nervous system; and • Acquired conditions such as viral hepatitis, severe drug toxicity, and nonalcoholic steatohepatitis (NASH). ## Management To establish the extent of disease and needs in an individual with symptomatic untreated Wilson disease, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Symptomatic Untreated Wilson Disease Establish baseline copper studies (serum ceruloplasmin & serum copper & 24-hr urinary copper excretion). Consider additional upper GI endoscopy to exclude or confirm esophageal varices. Movement disorders Gait & balance disturbance Tubular dysfunction (e.g., aminoaciduria, hypercalcuria, hyperphosphaturia) Nephrolithiasis, nephrocalcinosis Community or Social work involvement for parental/caregiver support; Home nursing referral. ADL = activities of daily living; GI = gastrointestinal; OT = occupational therapist; PT = physical therapist Adapted from Medical geneticist, certified genetic counselor, certified advanced genetic nurse See extensive review by the American Association for the Study of Liver Diseases [ Individuals with Wilson disease can be clinically categorized as: "Asymptomatic" (individuals who have no clinical manifestations or tissue damage related to Wilson disease); "Clinically asymptomatic" (individuals who have no clinical manifestations of Wilson disease but have Wilson disease-related tissue damage); or "Symptomatic" (individuals who have clinical manifestations of Wilson disease and Wilson disease-related tissue damage). The goal of therapy is to institute treatment with chelating agents as soon as possible in individuals with Wilson disease who are asymptomatic, clinically asymptomatic, or symptomatic. Treatment is lifelong, including during pregnancy. If one treatment is discontinued, an alternative modality must be substituted to prevent disease progression. Discontinuation of all treatment leads to hepatic and neurologic decompensation that is usually refractory to further medical intervention. During lifelong treatment, failure of any medication used to treat Wilson disease may occur, either at initiation of treatment or during maintenance therapy. Once concurrent disease and nonadherence are excluded, pharmacologic therapy should be re-evaluated and likely altered. For individuals who have more advanced liver disease or develop liver failure, evaluation for liver transplantation should be considered. Currently, no surrogate markers are established for evaluating treatment failure. Asymptomatic individuals should be treated either with lower dosages (10-15 mg/kg) of a copper chelating agent (D-penicillamine or trientine) or zinc salts. Clinically asymptomatic individuals should be treated with 15-20 mg/kg of a copper chelating agent (D-penicillamine or trientine). Symptomatic individuals should be treated with 15-20 mg/kg of a copper chelating agent (D-penicillamine or trientine). However, some individuals with advanced liver disease may require more intensive therapy, and temporally separated combination therapy may be utilized. Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ Zinc is taken as tablets by mouth at least twice (usually 3 times) daily before meals. The dose is based on the elemental zinc in the tablet. Twenty-four-hour urine copper excretion is used to monitor total body copper stores, which should decrease. Increase of urinary copper excretion under zinc therapy may indicate insufficient treatment efficacy [ Note: (1) Gastritis, a common side effect, can be reduced with the use of zinc acetate or zinc gluconate. (2) Zinc should NOT be used simultaneously with any chelator, pending further clinical investigation. Orthotopic liver transplantation (OLT) is reserved for individuals who fail to respond to medical therapy or cannot tolerate it because of serious adverse side effects [ It remains controversial whether orthotopic liver transplantation should be a primary treatment for individuals with Wilson disease who have severe neurologic disease [ The goals of supportive treatment for extrahepatic manifestations of individuals with symptomatic Wilson disease are individualized to maximize function and reduce complications. Ideally each individual consults with multidisciplinary specialists in fields such as neurology, occupational therapy, physical therapy, physiatry, orthopedics, nutrition, speech-language pathology, social work, and psychology/psychiatry, depending on the clinical manifestations. Monitoring of individuals under therapy should include routine assessments of treatment efficacy by biochemical testing and clinical evaluation. Insufficient therapy, underdosage, or poor adherence could lead to reaccumulation of copper and development of new symptoms. Adverse events related to medical treatment (especially under D-penicillamine treatment) should be evaluated. Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron (as observed in According to current guidelines (AASLD [ At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment Note: Individuals receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. At least once annually: 24-hour urinary excretion of copper Note: Measurements are recommended more frequently if there are questions on adherence or if dosage of medications is adjusted. To monitor the individual's response to supportive care and the emergence of new manifestations, the evaluations in Recommended Surveillance of Extrahepatic Manifestations for Individuals with Symptomatic Wilson Disease OT = occupational therapy; PT = physical therapy Foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts) should be avoided, especially at the beginning of treatment. In case of biochemical abnormalities in liver function tests or transaminases, alcohol consumption is strongly discouraged. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of medical interventions to prevent/treat copper accumulation (see Molecular genetic testing if the If the Note: Asymptomatic individuals with Wilson disease generally have a low serum concentration of ceruloplasmin and mildly increased basal 24-hour urinary copper excretion; however, sometimes asymptomatic individuals with Wilson disease cannot be easily distinguished from heterozygotes. Although Wilson disease is an autosomal recessive disorder and the risk to the parents and offspring of a proband is low, screening of all first-degree relatives is recommended in order to ascertain clinically asymptomatic family members in whom treatment may prevent liver disease and other manifestations of Wilson disease [ See D-penicillamine has been used in many pregnancies with no adverse outcomes; however, congenital connective tissue disorders encompassing inguinal hernias and skin laxity have been reported in some exposed infants. Such adverse outcomes may depend on dose, which should be kept as low as possible while still preventing copper deficiency in the pregnant woman and accounting for the need for fetal copper during development [ Trientine has been used successfully during pregnancy, but the total number of reported individuals is small. Reduction of the dose to the lowest effective dose is recommended using a comparable approach to that for D-penicillamine. Zinc has been used effectively in pregnant women and typically does not require a decreased dose during pregnancy. However, changing medical therapy to zinc during pregnancy does not appear to decrease the risk of either miscarriage or adverse fetal outcomes [ See Detoxifying non-ceruloplasmin-bound copper by creating a nonreactive tripartite complex with albumin and copper; Extracting copper from the endogenous cellular chelator metallothionein (based on its high affinity for copper); and Interfering with the intestinal uptake of copper when administered with food. In a Phase II study [ Search • Establish baseline copper studies (serum ceruloplasmin & serum copper & 24-hr urinary copper excretion). • Consider additional upper GI endoscopy to exclude or confirm esophageal varices. • Movement disorders • Gait & balance disturbance • Tubular dysfunction (e.g., aminoaciduria, hypercalcuria, hyperphosphaturia) • Nephrolithiasis, nephrocalcinosis • Community or • Social work involvement for parental/caregiver support; • Home nursing referral. • "Asymptomatic" (individuals who have no clinical manifestations or tissue damage related to Wilson disease); • "Clinically asymptomatic" (individuals who have no clinical manifestations of Wilson disease but have Wilson disease-related tissue damage); or • "Symptomatic" (individuals who have clinical manifestations of Wilson disease and Wilson disease-related tissue damage). • Treatment is lifelong, including during pregnancy. • If one treatment is discontinued, an alternative modality must be substituted to prevent disease progression. • Discontinuation of all treatment leads to hepatic and neurologic decompensation that is usually refractory to further medical intervention. • During lifelong treatment, failure of any medication used to treat Wilson disease may occur, either at initiation of treatment or during maintenance therapy. Once concurrent disease and nonadherence are excluded, pharmacologic therapy should be re-evaluated and likely altered. For individuals who have more advanced liver disease or develop liver failure, evaluation for liver transplantation should be considered. Currently, no surrogate markers are established for evaluating treatment failure. • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ • Insufficient therapy, underdosage, or poor adherence could lead to reaccumulation of copper and development of new symptoms. • Adverse events related to medical treatment (especially under D-penicillamine treatment) should be evaluated. • Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron (as observed in • At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment • Note: Individuals receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. • At least once annually: 24-hour urinary excretion of copper • Note: Measurements are recommended more frequently if there are questions on adherence or if dosage of medications is adjusted. • Molecular genetic testing if the • If the • Note: Asymptomatic individuals with Wilson disease generally have a low serum concentration of ceruloplasmin and mildly increased basal 24-hour urinary copper excretion; however, sometimes asymptomatic individuals with Wilson disease cannot be easily distinguished from heterozygotes. • D-penicillamine has been used in many pregnancies with no adverse outcomes; however, congenital connective tissue disorders encompassing inguinal hernias and skin laxity have been reported in some exposed infants. Such adverse outcomes may depend on dose, which should be kept as low as possible while still preventing copper deficiency in the pregnant woman and accounting for the need for fetal copper during development [ • Trientine has been used successfully during pregnancy, but the total number of reported individuals is small. Reduction of the dose to the lowest effective dose is recommended using a comparable approach to that for D-penicillamine. • Zinc has been used effectively in pregnant women and typically does not require a decreased dose during pregnancy. However, changing medical therapy to zinc during pregnancy does not appear to decrease the risk of either miscarriage or adverse fetal outcomes [ • Detoxifying non-ceruloplasmin-bound copper by creating a nonreactive tripartite complex with albumin and copper; • Extracting copper from the endogenous cellular chelator metallothionein (based on its high affinity for copper); and • Interfering with the intestinal uptake of copper when administered with food. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual with symptomatic untreated Wilson disease, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Symptomatic Untreated Wilson Disease Establish baseline copper studies (serum ceruloplasmin & serum copper & 24-hr urinary copper excretion). Consider additional upper GI endoscopy to exclude or confirm esophageal varices. Movement disorders Gait & balance disturbance Tubular dysfunction (e.g., aminoaciduria, hypercalcuria, hyperphosphaturia) Nephrolithiasis, nephrocalcinosis Community or Social work involvement for parental/caregiver support; Home nursing referral. ADL = activities of daily living; GI = gastrointestinal; OT = occupational therapist; PT = physical therapist Adapted from Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Establish baseline copper studies (serum ceruloplasmin & serum copper & 24-hr urinary copper excretion). • Consider additional upper GI endoscopy to exclude or confirm esophageal varices. • Movement disorders • Gait & balance disturbance • Tubular dysfunction (e.g., aminoaciduria, hypercalcuria, hyperphosphaturia) • Nephrolithiasis, nephrocalcinosis • Community or • Social work involvement for parental/caregiver support; • Home nursing referral. ## Treatment of Manifestations See extensive review by the American Association for the Study of Liver Diseases [ Individuals with Wilson disease can be clinically categorized as: "Asymptomatic" (individuals who have no clinical manifestations or tissue damage related to Wilson disease); "Clinically asymptomatic" (individuals who have no clinical manifestations of Wilson disease but have Wilson disease-related tissue damage); or "Symptomatic" (individuals who have clinical manifestations of Wilson disease and Wilson disease-related tissue damage). The goal of therapy is to institute treatment with chelating agents as soon as possible in individuals with Wilson disease who are asymptomatic, clinically asymptomatic, or symptomatic. Treatment is lifelong, including during pregnancy. If one treatment is discontinued, an alternative modality must be substituted to prevent disease progression. Discontinuation of all treatment leads to hepatic and neurologic decompensation that is usually refractory to further medical intervention. During lifelong treatment, failure of any medication used to treat Wilson disease may occur, either at initiation of treatment or during maintenance therapy. Once concurrent disease and nonadherence are excluded, pharmacologic therapy should be re-evaluated and likely altered. For individuals who have more advanced liver disease or develop liver failure, evaluation for liver transplantation should be considered. Currently, no surrogate markers are established for evaluating treatment failure. Asymptomatic individuals should be treated either with lower dosages (10-15 mg/kg) of a copper chelating agent (D-penicillamine or trientine) or zinc salts. Clinically asymptomatic individuals should be treated with 15-20 mg/kg of a copper chelating agent (D-penicillamine or trientine). Symptomatic individuals should be treated with 15-20 mg/kg of a copper chelating agent (D-penicillamine or trientine). However, some individuals with advanced liver disease may require more intensive therapy, and temporally separated combination therapy may be utilized. Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ Zinc is taken as tablets by mouth at least twice (usually 3 times) daily before meals. The dose is based on the elemental zinc in the tablet. Twenty-four-hour urine copper excretion is used to monitor total body copper stores, which should decrease. Increase of urinary copper excretion under zinc therapy may indicate insufficient treatment efficacy [ Note: (1) Gastritis, a common side effect, can be reduced with the use of zinc acetate or zinc gluconate. (2) Zinc should NOT be used simultaneously with any chelator, pending further clinical investigation. Orthotopic liver transplantation (OLT) is reserved for individuals who fail to respond to medical therapy or cannot tolerate it because of serious adverse side effects [ It remains controversial whether orthotopic liver transplantation should be a primary treatment for individuals with Wilson disease who have severe neurologic disease [ The goals of supportive treatment for extrahepatic manifestations of individuals with symptomatic Wilson disease are individualized to maximize function and reduce complications. Ideally each individual consults with multidisciplinary specialists in fields such as neurology, occupational therapy, physical therapy, physiatry, orthopedics, nutrition, speech-language pathology, social work, and psychology/psychiatry, depending on the clinical manifestations. • "Asymptomatic" (individuals who have no clinical manifestations or tissue damage related to Wilson disease); • "Clinically asymptomatic" (individuals who have no clinical manifestations of Wilson disease but have Wilson disease-related tissue damage); or • "Symptomatic" (individuals who have clinical manifestations of Wilson disease and Wilson disease-related tissue damage). • Treatment is lifelong, including during pregnancy. • If one treatment is discontinued, an alternative modality must be substituted to prevent disease progression. • Discontinuation of all treatment leads to hepatic and neurologic decompensation that is usually refractory to further medical intervention. • During lifelong treatment, failure of any medication used to treat Wilson disease may occur, either at initiation of treatment or during maintenance therapy. Once concurrent disease and nonadherence are excluded, pharmacologic therapy should be re-evaluated and likely altered. For individuals who have more advanced liver disease or develop liver failure, evaluation for liver transplantation should be considered. Currently, no surrogate markers are established for evaluating treatment failure. • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ ## Medical Interventions to Prevent/Treat Copper Accumulation in Individuals with Wilson Disease Who Are Asymptomatic, Clinically Asymptomatic, or Symptomatic See extensive review by the American Association for the Study of Liver Diseases [ Individuals with Wilson disease can be clinically categorized as: "Asymptomatic" (individuals who have no clinical manifestations or tissue damage related to Wilson disease); "Clinically asymptomatic" (individuals who have no clinical manifestations of Wilson disease but have Wilson disease-related tissue damage); or "Symptomatic" (individuals who have clinical manifestations of Wilson disease and Wilson disease-related tissue damage). The goal of therapy is to institute treatment with chelating agents as soon as possible in individuals with Wilson disease who are asymptomatic, clinically asymptomatic, or symptomatic. Treatment is lifelong, including during pregnancy. If one treatment is discontinued, an alternative modality must be substituted to prevent disease progression. Discontinuation of all treatment leads to hepatic and neurologic decompensation that is usually refractory to further medical intervention. During lifelong treatment, failure of any medication used to treat Wilson disease may occur, either at initiation of treatment or during maintenance therapy. Once concurrent disease and nonadherence are excluded, pharmacologic therapy should be re-evaluated and likely altered. For individuals who have more advanced liver disease or develop liver failure, evaluation for liver transplantation should be considered. Currently, no surrogate markers are established for evaluating treatment failure. Asymptomatic individuals should be treated either with lower dosages (10-15 mg/kg) of a copper chelating agent (D-penicillamine or trientine) or zinc salts. Clinically asymptomatic individuals should be treated with 15-20 mg/kg of a copper chelating agent (D-penicillamine or trientine). Symptomatic individuals should be treated with 15-20 mg/kg of a copper chelating agent (D-penicillamine or trientine). However, some individuals with advanced liver disease may require more intensive therapy, and temporally separated combination therapy may be utilized. Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ Zinc is taken as tablets by mouth at least twice (usually 3 times) daily before meals. The dose is based on the elemental zinc in the tablet. Twenty-four-hour urine copper excretion is used to monitor total body copper stores, which should decrease. Increase of urinary copper excretion under zinc therapy may indicate insufficient treatment efficacy [ Note: (1) Gastritis, a common side effect, can be reduced with the use of zinc acetate or zinc gluconate. (2) Zinc should NOT be used simultaneously with any chelator, pending further clinical investigation. • "Asymptomatic" (individuals who have no clinical manifestations or tissue damage related to Wilson disease); • "Clinically asymptomatic" (individuals who have no clinical manifestations of Wilson disease but have Wilson disease-related tissue damage); or • "Symptomatic" (individuals who have clinical manifestations of Wilson disease and Wilson disease-related tissue damage). • Treatment is lifelong, including during pregnancy. • If one treatment is discontinued, an alternative modality must be substituted to prevent disease progression. • Discontinuation of all treatment leads to hepatic and neurologic decompensation that is usually refractory to further medical intervention. • During lifelong treatment, failure of any medication used to treat Wilson disease may occur, either at initiation of treatment or during maintenance therapy. Once concurrent disease and nonadherence are excluded, pharmacologic therapy should be re-evaluated and likely altered. For individuals who have more advanced liver disease or develop liver failure, evaluation for liver transplantation should be considered. Currently, no surrogate markers are established for evaluating treatment failure. • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ • Complete blood count and urinalysis must be monitored regularly during D-penicillamine therapy. Serious side effects can occur in up to 30% of individuals, and include severe thrombocytopenia, leukopenia, aplastic anemia, proteinuria, nephrotic syndrome, polyserositis, Goodpasture syndrome, and severe skin reactions. An early allergic reaction with fever, rash, and proteinuria may occur. Evidence of any such side effects may require discontinuation of D-penicillamine and substitution of an alternate treatment. If such alternate therapies are unavailable, D-penicillamine-induced adverse events may be manageable by coadministration of steroids. • D-penicillamine inhibits collagen cross-linking and has some immunosuppressant properties. After decades of treatment, individuals may have abnormal skin and connective tissue collagen, and possible chronic depletion of copper and (possibly) other trace metals. • D-penicillamine should NOT be used simultaneously with zinc, pending adequate clinical assessment of this treatment strategy. • Complete blood count and urinalysis must be monitored regularly in all individuals on trientine. • Rare side effects include gastritis with nausea and, in cases of overtreatment, iron deficiency anemia. • Trientine should NOT be used simultaneously with zinc pending adequate assessment of this combination. Current reports suggest that the combination of trientine and zinc, temporally dispersed throughout the day such that each drug is administered five to six hours apart from the other, may be effective in severely decompensated hepatic Wilson disease [ ## Orthotopic Liver Transplantation Orthotopic liver transplantation (OLT) is reserved for individuals who fail to respond to medical therapy or cannot tolerate it because of serious adverse side effects [ It remains controversial whether orthotopic liver transplantation should be a primary treatment for individuals with Wilson disease who have severe neurologic disease [ ## Supportive Treatment for Extrahepatic Manifestations The goals of supportive treatment for extrahepatic manifestations of individuals with symptomatic Wilson disease are individualized to maximize function and reduce complications. Ideally each individual consults with multidisciplinary specialists in fields such as neurology, occupational therapy, physical therapy, physiatry, orthopedics, nutrition, speech-language pathology, social work, and psychology/psychiatry, depending on the clinical manifestations. ## Surveillance Monitoring of individuals under therapy should include routine assessments of treatment efficacy by biochemical testing and clinical evaluation. Insufficient therapy, underdosage, or poor adherence could lead to reaccumulation of copper and development of new symptoms. Adverse events related to medical treatment (especially under D-penicillamine treatment) should be evaluated. Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron (as observed in According to current guidelines (AASLD [ At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment Note: Individuals receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. At least once annually: 24-hour urinary excretion of copper Note: Measurements are recommended more frequently if there are questions on adherence or if dosage of medications is adjusted. To monitor the individual's response to supportive care and the emergence of new manifestations, the evaluations in Recommended Surveillance of Extrahepatic Manifestations for Individuals with Symptomatic Wilson Disease OT = occupational therapy; PT = physical therapy • Insufficient therapy, underdosage, or poor adherence could lead to reaccumulation of copper and development of new symptoms. • Adverse events related to medical treatment (especially under D-penicillamine treatment) should be evaluated. • Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron (as observed in • At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment • Note: Individuals receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. • At least once annually: 24-hour urinary excretion of copper • Note: Measurements are recommended more frequently if there are questions on adherence or if dosage of medications is adjusted. ## Assessment of Treatment Effectiveness and Adherence to Medical Interventions to Prevent/Treat Copper Accumulation Monitoring of individuals under therapy should include routine assessments of treatment efficacy by biochemical testing and clinical evaluation. Insufficient therapy, underdosage, or poor adherence could lead to reaccumulation of copper and development of new symptoms. Adverse events related to medical treatment (especially under D-penicillamine treatment) should be evaluated. Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron (as observed in According to current guidelines (AASLD [ At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment Note: Individuals receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. At least once annually: 24-hour urinary excretion of copper Note: Measurements are recommended more frequently if there are questions on adherence or if dosage of medications is adjusted. • Insufficient therapy, underdosage, or poor adherence could lead to reaccumulation of copper and development of new symptoms. • Adverse events related to medical treatment (especially under D-penicillamine treatment) should be evaluated. • Excessive long-term treatment could result in copper deficiency, leading to immobilization of iron (as observed in • At least twice annually: serum copper and ceruloplasmin, liver biochemistries, international normalized ratio, complete blood count, urinalysis, and physical examination including neurologic assessment • Note: Individuals receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. • At least once annually: 24-hour urinary excretion of copper • Note: Measurements are recommended more frequently if there are questions on adherence or if dosage of medications is adjusted. ## Supportive Care To monitor the individual's response to supportive care and the emergence of new manifestations, the evaluations in Recommended Surveillance of Extrahepatic Manifestations for Individuals with Symptomatic Wilson Disease OT = occupational therapy; PT = physical therapy ## Agents/Circumstances to Avoid Foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts) should be avoided, especially at the beginning of treatment. In case of biochemical abnormalities in liver function tests or transaminases, alcohol consumption is strongly discouraged. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of medical interventions to prevent/treat copper accumulation (see Molecular genetic testing if the If the Note: Asymptomatic individuals with Wilson disease generally have a low serum concentration of ceruloplasmin and mildly increased basal 24-hour urinary copper excretion; however, sometimes asymptomatic individuals with Wilson disease cannot be easily distinguished from heterozygotes. Although Wilson disease is an autosomal recessive disorder and the risk to the parents and offspring of a proband is low, screening of all first-degree relatives is recommended in order to ascertain clinically asymptomatic family members in whom treatment may prevent liver disease and other manifestations of Wilson disease [ See • Molecular genetic testing if the • If the • Note: Asymptomatic individuals with Wilson disease generally have a low serum concentration of ceruloplasmin and mildly increased basal 24-hour urinary copper excretion; however, sometimes asymptomatic individuals with Wilson disease cannot be easily distinguished from heterozygotes. ## Pregnancy and Lactation Concerns D-penicillamine has been used in many pregnancies with no adverse outcomes; however, congenital connective tissue disorders encompassing inguinal hernias and skin laxity have been reported in some exposed infants. Such adverse outcomes may depend on dose, which should be kept as low as possible while still preventing copper deficiency in the pregnant woman and accounting for the need for fetal copper during development [ Trientine has been used successfully during pregnancy, but the total number of reported individuals is small. Reduction of the dose to the lowest effective dose is recommended using a comparable approach to that for D-penicillamine. Zinc has been used effectively in pregnant women and typically does not require a decreased dose during pregnancy. However, changing medical therapy to zinc during pregnancy does not appear to decrease the risk of either miscarriage or adverse fetal outcomes [ See • D-penicillamine has been used in many pregnancies with no adverse outcomes; however, congenital connective tissue disorders encompassing inguinal hernias and skin laxity have been reported in some exposed infants. Such adverse outcomes may depend on dose, which should be kept as low as possible while still preventing copper deficiency in the pregnant woman and accounting for the need for fetal copper during development [ • Trientine has been used successfully during pregnancy, but the total number of reported individuals is small. Reduction of the dose to the lowest effective dose is recommended using a comparable approach to that for D-penicillamine. • Zinc has been used effectively in pregnant women and typically does not require a decreased dose during pregnancy. However, changing medical therapy to zinc during pregnancy does not appear to decrease the risk of either miscarriage or adverse fetal outcomes [ ## Therapies Under Investigation Detoxifying non-ceruloplasmin-bound copper by creating a nonreactive tripartite complex with albumin and copper; Extracting copper from the endogenous cellular chelator metallothionein (based on its high affinity for copper); and Interfering with the intestinal uptake of copper when administered with food. In a Phase II study [ Search • Detoxifying non-ceruloplasmin-bound copper by creating a nonreactive tripartite complex with albumin and copper; • Extracting copper from the endogenous cellular chelator metallothionein (based on its high affinity for copper); and • Interfering with the intestinal uptake of copper when administered with food. ## Genetic Counseling Wilson disease is inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). If both parents are known to be heterozygous for an Clinical symptoms may vary between sibs (including monozygotic twins) with untreated Wilson disease. The range of clinical variability observed between sibs with the same biallelic Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). Unless an affected individual's reproductive partner also has Wilson disease or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in Given the carrier rate of one in 90 in the general population, the likelihood that an affected individual will have an affected child is one in 180. A higher carrier frequency is observed in some population groups due to founder variants (see Because the risk that an individual with Wilson disease will have an affected child is low, testing of serum ceruloplasmin concentration after age one year should be an adequate screening in offspring of a proband, except in populations with a high incidence of Wilson disease and/or a high incidence of consanguinity. In these populations, molecular testing may be useful. If molecular testing is not performed, repeat biochemical testing (including ceruloplasmin and urinary copper excretion) of offspring is strongly encouraged if initial biochemical testing was performed before age three years. Molecular genetic carrier testing for at-risk relatives requires prior identification of the Heterozygotes may have low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight), which make these tests unreliable in clarifying carrier status. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for the reproductive partners of affected individuals and known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Founder variants have been identified in some populations (see Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Clinical symptoms may vary between sibs (including monozygotic twins) with untreated Wilson disease. The range of clinical variability observed between sibs with the same biallelic • Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). • Unless an affected individual's reproductive partner also has Wilson disease or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • Given the carrier rate of one in 90 in the general population, the likelihood that an affected individual will have an affected child is one in 180. A higher carrier frequency is observed in some population groups due to founder variants (see • Because the risk that an individual with Wilson disease will have an affected child is low, testing of serum ceruloplasmin concentration after age one year should be an adequate screening in offspring of a proband, except in populations with a high incidence of Wilson disease and/or a high incidence of consanguinity. In these populations, molecular testing may be useful. If molecular testing is not performed, repeat biochemical testing (including ceruloplasmin and urinary copper excretion) of offspring is strongly encouraged if initial biochemical testing was performed before age three years. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for the reproductive partners of affected individuals and known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Founder variants have been identified in some populations (see ## Mode of Inheritance Wilson disease is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). If both parents are known to be heterozygous for an Clinical symptoms may vary between sibs (including monozygotic twins) with untreated Wilson disease. The range of clinical variability observed between sibs with the same biallelic Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). Unless an affected individual's reproductive partner also has Wilson disease or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in Given the carrier rate of one in 90 in the general population, the likelihood that an affected individual will have an affected child is one in 180. A higher carrier frequency is observed in some population groups due to founder variants (see Because the risk that an individual with Wilson disease will have an affected child is low, testing of serum ceruloplasmin concentration after age one year should be an adequate screening in offspring of a proband, except in populations with a high incidence of Wilson disease and/or a high incidence of consanguinity. In these populations, molecular testing may be useful. If molecular testing is not performed, repeat biochemical testing (including ceruloplasmin and urinary copper excretion) of offspring is strongly encouraged if initial biochemical testing was performed before age three years. • The parents of an affected individual are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Clinical symptoms may vary between sibs (including monozygotic twins) with untreated Wilson disease. The range of clinical variability observed between sibs with the same biallelic • Clinical disease is not known to occur in heterozygotes (carriers), although the possibility has not been adequately excluded at older ages. Note: Heterozygotes may have subclinical biochemical findings including low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight). • Unless an affected individual's reproductive partner also has Wilson disease or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • Given the carrier rate of one in 90 in the general population, the likelihood that an affected individual will have an affected child is one in 180. A higher carrier frequency is observed in some population groups due to founder variants (see • Because the risk that an individual with Wilson disease will have an affected child is low, testing of serum ceruloplasmin concentration after age one year should be an adequate screening in offspring of a proband, except in populations with a high incidence of Wilson disease and/or a high incidence of consanguinity. In these populations, molecular testing may be useful. If molecular testing is not performed, repeat biochemical testing (including ceruloplasmin and urinary copper excretion) of offspring is strongly encouraged if initial biochemical testing was performed before age three years. ## Carrier Detection Molecular genetic carrier testing for at-risk relatives requires prior identification of the Heterozygotes may have low serum ceruloplasmin concentrations, borderline normal urinary copper, elevated urinary copper on provocative testing with D-penicillamine, and/or moderate elevation of hepatic copper (100-250 mg/g dry weight), which make these tests unreliable in clarifying carrier status. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for the reproductive partners of affected individuals and known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Founder variants have been identified in some populations (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for the reproductive partners of affected individuals and known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Founder variants have been identified in some populations (see ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources France Italy Germany Germany United Kingdom Canada Rare Disease Europe • • France • • • Italy • • • Germany • • • Germany • • • • • United Kingdom • • • • • Canada • • • Rare Disease Europe • • • ## Molecular Genetics Wilson Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Wilson Disease ( The product of Tissue damage occurs after excessive copper accumulation resulting from lack of copper transport from the liver. Even when no transporter function is present, accumulation of copper occurs over several years. Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The product of Tissue damage occurs after excessive copper accumulation resulting from lack of copper transport from the liver. Even when no transporter function is present, accumulation of copper occurs over several years. Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Michael Schilsky's clinical and research interests include transplant hepatology, acute liver failure, and inherited metabolic disorders of the liver, in particular Wilson disease and hemochromatosis. Dr Schilsky co-wrote the AASLD and EASL practice guidelines for Wilson disease and chaired the writing group for the newly released 2022 AASLD practice guidance on Wilson disease. He is author of numerous original manuscripts and reviews on the subject. He is the Principal Investigator on clinical trials of pharmacotherapy and gene therapy for Wilson disease. Dr Schilsky is the organizer and Principal Investigator for the multicenter, multinational registry trial for Wilson disease sponsored by the Wilson Disease Association with data coordinating center at Yale University. He is a member of the NIH-sponsored Acute Liver Failure Study Group. He currently serves as Chair of the Medical Advisory Committee for the Wilson Disease Association. Dr Karl Heinz Weiss's clinical and research interests include transplant hepatology, Wilson disease, and liver tumors. Dr Weiss co-wrote the 2022 AASLD practice guidance on Wilson disease. He is author of numerous original manuscripts and reviews on the subject. Drs Weiss and Schilsky are actively involved in clinical research regarding individuals with Wilson disease. They would be happy to communicate with persons who have any questions regarding diagnosis of Wilson disease or other considerations. Contact Drs Weiss and Schilsky to inquire about review of MLS receives research support from the Wilson Disease Association (USA), Alexion, Orphalan, and Vivet Therapeutics. KHW receives research support from Morbus Wilson e.V., Alexion, Orphalan, Univar, and Vivet Therapeutics. We would like to acknowledge the Wilson Disease Association for their support of patient care, research, and educational activities. Diane Cox, PhD, FCCMG, University of Alberta (1999-2013)Eve Roberts, MD, FRCP(C), University of Toronto (1999-2013)Michael Schilsky, MD (2023-present)Karl Heinz Weiss, MD (2013-present) 12 January 2023 (bp) Comprehensive update posted live 29 July 2016 (bp) Comprehensive update posted live 16 May 2013 (me) Comprehensive update posted live 24 January 2006 (me) Comprehensive update posted live 24 April 2003 (me) Comprehensive update posted live 22 October 1999 (me) Review posted live 12 May 1999 (dc) Original submission • 12 January 2023 (bp) Comprehensive update posted live • 29 July 2016 (bp) Comprehensive update posted live • 16 May 2013 (me) Comprehensive update posted live • 24 January 2006 (me) Comprehensive update posted live • 24 April 2003 (me) Comprehensive update posted live • 22 October 1999 (me) Review posted live • 12 May 1999 (dc) Original submission ## Author Notes Dr Michael Schilsky's clinical and research interests include transplant hepatology, acute liver failure, and inherited metabolic disorders of the liver, in particular Wilson disease and hemochromatosis. Dr Schilsky co-wrote the AASLD and EASL practice guidelines for Wilson disease and chaired the writing group for the newly released 2022 AASLD practice guidance on Wilson disease. He is author of numerous original manuscripts and reviews on the subject. He is the Principal Investigator on clinical trials of pharmacotherapy and gene therapy for Wilson disease. Dr Schilsky is the organizer and Principal Investigator for the multicenter, multinational registry trial for Wilson disease sponsored by the Wilson Disease Association with data coordinating center at Yale University. He is a member of the NIH-sponsored Acute Liver Failure Study Group. He currently serves as Chair of the Medical Advisory Committee for the Wilson Disease Association. Dr Karl Heinz Weiss's clinical and research interests include transplant hepatology, Wilson disease, and liver tumors. Dr Weiss co-wrote the 2022 AASLD practice guidance on Wilson disease. He is author of numerous original manuscripts and reviews on the subject. Drs Weiss and Schilsky are actively involved in clinical research regarding individuals with Wilson disease. They would be happy to communicate with persons who have any questions regarding diagnosis of Wilson disease or other considerations. Contact Drs Weiss and Schilsky to inquire about review of ## Acknowledgments MLS receives research support from the Wilson Disease Association (USA), Alexion, Orphalan, and Vivet Therapeutics. KHW receives research support from Morbus Wilson e.V., Alexion, Orphalan, Univar, and Vivet Therapeutics. We would like to acknowledge the Wilson Disease Association for their support of patient care, research, and educational activities. ## Author History Diane Cox, PhD, FCCMG, University of Alberta (1999-2013)Eve Roberts, MD, FRCP(C), University of Toronto (1999-2013)Michael Schilsky, MD (2023-present)Karl Heinz Weiss, MD (2013-present) ## Revision History 12 January 2023 (bp) Comprehensive update posted live 29 July 2016 (bp) Comprehensive update posted live 16 May 2013 (me) Comprehensive update posted live 24 January 2006 (me) Comprehensive update posted live 24 April 2003 (me) Comprehensive update posted live 22 October 1999 (me) Review posted live 12 May 1999 (dc) Original submission • 12 January 2023 (bp) Comprehensive update posted live • 29 July 2016 (bp) Comprehensive update posted live • 16 May 2013 (me) Comprehensive update posted live • 24 January 2006 (me) Comprehensive update posted live • 24 April 2003 (me) Comprehensive update posted live • 22 October 1999 (me) Review posted live • 12 May 1999 (dc) Original submission ## Key Sections in this ## References ## Literature Cited	[]	22/10/1999	12/1/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ws1	ws1	[ "Paired box protein Pax-3", "PAX3", "Waardenburg Syndrome Type I" ]	Waardenburg Syndrome Type I	Jeff Mark Milunsky	Summary Waardenburg syndrome type I (WS1) is an auditory-pigmentary disorder comprising congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin along with dystopia canthorum (lateral displacement of the inner canthi). The hearing loss in WS1, observed in approximately 60% of affected individuals, is congenital, typically non-progressive, either unilateral or bilateral, and sensorineural. Most commonly, hearing loss in WS1 is bilateral and profound (>100 dB). The majority of individuals with WS1 have either a white forelock or early graying of the scalp hair before age 30 years. The classic white forelock observed in approximately 45% of individuals is the most common hair pigmentation anomaly seen in WS1. Affected individuals may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides. Congenital leukoderma is frequently seen on the face, trunk, or limbs. The diagnosis of WS1 is established in most individuals by physical examination for clinical criteria including: sensorineural hearing loss, pigmentary changes in the hair and eyes, dystopia canthorum identified by calculation of the W index, and specific facial features. Identification of a heterozygous Waardenburg syndrome type I (WS1) is inherited in an autosomal dominant manner. The majority of probands have an affected parent. A minority of probands do not have an affected parent and are presumed to have WS1 as a result of a	## Diagnosis Waardenburg syndrome type I (WS1) Congenital sensorineural hearing loss White forelock, hair hypopigmentation Pigmentation abnormality of the iris: Complete heterochromia iridum (irides of different color) Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) Hypoplastic blue irides or brilliant blue irides Dystopia canthorum, W index >1.95 (See Affected first-degree relative Skin hypopigmentation (congenital leukoderma) Synophrys and/or medial eyebrow flare Broad/high nasal root, low-hanging columella Underdeveloped alae nasi Premature gray hair (age <30 years) Calculate X = (2a – [0.2119c + 3.909])/c Calculate Y = (2a – [0.2479b + 3.909])/b Calculate W = X + Y + a/b Click The clinical diagnosis of WS1 Identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Waardenburg Syndrome Type I NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One individual with a clinical diagnosis of Waardenburg syndrome type 1 (WS1) was found to have a heterozygous pathogenic variant in • Congenital sensorineural hearing loss • White forelock, hair hypopigmentation • Pigmentation abnormality of the iris: • Complete heterochromia iridum (irides of different color) • Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) • Hypoplastic blue irides or brilliant blue irides • Complete heterochromia iridum (irides of different color) • Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) • Hypoplastic blue irides or brilliant blue irides • Dystopia canthorum, W index >1.95 (See • Affected first-degree relative • Complete heterochromia iridum (irides of different color) • Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) • Hypoplastic blue irides or brilliant blue irides • Skin hypopigmentation (congenital leukoderma) • Synophrys and/or medial eyebrow flare • Broad/high nasal root, low-hanging columella • Underdeveloped alae nasi • Premature gray hair (age <30 years) ## Suggestive Findings Waardenburg syndrome type I (WS1) Congenital sensorineural hearing loss White forelock, hair hypopigmentation Pigmentation abnormality of the iris: Complete heterochromia iridum (irides of different color) Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) Hypoplastic blue irides or brilliant blue irides Dystopia canthorum, W index >1.95 (See Affected first-degree relative Skin hypopigmentation (congenital leukoderma) Synophrys and/or medial eyebrow flare Broad/high nasal root, low-hanging columella Underdeveloped alae nasi Premature gray hair (age <30 years) Calculate X = (2a – [0.2119c + 3.909])/c Calculate Y = (2a – [0.2479b + 3.909])/b Calculate W = X + Y + a/b Click • Congenital sensorineural hearing loss • White forelock, hair hypopigmentation • Pigmentation abnormality of the iris: • Complete heterochromia iridum (irides of different color) • Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) • Hypoplastic blue irides or brilliant blue irides • Complete heterochromia iridum (irides of different color) • Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) • Hypoplastic blue irides or brilliant blue irides • Dystopia canthorum, W index >1.95 (See • Affected first-degree relative • Complete heterochromia iridum (irides of different color) • Partial/segmental heterochromia (two different colors in same iris, typically brown and blue) • Hypoplastic blue irides or brilliant blue irides • Skin hypopigmentation (congenital leukoderma) • Synophrys and/or medial eyebrow flare • Broad/high nasal root, low-hanging columella • Underdeveloped alae nasi • Premature gray hair (age <30 years) ## Establishing the Diagnosis The clinical diagnosis of WS1 Identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Waardenburg Syndrome Type I NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One individual with a clinical diagnosis of Waardenburg syndrome type 1 (WS1) was found to have a heterozygous pathogenic variant in ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Waardenburg Syndrome Type I NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One individual with a clinical diagnosis of Waardenburg syndrome type 1 (WS1) was found to have a heterozygous pathogenic variant in ## Clinical Characteristics The phenotype of Waardenburg syndrome type I (WS1) is variable even within a family. Waardenburg Syndrome Type I: Frequency of Select Features Based on Various temporal bone abnormalities have been identified in persons with WS1 and hearing loss [ The hypopigmentation can also involve the eyebrows and eyelashes. Cleft lip and palate Spina bifida. This finding is not surprising given that WS1 is considered a neurocristopathy, with Vestibular symptoms, including vertigo, dizziness, and balance difficulties, even without hearing loss [ Penetrance is likely almost complete. It is difficult to quote a figure for the prevalence of WS1 without population-based molecular analysis. The prevalence figures vary from 1:20,000 to 1:40,000, accounting for approximately 3% of congenitally deaf children [ • Cleft lip and palate • Spina bifida. This finding is not surprising given that WS1 is considered a neurocristopathy, with • Vestibular symptoms, including vertigo, dizziness, and balance difficulties, even without hearing loss [ ## Clinical Description The phenotype of Waardenburg syndrome type I (WS1) is variable even within a family. Waardenburg Syndrome Type I: Frequency of Select Features Based on Various temporal bone abnormalities have been identified in persons with WS1 and hearing loss [ The hypopigmentation can also involve the eyebrows and eyelashes. Cleft lip and palate Spina bifida. This finding is not surprising given that WS1 is considered a neurocristopathy, with Vestibular symptoms, including vertigo, dizziness, and balance difficulties, even without hearing loss [ • Cleft lip and palate • Spina bifida. This finding is not surprising given that WS1 is considered a neurocristopathy, with • Vestibular symptoms, including vertigo, dizziness, and balance difficulties, even without hearing loss [ ## Genotype-Phenotype Correlations ## Penetrance Penetrance is likely almost complete. ## Prevalence It is difficult to quote a figure for the prevalence of WS1 without population-based molecular analysis. The prevalence figures vary from 1:20,000 to 1:40,000, accounting for approximately 3% of congenitally deaf children [ ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in WS1 = Waardenburg syndrome type 1 In a consanguineous Turkish family, both parents, who are heterozygous for the ## Differential Diagnosis Waardenburg syndrome type I (WS1) needs to be differentiated from other causes of congenital, non-progressive sensorineural hearing loss (see Comparison of Clinical Features in Waardenburg Syndrome Type I and Waardenburg Syndrome Type II Based on WS1 = Waardenburg syndrome type I; WS2 = Waardenburg syndrome type II Genes of Interest in the Differential Diagnosis of Waardenburg Syndrome Type I AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; WS = Waardenburg syndrome; WS2 = Waardenburg syndrome type II; WS4 = Waardenburg syndrome type IV Bilateral agenesis or hypoplasia of the semicircular canals with a cochlear deformity and enlarged vestibule ## Management To establish the extent of disease and needs in an individual diagnosed with Waardenburg syndrome type I (WS1), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Audiology evaluation Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of WS1 in order to facilitate medical and personal decision making Management of the hearing loss associated with WS1 depends on its severity (see The hearing loss in WS1 is typically non-progressive. Hence, repeat audiogram would usually not be necessary. It is appropriate to evaluate at-risk relatives of an affected individual to allow early screening of those at risk for hearing loss. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Physical examination for the clinical features of WS1 and audiology evaluation if the pathogenic variant in the family is not known. See Folic acid supplementation in pregnancy has been recommended for women at increased risk of having a child with WS1, given the possibly increased risk of neural tube defects in association with WS1 [ Search • Audiology evaluation • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of WS1 in order to facilitate medical and personal decision making • Molecular genetic testing if the pathogenic variant in the family is known; • Physical examination for the clinical features of WS1 and audiology evaluation if the pathogenic variant in the family is not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Waardenburg syndrome type I (WS1), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Audiology evaluation Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of WS1 in order to facilitate medical and personal decision making • Audiology evaluation • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of WS1 in order to facilitate medical and personal decision making ## Treatment of Manifestations Management of the hearing loss associated with WS1 depends on its severity (see ## Surveillance The hearing loss in WS1 is typically non-progressive. Hence, repeat audiogram would usually not be necessary. ## Evaluation of Relatives at Risk It is appropriate to evaluate at-risk relatives of an affected individual to allow early screening of those at risk for hearing loss. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Physical examination for the clinical features of WS1 and audiology evaluation if the pathogenic variant in the family is not known. See • Molecular genetic testing if the pathogenic variant in the family is known; • Physical examination for the clinical features of WS1 and audiology evaluation if the pathogenic variant in the family is not known. ## Pregnancy Management Folic acid supplementation in pregnancy has been recommended for women at increased risk of having a child with WS1, given the possibly increased risk of neural tube defects in association with WS1 [ ## Therapies Under Investigation Search ## Genetic Counseling Waardenburg syndrome type I (WS1) is inherited in an autosomal dominant manner. The majority of individuals diagnosed with WS1 have an affected parent. A minority of individuals diagnosed with WS1 do not have an affected parent and are presumed to have a Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) can include the following: Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ The family history of some individuals diagnosed with WS1 may appear to be negative because of a milder phenotypic presentation in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected and/or is known to have the Intrafamilial clinical variability is observed in WS1. The clinical manifestations in a sib who inherits a If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism [ Each child of an individual with WS1 has a 50% chance of inheriting the The clinical manifestations in the offspring who inherit a See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The majority of individuals diagnosed with WS1 have an affected parent. • A minority of individuals diagnosed with WS1 do not have an affected parent and are presumed to have a • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) can include the following: • Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram • If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling • Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram • If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The family history of some individuals diagnosed with WS1 may appear to be negative because of a milder phenotypic presentation in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram • If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • If a parent of the proband is affected and/or is known to have the • Intrafamilial clinical variability is observed in WS1. The clinical manifestations in a sib who inherits a • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism [ • Each child of an individual with WS1 has a 50% chance of inheriting the • The clinical manifestations in the offspring who inherit a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected. ## Mode of Inheritance Waardenburg syndrome type I (WS1) is inherited in an autosomal dominant manner. ## Risk to Family Members The majority of individuals diagnosed with WS1 have an affected parent. A minority of individuals diagnosed with WS1 do not have an affected parent and are presumed to have a Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) can include the following: Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ The family history of some individuals diagnosed with WS1 may appear to be negative because of a milder phenotypic presentation in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected and/or is known to have the Intrafamilial clinical variability is observed in WS1. The clinical manifestations in a sib who inherits a If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism [ Each child of an individual with WS1 has a 50% chance of inheriting the The clinical manifestations in the offspring who inherit a • The majority of individuals diagnosed with WS1 have an affected parent. • A minority of individuals diagnosed with WS1 do not have an affected parent and are presumed to have a • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) can include the following: • Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram • If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling • Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram • If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The family history of some individuals diagnosed with WS1 may appear to be negative because of a milder phenotypic presentation in a parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • Examination for clinical manifestations of WS1 by assessing facial features, calculating the W index, examining skin and hair for hypopigmentation, and obtaining an audiogram • If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • If a parent of the proband is affected and/or is known to have the • Intrafamilial clinical variability is observed in WS1. The clinical manifestations in a sib who inherits a • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism [ • Each child of an individual with WS1 has a 50% chance of inheriting the • The clinical manifestations in the offspring who inherit a ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • • • • • • ## Molecular Genetics Waardenburg Syndrome Type I: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Waardenburg Syndrome Type I ( Notable Variants listed in the table have been provided by the author. Somatic ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the author. ## Cancer and Benign Tumors Somatic ## Chapter Notes Dr Milunsky was previously a Professor in the Department of Pediatrics, Genetics, and Genomics at Boston University School of Medicine. He is currently the Co-Director of the Center for Human Genetics, Inc (Cambridge, MA), where he also serves as Senior Molecular Director and Director of Clinical Genetics. His interest in Waardenburg syndrome predates the identification of 20 October 2022 (sw) Comprehensive update posted live 4 May 2017 (sw) Revision: 12 January 2017 (sw) Comprehensive update posted live 7 August 2014 (me) Comprehensive update posted live 29 December 2011 (me) Comprehensive update posted live 4 August 2009 (me) Comprehensive update posted live 19 April 2007 (jm) Revision: deletion/duplication analysis clinically available 17 January 2006 (me) Comprehensive update posted live 22 October 2003 (me) Comprehensive update posted live 30 July 2001 (me) Review posted live 12 February 2001 (jm) Original submission • 20 October 2022 (sw) Comprehensive update posted live • 4 May 2017 (sw) Revision: • 12 January 2017 (sw) Comprehensive update posted live • 7 August 2014 (me) Comprehensive update posted live • 29 December 2011 (me) Comprehensive update posted live • 4 August 2009 (me) Comprehensive update posted live • 19 April 2007 (jm) Revision: deletion/duplication analysis clinically available • 17 January 2006 (me) Comprehensive update posted live • 22 October 2003 (me) Comprehensive update posted live • 30 July 2001 (me) Review posted live • 12 February 2001 (jm) Original submission ## Author Notes Dr Milunsky was previously a Professor in the Department of Pediatrics, Genetics, and Genomics at Boston University School of Medicine. He is currently the Co-Director of the Center for Human Genetics, Inc (Cambridge, MA), where he also serves as Senior Molecular Director and Director of Clinical Genetics. His interest in Waardenburg syndrome predates the identification of ## Revision History 20 October 2022 (sw) Comprehensive update posted live 4 May 2017 (sw) Revision: 12 January 2017 (sw) Comprehensive update posted live 7 August 2014 (me) Comprehensive update posted live 29 December 2011 (me) Comprehensive update posted live 4 August 2009 (me) Comprehensive update posted live 19 April 2007 (jm) Revision: deletion/duplication analysis clinically available 17 January 2006 (me) Comprehensive update posted live 22 October 2003 (me) Comprehensive update posted live 30 July 2001 (me) Review posted live 12 February 2001 (jm) Original submission • 20 October 2022 (sw) Comprehensive update posted live • 4 May 2017 (sw) Revision: • 12 January 2017 (sw) Comprehensive update posted live • 7 August 2014 (me) Comprehensive update posted live • 29 December 2011 (me) Comprehensive update posted live • 4 August 2009 (me) Comprehensive update posted live • 19 April 2007 (jm) Revision: deletion/duplication analysis clinically available • 17 January 2006 (me) Comprehensive update posted live • 22 October 2003 (me) Comprehensive update posted live • 30 July 2001 (me) Review posted live • 12 February 2001 (jm) Original submission ## References American College of Medical Genetics. Statement on universal newborn hearing screening. Available American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available • American College of Medical Genetics. Statement on universal newborn hearing screening. Available • American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available ## Published Guidelines / Consensus Statements American College of Medical Genetics. Statement on universal newborn hearing screening. Available American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available • American College of Medical Genetics. Statement on universal newborn hearing screening. Available • American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available ## Literature Cited	[ "S Amirsalari, M Ajallouyean, A Saburi, A Haddadi Fard, M Abed, Y. Ghazavi. Cochlear implantation outcomes in children with Waardenburg syndrome.. Eur Arch Otorhinolaryngol. 2012;269:2179-83", "JH Asher, A Sommer, R Morell, TB Friedman. Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome.. Hum Mutat. 1996;7:30-5", "G Birrane, A Soni, JA Ladias. Structural basis for DNA recognition by the human PAX3 homeodomain.. Biochemistry. 2009;48:1148-55", "FO Black, SC Pesznecker, K Allen, C Gianna. A vestibular phenotype for Waardenburg syndrome?. Otol Neurotol. 2001;22:188-94", "K Chen, Y Zhan, X Wu, L Zong, H. Jiang. Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I.. Int J Pediatr Otorhinolaryngol. 2018;104:200-4", "GN Corry, MJ Hendzel, DA Underhill. Subnuclear localization and mobility are key indicators of PAX3 dysfunction in Waardenburg syndrome.. Hum Mol Genet. 2008;17:1825-37", "GN Corry, DA Underhill. Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations.. Pigment Cell Res. 2005;18:427-38", "SM de Sousa Andrade, AR Monteiro, JH Martins, MC Alves, LF Santos Silva, JM Quadros, CA Ribeiro. Cochlear implant rehabilitation outcomes in Waardenburg syndrome children.. Int J Pediatr Otorhinolaryngol. 2012;76:1375-8", "AL DeStefano, LA Cupples, KS Arnos, JH Asher, CT Baldwin, S Blanton, ML Carey, EO da Silva, TB Friedman, J Greenberg, AK Lalwani, A Milunsky, WE Nance, A Pandya, RS Ramesar, AP Read, M Tassabejhi, ER Wilcox, LA Farrer. Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations.. Hum Genet. 1998;102:499-506", "M Elmaleh-Bergès, C Baumann, N Noel-Petroff, A Sekkal, V Couloigner, K Devriendt, M Wilson, S Marlin, G Sebag, V Pingault. Spectrum of temporal bone abnormalities in patients with Waardenburg syndrome and SOX10 mutations.. AJNR Am J Neuroradiol. 2013;34:1257-63", "W Fan, K Ni, F Chen, X Li. Hearing characteristics and cochlear implant effects in children with Waardenburg syndrome: a case series.. Transl Pediatr. 2022;11:1234-41", "LA Farrer, KM Grundfast, J Amos, KS Arnos, JH Asher, P Beighton, SR Diehl, J Fex, C Foy, TB Friedman, J Greenberg, C Hoth, M Marazita, A Milunsky, R Morell, W Nance, V Newton, R Ramesar, TB San Agustin, J Skare, CA Stevens, RG Wagner, ER Wilcox, I Winship, AP Read. Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium.. Am J Hum Genet. 1992;50:902-13", "A Fleming, AJ Copp. Embryonic folate metabolism and mouse neural tube defects.. Science. 1998;280:2107-9", "CF Hoth, A Milunsky, N Lipsky, R Sheffer, SK Clarren, CT Baldwin. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).. Am J Hum Genet. 1993;52:455-62", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97", "IA Jan, L Stroedter, AU Haq, ZU Din. Association of Shah-Waardenburgh syndrome: a review of 6 cases.. J Pediatr Surg. 2008;43:744-7", "S Kapur, S. Karam. Germ-line mosaicism in Waardenburg syndrome.. Clin Genet. 1991;39:194-8", "H Koyama, A Kashio, A Sakata, K Tsutsumiuchi, Y Matsumoto, S Karino, A Kakigi, S Iwasaki, T Yamasoba. The hearing outcomes of cochlear implantation in Waardenburg syndrome.. Biomed Res Int. 2016;2016", "A Kujat, VP Veith, R Faber, UG Froster. Prenatal diagnosis and genetic counseling in a case of spina bifida in a family with Waardenburg syndrome type I.. Fetal Diagn Ther. 2007;22:155-8", "P Lemay, MC Guyot, É Tremblay, A Dionne-Laporte, D Spiegelman, É Henrion, O Diallo, P De Marco, E Merello, C Massicotte, V Désilets, JL Michaud, GA Rouleau, V Capra, Z Kibar. Loss-of-function de novo mutations play an important role in severe human neural tube defects.. J Med Genet. 2015;52:493-7", "W Li, Y Feng, H Chen, C He, L Mei, XZ Liu, M Men. MITF Is Mutated in Type 1 Waardenburg Syndrome with Unusual Phenotype.. Otol Neurotol. 2020;41:e1250-5", "XZ Liu, VE Newton, AP Read. Waardenburg syndrome type II: phenotypic findings and diagnostic criteria.. Am J Med Genet. 1995;55:95-100", "C Madden, MJ Halsted, RJ Hopkin, DI Choo, C Benton, JH Greinwald. Temporal bone abnormalities associated with hearing loss in Waardenburg syndrome.. Laryngoscope. 2003;113:2035-41", "SN Merchant, MJ McKenna, CT Baldwin, A Milunsky, JB Nadol. Otopathology in a case of type I Waardenburg's syndrome.. Ann Otol Rhinol Laryngol. 2001;110:875-82", "JM Milunsky, TA Maher, M Ito, A Milunsky. The value of MLPA in Waardenburg syndrome.. Genet Test. 2007;11:179-82", "SB Minami, K Nara, H Mutai, N Morimoto, H Sakamoto, T Takiguchi, K Kaga, T Matsunaga. A clinical and genetic study of 16 Japanese families with Waardenburg syndrome.. Gene. 2019;704:86-90", "N Morimoto, H Mutai, K Namba, H Kaneko, R Kosaki, T. Matsunaga. Homozygous EDNRB mutation in a patient with Waardenburg syndrome type 1.. Auris Nasus Larynx. 2018;45:222-6", "VE Newton. Clinical features of the Waardenburg syndromes.. Adv Otorhinolaryngol. 2002;61:201-8", "E Pardono, Y van Bever, J van den Ende, PC Havrenne, P Iughetti, SR Maestrelli, F O Costa, A Richieri-Costa, O Frota-Pessoa, PA Otto. Waardenburg syndrome: clinical differentiation between types I and II.. Am J Med Genet A. 2003;117A:223-35", "V Pingault, D Ente, F Dastot-Le Moal, M Goossens, S Marlin, N. Bondurand. Review and update of mutations causing Waardenburg syndrome.. Hum Mutat. 2010;31:391-406", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "CL Shields, SJ Nickerson, S Al-Dahmash, JA Shields. Waardenburg syndrome: iris and choroidal hypopigmentation: findings on anterior and posterior segment imaging.. JAMA Ophthalmol. 2013;131:1167-73", "ML Tamayo, N Gelvez, M Rodriguez, S Florez, C Varon, D Medina, JE Bernal. Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability.. Am J Med Genet A. 2008;146A:1026-31", "Q Wang, WH Fang, J Krupinski, S Kumar, M Slevin, P Kumar. Pax genes in embryogenesis and oncogenesis.. J Cell Mol Med. 2008;12:2281-94", "G Wildhardt, B Zirn, LM Graul-Neumann, J Wechtenbruch, M Suckfull, A Buske, A Bohring, C Kubisch, S Vogt, G Strobl-Wildemann, M Greally, O Bartsch, D Steinberger. Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics.. BMJ Open. 2013;3", "B Wollnik, T Tukel, O Uyguner, A Ghanbari, H Kayserili, M Emiroglu, M Yuksel-Apak. Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome.. Am J Med Genet A. 2003;122A:42-5", "TF Wu, YL Yao, IL Lai, CC Lai, PL Lin, WM Yang. Loading of PAX3 to Mitotic Chromosomes Is Mediated by Arginine Methylation and Associated with Waardenburg Syndrome.. J Biol Chem. 2015;290:20556-64", "S Yang, P Dai, X Liu, D Kang, X Zhang, W Yang, C Zhou, S Yang, H Yuan. Genetic and phenotypic heterogeneity in Chinese patients with Waardenburg syndrome type II.. PLoS One. 2013;8" ]	30/7/2001	20/10/2022	4/5/2017	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
wss	wss	[ "Hypogonadism, Alopecia, Diabetes Mellitus, Intellectual Disability, and Extrapyramidal Syndrome", "Hypogonadism, Alopecia, Diabetes Mellitus, Intellectual Disability, and Extrapyramidal Syndrome", "DDB1- and CUL4-associated factor 17", "DCAF17", "Woodhouse-Sakati Syndrome" ]	Woodhouse-Sakati Syndrome	Saeed A Bohlega, Ali Abusrair	Summary Virtually all individuals with Woodhouse-Sakati syndrome (WSS) have the endocrine findings of hypogonadism (evident at puberty) and progressive childhood-onset hair thinning that often progresses to alopecia totalis in adulthood. More than half of individuals have the neurologic findings of progressive extrapyramidal movements (dystonic spasms with dystonic posturing with dysarthria and dysphagia), moderate bilateral postlingual sensorineural hearing loss, and mild intellectual disability. To date, more than 40 families (including 33 with a molecularly confirmed diagnosis) with a total of 88 affected individuals have been reported in the literature. The diagnosis of WSS is established in a proband with suggestive clinical, neuroimaging, and neurophysiologic findings by identification of biallelic pathogenic variants in WSS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic	## Diagnosis No consensus clinical diagnostic criteria for Woodhouse-Sakati syndrome (WSS) have been published. WSS Hypogonadism (100% of individuals), hypogonadotropic in males and hypergonadotropic in females Primary amenorrhea in females Lack of development of secondary sexual characteristics in males and females Low insulin-like growth factor 1 (IGF-1) (100%) Adolescent- to young adult-onset diabetes mellitus (66%) Hypothyroidism (30%) Adolescent to young-adult onset of extrapyramidal findings including focal (later generalized) dystonia (65%), chorea, dysarthria, and dysphagia Sensorineural hearing loss (SNHL) with onset in childhood (62%) Intellectual disability (58%) Partially empty sella and a small pituitary gland ( Progressive frontoparietal/periventricular white matter lesions ( Iron deposition in the globus pallidus ( Rarely, prominent perivascular spaces and diffusion restriction involving the splenium of the corpus callosum ( Prolonged P100 latencies on pattern reversal visual EPs Prolonged cortical N19 response on median somatosensory EPs Absent or prolonged P37 cortical response on tibial somatosensory EPs The diagnosis of WSS Molecular testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: Targeted analysis for individuals who are Saudi Arabian or Qatari may be performed first. To date, all affected individuals in these populations have been homozygous for the same founder pathogenic variant, For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Woodhouse-Sakati Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Hypogonadism (100% of individuals), hypogonadotropic in males and hypergonadotropic in females • Primary amenorrhea in females • Lack of development of secondary sexual characteristics in males and females • Primary amenorrhea in females • Lack of development of secondary sexual characteristics in males and females • Low insulin-like growth factor 1 (IGF-1) (100%) • Adolescent- to young adult-onset diabetes mellitus (66%) • Hypothyroidism (30%) • Primary amenorrhea in females • Lack of development of secondary sexual characteristics in males and females • Adolescent to young-adult onset of extrapyramidal findings including focal (later generalized) dystonia (65%), chorea, dysarthria, and dysphagia • Sensorineural hearing loss (SNHL) with onset in childhood (62%) • Intellectual disability (58%) • Partially empty sella and a small pituitary gland ( • Progressive frontoparietal/periventricular white matter lesions ( • Iron deposition in the globus pallidus ( • Rarely, prominent perivascular spaces and diffusion restriction involving the splenium of the corpus callosum ( • Prolonged P100 latencies on pattern reversal visual EPs • Prolonged cortical N19 response on median somatosensory EPs • Absent or prolonged P37 cortical response on tibial somatosensory EPs ## Suggestive Findings WSS Hypogonadism (100% of individuals), hypogonadotropic in males and hypergonadotropic in females Primary amenorrhea in females Lack of development of secondary sexual characteristics in males and females Low insulin-like growth factor 1 (IGF-1) (100%) Adolescent- to young adult-onset diabetes mellitus (66%) Hypothyroidism (30%) Adolescent to young-adult onset of extrapyramidal findings including focal (later generalized) dystonia (65%), chorea, dysarthria, and dysphagia Sensorineural hearing loss (SNHL) with onset in childhood (62%) Intellectual disability (58%) Partially empty sella and a small pituitary gland ( Progressive frontoparietal/periventricular white matter lesions ( Iron deposition in the globus pallidus ( Rarely, prominent perivascular spaces and diffusion restriction involving the splenium of the corpus callosum ( Prolonged P100 latencies on pattern reversal visual EPs Prolonged cortical N19 response on median somatosensory EPs Absent or prolonged P37 cortical response on tibial somatosensory EPs • Hypogonadism (100% of individuals), hypogonadotropic in males and hypergonadotropic in females • Primary amenorrhea in females • Lack of development of secondary sexual characteristics in males and females • Primary amenorrhea in females • Lack of development of secondary sexual characteristics in males and females • Low insulin-like growth factor 1 (IGF-1) (100%) • Adolescent- to young adult-onset diabetes mellitus (66%) • Hypothyroidism (30%) • Primary amenorrhea in females • Lack of development of secondary sexual characteristics in males and females • Adolescent to young-adult onset of extrapyramidal findings including focal (later generalized) dystonia (65%), chorea, dysarthria, and dysphagia • Sensorineural hearing loss (SNHL) with onset in childhood (62%) • Intellectual disability (58%) • Partially empty sella and a small pituitary gland ( • Progressive frontoparietal/periventricular white matter lesions ( • Iron deposition in the globus pallidus ( • Rarely, prominent perivascular spaces and diffusion restriction involving the splenium of the corpus callosum ( • Prolonged P100 latencies on pattern reversal visual EPs • Prolonged cortical N19 response on median somatosensory EPs • Absent or prolonged P37 cortical response on tibial somatosensory EPs ## Supportive Findings Partially empty sella and a small pituitary gland ( Progressive frontoparietal/periventricular white matter lesions ( Iron deposition in the globus pallidus ( Rarely, prominent perivascular spaces and diffusion restriction involving the splenium of the corpus callosum ( Prolonged P100 latencies on pattern reversal visual EPs Prolonged cortical N19 response on median somatosensory EPs Absent or prolonged P37 cortical response on tibial somatosensory EPs • Partially empty sella and a small pituitary gland ( • Progressive frontoparietal/periventricular white matter lesions ( • Iron deposition in the globus pallidus ( • Rarely, prominent perivascular spaces and diffusion restriction involving the splenium of the corpus callosum ( • Prolonged P100 latencies on pattern reversal visual EPs • Prolonged cortical N19 response on median somatosensory EPs • Absent or prolonged P37 cortical response on tibial somatosensory EPs ## Establishing the Diagnosis The diagnosis of WSS Molecular testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: Targeted analysis for individuals who are Saudi Arabian or Qatari may be performed first. To date, all affected individuals in these populations have been homozygous for the same founder pathogenic variant, For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Woodhouse-Sakati Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 Note: Targeted analysis for individuals who are Saudi Arabian or Qatari may be performed first. To date, all affected individuals in these populations have been homozygous for the same founder pathogenic variant, For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Woodhouse-Sakati Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Woodhouse-Sakati syndrome (WSS) is characterized by the endocrine findings of hypogonadism, diabetes mellitus, and hypothyroidism and progressive childhood-onset alopecia along with neurologic findings of progressive extrapyramidal movements, sensorineural hearing loss, and intellectual disability. To date, 88 individuals from more than 40 families have been reported [ Two clinical types of WSS have been described [ Women typically have primary amenorrhea. Detailed endocrine investigation in more than 50 of the women described in the literature typically revealed severely reduced or absent estradiol and high FSH and LH, consistent with hypergonadotropic hypogonadism. There appears to be decreased hypothalamic-pituitary responsiveness, as the FSH and LH are not as high as expected for the degree of ovarian failure [ The ovaries are streak or underdeveloped, and not visualized by laparotomy, laparoscopy, or autopsy [ Men have moderately low testosterone and – in contrast to women – inappropriately low gonadotropins, consistent with hypogonadotropic hypogonadism, which may be of central or central and peripheral etiology. Semen analysis may show azoospermia [ Although the testes are of normal size, testicular biopsy reveals reduced spermatogenesis with predominance of Sertoli cells and few Leydig cells [ The growth pattern is normal and growth hormone levels are usually normal; short stature is not a part of this syndrome [ Scanning electron microscopy of the hair shows longitudinal grooves with no specific abnormalities [ In a majority of individuals, dystonia becomes generalized and disabling ( Inter- and intrafamilial variability is common [ Polyneuropathy with stocking glove sensory loss and diminished deep tendon reflexes but normal strength has been reported [ There is no clear genotype-phenotype correlation. Even individuals with the same Saudi Arabian founder To date, more than 40 families with an estimated 88 affected individuals have been reported. Of these, 51 individuals from 33 families have had the diagnosis confirmed molecularly. The carrier frequency of the Saudi Arabian founder variant ( ## Clinical Description Woodhouse-Sakati syndrome (WSS) is characterized by the endocrine findings of hypogonadism, diabetes mellitus, and hypothyroidism and progressive childhood-onset alopecia along with neurologic findings of progressive extrapyramidal movements, sensorineural hearing loss, and intellectual disability. To date, 88 individuals from more than 40 families have been reported [ Two clinical types of WSS have been described [ Women typically have primary amenorrhea. Detailed endocrine investigation in more than 50 of the women described in the literature typically revealed severely reduced or absent estradiol and high FSH and LH, consistent with hypergonadotropic hypogonadism. There appears to be decreased hypothalamic-pituitary responsiveness, as the FSH and LH are not as high as expected for the degree of ovarian failure [ The ovaries are streak or underdeveloped, and not visualized by laparotomy, laparoscopy, or autopsy [ Men have moderately low testosterone and – in contrast to women – inappropriately low gonadotropins, consistent with hypogonadotropic hypogonadism, which may be of central or central and peripheral etiology. Semen analysis may show azoospermia [ Although the testes are of normal size, testicular biopsy reveals reduced spermatogenesis with predominance of Sertoli cells and few Leydig cells [ The growth pattern is normal and growth hormone levels are usually normal; short stature is not a part of this syndrome [ Scanning electron microscopy of the hair shows longitudinal grooves with no specific abnormalities [ In a majority of individuals, dystonia becomes generalized and disabling ( Inter- and intrafamilial variability is common [ Polyneuropathy with stocking glove sensory loss and diminished deep tendon reflexes but normal strength has been reported [ ## Endocrine Women typically have primary amenorrhea. Detailed endocrine investigation in more than 50 of the women described in the literature typically revealed severely reduced or absent estradiol and high FSH and LH, consistent with hypergonadotropic hypogonadism. There appears to be decreased hypothalamic-pituitary responsiveness, as the FSH and LH are not as high as expected for the degree of ovarian failure [ The ovaries are streak or underdeveloped, and not visualized by laparotomy, laparoscopy, or autopsy [ Men have moderately low testosterone and – in contrast to women – inappropriately low gonadotropins, consistent with hypogonadotropic hypogonadism, which may be of central or central and peripheral etiology. Semen analysis may show azoospermia [ Although the testes are of normal size, testicular biopsy reveals reduced spermatogenesis with predominance of Sertoli cells and few Leydig cells [ The growth pattern is normal and growth hormone levels are usually normal; short stature is not a part of this syndrome [ ## Ectodermal Scanning electron microscopy of the hair shows longitudinal grooves with no specific abnormalities [ ## Neurologic In a majority of individuals, dystonia becomes generalized and disabling ( Inter- and intrafamilial variability is common [ Polyneuropathy with stocking glove sensory loss and diminished deep tendon reflexes but normal strength has been reported [ ## Other Findings ## Genotype-Phenotype Correlations There is no clear genotype-phenotype correlation. Even individuals with the same Saudi Arabian founder ## Prevalence To date, more than 40 families with an estimated 88 affected individuals have been reported. Of these, 51 individuals from 33 families have had the diagnosis confirmed molecularly. The carrier frequency of the Saudi Arabian founder variant ( ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders/Phenotypes to Consider in the Differential Diagnosis of Woodhouse-Sakati Syndrome – = not associated with this disorder; + = associated with this disorder; AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GnRH gonadotropin-releasing hormone; IGD = isolated gonadotropin-releasing hormone deficiency; KS = Kallmann syndrome; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked Listed genes represent the most common genetic causes; see Eight of the ten genetically defined types of neurodegeneration with brain iron accumulation are inherited in an autosomal recessive manner. Exceptions are: Almost all individuals with Hutchinson-Gilford progeria syndrome have the disorder as the result of a Only one family reported to date according to OMIM See The diagnosis of deafness-dystonia-optic neuronopathy is established in either a male proband who has a hemizygous Other disorders to consider in the differential diagnosis of Woodhouse-Sakati syndrome (WSS): ## Management To establish the extent of disease and needs in an individual diagnosed with Woodhouse-Sakati syndrome (WSS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Woodhouse-Sakati Syndrome Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism. Serum IGF-1 Fasting glucose level, hemoglobin A1c, or oral glucose tolerance test Thyroid function studies incl TSH & free T4 MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse No specific treatment exists for WSS. Treatment is aimed at relieving symptoms [ Treatment of Manifestations in Individuals with Woodhouse-Sakati Syndrome Anticholinergics (e.g., trihexyphenidyl) are moderately effective in 40%-50%. Baclofen (Lioresal Benzodiazepines, especially clonazepam Other medications tried alone or in combination w/the above: levodopa, carbamazepine, & dopamine depleting agents (reserpine, tetrabenazine) Trihexyphenidyl can be titrated to high doses (~100 mg/day) in younger persons. Anticholinergic side effects, esp cognitive effects, must be monitored closely. If medications fail, surgery to enable deep-brain stimulation of the globus pallidus interna has been an effective treatment for some forms of medically refractory primary generalized dystonia [ Oral secretions in those w/bulbar symptoms can be ↓ w/tricylic antidepressants & anticholinergic agents, thus reducing need for suctioning. Swallowing difficulties can be alleviated by thickening liquids & pureeing solid food, & eventually using a gastrostomy tube to help maintain caloric intake & hydration. Nutritional mgmt by a knowledgeable nutritionist is helpful. Recommended Surveillance for Individuals with Woodhouse-Sakati Syndrome Persons with dystonia should avoid situations in which the risk of falling is increased. Molecular genetic testing for known familial See Search • Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism. • Serum IGF-1 • Fasting glucose level, hemoglobin A1c, or oral glucose tolerance test • Thyroid function studies incl TSH & free T4 • Anticholinergics (e.g., trihexyphenidyl) are moderately effective in 40%-50%. • Baclofen (Lioresal • Benzodiazepines, especially clonazepam • Other medications tried alone or in combination w/the above: levodopa, carbamazepine, & dopamine depleting agents (reserpine, tetrabenazine) • Trihexyphenidyl can be titrated to high doses (~100 mg/day) in younger persons. • Anticholinergic side effects, esp cognitive effects, must be monitored closely. • If medications fail, surgery to enable deep-brain stimulation of the globus pallidus interna has been an effective treatment for some forms of medically refractory primary generalized dystonia [ • Oral secretions in those w/bulbar symptoms can be ↓ w/tricylic antidepressants & anticholinergic agents, thus reducing need for suctioning. • Swallowing difficulties can be alleviated by thickening liquids & pureeing solid food, & eventually using a gastrostomy tube to help maintain caloric intake & hydration. • Nutritional mgmt by a knowledgeable nutritionist is helpful. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Woodhouse-Sakati syndrome (WSS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Woodhouse-Sakati Syndrome Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism. Serum IGF-1 Fasting glucose level, hemoglobin A1c, or oral glucose tolerance test Thyroid function studies incl TSH & free T4 MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism. • Serum IGF-1 • Fasting glucose level, hemoglobin A1c, or oral glucose tolerance test • Thyroid function studies incl TSH & free T4 ## Treatment of Manifestations No specific treatment exists for WSS. Treatment is aimed at relieving symptoms [ Treatment of Manifestations in Individuals with Woodhouse-Sakati Syndrome Anticholinergics (e.g., trihexyphenidyl) are moderately effective in 40%-50%. Baclofen (Lioresal Benzodiazepines, especially clonazepam Other medications tried alone or in combination w/the above: levodopa, carbamazepine, & dopamine depleting agents (reserpine, tetrabenazine) Trihexyphenidyl can be titrated to high doses (~100 mg/day) in younger persons. Anticholinergic side effects, esp cognitive effects, must be monitored closely. If medications fail, surgery to enable deep-brain stimulation of the globus pallidus interna has been an effective treatment for some forms of medically refractory primary generalized dystonia [ Oral secretions in those w/bulbar symptoms can be ↓ w/tricylic antidepressants & anticholinergic agents, thus reducing need for suctioning. Swallowing difficulties can be alleviated by thickening liquids & pureeing solid food, & eventually using a gastrostomy tube to help maintain caloric intake & hydration. Nutritional mgmt by a knowledgeable nutritionist is helpful. • Anticholinergics (e.g., trihexyphenidyl) are moderately effective in 40%-50%. • Baclofen (Lioresal • Benzodiazepines, especially clonazepam • Other medications tried alone or in combination w/the above: levodopa, carbamazepine, & dopamine depleting agents (reserpine, tetrabenazine) • Trihexyphenidyl can be titrated to high doses (~100 mg/day) in younger persons. • Anticholinergic side effects, esp cognitive effects, must be monitored closely. • If medications fail, surgery to enable deep-brain stimulation of the globus pallidus interna has been an effective treatment for some forms of medically refractory primary generalized dystonia [ • Oral secretions in those w/bulbar symptoms can be ↓ w/tricylic antidepressants & anticholinergic agents, thus reducing need for suctioning. • Swallowing difficulties can be alleviated by thickening liquids & pureeing solid food, & eventually using a gastrostomy tube to help maintain caloric intake & hydration. • Nutritional mgmt by a knowledgeable nutritionist is helpful. ## Surveillance Recommended Surveillance for Individuals with Woodhouse-Sakati Syndrome ## Agents/Circumstances to Avoid Persons with dystonia should avoid situations in which the risk of falling is increased. ## Evaluation of Relatives at Risk Molecular genetic testing for known familial See ## Therapies Under Investigation Search ## Genetic Counseling Woodhouse-Sakati syndrome (WSS) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a The neurologic phenotype in a sib who inherits biallelic pathogenic variants cannot be predicted based on the phenotype in the proband; an affected sib may have a neurologic phenotype ranging from normal to severe regardless of the neurologic features observed in the proband [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • The neurologic phenotype in a sib who inherits biallelic pathogenic variants cannot be predicted based on the phenotype in the proband; an affected sib may have a neurologic phenotype ranging from normal to severe regardless of the neurologic features observed in the proband [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Woodhouse-Sakati syndrome (WSS) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a The neurologic phenotype in a sib who inherits biallelic pathogenic variants cannot be predicted based on the phenotype in the proband; an affected sib may have a neurologic phenotype ranging from normal to severe regardless of the neurologic features observed in the proband [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • The neurologic phenotype in a sib who inherits biallelic pathogenic variants cannot be predicted based on the phenotype in the proband; an affected sib may have a neurologic phenotype ranging from normal to severe regardless of the neurologic features observed in the proband [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Center of Excellence for NBIA Clinical Care and Research International Registry for NBIA and Related Disorders Oregon Health & Science University Germany • • • • • • United Kingdom • • • Center of Excellence for NBIA Clinical Care and Research • International Registry for NBIA and Related Disorders • Oregon Health & Science University • • • Germany • ## Molecular Genetics Woodhouse-Sakati Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Woodhouse-Sakati Syndrome ( Alternate splicing of Reported Of the 33 families with molecularly confirmed WSS, biallelic compound heterozygous Notable Variants listed in the table have been provided by the authors. This variant has the same nucleotide and protein change designations for either transcript variant ## Molecular Pathogenesis Alternate splicing of Reported Of the 33 families with molecularly confirmed WSS, biallelic compound heterozygous Notable Variants listed in the table have been provided by the authors. This variant has the same nucleotide and protein change designations for either transcript variant ## Chapter Notes Ali Abusrair, MD (2021-present)Fowzan S Alkuraya, MD (Hons), ABP, ABMGG; King Faisal Specialist Hospital and Research Center (2016-2021)Saeed A Bohlega, MD, FRCPC, FAAN (2016-present) 8 July 2021 (sw) Comprehensive update posted live 4 August 2016 (bp) Review posted live 2 February 2016 (sab) Original submission • 8 July 2021 (sw) Comprehensive update posted live • 4 August 2016 (bp) Review posted live • 2 February 2016 (sab) Original submission ## Author History Ali Abusrair, MD (2021-present)Fowzan S Alkuraya, MD (Hons), ABP, ABMGG; King Faisal Specialist Hospital and Research Center (2016-2021)Saeed A Bohlega, MD, FRCPC, FAAN (2016-present) ## Revision History 8 July 2021 (sw) Comprehensive update posted live 4 August 2016 (bp) Review posted live 2 February 2016 (sab) Original submission • 8 July 2021 (sw) Comprehensive update posted live • 4 August 2016 (bp) Review posted live • 2 February 2016 (sab) Original submission ## References ## Literature Cited Affected individuals from different families with WSS who have variable degrees of alopecia or hair loss and neurologic involvement A. Male age 23 with flat occiput; temporal and frontal alopecia B. Female age 19 with dystonia involving neck, face, mouth, and tongue, arms, and hands C. Female age 35 with sparse, short hair, flat occiput, low-set ears, and retrocollis D. Male age 14 with sparse hair E. Female age 25 with alopecia and wasting of the facial and temporal muscles F. Male age 17 with dystonic posturing and lack of breast tissue G. Male age 21 with sparse hair with temporal hair loss; long face H. Male age 32 with severe generalized dystonia with alopecia totalis Brain MRI of individuals with WSS. Arrows indicate the following findings: A. Sagittal T B-C. Fluid-attenuated inversion recovery (FLAIR) demonstrating variable degrees of white matter signal intensities at different stages of the disease. D. T E-F. Diffusion-weighted imaging (DWI) showing diffusion restriction involving the splenium of the corpus callosum.	[ "MC Abdulla, AM Alazami, J Alungal, JM Koya, M Musambil. Novel compound heterozygous frameshift mutations of C2orf37 in a familial Indian case of Woodhouse-Sakati syndrome.. J Genet. 2015;94:489-92", "M Abouelhoda, T Sobahy, M El-Kalioby, N Patel, H Shamseldin, D Monies, N Al-Tassan, K Ramzan, F Imtiaz, R Shaheen, FS Alkuraya. Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden.. Genet Med. 2016;18:1244-9", "A Abusrair, I AlHamoud, S Bohlega. Multimodal evoked potential profiles in Woodhouse-Sakati syndrome.. J Clin Neurophysiol. 2020", "AH Abusrair, S Bohlega, A Al-Semari, FS Al-Ajlan, K Al-Ahmadi, B Mohamed, A AlDakheel. Brain MR imaging findings in Woodhouse-Sakati syndrome.. AJNR Am J Neuroradiol. 2018;39:2256-62", "M Agopiantz, P Corbonnois, A Sorlin, C Bonnet, M Klein, N Hubert, V Pascal-Vigneron, P Jonveaux, T Cuny, B Leheup, G. Weryha. Endocrine disorders in Woodhouse-Sakati syndrome: a systematic review of the literature.. J Endocrinol Invest. 2014;37:1-7", "AM Alazami, A Al-Saif, A Al-Semari, S Bohlega, S Zlitni, F Alzahrani, P Bavi, N Kaya, D Colak, H Khalak, A Baltus, B Peterlin, S Danda, KP Bhatia, SA Schneider, N Sakati, CA Walsh, F Al-Mohanna, B Meyer, FS Alkuraya. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome.. Am J Hum Genet. 2008;83:684-91", "AM Alazami, SA Schneider, D Bonneau, L Pasquier, M Carecchio, M Kojovic, K Steindl, M de Kerdanet, MM Nezarati, KP Bhatia, B Degos, E Goh, FS Alkuraya. C2orf37 mutational spectrum in Woodhouse-Sakati syndrome patients.. Clin Genet. 2010;78:585-90", "A Albanese, LM Romito, D Calandrella. Therapeutic advances in dystonia.. Mov Disord. 2015;30:1547-56", "RH Ali, K Shah, A Nasir, W Steyaert, PJ Coucke, W Ahmad. Exome sequencing revealed a novel biallelic deletion in the DCAF17 gene underlying Woodhouse Sakati syndrome (WSS).. Clin Genet. 2016;90:263-9", "A Al-Semari, S Bohlega. Autosomal-recessive syndrome with alopecia, hypogonadism, progressive extra-pyramidal disorder, white matter disease, sensory neural deafness, diabetes mellitus, and low IGF1.. Am J Med Genet A. 2007;143A:149-60", "SA Al-Swailem, AA Al-Assiri, AA Al-Torbak. Woodhouse Sakati syndrome associated with bilateral keratoconus.. Br J Ophthalmol. 2006;90:116-7", "T Ben-Omran, R Ali, M Almureikhi, S Alameer, M Al-Saffar, CA Walsh, JM Felie, A Teebi. Phenotypic heterogeneity in Woodhouse-Sakati syndrome: two new families with a mutation in the C2orf37 gene.. Am J Med Genet A. 2011;155A:2647-53", "S Bohlega, AH Abusrair, FS Al-Ajlan, N Alharbi, A Al-Semari, B Bohlega, D Abualsaud, F Alkuraya. Patterns of neurological manifestations in Woodhouse-Sakati syndrome.. Parkinsonism Relat Disord. 2019;69:99-103", "JL Crowell, BB Shah. Surgery for dystonia and tremor.. Curr Neurol Neurosci Rep. 2016;16:22", "R Habib, S Basit, S Khan, MN Khan, W Ahmad. A novel splice site mutation in gene C2orf37 underlying Woodhouse-Sakati syndrome (WSS) in a consanguineous family of Pakistani origin.. Gene. 2011;490:26-31", "H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22", "G Koshy, S Danda, N Thomas, V Mathews, V. Viswanathan. Three siblings with Woodhouse-Sakati syndrome in an Indian family.. Clin Dysmorphol. 2008;17:57-60", "JH Lee, JY Yun, A Gregory, P Hogarth, SJ Hayflick. Brain MRI pattern recognition in neurodegeneration with brain iron accumulation.. Front Neurol. 2020;11:1024", "S Lehéricy, E Roze, C Goizet, F. Mochel. MRI of neurodegeneration with brain iron accumulation.. Curr Opin Neurol. 2020;33:462-73", "A Nanda, SM Pasternack, H Mahmoudi, N Ishorst, R Grimalt, RC Betz. Alopecia and hypotrichosis as characteristic findings in Woodhouse-Sakati syndrome: report of a family with mutation in the C2orf37 gene.. Pediatr Dermatol. 2014;31:83-7", "M Rachmiel, T Bistritzer, E Hershkoviz, A Khahil, O Epstein, R Parvari. Woodhouse-Sakati syndrome in an Israeli-Arab family presenting with youth-onset diabetes mellitus and delayed puberty.. Horm Res Paediatr. 2011;75:362-6", "SA Schneider, KP Bhatia. Dystonia in the Woodhouse Sakati syndrome: A new family and literature review.. Mov Disord. 2008;23:592-6", "K Steindl, AM Alazami, KP Bhatia, JT Wuerfel, D Petersen, R Cartolari, G Neri, C Klein, B Mongiardo, FS Alkuraya, SA Schneider. A novel C2orf37 mutation causes the first Italian cases of Woodhouse Sakati syndrome.. Clin Genet. 2010;78:594-7", "NJ Woodhouse, NA Sakati. A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities.. J Med Genet. 1983;20:216-9" ]	4/8/2016	8/7/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
wt1-dis	wt1-dis	[ "Meacham Syndrome", "Denys-Drash Syndrome", "Frasier Syndrome", "Wilms tumor protein", "WT1", "WT1 Disorder" ]		Beata S Lipska-Ziętkiewicz	Summary The diagnosis of	## Diagnosis Formal diagnostic criteria for Note: This chapter on Onset from infancy to the second or third decade of life Manifestations in the order in which they typically (but not invariably) appear: 46,XY disorder of sex development (46,XY DSD) External genitalia that can range over the following spectrum: Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee Microphallus Abnormalities of scrotal formation Normal-appearing female Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: Absent Fully developed uterus and fallopian tubes Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: Normal testis Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) Streak gonad 46,XY complete gonadal dysgenesis (46,XY CGD) External genitalia. Normal female Müllerian structures. Uterus and fallopian tubes present Gonadal findings. Streak gonads or dysgenetic testes Note: 46,XX individuals with Early-onset Wilms tumor (i.e., median age 1.3-1.6 years vs median age of 3 years in children without a Bilateral Wilms tumors Duplex kidney; horseshoe kidney; kidney malrotation Vesicoureteral reflux; ureteropelvic junction stenosis; urogenital sinus Normal 46,XX karyotype or normal 46,XY karyotype determined by either: Chromosome analysis with FISH to determine the integrity of Chromosomal microarray analysis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Several exon and multiexon deletions have been reported [ • Onset from infancy to the second or third decade of life • Manifestations in the order in which they typically (but not invariably) appear: • 46,XY disorder of sex development (46,XY DSD) • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • 46,XY complete gonadal dysgenesis (46,XY CGD) • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Absent • Fully developed uterus and fallopian tubes • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • Early-onset Wilms tumor (i.e., median age 1.3-1.6 years vs median age of 3 years in children without a • Bilateral Wilms tumors • Duplex kidney; horseshoe kidney; kidney malrotation • Vesicoureteral reflux; ureteropelvic junction stenosis; urogenital sinus • Chromosome analysis with FISH to determine the integrity of • Chromosomal microarray analysis ## Suggestive Findings Onset from infancy to the second or third decade of life Manifestations in the order in which they typically (but not invariably) appear: 46,XY disorder of sex development (46,XY DSD) External genitalia that can range over the following spectrum: Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee Microphallus Abnormalities of scrotal formation Normal-appearing female Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: Absent Fully developed uterus and fallopian tubes Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: Normal testis Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) Streak gonad 46,XY complete gonadal dysgenesis (46,XY CGD) External genitalia. Normal female Müllerian structures. Uterus and fallopian tubes present Gonadal findings. Streak gonads or dysgenetic testes Note: 46,XX individuals with Early-onset Wilms tumor (i.e., median age 1.3-1.6 years vs median age of 3 years in children without a Bilateral Wilms tumors Duplex kidney; horseshoe kidney; kidney malrotation Vesicoureteral reflux; ureteropelvic junction stenosis; urogenital sinus Normal 46,XX karyotype or normal 46,XY karyotype determined by either: Chromosome analysis with FISH to determine the integrity of Chromosomal microarray analysis • Onset from infancy to the second or third decade of life • Manifestations in the order in which they typically (but not invariably) appear: • 46,XY disorder of sex development (46,XY DSD) • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • 46,XY complete gonadal dysgenesis (46,XY CGD) • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Absent • Fully developed uterus and fallopian tubes • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • Early-onset Wilms tumor (i.e., median age 1.3-1.6 years vs median age of 3 years in children without a • Bilateral Wilms tumors • Duplex kidney; horseshoe kidney; kidney malrotation • Vesicoureteral reflux; ureteropelvic junction stenosis; urogenital sinus • Chromosome analysis with FISH to determine the integrity of • Chromosomal microarray analysis ## Clinical Findings Onset from infancy to the second or third decade of life Manifestations in the order in which they typically (but not invariably) appear: 46,XY disorder of sex development (46,XY DSD) External genitalia that can range over the following spectrum: Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee Microphallus Abnormalities of scrotal formation Normal-appearing female Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: Absent Fully developed uterus and fallopian tubes Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: Normal testis Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) Streak gonad 46,XY complete gonadal dysgenesis (46,XY CGD) External genitalia. Normal female Müllerian structures. Uterus and fallopian tubes present Gonadal findings. Streak gonads or dysgenetic testes Note: 46,XX individuals with Early-onset Wilms tumor (i.e., median age 1.3-1.6 years vs median age of 3 years in children without a Bilateral Wilms tumors Duplex kidney; horseshoe kidney; kidney malrotation Vesicoureteral reflux; ureteropelvic junction stenosis; urogenital sinus • Onset from infancy to the second or third decade of life • Manifestations in the order in which they typically (but not invariably) appear: • 46,XY disorder of sex development (46,XY DSD) • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • 46,XY complete gonadal dysgenesis (46,XY CGD) • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • External genitalia that can range over the following spectrum: • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Müllerian structures that on ultrasound (US) examination, MRI, and/or laparoscopy can range over the following spectrum: • Absent • Fully developed uterus and fallopian tubes • Absent • Fully developed uterus and fallopian tubes • Gonadal findings as determined by a combination of physical examination, imaging, and hormonal testing (and on occasion histologic examination) that can range over the following spectrum: • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee • Microphallus • Abnormalities of scrotal formation • Normal-appearing female • Absent • Fully developed uterus and fallopian tubes • Normal testis • Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells) • Streak gonad • External genitalia. Normal female • Müllerian structures. Uterus and fallopian tubes present • Gonadal findings. Streak gonads or dysgenetic testes • Early-onset Wilms tumor (i.e., median age 1.3-1.6 years vs median age of 3 years in children without a • Bilateral Wilms tumors • Duplex kidney; horseshoe kidney; kidney malrotation • Vesicoureteral reflux; ureteropelvic junction stenosis; urogenital sinus ## Supportive Laboratory Findings Normal 46,XX karyotype or normal 46,XY karyotype determined by either: Chromosome analysis with FISH to determine the integrity of Chromosomal microarray analysis • Chromosome analysis with FISH to determine the integrity of • Chromosomal microarray analysis ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Several exon and multiexon deletions have been reported [ ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Several exon and multiexon deletions have been reported [ ## Clinical Characteristics Spontaneous puberty in 94% of 46,XX & 60% of 46,XY persons ↑ FSH & LH; ↓ AMH or inhibin B plasma levels in majority of persons Median age at diagnosis: 1.3-1.6 yrs Significant fraction is bilateral synchronous &/or metachronous Kidney: duplex; horseshoe; malrotation Urinary tract: vesicoureteral reflux; ureteropelvic junction stenosis; urinary sinus To date, reported only in persons w/a disorder of testicular development See AMH = anti-műllerian hormone; CAKUT = congenital anomalies of the kidney and urinary tract; CGD = complete gonadal dysgenesis; CNS = congenital nephrotic syndrome; DSD = disorder of sex development; FSH = follicle-stimulating hormone; LH = luteinizing hormone; SRNS = steroid-resistant nephrotic syndrome Nephrotic syndrome (proteinuria, hypoalbuminemia, edema, and hyperlipidemia) that does not respond to standard steroid therapy Two instances of 46,XX complete gonadal dysgenesis have been reported [ Steroid-resistant nephrotic syndrome (SRNS) – proteinuria, hypoalbuminemia, edema, and hyperlipidemia that does not respond to standard steroid therapy – is the characteristic kidney finding in SRNS results in irreversible and progressive decline of kidney function and inevitably leads to end-stage kidney failure. Congenital nephrotic syndrome (nephrotic syndrome that presents in the first 3 months of life) is more rapidly progressive, resulting in end stage kidney failure within weeks to months [ Typical findings of the glomerulopathy on kidney biopsy are diffuse mesangial sclerosis reported primarily in children younger than age two years and focal segmental glomerulosclerosis in older individuals, although other diagnoses, including membranoproliferative glomerulonephritis, have also been reported [ The median age at Wilms tumor diagnosis in Bilateral tumors are more frequent in individuals with a truncating The survival rates for individuals with Wilms tumor caused by 46,XX individuals with a In adulthood, most individuals are affected by early gonadal insufficiency of variable severity with potential impact on puberty and fertility [ Because of the lack of long-term follow-up data, exact penetrance and long-term outcome are unknown. The survival rates for gonadoblastoma are excellent; however, if not treated it may result in malignant transformation of germ cells. A few instances of Sertoli tumor or other malignant testicular germ cell tumors have been reported [ Post-transplant lymphoproliferative disorder (PTLD) was reported in 7%-17% of individuals with Recent developments have allowed delineation of genotype-phenotype correlations for certain subgroups of Wilms tumor is often the first clinical manifestation. Glomerulopathy. Proteinuria is typically diagnosed in the second decade of life in individuals who underwent unilateral or partial nephrectomy for Wilms tumor. The course of SRNS is slower. Genital anomalies secondary to a 46,XY DSD affect the vast majority of phenotypic males; 46,XY CGD is unlikely. The risk for bilateral Wilms tumor is the highest (odds ratio = 18.4). One in five individuals has CAKUT. The risk for congenital nephrotic syndrome or early-onset rapidly progressive SRNS is the highest. By age 2.5 years, 50% of affected children have end-stage kidney failure. Of 46,XY individuals, approximately 80% have 46,XY DSD and 20% 46,XY CGD [BS Lipska-Ziętkiewicz, personal observation]. Later onset and relatively slow progression of glomerulopathy that typically leads to end-stage kidney failure in adolescence 46,XY CGD in the majority of (but not all) 46,XY individuals and 46,XY DSD in a few individuals Highest risk for gonadoblastoma in CGD/DSD individuals, with risk of Wilms tumor significantly lower (≤3%) The penetrance of A few asymptomatic parents heterozygous for the same germline Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome were originally described as distinct disorders on the basis of clinical findings but are now understood to represent a continuum of features caused by a The prevalence of There are no • Spontaneous puberty in 94% of 46,XX & 60% of 46,XY persons • ↑ FSH & LH; ↓ AMH or inhibin B plasma levels in majority of persons • Median age at diagnosis: 1.3-1.6 yrs • Significant fraction is bilateral synchronous &/or metachronous • Kidney: duplex; horseshoe; malrotation • Urinary tract: vesicoureteral reflux; ureteropelvic junction stenosis; urinary sinus • To date, reported only in persons w/a disorder of testicular development • See • Wilms tumor is often the first clinical manifestation. • Glomerulopathy. Proteinuria is typically diagnosed in the second decade of life in individuals who underwent unilateral or partial nephrectomy for Wilms tumor. The course of SRNS is slower. • Genital anomalies secondary to a 46,XY DSD affect the vast majority of phenotypic males; 46,XY CGD is unlikely. • The risk for bilateral Wilms tumor is the highest (odds ratio = 18.4). • One in five individuals has CAKUT. • The risk for congenital nephrotic syndrome or early-onset rapidly progressive SRNS is the highest. By age 2.5 years, 50% of affected children have end-stage kidney failure. • Of 46,XY individuals, approximately 80% have 46,XY DSD and 20% 46,XY CGD [BS Lipska-Ziętkiewicz, personal observation]. • Later onset and relatively slow progression of glomerulopathy that typically leads to end-stage kidney failure in adolescence • 46,XY CGD in the majority of (but not all) 46,XY individuals and 46,XY DSD in a few individuals • Highest risk for gonadoblastoma in CGD/DSD individuals, with risk of Wilms tumor significantly lower (≤3%) ## Clinical Description Spontaneous puberty in 94% of 46,XX & 60% of 46,XY persons ↑ FSH & LH; ↓ AMH or inhibin B plasma levels in majority of persons Median age at diagnosis: 1.3-1.6 yrs Significant fraction is bilateral synchronous &/or metachronous Kidney: duplex; horseshoe; malrotation Urinary tract: vesicoureteral reflux; ureteropelvic junction stenosis; urinary sinus To date, reported only in persons w/a disorder of testicular development See AMH = anti-műllerian hormone; CAKUT = congenital anomalies of the kidney and urinary tract; CGD = complete gonadal dysgenesis; CNS = congenital nephrotic syndrome; DSD = disorder of sex development; FSH = follicle-stimulating hormone; LH = luteinizing hormone; SRNS = steroid-resistant nephrotic syndrome Nephrotic syndrome (proteinuria, hypoalbuminemia, edema, and hyperlipidemia) that does not respond to standard steroid therapy Two instances of 46,XX complete gonadal dysgenesis have been reported [ Steroid-resistant nephrotic syndrome (SRNS) – proteinuria, hypoalbuminemia, edema, and hyperlipidemia that does not respond to standard steroid therapy – is the characteristic kidney finding in SRNS results in irreversible and progressive decline of kidney function and inevitably leads to end-stage kidney failure. Congenital nephrotic syndrome (nephrotic syndrome that presents in the first 3 months of life) is more rapidly progressive, resulting in end stage kidney failure within weeks to months [ Typical findings of the glomerulopathy on kidney biopsy are diffuse mesangial sclerosis reported primarily in children younger than age two years and focal segmental glomerulosclerosis in older individuals, although other diagnoses, including membranoproliferative glomerulonephritis, have also been reported [ The median age at Wilms tumor diagnosis in Bilateral tumors are more frequent in individuals with a truncating The survival rates for individuals with Wilms tumor caused by 46,XX individuals with a In adulthood, most individuals are affected by early gonadal insufficiency of variable severity with potential impact on puberty and fertility [ Because of the lack of long-term follow-up data, exact penetrance and long-term outcome are unknown. The survival rates for gonadoblastoma are excellent; however, if not treated it may result in malignant transformation of germ cells. A few instances of Sertoli tumor or other malignant testicular germ cell tumors have been reported [ Post-transplant lymphoproliferative disorder (PTLD) was reported in 7%-17% of individuals with • Spontaneous puberty in 94% of 46,XX & 60% of 46,XY persons • ↑ FSH & LH; ↓ AMH or inhibin B plasma levels in majority of persons • Median age at diagnosis: 1.3-1.6 yrs • Significant fraction is bilateral synchronous &/or metachronous • Kidney: duplex; horseshoe; malrotation • Urinary tract: vesicoureteral reflux; ureteropelvic junction stenosis; urinary sinus • To date, reported only in persons w/a disorder of testicular development • See ## Genotype-Phenotype Correlations Recent developments have allowed delineation of genotype-phenotype correlations for certain subgroups of Wilms tumor is often the first clinical manifestation. Glomerulopathy. Proteinuria is typically diagnosed in the second decade of life in individuals who underwent unilateral or partial nephrectomy for Wilms tumor. The course of SRNS is slower. Genital anomalies secondary to a 46,XY DSD affect the vast majority of phenotypic males; 46,XY CGD is unlikely. The risk for bilateral Wilms tumor is the highest (odds ratio = 18.4). One in five individuals has CAKUT. The risk for congenital nephrotic syndrome or early-onset rapidly progressive SRNS is the highest. By age 2.5 years, 50% of affected children have end-stage kidney failure. Of 46,XY individuals, approximately 80% have 46,XY DSD and 20% 46,XY CGD [BS Lipska-Ziętkiewicz, personal observation]. Later onset and relatively slow progression of glomerulopathy that typically leads to end-stage kidney failure in adolescence 46,XY CGD in the majority of (but not all) 46,XY individuals and 46,XY DSD in a few individuals Highest risk for gonadoblastoma in CGD/DSD individuals, with risk of Wilms tumor significantly lower (≤3%) • Wilms tumor is often the first clinical manifestation. • Glomerulopathy. Proteinuria is typically diagnosed in the second decade of life in individuals who underwent unilateral or partial nephrectomy for Wilms tumor. The course of SRNS is slower. • Genital anomalies secondary to a 46,XY DSD affect the vast majority of phenotypic males; 46,XY CGD is unlikely. • The risk for bilateral Wilms tumor is the highest (odds ratio = 18.4). • One in five individuals has CAKUT. • The risk for congenital nephrotic syndrome or early-onset rapidly progressive SRNS is the highest. By age 2.5 years, 50% of affected children have end-stage kidney failure. • Of 46,XY individuals, approximately 80% have 46,XY DSD and 20% 46,XY CGD [BS Lipska-Ziętkiewicz, personal observation]. • Later onset and relatively slow progression of glomerulopathy that typically leads to end-stage kidney failure in adolescence • 46,XY CGD in the majority of (but not all) 46,XY individuals and 46,XY DSD in a few individuals • Highest risk for gonadoblastoma in CGD/DSD individuals, with risk of Wilms tumor significantly lower (≤3%) ## Penetrance The penetrance of A few asymptomatic parents heterozygous for the same germline ## Nomenclature Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome were originally described as distinct disorders on the basis of clinical findings but are now understood to represent a continuum of features caused by a ## Prevalence The prevalence of There are no ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis For the differential diagnosis of: Steroid-resistant nephrotic syndrome, see Wilms tumor, see 46,XY disorders of testicular development, see Diaphragmatic hernia, see • Steroid-resistant nephrotic syndrome, see • Wilms tumor, see • 46,XY disorders of testicular development, see • Diaphragmatic hernia, see ## Management See To establish the extent of disease and needs in an individual diagnosed with 24-hr urine protein test Serum protein, albumin, creatinine, cholesterol, IgG, C3 Blood pressure measurements Community or Social work involvement for parental support Home nursing referral CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CMA = chromosomal microarray analysis; CNS = congenital nephrotic syndrome; IgG = immunoglobulin G; MOI = mode of inheritance; SRNS = steroid-resistant nephrotic syndrome; US = ultrasound Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Avoid immunosuppressants, which are ineffective & potentially toxic. Nephropathy does not recur post kidney transplantation. ACE = angiotensin-converting enzyme; AT1 = angiotensin II type 1; CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CNS = congenital nephrotic syndrome; DSD = disorders of sex development; RAAS = renin-angiotensin-aldosterone system; SRNS = steroid-resistant nephrotic syndrome For a child to be eligible for kidney transplantation, most centers require that children weigh 10 kg and/or be at least one year post completion of treatment for Wilms tumor. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CNS = congenital nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome; US = ultrasound Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual with See Because kidney disease may progress during pregnancy, a pregnant woman with Search • 24-hr urine protein test • Serum protein, albumin, creatinine, cholesterol, IgG, C3 • Blood pressure measurements • Community or • Social work involvement for parental support • Home nursing referral • Avoid immunosuppressants, which are ineffective & potentially toxic. • Nephropathy does not recur post kidney transplantation. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with 24-hr urine protein test Serum protein, albumin, creatinine, cholesterol, IgG, C3 Blood pressure measurements Community or Social work involvement for parental support Home nursing referral CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CMA = chromosomal microarray analysis; CNS = congenital nephrotic syndrome; IgG = immunoglobulin G; MOI = mode of inheritance; SRNS = steroid-resistant nephrotic syndrome; US = ultrasound Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • 24-hr urine protein test • Serum protein, albumin, creatinine, cholesterol, IgG, C3 • Blood pressure measurements • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Avoid immunosuppressants, which are ineffective & potentially toxic. Nephropathy does not recur post kidney transplantation. ACE = angiotensin-converting enzyme; AT1 = angiotensin II type 1; CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CNS = congenital nephrotic syndrome; DSD = disorders of sex development; RAAS = renin-angiotensin-aldosterone system; SRNS = steroid-resistant nephrotic syndrome For a child to be eligible for kidney transplantation, most centers require that children weigh 10 kg and/or be at least one year post completion of treatment for Wilms tumor. • Avoid immunosuppressants, which are ineffective & potentially toxic. • Nephropathy does not recur post kidney transplantation. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; CNS = congenital nephrotic syndrome; SRNS = steroid-resistant nephrotic syndrome; US = ultrasound ## Agents/Circumstances to Avoid Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual with See ## Pregnancy Management Because kidney disease may progress during pregnancy, a pregnant woman with ## Therapies Under Investigation Search ## Genetic Counseling Most individuals diagnosed with In rare families, a parent of an individual with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ * If the parent is the individual in whom the If a parent of the proband is affected and/or is known to have the If the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with • In rare families, a parent of an individual with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * If the parent is the individual in whom the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * If the parent is the individual in whom the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * If the parent is the individual in whom the • If a parent of the proband is affected and/or is known to have the • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Most individuals diagnosed with In rare families, a parent of an individual with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ * If the parent is the individual in whom the If a parent of the proband is affected and/or is known to have the If the If the parents have not been tested for the • Most individuals diagnosed with • In rare families, a parent of an individual with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * If the parent is the individual in whom the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * If the parent is the individual in whom the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * If the parent is the individual in whom the • If a parent of the proband is affected and/or is known to have the • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics WT1 Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for WT1 Disorder ( WT1 is a major transcription factor involved in cell differentiation and survival in the developing kidney, urinary tract, and gonads. WT1 regulates the expression of numerous target genes, including many genes encoding proteins that localize to the slit diaphragm of the glomeruli, such as nephrin and podocin. WT1 controls the polarity of podocytes, cytoskeleton arrangement, and the cell-matrix adhesion of podocytes. It has a tumor suppressor as well as an oncogenic role in tumor formation [ Missense variants affecting nucleotides coding for DNA-binding helices of zinc fingers 2 and 3 (residues: 439-454[RSDQLKRHQRRHTGVK] from exon 8 and 467-474[RSDHLKTH] from exon 9 [ Certain splice site pathogenic single-nucleotide variants in the splice donor site of intron 9 that change the ratio of +KTS:−KTS isoforms (see Note: Originally, A few recurrent pathogenic variants, both exon and intron, have been identified (see CGD = complete gonadal dysgenesis Variants listed in the table have been provided by the author. Alternate variant designations exist (e.g., c.1384C>T, 1180C>T, p. Arg462Trp, Arg394Trp). Originally reported as p.Arg394Trp [ Alternate variant designations exist (e.g., 1432+4C>T, IVS9+4C>T). See Alternate variant designations using other reference sequences exist (e.g., 1432+5G>A, IVS9+5G>A). See Somatic Loss-of-function In hematologic malignancies, somatic The • Missense variants affecting nucleotides coding for DNA-binding helices of zinc fingers 2 and 3 (residues: 439-454[RSDQLKRHQRRHTGVK] from exon 8 and 467-474[RSDHLKTH] from exon 9 [ • Certain splice site pathogenic single-nucleotide variants in the splice donor site of intron 9 that change the ratio of +KTS:−KTS isoforms (see ## Molecular Pathogenesis WT1 is a major transcription factor involved in cell differentiation and survival in the developing kidney, urinary tract, and gonads. WT1 regulates the expression of numerous target genes, including many genes encoding proteins that localize to the slit diaphragm of the glomeruli, such as nephrin and podocin. WT1 controls the polarity of podocytes, cytoskeleton arrangement, and the cell-matrix adhesion of podocytes. It has a tumor suppressor as well as an oncogenic role in tumor formation [ Missense variants affecting nucleotides coding for DNA-binding helices of zinc fingers 2 and 3 (residues: 439-454[RSDQLKRHQRRHTGVK] from exon 8 and 467-474[RSDHLKTH] from exon 9 [ Certain splice site pathogenic single-nucleotide variants in the splice donor site of intron 9 that change the ratio of +KTS:−KTS isoforms (see Note: Originally, A few recurrent pathogenic variants, both exon and intron, have been identified (see CGD = complete gonadal dysgenesis Variants listed in the table have been provided by the author. Alternate variant designations exist (e.g., c.1384C>T, 1180C>T, p. Arg462Trp, Arg394Trp). Originally reported as p.Arg394Trp [ Alternate variant designations exist (e.g., 1432+4C>T, IVS9+4C>T). See Alternate variant designations using other reference sequences exist (e.g., 1432+5G>A, IVS9+5G>A). See • Missense variants affecting nucleotides coding for DNA-binding helices of zinc fingers 2 and 3 (residues: 439-454[RSDQLKRHQRRHTGVK] from exon 8 and 467-474[RSDHLKTH] from exon 9 [ • Certain splice site pathogenic single-nucleotide variants in the splice donor site of intron 9 that change the ratio of +KTS:−KTS isoforms (see ## Cancer and Benign Tumors Somatic Loss-of-function In hematologic malignancies, somatic The ## Chapter Notes Beata S Lipska-Ziętkiewicz is the genetic coordinator at PodoNet ( 15 May 2025 (sw) Comprehensive update posted live 30 April 2020 (bp) Review posted live 2 October 2019 (blz) Original submission • 15 May 2025 (sw) Comprehensive update posted live • 30 April 2020 (bp) Review posted live • 2 October 2019 (blz) Original submission ## Author Notes Beata S Lipska-Ziętkiewicz is the genetic coordinator at PodoNet ( ## Revision History 15 May 2025 (sw) Comprehensive update posted live 30 April 2020 (bp) Review posted live 2 October 2019 (blz) Original submission • 15 May 2025 (sw) Comprehensive update posted live • 30 April 2020 (bp) Review posted live • 2 October 2019 (blz) Original submission ## References ## Literature Cited	[]	30/4/2020	15/5/2025	29/4/2021	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
x-ag	x-ag	[ "Chromosome Xq26.3 Duplication Syndrome", "X-LAG", "XLAG", "XLAG", "X-LAG", "Chromosome Xq26.3 Duplication Syndrome", "Probable G-protein coupled receptor 101", "GPR101", "X-Linked Acrogigantism" ]	X-Linked Acrogigantism	Donato Iacovazzo, Márta Korbonits	Summary X-linked acrogigantism is the occurrence of pituitary gigantism in an individual heterozygous or hemizygous for a germline or somatic duplication of The diagnosis of X-linked acrogigantism is established in an individual with pituitary gigantism and a germline or somatic duplication of In patients with radiologic evidence of a pituitary adenoma: transsphenoidal surgery should be considered as first-line treatment as it can provide long-term control of the disease (although often at the cost of permanent hypopituitarism) and prevent excessive tumor growth; in those with persistent disease, GH receptor antagonist treatment should be promptly initiated and tailored to growth velocity and IGF-1 levels. In patients with radiologic evidence of hyperplasia without a pituitary tumor: first-line treatment with GH receptor antagonist should be considered as surgery (which is not usually recommended) can lead to disease remission only by means of a total hypophysectomy, invariably resulting in the need for lifelong pituitary hormone replacement treatment. In patients with associated hyperprolactinemia: a dopamine agonist should be employed. X-linked acrogigantism is inherited in an X-linked manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a	## Diagnosis X-linked acrogigantism Accelerated growth velocity (>+2 SD) and/or abnormally tall stature (>+2 SD, adjusted for parental height). Note: When available, country-specific growth curves should be employed. Other frequently observed clinical features of GH excess: acral enlargement, coarse facial features, and increased appetite (~1/3 of cases) GH excess as demonstrated by: Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) Increased circulating age-adjusted IGF-1 levels Hyperprolactinemia (seen in 26/28 reported individuals for whom data were available) Pituitary macroadenoma (>10 mm in diameter) with or without associated hyperplasia (in 24 of 30 reported individuals with available data) Diffusely (even slightly) enlarged pituitary gland secondary to pituitary hyperplasia without an adenoma (in 6 of 30 reported individuals with available data) Note: Although none of the reported individuals presented with a microadenoma, this presentation is theoretically possible. The diagnosis of X-linked acrogigantism is established in an individual with pituitary gigantism and a germline or somatic duplication of If the proband: Is female and a simplex case (i.e., a single occurrence in a family), the Is male and a simplex case, the Has a family history consistent with an X-linked pattern of early-onset pituitary gigantism, the Molecular testing approaches used to identify germline and somatic duplications can include In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ Low-level mosaicism may not be identified. Targeted CMA with a higher density of probes in the Xq26.3 region – if available – can overcome such limitations [ Molecular Genetic Testing Used in X-Linked Acrogigantism See Thirty-three affected individuals have been described to date. Not all 33 were tested using both techniques; the authors have calculated the number of probands whose duplication would have been identified using both techniques. See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. These methods will detect from single-exon to whole-gene deletions or duplications; however, breakpoints of large deletions/duplications and/or deletion/duplication of adjacent genes may not be detected by these methods. (Note: In one male with somatic mosaicism, the duplication was not detected in leukocyte DNA but was detected in other tissues, including the pituitary [ In two individuals, standard CMA did not identify the duplication (because of either its small size or low-level mosaicism) [ • Accelerated growth velocity (>+2 SD) and/or abnormally tall stature (>+2 SD, adjusted for parental height). Note: When available, country-specific growth curves should be employed. • Other frequently observed clinical features of GH excess: acral enlargement, coarse facial features, and increased appetite (~1/3 of cases) • GH excess as demonstrated by: • Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) • Increased circulating age-adjusted IGF-1 levels • Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) • Increased circulating age-adjusted IGF-1 levels • Hyperprolactinemia (seen in 26/28 reported individuals for whom data were available) • Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) • Increased circulating age-adjusted IGF-1 levels • Pituitary macroadenoma (>10 mm in diameter) with or without associated hyperplasia (in 24 of 30 reported individuals with available data) • Diffusely (even slightly) enlarged pituitary gland secondary to pituitary hyperplasia without an adenoma (in 6 of 30 reported individuals with available data) • Is female and a simplex case (i.e., a single occurrence in a family), the • Is male and a simplex case, the • Has a family history consistent with an X-linked pattern of early-onset pituitary gigantism, the • In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ • Low-level mosaicism may not be identified. • Targeted CMA with a higher density of probes in the Xq26.3 region – if available – can overcome such limitations [ • In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ • Low-level mosaicism may not be identified. • In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ • Low-level mosaicism may not be identified. ## Suggestive Findings X-linked acrogigantism Accelerated growth velocity (>+2 SD) and/or abnormally tall stature (>+2 SD, adjusted for parental height). Note: When available, country-specific growth curves should be employed. Other frequently observed clinical features of GH excess: acral enlargement, coarse facial features, and increased appetite (~1/3 of cases) GH excess as demonstrated by: Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) Increased circulating age-adjusted IGF-1 levels Hyperprolactinemia (seen in 26/28 reported individuals for whom data were available) Pituitary macroadenoma (>10 mm in diameter) with or without associated hyperplasia (in 24 of 30 reported individuals with available data) Diffusely (even slightly) enlarged pituitary gland secondary to pituitary hyperplasia without an adenoma (in 6 of 30 reported individuals with available data) Note: Although none of the reported individuals presented with a microadenoma, this presentation is theoretically possible. • Accelerated growth velocity (>+2 SD) and/or abnormally tall stature (>+2 SD, adjusted for parental height). Note: When available, country-specific growth curves should be employed. • Other frequently observed clinical features of GH excess: acral enlargement, coarse facial features, and increased appetite (~1/3 of cases) • GH excess as demonstrated by: • Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) • Increased circulating age-adjusted IGF-1 levels • Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) • Increased circulating age-adjusted IGF-1 levels • Hyperprolactinemia (seen in 26/28 reported individuals for whom data were available) • Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g) • Increased circulating age-adjusted IGF-1 levels • Pituitary macroadenoma (>10 mm in diameter) with or without associated hyperplasia (in 24 of 30 reported individuals with available data) • Diffusely (even slightly) enlarged pituitary gland secondary to pituitary hyperplasia without an adenoma (in 6 of 30 reported individuals with available data) ## Establishing the Diagnosis The diagnosis of X-linked acrogigantism is established in an individual with pituitary gigantism and a germline or somatic duplication of If the proband: Is female and a simplex case (i.e., a single occurrence in a family), the Is male and a simplex case, the Has a family history consistent with an X-linked pattern of early-onset pituitary gigantism, the Molecular testing approaches used to identify germline and somatic duplications can include In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ Low-level mosaicism may not be identified. Targeted CMA with a higher density of probes in the Xq26.3 region – if available – can overcome such limitations [ Molecular Genetic Testing Used in X-Linked Acrogigantism See Thirty-three affected individuals have been described to date. Not all 33 were tested using both techniques; the authors have calculated the number of probands whose duplication would have been identified using both techniques. See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. These methods will detect from single-exon to whole-gene deletions or duplications; however, breakpoints of large deletions/duplications and/or deletion/duplication of adjacent genes may not be detected by these methods. (Note: In one male with somatic mosaicism, the duplication was not detected in leukocyte DNA but was detected in other tissues, including the pituitary [ In two individuals, standard CMA did not identify the duplication (because of either its small size or low-level mosaicism) [ • Is female and a simplex case (i.e., a single occurrence in a family), the • Is male and a simplex case, the • Has a family history consistent with an X-linked pattern of early-onset pituitary gigantism, the • In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ • Low-level mosaicism may not be identified. • Targeted CMA with a higher density of probes in the Xq26.3 region – if available – can overcome such limitations [ • In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ • Low-level mosaicism may not be identified. • In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [ • Low-level mosaicism may not be identified. ## Clinical Characteristics X-linked acrogigantism is characterized by marked growth acceleration due to growth hormone (GH) excess starting at an early age (see The presenting feature in all affected individuals is growth acceleration, which can manifest as early as age two months [ Other manifestations – in order of frequency – include enlargement of hands and feet, coarsening of the facial features, and increased appetite [ Untreated X-linked acrogigantism can lead to markedly increased stature with obvious severe physical and psychological sequelae. Moreover – as occurs in individuals with gigantism or acromegaly secondary to other causes – uncontrolled GH excess is associated with a significantly increased risk of cardiovascular, cerebrovascular, metabolic, neurologic, and orthopedic complications as well as decreased life expectancy [ To date, no genotype-phenotype correlations are evident as the clinical phenotype of the single individual harboring a smaller duplication (encompassing While a limited number of simplex males with X-linked acrogigantism have been reported to date, no differences have been observed between individuals with germline duplications and those with somatic mosaic duplications [ All heterozygous females and hemizygous males described to date were affected. In females who are simplex cases, the The abbreviation X-LAG has traditionally been used in the medical literature as an abbreviation for X-linked acrogigantism and the abbreviation XLAG for X-linked lissencephaly with ambiguous genitalia. X-linked acrogigantism is extremely rare. To date, 33 individuals with a molecularly confirmed diagnosis have been reported [ In two series of individuals with pituitary gigantism who underwent genetic testing, X-linked acrogigantism accounted for 10% of 143 affected individuals [ X-linked acrogigantism accounts for approximately 20% of females with pituitary gigantism [ ## Clinical Description X-linked acrogigantism is characterized by marked growth acceleration due to growth hormone (GH) excess starting at an early age (see The presenting feature in all affected individuals is growth acceleration, which can manifest as early as age two months [ Other manifestations – in order of frequency – include enlargement of hands and feet, coarsening of the facial features, and increased appetite [ Untreated X-linked acrogigantism can lead to markedly increased stature with obvious severe physical and psychological sequelae. Moreover – as occurs in individuals with gigantism or acromegaly secondary to other causes – uncontrolled GH excess is associated with a significantly increased risk of cardiovascular, cerebrovascular, metabolic, neurologic, and orthopedic complications as well as decreased life expectancy [ ## Genotype-Phenotype Correlations To date, no genotype-phenotype correlations are evident as the clinical phenotype of the single individual harboring a smaller duplication (encompassing While a limited number of simplex males with X-linked acrogigantism have been reported to date, no differences have been observed between individuals with germline duplications and those with somatic mosaic duplications [ ## Penetrance All heterozygous females and hemizygous males described to date were affected. In females who are simplex cases, the ## Nomenclature The abbreviation X-LAG has traditionally been used in the medical literature as an abbreviation for X-linked acrogigantism and the abbreviation XLAG for X-linked lissencephaly with ambiguous genitalia. ## Prevalence X-linked acrogigantism is extremely rare. To date, 33 individuals with a molecularly confirmed diagnosis have been reported [ In two series of individuals with pituitary gigantism who underwent genetic testing, X-linked acrogigantism accounted for 10% of 143 affected individuals [ X-linked acrogigantism accounts for approximately 20% of females with pituitary gigantism [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Pituitary gigantism can be nonsyndromic or can be associated with other manifestations as part of a syndrome ( Approximately 50% of all individuals with pituitary gigantism have a known predisposing genetic variant [ The very young age at disease onset, female preponderance, and the absence of extrapituitary manifestations can help with the differential diagnosis of X-linked acrogigantism ( Disorders to Consider in the Differential Diagnosis of Pituitary Gigantism GH = growth hormone; GHRH = growth hormone-releasing hormone; NFPA = nonfunctioning pituitary adenoma; PPNAD = primary pigmented nodular adrenal disease Syndromic McCune-Albright syndrome is caused by early embryonic postzygotic somatic activating mutation of Subclinical growth hormone excess has been described. Approximately 20% of families with Carney complex have been linked to 2p16. One individual with Carney complex (<1% of families with Carney complex) had a germline rearrangement resulting in four copies of Most patients have subclinical GH excess. Nonsyndromic ## Management To establish the extent of disease and further management needs in an individual diagnosed with X-linked acrogigantism, the following evaluations are recommended: Consultation with a specialist in pediatric endocrinology or endocrinology Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. Visual field evaluation to assess for mass effects due to an expanding pituitary tumor. Young children may need informal testing (e.g., observing eye movements toward small objects in different areas of the visual field). Pituitary MRI for evidence of pituitary hyperplasia or a pituitary tumor. In case of a pituitary tumor, extrasellar extension should be evaluated. Consultation with a clinical geneticist and/or genetic counselor Pituitary gigantism secondary to X-linked acrogigantism can be treated medically, surgically, and/or with radiotherapy. In case of persistent GH excess following surgery, the following are options: Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. Dopamine agonists (in appropriate dosages) can significantly reduce or normalize the prolactin levels and should be employed in patients with associated hyperprolactinemia [ Patients with X-linked acrogigantism require the following: Intensive monitoring of height and growth velocity, and frequent clinical assessment for other manifestations of GH excess (including enlargement of the extremities, hyperhydrosis, headache, joint pain) and/or enlargement of a pituitary adenoma (visual field deficits) Intensive monitoring of pituitary function tests (spot GH, IGF-1, prolactin) to determine disease activity and response to treatment. Note: Frequency depends on control of GH excess, clinical status, compliance with treatment, treatment modality, and presence of comorbidities. Periodic evaluation of basal hormone tests (9 a.m. cortisol, TSH, fT4, LH, FSH, estradiol/testosterone), and, if necessary, dynamic testing (e.g., growth hormone stimulation tests, ACTH stimulation test) to evaluate for hypopituitarism. Note: Patients treated with radical neurosurgery and/or radiotherapy may develop GH deficiency and should receive GH replacement treatment as appropriate. Repeat pituitary MRI. Note: Frequency depends on previous extent of the tumor, treatment modality, clinical status, and disease activity. The established guidelines regarding surveillance for associated comorbidities and risk of secondary neoplasms for patients with acromegaly [ Evaluation for associated comorbidities of GH excess (including hypertension, diabetes mellitus, sleep apnea, cardiovascular disease, osteoarthritis). Although this complication has not been reported in X-linked acrogigantism, adults with active acromegaly (increased GH and age-adjusted IGF-1 levels) are at higher risk of developing colonic neoplasms. Thus, colonoscopy at age 40 years is advised with further surveillance at three- to ten-year intervals depending on the presence/absence of abnormalities in the initial colonoscopy and levels of GH and IGF-1 [ See Considering the need for multimodal treatment and the associated high frequency of hypopituitarism, women with X-linked acrogigantism may need specific fertility treatment in order to conceive. As medical treatment does not result in significant tumor shrinkage in patients with X-linked acrogigantism, the authors recommend that women with macroadenomas undergo surgery to reduce the adenoma size prior to consideration of pregnancy. Women with X-linked acrogigantism who have a pituitary macroadenoma may experience clinically significant enlargement of the adenoma during pregnancy. Thus, they should be questioned about symptoms that could indicate tumor growth (increased frequency of headaches, visual changes) and monitored clinically with serial visual field testing. In the presence of symptoms or new visual field abnormalities, an MRI should be performed. Search • Consultation with a specialist in pediatric endocrinology or endocrinology • Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. • Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. • Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. • Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. • Visual field evaluation to assess for mass effects due to an expanding pituitary tumor. Young children may need informal testing (e.g., observing eye movements toward small objects in different areas of the visual field). • Pituitary MRI for evidence of pituitary hyperplasia or a pituitary tumor. In case of a pituitary tumor, extrasellar extension should be evaluated. • Consultation with a clinical geneticist and/or genetic counselor • Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. • Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. • In case of persistent GH excess following surgery, the following are options: • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • Intensive monitoring of height and growth velocity, and frequent clinical assessment for other manifestations of GH excess (including enlargement of the extremities, hyperhydrosis, headache, joint pain) and/or enlargement of a pituitary adenoma (visual field deficits) • Intensive monitoring of pituitary function tests (spot GH, IGF-1, prolactin) to determine disease activity and response to treatment. Note: Frequency depends on control of GH excess, clinical status, compliance with treatment, treatment modality, and presence of comorbidities. • Periodic evaluation of basal hormone tests (9 a.m. cortisol, TSH, fT4, LH, FSH, estradiol/testosterone), and, if necessary, dynamic testing (e.g., growth hormone stimulation tests, ACTH stimulation test) to evaluate for hypopituitarism. Note: Patients treated with radical neurosurgery and/or radiotherapy may develop GH deficiency and should receive GH replacement treatment as appropriate. • Repeat pituitary MRI. Note: Frequency depends on previous extent of the tumor, treatment modality, clinical status, and disease activity. • Evaluation for associated comorbidities of GH excess (including hypertension, diabetes mellitus, sleep apnea, cardiovascular disease, osteoarthritis). • Although this complication has not been reported in X-linked acrogigantism, adults with active acromegaly (increased GH and age-adjusted IGF-1 levels) are at higher risk of developing colonic neoplasms. Thus, colonoscopy at age 40 years is advised with further surveillance at three- to ten-year intervals depending on the presence/absence of abnormalities in the initial colonoscopy and levels of GH and IGF-1 [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and further management needs in an individual diagnosed with X-linked acrogigantism, the following evaluations are recommended: Consultation with a specialist in pediatric endocrinology or endocrinology Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. Visual field evaluation to assess for mass effects due to an expanding pituitary tumor. Young children may need informal testing (e.g., observing eye movements toward small objects in different areas of the visual field). Pituitary MRI for evidence of pituitary hyperplasia or a pituitary tumor. In case of a pituitary tumor, extrasellar extension should be evaluated. Consultation with a clinical geneticist and/or genetic counselor • Consultation with a specialist in pediatric endocrinology or endocrinology • Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. • Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. • Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. • Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. • Visual field evaluation to assess for mass effects due to an expanding pituitary tumor. Young children may need informal testing (e.g., observing eye movements toward small objects in different areas of the visual field). • Pituitary MRI for evidence of pituitary hyperplasia or a pituitary tumor. In case of a pituitary tumor, extrasellar extension should be evaluated. • Consultation with a clinical geneticist and/or genetic counselor • Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia. • Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism. ## Treatment of Manifestations Pituitary gigantism secondary to X-linked acrogigantism can be treated medically, surgically, and/or with radiotherapy. In case of persistent GH excess following surgery, the following are options: Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. Dopamine agonists (in appropriate dosages) can significantly reduce or normalize the prolactin levels and should be employed in patients with associated hyperprolactinemia [ • In case of persistent GH excess following surgery, the following are options: • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. ## GH Hypersecretion Pituitary gigantism secondary to X-linked acrogigantism can be treated medically, surgically, and/or with radiotherapy. In case of persistent GH excess following surgery, the following are options: Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • In case of persistent GH excess following surgery, the following are options: • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. • Prompt initiation of GH receptor antagonist treatment with doses tailored to linear growth and IGF-1 levels. In most instances this treatment effectively controls GH excess and accelerated growth [ • Repeat surgery or radiotherapy (conventional or radiosurgery). Note that because the effects of radiotherapy are often not immediately apparent, GH receptor antagonist therapy should be used while waiting to assess the efficacy of radiotherapy. ## Hyperprolactinemia Dopamine agonists (in appropriate dosages) can significantly reduce or normalize the prolactin levels and should be employed in patients with associated hyperprolactinemia [ ## Surveillance Patients with X-linked acrogigantism require the following: Intensive monitoring of height and growth velocity, and frequent clinical assessment for other manifestations of GH excess (including enlargement of the extremities, hyperhydrosis, headache, joint pain) and/or enlargement of a pituitary adenoma (visual field deficits) Intensive monitoring of pituitary function tests (spot GH, IGF-1, prolactin) to determine disease activity and response to treatment. Note: Frequency depends on control of GH excess, clinical status, compliance with treatment, treatment modality, and presence of comorbidities. Periodic evaluation of basal hormone tests (9 a.m. cortisol, TSH, fT4, LH, FSH, estradiol/testosterone), and, if necessary, dynamic testing (e.g., growth hormone stimulation tests, ACTH stimulation test) to evaluate for hypopituitarism. Note: Patients treated with radical neurosurgery and/or radiotherapy may develop GH deficiency and should receive GH replacement treatment as appropriate. Repeat pituitary MRI. Note: Frequency depends on previous extent of the tumor, treatment modality, clinical status, and disease activity. The established guidelines regarding surveillance for associated comorbidities and risk of secondary neoplasms for patients with acromegaly [ Evaluation for associated comorbidities of GH excess (including hypertension, diabetes mellitus, sleep apnea, cardiovascular disease, osteoarthritis). Although this complication has not been reported in X-linked acrogigantism, adults with active acromegaly (increased GH and age-adjusted IGF-1 levels) are at higher risk of developing colonic neoplasms. Thus, colonoscopy at age 40 years is advised with further surveillance at three- to ten-year intervals depending on the presence/absence of abnormalities in the initial colonoscopy and levels of GH and IGF-1 [ • Intensive monitoring of height and growth velocity, and frequent clinical assessment for other manifestations of GH excess (including enlargement of the extremities, hyperhydrosis, headache, joint pain) and/or enlargement of a pituitary adenoma (visual field deficits) • Intensive monitoring of pituitary function tests (spot GH, IGF-1, prolactin) to determine disease activity and response to treatment. Note: Frequency depends on control of GH excess, clinical status, compliance with treatment, treatment modality, and presence of comorbidities. • Periodic evaluation of basal hormone tests (9 a.m. cortisol, TSH, fT4, LH, FSH, estradiol/testosterone), and, if necessary, dynamic testing (e.g., growth hormone stimulation tests, ACTH stimulation test) to evaluate for hypopituitarism. Note: Patients treated with radical neurosurgery and/or radiotherapy may develop GH deficiency and should receive GH replacement treatment as appropriate. • Repeat pituitary MRI. Note: Frequency depends on previous extent of the tumor, treatment modality, clinical status, and disease activity. • Evaluation for associated comorbidities of GH excess (including hypertension, diabetes mellitus, sleep apnea, cardiovascular disease, osteoarthritis). • Although this complication has not been reported in X-linked acrogigantism, adults with active acromegaly (increased GH and age-adjusted IGF-1 levels) are at higher risk of developing colonic neoplasms. Thus, colonoscopy at age 40 years is advised with further surveillance at three- to ten-year intervals depending on the presence/absence of abnormalities in the initial colonoscopy and levels of GH and IGF-1 [ ## Evaluation of Relatives at Risk See ## Pregnancy Management Considering the need for multimodal treatment and the associated high frequency of hypopituitarism, women with X-linked acrogigantism may need specific fertility treatment in order to conceive. As medical treatment does not result in significant tumor shrinkage in patients with X-linked acrogigantism, the authors recommend that women with macroadenomas undergo surgery to reduce the adenoma size prior to consideration of pregnancy. Women with X-linked acrogigantism who have a pituitary macroadenoma may experience clinically significant enlargement of the adenoma during pregnancy. Thus, they should be questioned about symptoms that could indicate tumor growth (increased frequency of headaches, visual changes) and monitored clinically with serial visual field testing. In the presence of symptoms or new visual field abnormalities, an MRI should be performed. ## Therapies Under Investigation Search ## Genetic Counseling X-linked acrogigantism is inherited in an X-linked manner; however, most individuals with X-linked acrogigantism have a All female probands reported to date have a Recommendations for the evaluation of parents of a proband with an apparent If a male is the only affected family member (i.e., a simplex case), the affected male most likely has somatic mosaicism for a If a male proband has an affected sib, his mother is most likely heterozygous for the Clinical evaluation of the mother and review of the family history may help distinguish male probands with a The father of an affected male will not have the disorder nor will he be hemizygous for the Risk to sibs depends on the genetic status of the parents. All females reported to date have had a If the mother of a male proband is not affected and the proband represents a simplex case (i.e., a single occurrence in a family), sibs are presumed to be at low risk as all simplex males reported to date have a somatic mosaic If the mother of the proband is affected/has the If a male proband has a somatic mosaic A male proband with a germline A male proband will not transmit the duplication to his sons. The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All female probands reported to date have a • Recommendations for the evaluation of parents of a proband with an apparent • If a male is the only affected family member (i.e., a simplex case), the affected male most likely has somatic mosaicism for a • If a male proband has an affected sib, his mother is most likely heterozygous for the • Clinical evaluation of the mother and review of the family history may help distinguish male probands with a • The father of an affected male will not have the disorder nor will he be hemizygous for the • Risk to sibs depends on the genetic status of the parents. • All females reported to date have had a • If the mother of a male proband is not affected and the proband represents a simplex case (i.e., a single occurrence in a family), sibs are presumed to be at low risk as all simplex males reported to date have a somatic mosaic • If the mother of the proband is affected/has the • If a male proband has a somatic mosaic • A male proband with a germline • A male proband will not transmit the duplication to his sons. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance X-linked acrogigantism is inherited in an X-linked manner; however, most individuals with X-linked acrogigantism have a ## Risk to Family Members All female probands reported to date have a Recommendations for the evaluation of parents of a proband with an apparent If a male is the only affected family member (i.e., a simplex case), the affected male most likely has somatic mosaicism for a If a male proband has an affected sib, his mother is most likely heterozygous for the Clinical evaluation of the mother and review of the family history may help distinguish male probands with a The father of an affected male will not have the disorder nor will he be hemizygous for the Risk to sibs depends on the genetic status of the parents. All females reported to date have had a If the mother of a male proband is not affected and the proband represents a simplex case (i.e., a single occurrence in a family), sibs are presumed to be at low risk as all simplex males reported to date have a somatic mosaic If the mother of the proband is affected/has the If a male proband has a somatic mosaic A male proband with a germline A male proband will not transmit the duplication to his sons. • All female probands reported to date have a • Recommendations for the evaluation of parents of a proband with an apparent • If a male is the only affected family member (i.e., a simplex case), the affected male most likely has somatic mosaicism for a • If a male proband has an affected sib, his mother is most likely heterozygous for the • Clinical evaluation of the mother and review of the family history may help distinguish male probands with a • The father of an affected male will not have the disorder nor will he be hemizygous for the • Risk to sibs depends on the genetic status of the parents. • All females reported to date have had a • If the mother of a male proband is not affected and the proband represents a simplex case (i.e., a single occurrence in a family), sibs are presumed to be at low risk as all simplex males reported to date have a somatic mosaic • If the mother of the proband is affected/has the • If a male proband has a somatic mosaic • A male proband with a germline • A male proband will not transmit the duplication to his sons. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Association for Multiple Endocrine Neoplasia Disorders United Kingdom • • United Kingdom • • • Association for Multiple Endocrine Neoplasia Disorders • United Kingdom • • • • ## Molecular Genetics X-Linked Acrogigantism: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Acrogigantism ( The individuals originally described with X-linked acrogigantism harbored duplications of chromosome Xq26.3 with a smallest region of overlap (SRO) encompassing four genes ( More recently, an individual with a typical phenotype and a complex genomic rearrangement was described [ Microhomologies, small insertions, or complex genomic rearrangements were identified at the breakpoint junctions in most individuals with X-linked acrogigantism. These mutational signatures suggest fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) as the causative mechanism [ For information on ## Molecular Pathogenesis The individuals originally described with X-linked acrogigantism harbored duplications of chromosome Xq26.3 with a smallest region of overlap (SRO) encompassing four genes ( More recently, an individual with a typical phenotype and a complex genomic rearrangement was described [ Microhomologies, small insertions, or complex genomic rearrangements were identified at the breakpoint junctions in most individuals with X-linked acrogigantism. These mutational signatures suggest fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) as the causative mechanism [ For information on ## For information on ## References ## Literature Cited ## Chapter Notes The FIPA patients website, established by Dr Korbonits in collaboration with the The authors welcome comments and inquiries to Contact information for the laboratories that originally reported the genetic etiology of X-linked acrogigantism and continue to actively conduct research on the condition is provided below: We are grateful to referring colleagues and patients for providing information on this disease. We gratefully acknowledge Dr Celia Rodd (University of Manitoba, Winnipeg, Canada) and Dr Christine Burren (University Hospitals Bristol NHS Foundation Trust, Bristol, UK) for providing the patients' pictures. 1 February 2018 (bp) Review posted live 19 October 2016 (mk) Original submission • 1 February 2018 (bp) Review posted live • 19 October 2016 (mk) Original submission ## Author Notes The FIPA patients website, established by Dr Korbonits in collaboration with the The authors welcome comments and inquiries to Contact information for the laboratories that originally reported the genetic etiology of X-linked acrogigantism and continue to actively conduct research on the condition is provided below: ## Acknowledgments We are grateful to referring colleagues and patients for providing information on this disease. We gratefully acknowledge Dr Celia Rodd (University of Manitoba, Winnipeg, Canada) and Dr Christine Burren (University Hospitals Bristol NHS Foundation Trust, Bristol, UK) for providing the patients' pictures. ## Revision History 1 February 2018 (bp) Review posted live 19 October 2016 (mk) Original submission • 1 February 2018 (bp) Review posted live • 19 October 2016 (mk) Original submission Growth curve of a female patient with molecularly confirmed X-linked acrogigantism who presented at age five years with abnormally tall stature. Her growth proceeded at a rapid pace despite treatment with somatostatin analogs (SSA) and dopamine agonists (DA) and was only controlled with the use of the GH receptor (GHR) antagonist. Clinical and radiologic features of individuals with molecularly confirmed X-linked acrogigantism A-D. Girl (same patient as in B,C. At age 11 years with evidence of enlargement of the hands and feet D. MRI at initial presentation showing mild pituitary enlargement (arrow) consistent with pituitary hyperplasia E. Girl age 5.7 years; MRI at initial presentation showing a pituitary macroadenoma with suprasellar extension (arrow) Patient age three years (right) at initial presentation, with her unaffected sister, age six years (left). 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x-ald	x-ald	[ "X-ALD", "X-ALD", "Adrenomyeloneuropathy (AMN)", "Childhood Cerebral Adrenoleukodystrophy (cCALD)", "Primary Adrenocortical Insufficiency (Addison Disease)", "ATP-binding cassette sub-family D member 1", "ABCD1", "X-Linked Adrenoleukodystrophy" ]	X-Linked Adrenoleukodystrophy	Gerald V Raymond, Ann B Moser, Ali Fatemi	Summary X-linked adrenoleukodystrophy (X-ALD) involves the central or peripheral nervous system and the adrenal cortex. The nervous system and adrenal glands are involved independently; thus, an affected male may be diagnosed with cerebral adrenoleukodystrophy (CALD), adrenomyeloneuropathy (AMN), and/or primary adrenocortical insufficiency. CALD is characterized by progressive behavioral, cognitive, and neurologic deficits; onset of symptoms ranges from childhood (typically ages 4 to 8 years) to adolescence (ages 11 to 21 years) and adulthood. AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and bladder and bowel dysfunction; onset is typically in the 20s and 30s. Onset of primary adrenocortical insufficiency ranges from age two years to adulthood (most commonly by age 7.5 years). Heterozygous females are not at increased risk to develop CALD, but are at increased risk to develop AMN and primary adrenocortical insufficiency with increasing age. Three scenarios for suspecting the diagnosis are: (1) positive newborn screening result, which to date is performed in more than half of the United States; (2) a male or female proband with suggestive clinical and laboratory findings; (3) a male not known to have X-ALD ascertained and diagnosed via family screening. The diagnosis is established by identification of a hemizygous X-ALD is inherited in an X-linked manner. Approximately 95% of probands inherit an	X-Linked Adrenoleukodystrophy: Included Clinical Scenarios and Key Management Issues A pediatric endocrinologist for screening for primary adrenocortical insufficiency to prevent life-threatening complications of adrenal insufficiency; A neurologist or biochemical geneticist to develop a plan to monitor neurologic & brain MRI findings to identify promptly those at risk for cCALD &, thus, candidates for targeted therapy to prevent progression of CNS disease. Adrenal assessment; Consultation w/center w/expertise in evaluating males for possible HSCT Measure cortisol & ACTH levels to evaluate for concomitant adrenal insufficiency. Brain MRI to evaluate for cerebral disease ACTH = adrenocorticotropic hormone; CALD = cerebral adrenoleukodystrophy; CNS = central nervous system; HSCT = hematopoietic stem cell transplantation; X-ALD = X-linked adrenoleukodystrophy For synonyms and outdated names see Childhood CALD (cCALD) is also referred to as cerebral adrenoleukodystrophy (CALD), but cerebral disease is not exclusive to children. Confirmed in males with elevated very long-chain fatty acids (VLCFAs) and identification of a hemizygous pathogenic variant in • A pediatric endocrinologist for screening for primary adrenocortical insufficiency to prevent life-threatening complications of adrenal insufficiency; • A neurologist or biochemical geneticist to develop a plan to monitor neurologic & brain MRI findings to identify promptly those at risk for cCALD &, thus, candidates for targeted therapy to prevent progression of CNS disease. • Adrenal assessment; • Consultation w/center w/expertise in evaluating males for possible HSCT • Measure cortisol & ACTH levels to evaluate for concomitant adrenal insufficiency. • Brain MRI to evaluate for cerebral disease ## Diagnosis Note: For the purposes of this The three scenarios in which X-linked adrenoleukodystrophy (X-ALD) may be considered are a Newborn screening (NBS) for X-ALD has been added to the recommended uniform screening panel in the United States and, to date, more than half the states have begun screening. While the specific methodologies vary, testing is presently performed measuring the concentration of C26:0-lysophosphatidylcholine (C26:0-LPC) [ A pediatric endocrinologist for screening for primary adrenocortical insufficiency and prompt treatment to prevent life-threatening complications of primary adrenal insufficiency (see A biochemical geneticist or neurologist familiar with targeted treatment for childhood cerebral adrenoleukodystrophy (cCALD) to develop a plan for routine brain MRI monitoring and neurologic evaluations to identify those with early cerebral disease who may be candidates for targeted therapy to prevent progression of central nervous system disease (see Management, X-ALD Suggestive Findings in Males and Females with Symptomatic X-Linked Adrenoleukodystrophy Based on AMN = adrenomyeloneuropathy; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy Males identified by family screening may be any age, and the urgency of evaluation will depend on age at diagnosis. Boys who are at risk for cCALD should be promptly diagnosed and receive appropriate evaluations (see Note: Male children and adults ascertained and diagnosed with X-ALD via family screening may be asymptomatic or have features consistent with X-ALD but erroneously attributed to other causes (e.g., young males diagnosed as having worsening learning issues or autism spectrum disorder) [G Raymond, personal observation]. The diagnosis of X-ALD is established in a proband by identification of abnormally elevated very long-chain fatty acids (VLCFAs) on Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ VLCFAs may be determined in serum or plasma. The characteristic elevation is in the saturated VLCFAs (especially hexacosanoic acid, abbreviated as C26:0). The derivative species of C26:0-lysophosphatidylcholine (C26:0-LPC) is also elevated and is used in newborn screening and in some centers for all diagnostic testing [ Since elevated VLCFAs are not specific to X-ALD and may be seen in other peroxisomal disorders of beta-oxidation, determination of VLCFAs should be paired with Note: Many Molecular genetic testing approaches can include a combination of When the phenotypic, laboratory, and brain MRI findings strongly suggest the diagnosis of X-ALD, molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Adrenoleukodystrophy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • A pediatric endocrinologist for screening for primary adrenocortical insufficiency and prompt treatment to prevent life-threatening complications of primary adrenal insufficiency (see • A biochemical geneticist or neurologist familiar with targeted treatment for childhood cerebral adrenoleukodystrophy (cCALD) to develop a plan for routine brain MRI monitoring and neurologic evaluations to identify those with early cerebral disease who may be candidates for targeted therapy to prevent progression of central nervous system disease (see Management, • For an introduction to multigene panels click ## Suggestive Findings The three scenarios in which X-linked adrenoleukodystrophy (X-ALD) may be considered are a Newborn screening (NBS) for X-ALD has been added to the recommended uniform screening panel in the United States and, to date, more than half the states have begun screening. While the specific methodologies vary, testing is presently performed measuring the concentration of C26:0-lysophosphatidylcholine (C26:0-LPC) [ A pediatric endocrinologist for screening for primary adrenocortical insufficiency and prompt treatment to prevent life-threatening complications of primary adrenal insufficiency (see A biochemical geneticist or neurologist familiar with targeted treatment for childhood cerebral adrenoleukodystrophy (cCALD) to develop a plan for routine brain MRI monitoring and neurologic evaluations to identify those with early cerebral disease who may be candidates for targeted therapy to prevent progression of central nervous system disease (see Management, X-ALD Suggestive Findings in Males and Females with Symptomatic X-Linked Adrenoleukodystrophy Based on AMN = adrenomyeloneuropathy; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy Males identified by family screening may be any age, and the urgency of evaluation will depend on age at diagnosis. Boys who are at risk for cCALD should be promptly diagnosed and receive appropriate evaluations (see Note: Male children and adults ascertained and diagnosed with X-ALD via family screening may be asymptomatic or have features consistent with X-ALD but erroneously attributed to other causes (e.g., young males diagnosed as having worsening learning issues or autism spectrum disorder) [G Raymond, personal observation]. • A pediatric endocrinologist for screening for primary adrenocortical insufficiency and prompt treatment to prevent life-threatening complications of primary adrenal insufficiency (see • A biochemical geneticist or neurologist familiar with targeted treatment for childhood cerebral adrenoleukodystrophy (cCALD) to develop a plan for routine brain MRI monitoring and neurologic evaluations to identify those with early cerebral disease who may be candidates for targeted therapy to prevent progression of central nervous system disease (see Management, ## Scenario 1: Positive Newborn Screening Result Newborn screening (NBS) for X-ALD has been added to the recommended uniform screening panel in the United States and, to date, more than half the states have begun screening. While the specific methodologies vary, testing is presently performed measuring the concentration of C26:0-lysophosphatidylcholine (C26:0-LPC) [ A pediatric endocrinologist for screening for primary adrenocortical insufficiency and prompt treatment to prevent life-threatening complications of primary adrenal insufficiency (see A biochemical geneticist or neurologist familiar with targeted treatment for childhood cerebral adrenoleukodystrophy (cCALD) to develop a plan for routine brain MRI monitoring and neurologic evaluations to identify those with early cerebral disease who may be candidates for targeted therapy to prevent progression of central nervous system disease (see Management, • A pediatric endocrinologist for screening for primary adrenocortical insufficiency and prompt treatment to prevent life-threatening complications of primary adrenal insufficiency (see • A biochemical geneticist or neurologist familiar with targeted treatment for childhood cerebral adrenoleukodystrophy (cCALD) to develop a plan for routine brain MRI monitoring and neurologic evaluations to identify those with early cerebral disease who may be candidates for targeted therapy to prevent progression of central nervous system disease (see Management, ## Scenario 2: Symptomatic Individual X-ALD Suggestive Findings in Males and Females with Symptomatic X-Linked Adrenoleukodystrophy Based on AMN = adrenomyeloneuropathy; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy ## Scenario 3: Male Identified by Family Screening Males identified by family screening may be any age, and the urgency of evaluation will depend on age at diagnosis. Boys who are at risk for cCALD should be promptly diagnosed and receive appropriate evaluations (see Note: Male children and adults ascertained and diagnosed with X-ALD via family screening may be asymptomatic or have features consistent with X-ALD but erroneously attributed to other causes (e.g., young males diagnosed as having worsening learning issues or autism spectrum disorder) [G Raymond, personal observation]. ## Establishing the Diagnosis The diagnosis of X-ALD is established in a proband by identification of abnormally elevated very long-chain fatty acids (VLCFAs) on Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ VLCFAs may be determined in serum or plasma. The characteristic elevation is in the saturated VLCFAs (especially hexacosanoic acid, abbreviated as C26:0). The derivative species of C26:0-lysophosphatidylcholine (C26:0-LPC) is also elevated and is used in newborn screening and in some centers for all diagnostic testing [ Since elevated VLCFAs are not specific to X-ALD and may be seen in other peroxisomal disorders of beta-oxidation, determination of VLCFAs should be paired with Note: Many Molecular genetic testing approaches can include a combination of When the phenotypic, laboratory, and brain MRI findings strongly suggest the diagnosis of X-ALD, molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Adrenoleukodystrophy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Biochemical Testing VLCFAs may be determined in serum or plasma. The characteristic elevation is in the saturated VLCFAs (especially hexacosanoic acid, abbreviated as C26:0). The derivative species of C26:0-lysophosphatidylcholine (C26:0-LPC) is also elevated and is used in newborn screening and in some centers for all diagnostic testing [ Since elevated VLCFAs are not specific to X-ALD and may be seen in other peroxisomal disorders of beta-oxidation, determination of VLCFAs should be paired with ## Molecular Genetic Testing Note: Many Molecular genetic testing approaches can include a combination of When the phenotypic, laboratory, and brain MRI findings strongly suggest the diagnosis of X-ALD, molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Adrenoleukodystrophy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## When the phenotypic, laboratory, and brain MRI findings strongly suggest the diagnosis of X-ALD, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Adrenoleukodystrophy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics X-linked adrenoleukodystrophy (X-ALD) affects the nervous system and the adrenal cortex. The involvement of nervous system and adrenal gland is independent and determines whether the affected male is diagnosed with cerebral disease, adrenomyeloneuropathy, or primary adrenocortical insufficiency. The range of phenotypic expression in X-ALD is wide and cannot be predicted by very long-chain fatty acid (VLCFA) levels, the Inflammatory cerebral demyelination may occur at almost any age in X-ALD, but it is characteristically seen as a childhood presentation. It most commonly occurs between ages four and eight years, with a peak at age seven years. It rarely occurs before age three years. It is important to identify as early as possible males with neuroimaging findings of cCALD in order to refer them promptly to determine if they are candidates for targeted therapy that can slow the disease course (see Management, Affected males present with behavioral or learning deficits, often diagnosed as attention-deficit/hyperactivity disorder, which may respond to stimulant medication. These behaviors may persist for months or longer, and are followed by symptoms suggestive of a more serious underlying disorder, including "spacing out" in school (inattention, deterioration in handwriting skills, and diminishing school performance); difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior. Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild. The presence of advanced disease on MRI even with seemingly mild neurologic findings may preclude an attempt at targeted therapy. In some males, seizures may be the first manifestation. While variable, the rate of disease progression may be rapid, with total disability occurring within six months to two years, followed by death at varying ages. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. The typical presentation is a man in his adult years who develops progressive stiffness and weakness in the legs (due to spastic paraparesis), abnormalities of bladder and bowel control, abnormal sensory perception (especially of vibratory sense), and sexual dysfunction. All manifestations progress over decades. Approximately 40%-45% of individuals with AMN show some degree of involvement on brain MRI or clinical examination. In 20%-63% of individuals with AMN, progressive brain involvement leads to serious cognitive and behavioral disturbances that may progress to total disability and death [ Approximately 70% of men with AMN have impaired adrenocortical function at the time that neurologic manifestations are first noted. Males can present with signs of adrenal insufficiency at any age, although commonly by age 7.5 years. Presenting signs include unexplained vomiting and weakness or coma, leading to the diagnosis of primary adrenocortical insufficiency. A variable finding is increased skin pigmentation resulting from excessive adrenocorticotropic hormone secretion. Overall, adrenocortical function is abnormal in 90% of neurologically symptomatic boys and 70% of men with AMN. Most males who are initially diagnosed as having only primary adrenocortical insufficiency will develop some neurologic manifestations; however, it may be decades later. Heterozygous females are symptom-free in childhood. In adulthood, an AMN-like phenotype in females is reported as mild-to-moderate spastic paraparesis with bladder and bowel issues. The onset of these issues is often subtle and – if not specifically examined for – easily overlooked. The findings do correlate with age, and may not become evident until later in life. Progression is also slower than that seen in males with AMN [ It may be stated that adrenal insufficiency in heterozygous females is rare, and the present recommendation is not to routinely screen females for this feature. There are also rare reports of cerebral myelin involvement caused, in some females, by genetic mechanisms such as chromosomal rearrangement or skewed X-inactivation [ The X-ALD phenotype cannot be predicted by VLCFA plasma concentration or by the nature of the Likewise, the same phenotype can be observed both with large deletions that result in absence of the gene product and with missense pathogenic variants associated with abundant immunoreactive protein product [ Although the variation in X-ALD clinical phenotypes is great, neurologic manifestations are present in nearly all males by adulthood [ The X-ALD biochemical phenotype of elevated plasma concentration of VLCFAs has 100% penetrance in males regardless of age [ Siemerling-Creuzfeldt disease is the eponym for X-ALD. Historically, the eponym Schilder's disease referred to several clinical entities including X-ALD; on occasion, families may have been given this diagnosis. Schilder's disease is still sometimes (incorrectly) used to refer to sudanophilic cerebral sclerosis and certain forms of multiple sclerosis, which may lead to diagnostic confusion. Childhood cerebral adrenoleukodystrophy (cCALD) may also be referred to as cerebral adrenoleukodystrophy (CALD), but it should be emphasized that cerebral involvement may occur at any age. Primary adrenocortical insufficiency may also be referred to as Addison disease. The prevalence of X-ALD is estimated at between one in 14,000 and one in 17,000 male births [ ## Clinical Description X-linked adrenoleukodystrophy (X-ALD) affects the nervous system and the adrenal cortex. The involvement of nervous system and adrenal gland is independent and determines whether the affected male is diagnosed with cerebral disease, adrenomyeloneuropathy, or primary adrenocortical insufficiency. The range of phenotypic expression in X-ALD is wide and cannot be predicted by very long-chain fatty acid (VLCFA) levels, the Inflammatory cerebral demyelination may occur at almost any age in X-ALD, but it is characteristically seen as a childhood presentation. It most commonly occurs between ages four and eight years, with a peak at age seven years. It rarely occurs before age three years. It is important to identify as early as possible males with neuroimaging findings of cCALD in order to refer them promptly to determine if they are candidates for targeted therapy that can slow the disease course (see Management, Affected males present with behavioral or learning deficits, often diagnosed as attention-deficit/hyperactivity disorder, which may respond to stimulant medication. These behaviors may persist for months or longer, and are followed by symptoms suggestive of a more serious underlying disorder, including "spacing out" in school (inattention, deterioration in handwriting skills, and diminishing school performance); difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior. Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild. The presence of advanced disease on MRI even with seemingly mild neurologic findings may preclude an attempt at targeted therapy. In some males, seizures may be the first manifestation. While variable, the rate of disease progression may be rapid, with total disability occurring within six months to two years, followed by death at varying ages. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. The typical presentation is a man in his adult years who develops progressive stiffness and weakness in the legs (due to spastic paraparesis), abnormalities of bladder and bowel control, abnormal sensory perception (especially of vibratory sense), and sexual dysfunction. All manifestations progress over decades. Approximately 40%-45% of individuals with AMN show some degree of involvement on brain MRI or clinical examination. In 20%-63% of individuals with AMN, progressive brain involvement leads to serious cognitive and behavioral disturbances that may progress to total disability and death [ Approximately 70% of men with AMN have impaired adrenocortical function at the time that neurologic manifestations are first noted. Males can present with signs of adrenal insufficiency at any age, although commonly by age 7.5 years. Presenting signs include unexplained vomiting and weakness or coma, leading to the diagnosis of primary adrenocortical insufficiency. A variable finding is increased skin pigmentation resulting from excessive adrenocorticotropic hormone secretion. Overall, adrenocortical function is abnormal in 90% of neurologically symptomatic boys and 70% of men with AMN. Most males who are initially diagnosed as having only primary adrenocortical insufficiency will develop some neurologic manifestations; however, it may be decades later. Heterozygous females are symptom-free in childhood. In adulthood, an AMN-like phenotype in females is reported as mild-to-moderate spastic paraparesis with bladder and bowel issues. The onset of these issues is often subtle and – if not specifically examined for – easily overlooked. The findings do correlate with age, and may not become evident until later in life. Progression is also slower than that seen in males with AMN [ It may be stated that adrenal insufficiency in heterozygous females is rare, and the present recommendation is not to routinely screen females for this feature. There are also rare reports of cerebral myelin involvement caused, in some females, by genetic mechanisms such as chromosomal rearrangement or skewed X-inactivation [ ## Affected Males Inflammatory cerebral demyelination may occur at almost any age in X-ALD, but it is characteristically seen as a childhood presentation. It most commonly occurs between ages four and eight years, with a peak at age seven years. It rarely occurs before age three years. It is important to identify as early as possible males with neuroimaging findings of cCALD in order to refer them promptly to determine if they are candidates for targeted therapy that can slow the disease course (see Management, Affected males present with behavioral or learning deficits, often diagnosed as attention-deficit/hyperactivity disorder, which may respond to stimulant medication. These behaviors may persist for months or longer, and are followed by symptoms suggestive of a more serious underlying disorder, including "spacing out" in school (inattention, deterioration in handwriting skills, and diminishing school performance); difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior. Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild. The presence of advanced disease on MRI even with seemingly mild neurologic findings may preclude an attempt at targeted therapy. In some males, seizures may be the first manifestation. While variable, the rate of disease progression may be rapid, with total disability occurring within six months to two years, followed by death at varying ages. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. The typical presentation is a man in his adult years who develops progressive stiffness and weakness in the legs (due to spastic paraparesis), abnormalities of bladder and bowel control, abnormal sensory perception (especially of vibratory sense), and sexual dysfunction. All manifestations progress over decades. Approximately 40%-45% of individuals with AMN show some degree of involvement on brain MRI or clinical examination. In 20%-63% of individuals with AMN, progressive brain involvement leads to serious cognitive and behavioral disturbances that may progress to total disability and death [ Approximately 70% of men with AMN have impaired adrenocortical function at the time that neurologic manifestations are first noted. Males can present with signs of adrenal insufficiency at any age, although commonly by age 7.5 years. Presenting signs include unexplained vomiting and weakness or coma, leading to the diagnosis of primary adrenocortical insufficiency. A variable finding is increased skin pigmentation resulting from excessive adrenocorticotropic hormone secretion. Overall, adrenocortical function is abnormal in 90% of neurologically symptomatic boys and 70% of men with AMN. Most males who are initially diagnosed as having only primary adrenocortical insufficiency will develop some neurologic manifestations; however, it may be decades later. ## Inflammatory cerebral demyelination may occur at almost any age in X-ALD, but it is characteristically seen as a childhood presentation. It most commonly occurs between ages four and eight years, with a peak at age seven years. It rarely occurs before age three years. It is important to identify as early as possible males with neuroimaging findings of cCALD in order to refer them promptly to determine if they are candidates for targeted therapy that can slow the disease course (see Management, Affected males present with behavioral or learning deficits, often diagnosed as attention-deficit/hyperactivity disorder, which may respond to stimulant medication. These behaviors may persist for months or longer, and are followed by symptoms suggestive of a more serious underlying disorder, including "spacing out" in school (inattention, deterioration in handwriting skills, and diminishing school performance); difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior. Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild. The presence of advanced disease on MRI even with seemingly mild neurologic findings may preclude an attempt at targeted therapy. In some males, seizures may be the first manifestation. While variable, the rate of disease progression may be rapid, with total disability occurring within six months to two years, followed by death at varying ages. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. ## The typical presentation is a man in his adult years who develops progressive stiffness and weakness in the legs (due to spastic paraparesis), abnormalities of bladder and bowel control, abnormal sensory perception (especially of vibratory sense), and sexual dysfunction. All manifestations progress over decades. Approximately 40%-45% of individuals with AMN show some degree of involvement on brain MRI or clinical examination. In 20%-63% of individuals with AMN, progressive brain involvement leads to serious cognitive and behavioral disturbances that may progress to total disability and death [ Approximately 70% of men with AMN have impaired adrenocortical function at the time that neurologic manifestations are first noted. ## Males can present with signs of adrenal insufficiency at any age, although commonly by age 7.5 years. Presenting signs include unexplained vomiting and weakness or coma, leading to the diagnosis of primary adrenocortical insufficiency. A variable finding is increased skin pigmentation resulting from excessive adrenocorticotropic hormone secretion. Overall, adrenocortical function is abnormal in 90% of neurologically symptomatic boys and 70% of men with AMN. Most males who are initially diagnosed as having only primary adrenocortical insufficiency will develop some neurologic manifestations; however, it may be decades later. ## Heterozygous Females Heterozygous females are symptom-free in childhood. In adulthood, an AMN-like phenotype in females is reported as mild-to-moderate spastic paraparesis with bladder and bowel issues. The onset of these issues is often subtle and – if not specifically examined for – easily overlooked. The findings do correlate with age, and may not become evident until later in life. Progression is also slower than that seen in males with AMN [ It may be stated that adrenal insufficiency in heterozygous females is rare, and the present recommendation is not to routinely screen females for this feature. There are also rare reports of cerebral myelin involvement caused, in some females, by genetic mechanisms such as chromosomal rearrangement or skewed X-inactivation [ ## Genotype-Phenotype Correlations The X-ALD phenotype cannot be predicted by VLCFA plasma concentration or by the nature of the Likewise, the same phenotype can be observed both with large deletions that result in absence of the gene product and with missense pathogenic variants associated with abundant immunoreactive protein product [ ## Penetrance Although the variation in X-ALD clinical phenotypes is great, neurologic manifestations are present in nearly all males by adulthood [ The X-ALD biochemical phenotype of elevated plasma concentration of VLCFAs has 100% penetrance in males regardless of age [ ## Nomenclature Siemerling-Creuzfeldt disease is the eponym for X-ALD. Historically, the eponym Schilder's disease referred to several clinical entities including X-ALD; on occasion, families may have been given this diagnosis. Schilder's disease is still sometimes (incorrectly) used to refer to sudanophilic cerebral sclerosis and certain forms of multiple sclerosis, which may lead to diagnostic confusion. Childhood cerebral adrenoleukodystrophy (cCALD) may also be referred to as cerebral adrenoleukodystrophy (CALD), but it should be emphasized that cerebral involvement may occur at any age. Primary adrenocortical insufficiency may also be referred to as Addison disease. ## Prevalence The prevalence of X-ALD is estimated at between one in 14,000 and one in 17,000 male births [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this A ## Differential Diagnosis Peroxisomal biogenesis disorders with elevated plasma very long-chain fatty acids are summarized in Peroxisomal Biogenesis Disorders with Elevated Plasma Very Long-Chain Fatty Acids AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner; however, one ## Management With the institution of newborn screening and increasing numbers of individuals being diagnosed with X-linked adrenoleukodystrophy (X-ALD), clinical practice guidelines have been developed for diagnosis and treatment; see For male infants with a positive newborn screening (NBS) result for X-ALD, the initial evaluations summarized in Recommended Evaluations and Next Steps for Infants with a Confirmed Positive Newborn Screening Result for X-Linked Adrenoleukodystrophy Screening for ACTH & cortisol levels Follow up per Pediatric Endocrine Society published guidance recommendations To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or ACTH = adrenocorticotropic hormone; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Recommended initial evaluations for symptomatic males with cCALD are summarized in Recommended Evaluations Following Initial Diagnosis in Symptomatic Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Specific neurologic deficits (e.g., hemiparesis, visual field defect); Seizures if history is suggestive. Behaviors that may respond to medication; Aggressive or disinhibited behavior. Educational needs; Need for OT service; Need for PT services incl durable medical equipment. To inform affected persons & their families re nature, MOI, & implications of cCALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or Community or Social work involvement for parental/family support; Home nursing referral. cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse For recommended initial evaluations for males and females who have adrenomyeloneuropathy (AMN), see Recommended Evaluations Following Initial Diagnosis in Males and Females with Adrenomyeloneuropathy (AMN) Assess for cognitive impairment, progressive spastic gait disturbance, paralysis, ataxia, weakness, & restless legs syndrome. Brain MRI to assess for cerebral disease (Spine MRIs are generally not helpful.) Further services such as mental health, speech, & behavior if appropriate To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or Community or Social work involvement for parental/family support. ACTH = adrenocorticotropic hormone; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Males identified by family screening may be any age (infancy through adulthood), and the urgency of evaluation will depend on age at diagnosis. See Recommended Evaluations and Next Steps for Males Identified by Family Screening Assess for presence of cerebral disease. Urgency will depend on age of affected person. Males age <2-10 yrs need expedited imaging (see ACTH & cortisol levels Referral to pediatric endocrinology To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic eval & treatment/screening as recommended in Community or Social work involvement for parental/family support. ACTH = adrenocorticotropic hormone; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for X-linked adrenoleukodystrophy (X-ALD). Evidence clearly shows that hematopoietic stem cell transplantation (HSCT) has the best outcome when performed on an asymptomatic individual with minimal but characteristic imaging findings of cCALD [ Early-stage cCALD brain MRI findings are characterized by small T See Recommended Brain MRI Schedule for Early Detection of Childhood Cerebral Adrenoleukodystrophy (cCALD) Abnormalities in At-Risk Males Based on cCALD = childhood cerebral adrenoleukodystrophy If early-stage cCALD is diagnosed, the boy should be referred to a center with expertise in monitoring and treating cCALD. The following are NOT presently recommended for screening males at risk for cCALD: The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval The routine use of neuropsychological testing [ Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ Individuals should have early cCALD as seen on contrast-enhanced MRI. They should not have neurologic signs. Neuropsychological testing should indicate a performance IQ greater than 80. An added criterion is absence of a matched-sib donor. The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. Boys whose neurologic disease is too advanced at the time of diagnosis are not candidates for targeted therapy. Thus, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Speech-language therapy or OT Discuss gastrostomy tube placement. Children: per treating pediatric endocrinologist Adults: per treating endocrinologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement w/home nursing Discussion of hospice ADL = activities of daily living; ASM = anti-seizure medication; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. Supportive care for males and females with adrenomyeloneuropathy (AMN) to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males and Females with Adrenomyeloneuropathy (AMN) Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as onset of seizures, changes in tone, & movement disorders. For those not yet known to have adrenocortical insufficiency: ACTH & cortisol levels every 6 mos For those w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Males and Females with Adrenomyeloneuropathy (AMN) Males not yet known to have adrenocortical insufficiency: yearly ACTH & cortisol levels Males w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly Females: not warranted given rarity of adrenocortical insufficiency ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy Recommended surveillance for primary adrenocortical insufficiency in males is summarized in Recommended Ages/Intervals of Surveillance for Primary Adrenocortical Insufficiency for At-Risk but Not Yet Symptomatic Males Based on ACTH = adrenocorticotropic hormone Significant head injury has been associated with activation of cerebral disease [ It is appropriate to evaluate at-risk male relatives (i.e., male relatives not known to have X-ALD) of an affected individual in order to identify as early as possible those who would benefit from screening for primary adrenocortical insufficiency and to facilitate timely identification of young males who might benefit from targeted treatment for cCALD. Such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms. Because these issues are not limited by age, all at-risk males should be offered diagnostic testing. If born in the United States, males affected with X-ALD may be diagnosed by universal newborn screening soon after birth. If newborn screening data are not available for at-risk sibs, several evaluations can be considered: If the If the See Search • Screening for ACTH & cortisol levels • Follow up per Pediatric Endocrine Society published guidance recommendations • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Specific neurologic deficits (e.g., hemiparesis, visual field defect); • Seizures if history is suggestive. • Behaviors that may respond to medication; • Aggressive or disinhibited behavior. • Educational needs; • Need for OT service; • Need for PT services incl durable medical equipment. • To inform affected persons & their families re nature, MOI, & implications of cCALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Community or • Social work involvement for parental/family support; • Home nursing referral. • Assess for cognitive impairment, progressive spastic gait disturbance, paralysis, ataxia, weakness, & restless legs syndrome. • Brain MRI to assess for cerebral disease (Spine MRIs are generally not helpful.) • Further services such as mental health, speech, & behavior if appropriate • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Community or • Social work involvement for parental/family support. • Assess for presence of cerebral disease. • Urgency will depend on age of affected person. Males age <2-10 yrs need expedited imaging (see • ACTH & cortisol levels • Referral to pediatric endocrinology • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic eval & treatment/screening as recommended in • Community or • Social work involvement for parental/family support. • The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval • The routine use of neuropsychological testing [ • Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • An added criterion is absence of a matched-sib donor. • The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • Speech-language therapy or OT • Discuss gastrostomy tube placement. • Children: per treating pediatric endocrinologist • Adults: per treating endocrinologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement w/home nursing • Discussion of hospice • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as onset of seizures, changes in tone, & movement disorders. • For those not yet known to have adrenocortical insufficiency: ACTH & cortisol levels every 6 mos • For those w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly • Males not yet known to have adrenocortical insufficiency: yearly ACTH & cortisol levels • Males w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly • Females: not warranted given rarity of adrenocortical insufficiency • If the • If the ## Evaluations Following Initial Diagnosis For male infants with a positive newborn screening (NBS) result for X-ALD, the initial evaluations summarized in Recommended Evaluations and Next Steps for Infants with a Confirmed Positive Newborn Screening Result for X-Linked Adrenoleukodystrophy Screening for ACTH & cortisol levels Follow up per Pediatric Endocrine Society published guidance recommendations To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or ACTH = adrenocorticotropic hormone; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Recommended initial evaluations for symptomatic males with cCALD are summarized in Recommended Evaluations Following Initial Diagnosis in Symptomatic Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Specific neurologic deficits (e.g., hemiparesis, visual field defect); Seizures if history is suggestive. Behaviors that may respond to medication; Aggressive or disinhibited behavior. Educational needs; Need for OT service; Need for PT services incl durable medical equipment. To inform affected persons & their families re nature, MOI, & implications of cCALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or Community or Social work involvement for parental/family support; Home nursing referral. cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse For recommended initial evaluations for males and females who have adrenomyeloneuropathy (AMN), see Recommended Evaluations Following Initial Diagnosis in Males and Females with Adrenomyeloneuropathy (AMN) Assess for cognitive impairment, progressive spastic gait disturbance, paralysis, ataxia, weakness, & restless legs syndrome. Brain MRI to assess for cerebral disease (Spine MRIs are generally not helpful.) Further services such as mental health, speech, & behavior if appropriate To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or Community or Social work involvement for parental/family support. ACTH = adrenocorticotropic hormone; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Males identified by family screening may be any age (infancy through adulthood), and the urgency of evaluation will depend on age at diagnosis. See Recommended Evaluations and Next Steps for Males Identified by Family Screening Assess for presence of cerebral disease. Urgency will depend on age of affected person. Males age <2-10 yrs need expedited imaging (see ACTH & cortisol levels Referral to pediatric endocrinology To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic eval & treatment/screening as recommended in Community or Social work involvement for parental/family support. ACTH = adrenocorticotropic hormone; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Screening for ACTH & cortisol levels • Follow up per Pediatric Endocrine Society published guidance recommendations • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Specific neurologic deficits (e.g., hemiparesis, visual field defect); • Seizures if history is suggestive. • Behaviors that may respond to medication; • Aggressive or disinhibited behavior. • Educational needs; • Need for OT service; • Need for PT services incl durable medical equipment. • To inform affected persons & their families re nature, MOI, & implications of cCALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Community or • Social work involvement for parental/family support; • Home nursing referral. • Assess for cognitive impairment, progressive spastic gait disturbance, paralysis, ataxia, weakness, & restless legs syndrome. • Brain MRI to assess for cerebral disease (Spine MRIs are generally not helpful.) • Further services such as mental health, speech, & behavior if appropriate • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Community or • Social work involvement for parental/family support. • Assess for presence of cerebral disease. • Urgency will depend on age of affected person. Males age <2-10 yrs need expedited imaging (see • ACTH & cortisol levels • Referral to pediatric endocrinology • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic eval & treatment/screening as recommended in • Community or • Social work involvement for parental/family support. ## Confirmed Positive Newborn Screening Result: Initial Evaluations For male infants with a positive newborn screening (NBS) result for X-ALD, the initial evaluations summarized in Recommended Evaluations and Next Steps for Infants with a Confirmed Positive Newborn Screening Result for X-Linked Adrenoleukodystrophy Screening for ACTH & cortisol levels Follow up per Pediatric Endocrine Society published guidance recommendations To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or ACTH = adrenocorticotropic hormone; CALD = cerebral adrenoleukodystrophy; cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Screening for ACTH & cortisol levels • Follow up per Pediatric Endocrine Society published guidance recommendations • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or ## Males with Symptomatic cCALD: Initial Evaluations Recommended initial evaluations for symptomatic males with cCALD are summarized in Recommended Evaluations Following Initial Diagnosis in Symptomatic Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Specific neurologic deficits (e.g., hemiparesis, visual field defect); Seizures if history is suggestive. Behaviors that may respond to medication; Aggressive or disinhibited behavior. Educational needs; Need for OT service; Need for PT services incl durable medical equipment. To inform affected persons & their families re nature, MOI, & implications of cCALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or Community or Social work involvement for parental/family support; Home nursing referral. cCALD = childhood cerebral adrenoleukodystrophy; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Specific neurologic deficits (e.g., hemiparesis, visual field defect); • Seizures if history is suggestive. • Behaviors that may respond to medication; • Aggressive or disinhibited behavior. • Educational needs; • Need for OT service; • Need for PT services incl durable medical equipment. • To inform affected persons & their families re nature, MOI, & implications of cCALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Community or • Social work involvement for parental/family support; • Home nursing referral. ## Males and Females with Adrenomyeloneuropathy (AMN): Initial Evaluations For recommended initial evaluations for males and females who have adrenomyeloneuropathy (AMN), see Recommended Evaluations Following Initial Diagnosis in Males and Females with Adrenomyeloneuropathy (AMN) Assess for cognitive impairment, progressive spastic gait disturbance, paralysis, ataxia, weakness, & restless legs syndrome. Brain MRI to assess for cerebral disease (Spine MRIs are generally not helpful.) Further services such as mental health, speech, & behavior if appropriate To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or Community or Social work involvement for parental/family support. ACTH = adrenocorticotropic hormone; VLCFA = very long-chain fatty acid; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assess for cognitive impairment, progressive spastic gait disturbance, paralysis, ataxia, weakness, & restless legs syndrome. • Brain MRI to assess for cerebral disease (Spine MRIs are generally not helpful.) • Further services such as mental health, speech, & behavior if appropriate • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD (At-risk males may be identified by use of plasma or serum VLCFA levels or • Community or • Social work involvement for parental/family support. ## Males Identified by Family Screening: Initial Evaluations and Next Steps Males identified by family screening may be any age (infancy through adulthood), and the urgency of evaluation will depend on age at diagnosis. See Recommended Evaluations and Next Steps for Males Identified by Family Screening Assess for presence of cerebral disease. Urgency will depend on age of affected person. Males age <2-10 yrs need expedited imaging (see ACTH & cortisol levels Referral to pediatric endocrinology To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making To identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic eval & treatment/screening as recommended in Community or Social work involvement for parental/family support. ACTH = adrenocorticotropic hormone; X-ALD = X-linked adrenoleukodystrophy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assess for presence of cerebral disease. • Urgency will depend on age of affected person. Males age <2-10 yrs need expedited imaging (see • ACTH & cortisol levels • Referral to pediatric endocrinology • To inform affected persons & their families re nature, MOI, & implications of X-ALD to facilitate medical & personal decision making • To identify male relatives at risk for X-ALD & primary adrenocortical insufficiency who might warrant diagnostic eval & treatment/screening as recommended in • Community or • Social work involvement for parental/family support. ## Treatment of Manifestations There is no cure for X-linked adrenoleukodystrophy (X-ALD). Evidence clearly shows that hematopoietic stem cell transplantation (HSCT) has the best outcome when performed on an asymptomatic individual with minimal but characteristic imaging findings of cCALD [ Early-stage cCALD brain MRI findings are characterized by small T See Recommended Brain MRI Schedule for Early Detection of Childhood Cerebral Adrenoleukodystrophy (cCALD) Abnormalities in At-Risk Males Based on cCALD = childhood cerebral adrenoleukodystrophy If early-stage cCALD is diagnosed, the boy should be referred to a center with expertise in monitoring and treating cCALD. The following are NOT presently recommended for screening males at risk for cCALD: The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval The routine use of neuropsychological testing [ Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ Individuals should have early cCALD as seen on contrast-enhanced MRI. They should not have neurologic signs. Neuropsychological testing should indicate a performance IQ greater than 80. An added criterion is absence of a matched-sib donor. The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. Boys whose neurologic disease is too advanced at the time of diagnosis are not candidates for targeted therapy. Thus, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Speech-language therapy or OT Discuss gastrostomy tube placement. Children: per treating pediatric endocrinologist Adults: per treating endocrinologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement w/home nursing Discussion of hospice ADL = activities of daily living; ASM = anti-seizure medication; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. Supportive care for males and females with adrenomyeloneuropathy (AMN) to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males and Females with Adrenomyeloneuropathy (AMN) Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. • The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval • The routine use of neuropsychological testing [ • Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • An added criterion is absence of a matched-sib donor. • The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • Speech-language therapy or OT • Discuss gastrostomy tube placement. • Children: per treating pediatric endocrinologist • Adults: per treating endocrinologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement w/home nursing • Discussion of hospice • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Targeted Therapy Evidence clearly shows that hematopoietic stem cell transplantation (HSCT) has the best outcome when performed on an asymptomatic individual with minimal but characteristic imaging findings of cCALD [ Early-stage cCALD brain MRI findings are characterized by small T See Recommended Brain MRI Schedule for Early Detection of Childhood Cerebral Adrenoleukodystrophy (cCALD) Abnormalities in At-Risk Males Based on cCALD = childhood cerebral adrenoleukodystrophy If early-stage cCALD is diagnosed, the boy should be referred to a center with expertise in monitoring and treating cCALD. The following are NOT presently recommended for screening males at risk for cCALD: The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval The routine use of neuropsychological testing [ Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ Individuals should have early cCALD as seen on contrast-enhanced MRI. They should not have neurologic signs. Neuropsychological testing should indicate a performance IQ greater than 80. An added criterion is absence of a matched-sib donor. The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. • The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval • The routine use of neuropsychological testing [ • Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • An added criterion is absence of a matched-sib donor. • The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. ## Evidence clearly shows that hematopoietic stem cell transplantation (HSCT) has the best outcome when performed on an asymptomatic individual with minimal but characteristic imaging findings of cCALD [ Early-stage cCALD brain MRI findings are characterized by small T See Recommended Brain MRI Schedule for Early Detection of Childhood Cerebral Adrenoleukodystrophy (cCALD) Abnormalities in At-Risk Males Based on cCALD = childhood cerebral adrenoleukodystrophy If early-stage cCALD is diagnosed, the boy should be referred to a center with expertise in monitoring and treating cCALD. The following are NOT presently recommended for screening males at risk for cCALD: The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval The routine use of neuropsychological testing [ Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ Individuals should have early cCALD as seen on contrast-enhanced MRI. They should not have neurologic signs. Neuropsychological testing should indicate a performance IQ greater than 80. An added criterion is absence of a matched-sib donor. The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. • The routine use of advanced imaging techniques such as spectroscopy or diffusion tensor imaging outside of a research protocol with IRB approval • The routine use of neuropsychological testing [ • Note: HSCT is not recommended for individuals with severe neurologic and neuropsychological dysfunction (i.e., performance IQ <80) [ • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • An added criterion is absence of a matched-sib donor. • The potential benefit is that risk of graft versus host disease is less than that associated with HSCT. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. • Individuals should have early cCALD as seen on contrast-enhanced MRI. • They should not have neurologic signs. • Neuropsychological testing should indicate a performance IQ greater than 80. ## Supportive Care Boys whose neurologic disease is too advanced at the time of diagnosis are not candidates for targeted therapy. Thus, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Speech-language therapy or OT Discuss gastrostomy tube placement. Children: per treating pediatric endocrinologist Adults: per treating endocrinologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement w/home nursing Discussion of hospice ADL = activities of daily living; ASM = anti-seizure medication; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. Supportive care for males and females with adrenomyeloneuropathy (AMN) to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males and Females with Adrenomyeloneuropathy (AMN) Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. • Speech-language therapy or OT • Discuss gastrostomy tube placement. • Children: per treating pediatric endocrinologist • Adults: per treating endocrinologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement w/home nursing • Discussion of hospice • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Boys whose neurologic disease is too advanced at the time of diagnosis are not candidates for targeted therapy. Thus, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Speech-language therapy or OT Discuss gastrostomy tube placement. Children: per treating pediatric endocrinologist Adults: per treating endocrinologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement w/home nursing Discussion of hospice ADL = activities of daily living; ASM = anti-seizure medication; IEP = individualized education plan; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. • Speech-language therapy or OT • Discuss gastrostomy tube placement. • Children: per treating pediatric endocrinologist • Adults: per treating endocrinologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement w/home nursing • Discussion of hospice ## Supportive care for males and females with adrenomyeloneuropathy (AMN) to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Males and Females with Adrenomyeloneuropathy (AMN) Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Corticosteroid replacement therapy has no effect on nervous system involvement. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as onset of seizures, changes in tone, & movement disorders. For those not yet known to have adrenocortical insufficiency: ACTH & cortisol levels every 6 mos For those w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Males and Females with Adrenomyeloneuropathy (AMN) Males not yet known to have adrenocortical insufficiency: yearly ACTH & cortisol levels Males w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly Females: not warranted given rarity of adrenocortical insufficiency ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy Recommended surveillance for primary adrenocortical insufficiency in males is summarized in Recommended Ages/Intervals of Surveillance for Primary Adrenocortical Insufficiency for At-Risk but Not Yet Symptomatic Males Based on ACTH = adrenocorticotropic hormone • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as onset of seizures, changes in tone, & movement disorders. • For those not yet known to have adrenocortical insufficiency: ACTH & cortisol levels every 6 mos • For those w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly • Males not yet known to have adrenocortical insufficiency: yearly ACTH & cortisol levels • Males w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly • Females: not warranted given rarity of adrenocortical insufficiency ## Childhood Cerebral Adrenoleukodystrophy (cCALD) To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Males with Childhood Cerebral Adrenoleukodystrophy (cCALD) Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as onset of seizures, changes in tone, & movement disorders. For those not yet known to have adrenocortical insufficiency: ACTH & cortisol levels every 6 mos For those w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as onset of seizures, changes in tone, & movement disorders. • For those not yet known to have adrenocortical insufficiency: ACTH & cortisol levels every 6 mos • For those w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly ## Adrenomyeloneuropathy (AMN) To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Males and Females with Adrenomyeloneuropathy (AMN) Males not yet known to have adrenocortical insufficiency: yearly ACTH & cortisol levels Males w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly Females: not warranted given rarity of adrenocortical insufficiency ACTH = adrenocorticotropic hormone; OT = occupational therapy; PT = physical therapy • Males not yet known to have adrenocortical insufficiency: yearly ACTH & cortisol levels • Males w/known adrenocortical insufficiency: per treating endocrinologist, but at least yearly • Females: not warranted given rarity of adrenocortical insufficiency ## Primary Adrenocortical Insufficiency Recommended surveillance for primary adrenocortical insufficiency in males is summarized in Recommended Ages/Intervals of Surveillance for Primary Adrenocortical Insufficiency for At-Risk but Not Yet Symptomatic Males Based on ACTH = adrenocorticotropic hormone ## Agents/Circumstances to Avoid Significant head injury has been associated with activation of cerebral disease [ ## Evaluation of Relatives at Risk It is appropriate to evaluate at-risk male relatives (i.e., male relatives not known to have X-ALD) of an affected individual in order to identify as early as possible those who would benefit from screening for primary adrenocortical insufficiency and to facilitate timely identification of young males who might benefit from targeted treatment for cCALD. Such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms. Because these issues are not limited by age, all at-risk males should be offered diagnostic testing. If born in the United States, males affected with X-ALD may be diagnosed by universal newborn screening soon after birth. If newborn screening data are not available for at-risk sibs, several evaluations can be considered: If the If the See • If the • If the ## Therapies Under Investigation Search ## Genetic Counseling By definition, X-linked adrenoleukodystrophy (X-ALD) is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother: May be a heterozygote. Approximately 95% of probands inherit an May not be heterozygous, and the affected male has a May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. If an A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a Recommendations for the evaluation of the parents of a female proband: If an Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see If the mother of the proband has an Males who inherit the pathogenic variant will be affected. Note: The phenotype in a male sib who inherits an Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, If the proband represents a simplex case and if the If the mother of the proband has an If the father of the proband is affected (i.e., hemizygous for an Affected males transmit the Heterozygous females have a 50% chance of transmitting the Note: Varying phenotypes often coexist in the same family. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the Females who are heterozygous for this X-linked disorder are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, Identification of female heterozygotes requires either prior identification of the Note: VLCFA analysis is not recommended as a screening method for females known to be at risk (see See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother: • May be a heterozygote. Approximately 95% of probands inherit an • May not be heterozygous, and the affected male has a • May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. • May be a heterozygote. Approximately 95% of probands inherit an • May not be heterozygous, and the affected male has a • May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. • If an • May be a heterozygote. Approximately 95% of probands inherit an • May not be heterozygous, and the affected male has a • May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • Recommendations for the evaluation of the parents of a female proband: • If an • Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see • If an • Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see • If an • Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. • Note: The phenotype in a male sib who inherits an • Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • Males who inherit the pathogenic variant will be affected. • Note: The phenotype in a male sib who inherits an • Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. • Note: The phenotype in a male sib who inherits an • Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • If the mother of the proband has an • If the father of the proband is affected (i.e., hemizygous for an • Affected males transmit the • Heterozygous females have a 50% chance of transmitting the • Note: Varying phenotypes often coexist in the same family. • Females who are heterozygous for this X-linked disorder are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • Identification of female heterozygotes requires either prior identification of the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance By definition, X-linked adrenoleukodystrophy (X-ALD) is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother: May be a heterozygote. Approximately 95% of probands inherit an May not be heterozygous, and the affected male has a May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. If an A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a Recommendations for the evaluation of the parents of a female proband: If an Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see If the mother of the proband has an Males who inherit the pathogenic variant will be affected. Note: The phenotype in a male sib who inherits an Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, If the proband represents a simplex case and if the If the mother of the proband has an If the father of the proband is affected (i.e., hemizygous for an Affected males transmit the Heterozygous females have a 50% chance of transmitting the Note: Varying phenotypes often coexist in the same family. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother: • May be a heterozygote. Approximately 95% of probands inherit an • May not be heterozygous, and the affected male has a • May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. • May be a heterozygote. Approximately 95% of probands inherit an • May not be heterozygous, and the affected male has a • May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. • If an • May be a heterozygote. Approximately 95% of probands inherit an • May not be heterozygous, and the affected male has a • May have somatic/germline mosaicism. Evidence of germline or somatic/germline mosaicism is present in <1% of parents. • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • Recommendations for the evaluation of the parents of a female proband: • If an • Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see • If an • Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see • If an • Fathers of newly identified heterozygous females may be evaluated by very long-chain fatty acid (VLCFA) testing (see • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. • Note: The phenotype in a male sib who inherits an • Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • Males who inherit the pathogenic variant will be affected. • Note: The phenotype in a male sib who inherits an • Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. • Note: The phenotype in a male sib who inherits an • Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • If the mother of the proband has an • If the father of the proband is affected (i.e., hemizygous for an • Affected males transmit the • Heterozygous females have a 50% chance of transmitting the • Note: Varying phenotypes often coexist in the same family. ## Heterozygote Detection Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the Females who are heterozygous for this X-linked disorder are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, Identification of female heterozygotes requires either prior identification of the Note: VLCFA analysis is not recommended as a screening method for females known to be at risk (see • Females who are heterozygous for this X-linked disorder are symptom-free in childhood but may manifest findings in adulthood (see Clinical Characteristics, • Identification of female heterozygotes requires either prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Australia PO Box 5801 Bethesda MD 20824 Health Resources & Services Administration • • • • • • Australia • • • PO Box 5801 • Bethesda MD 20824 • • • • • Health Resources & Services Administration • • • • • ## Molecular Genetics X-Linked Adrenoleukodystrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Adrenoleukodystrophy ( ## Molecular Pathogenesis ## Chapter Notes Gerald Raymond ( Drs Raymond and Fatemi are also interested in hearing from clinicians treating families affected by X-ALD in whom no causative variant has been identified through molecular genetic testing. Contact Dr Raymond to inquire about review of Contact Ms Ann Moser ( The authors' work has been supported in the past by the National Institutes of Health and the Food and Drug Administration. Corinne D Boehm, MS; Johns Hopkins Hospital (1999-2002)Ali Fatemi, MD (2018-present)Ann B Moser, BA (1999-present)Hugo W Moser, MD; Johns Hopkins University School of Medicine (1999-2007)Gerald V Raymond, MD (2006-present)Steven J Steinberg, PhD; Johns Hopkins University School of Medicine (2002-2018) Hugo W Moser, MD, was Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine and former Director of the Kennedy Krieger Institute in Baltimore. He was a world-renowned expert in the field of neurogenetics. He was best known for his leadership role in understanding, diagnosing, and treating adrenoleukodystrophy. Dr Moser died of cancer on January 20, 2007, at age 82. He is greatly missed by his family, friends, colleagues, and patients. 6 April 2023 (bp) Comprehensive update posted live 15 February 2018 (ha) Comprehensive update posted live 9 April 2015 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 2 June 2009 (me) Comprehensive update posted live 27 July 2006 (me) Comprehensive update posted live 15 April 2004 (me) Comprehensive update posted live 26 August 2002 (ss) Author revisions 26 February 2002 (me) Comprehensive update posted live 26 March 1999 (pb) Review posted live 2 February 1999 (hm) Original submission • 6 April 2023 (bp) Comprehensive update posted live • 15 February 2018 (ha) Comprehensive update posted live • 9 April 2015 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 2 June 2009 (me) Comprehensive update posted live • 27 July 2006 (me) Comprehensive update posted live • 15 April 2004 (me) Comprehensive update posted live • 26 August 2002 (ss) Author revisions • 26 February 2002 (me) Comprehensive update posted live • 26 March 1999 (pb) Review posted live • 2 February 1999 (hm) Original submission ## Author Notes Gerald Raymond ( Drs Raymond and Fatemi are also interested in hearing from clinicians treating families affected by X-ALD in whom no causative variant has been identified through molecular genetic testing. Contact Dr Raymond to inquire about review of Contact Ms Ann Moser ( ## Acknowledgments The authors' work has been supported in the past by the National Institutes of Health and the Food and Drug Administration. ## Author History Corinne D Boehm, MS; Johns Hopkins Hospital (1999-2002)Ali Fatemi, MD (2018-present)Ann B Moser, BA (1999-present)Hugo W Moser, MD; Johns Hopkins University School of Medicine (1999-2007)Gerald V Raymond, MD (2006-present)Steven J Steinberg, PhD; Johns Hopkins University School of Medicine (2002-2018) Hugo W Moser, MD, was Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine and former Director of the Kennedy Krieger Institute in Baltimore. He was a world-renowned expert in the field of neurogenetics. He was best known for his leadership role in understanding, diagnosing, and treating adrenoleukodystrophy. Dr Moser died of cancer on January 20, 2007, at age 82. He is greatly missed by his family, friends, colleagues, and patients. ## Revision History 6 April 2023 (bp) Comprehensive update posted live 15 February 2018 (ha) Comprehensive update posted live 9 April 2015 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 2 June 2009 (me) Comprehensive update posted live 27 July 2006 (me) Comprehensive update posted live 15 April 2004 (me) Comprehensive update posted live 26 August 2002 (ss) Author revisions 26 February 2002 (me) Comprehensive update posted live 26 March 1999 (pb) Review posted live 2 February 1999 (hm) Original submission • 6 April 2023 (bp) Comprehensive update posted live • 15 February 2018 (ha) Comprehensive update posted live • 9 April 2015 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 2 June 2009 (me) Comprehensive update posted live • 27 July 2006 (me) Comprehensive update posted live • 15 April 2004 (me) Comprehensive update posted live • 26 August 2002 (ss) Author revisions • 26 February 2002 (me) Comprehensive update posted live • 26 March 1999 (pb) Review posted live • 2 February 1999 (hm) Original submission ## Key Sections in this ## References ## Literature Cited	[]	26/3/1999	6/4/2023	15/8/2002	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
x-dcdp	x-dcdp	[ "CDPX2", "Conradi-Hünermann Syndrome", "Happle Syndrome", "Conradi-Hunermann Syndrome", "Happle Syndrome", "3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase", "EBP", "Chondrodysplasia Punctata 2, X-Linked" ]	Chondrodysplasia Punctata 2, X-Linked	Smitha Kumble, Ravi Savarirayan	Summary The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including females with no recognizable physical abnormalities. At least 95% of live-born individuals with CDPX2 are female. Characteristic features include growth deficiency; distinctive craniofacial appearance; chondrodysplasia punctata (stippling of the epiphyses of the long bones, vertebrae, trachea, and distal ends of the ribs); often asymmetric rhizomelic shortening of limbs; scoliosis; linear or blotchy scaling ichthyosis in the newborn; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; and cataracts. The diagnosis of CDPX2 is established in a female proband with: typical clinical findings, increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts; and/or a heterozygous pathogenic variant in The diagnosis of CDPX2 is established in a male proband with: typical clinical findings, increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts; and/or a hemizygous pathogenic variant in CDPX2 is inherited in an X-linked manner with early gestational male lethality. Women with an	## Diagnosis X-linked chondrodysplasia punctata 2 (CDPX2) is a skeletal dysplasia that also affects the skin and eyes. Specific diagnostic criteria for CDPX2 have not been published. Classic CDPX2 occurs almost exclusively in females. There are reports of affected males with an XXY karyotype [ CDPX2 Growth deficiency / short stature Craniofacial findings Frontal bossing Depressed nasal bridge Sparse eyebrows and lashes, often asymmetric Skeletal abnormality Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric Scoliosis, occasionally congenital Postaxial polydactyly (uncommon) Abnormality of skin, hair, and nails Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see Coarse scalp hair with scarring alopecia (see Occasional flattened or split nails Note: Teeth are normal. Ocular anomaly Cataracts often congenital, asymmetric, and/or sectorial Microphthalmia and/or microcornea Note: Males with Concentrations of 8(9)-Cholestenol and 8-Dehydrocholesterol Observed in Chondrodysplasia Punctata 2, X-Linked Data from 105 females with presumed CDPX2 [R Kelley, personal communication] In centers where it is readily available, molecular genetic testing should be considered first. Biochemical testing can be used to support a diagnosis in individuals with inconclusive molecular variants. Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CDPX2 is broad, individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Chondrodysplasia Punctata 2, X-Linked See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Review of approximately 80 pathogenic variants in all available published case literature, ClinVar [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Growth deficiency / short stature • Craniofacial findings • Frontal bossing • Depressed nasal bridge • Sparse eyebrows and lashes, often asymmetric • Frontal bossing • Depressed nasal bridge • Sparse eyebrows and lashes, often asymmetric • Skeletal abnormality • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric • Scoliosis, occasionally congenital • Postaxial polydactyly (uncommon) • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric • Scoliosis, occasionally congenital • Postaxial polydactyly (uncommon) • Abnormality of skin, hair, and nails • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see • Coarse scalp hair with scarring alopecia (see • Occasional flattened or split nails • Note: Teeth are normal. • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see • Coarse scalp hair with scarring alopecia (see • Occasional flattened or split nails • Ocular anomaly • Cataracts often congenital, asymmetric, and/or sectorial • Microphthalmia and/or microcornea • Cataracts often congenital, asymmetric, and/or sectorial • Microphthalmia and/or microcornea • Frontal bossing • Depressed nasal bridge • Sparse eyebrows and lashes, often asymmetric • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric • Scoliosis, occasionally congenital • Postaxial polydactyly (uncommon) • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see • Coarse scalp hair with scarring alopecia (see • Occasional flattened or split nails • Cataracts often congenital, asymmetric, and/or sectorial • Microphthalmia and/or microcornea • For an introduction to multigene panels click ## Suggestive Findings CDPX2 Growth deficiency / short stature Craniofacial findings Frontal bossing Depressed nasal bridge Sparse eyebrows and lashes, often asymmetric Skeletal abnormality Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric Scoliosis, occasionally congenital Postaxial polydactyly (uncommon) Abnormality of skin, hair, and nails Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see Coarse scalp hair with scarring alopecia (see Occasional flattened or split nails Note: Teeth are normal. Ocular anomaly Cataracts often congenital, asymmetric, and/or sectorial Microphthalmia and/or microcornea • Growth deficiency / short stature • Craniofacial findings • Frontal bossing • Depressed nasal bridge • Sparse eyebrows and lashes, often asymmetric • Frontal bossing • Depressed nasal bridge • Sparse eyebrows and lashes, often asymmetric • Skeletal abnormality • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric • Scoliosis, occasionally congenital • Postaxial polydactyly (uncommon) • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric • Scoliosis, occasionally congenital • Postaxial polydactyly (uncommon) • Abnormality of skin, hair, and nails • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see • Coarse scalp hair with scarring alopecia (see • Occasional flattened or split nails • Note: Teeth are normal. • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see • Coarse scalp hair with scarring alopecia (see • Occasional flattened or split nails • Ocular anomaly • Cataracts often congenital, asymmetric, and/or sectorial • Microphthalmia and/or microcornea • Cataracts often congenital, asymmetric, and/or sectorial • Microphthalmia and/or microcornea • Frontal bossing • Depressed nasal bridge • Sparse eyebrows and lashes, often asymmetric • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric • Scoliosis, occasionally congenital • Postaxial polydactyly (uncommon) • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see • Coarse scalp hair with scarring alopecia (see • Occasional flattened or split nails • Cataracts often congenital, asymmetric, and/or sectorial • Microphthalmia and/or microcornea ## Establishing the Diagnosis Note: Males with Concentrations of 8(9)-Cholestenol and 8-Dehydrocholesterol Observed in Chondrodysplasia Punctata 2, X-Linked Data from 105 females with presumed CDPX2 [R Kelley, personal communication] In centers where it is readily available, molecular genetic testing should be considered first. Biochemical testing can be used to support a diagnosis in individuals with inconclusive molecular variants. Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CDPX2 is broad, individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Chondrodysplasia Punctata 2, X-Linked See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Review of approximately 80 pathogenic variants in all available published case literature, ClinVar [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Molecular Genetic Testing In centers where it is readily available, molecular genetic testing should be considered first. Biochemical testing can be used to support a diagnosis in individuals with inconclusive molecular variants. Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CDPX2 is broad, individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Chondrodysplasia Punctata 2, X-Linked See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Review of approximately 80 pathogenic variants in all available published case literature, ClinVar [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Clinical Characteristics Approximately 90% of individuals have asymmetric (or occasionally symmetric) shortening of limbs involving mostly the femur, humerus, and other tubular bones [ Moderate-to-severe kyphoscoliosis is common and can present in infancy or early childhood. Lung disease may develop secondary to progressive kyphoscoliosis and can lead to death [ Hair findings include scarring alopecia in patches, sparse eyelashes and eyebrows, and coarse, lusterless hair. Minor nail findings include flattening and splitting of the nail plates [ Individuals with CDPX2 may also have bilateral or unilateral clubfoot [ Hydronephrosis has been seen in several affected females [ Hypoglycemia in the neonatal period has been reported [ Null Hypomorphic hemizygous A few clinically unaffected females with molecularly confirmed CDPX2 have been reported [ CDPX2 has also been referred to as: Conradi-Hünermann syndrome, named after Happle syndrome, named after Rudolph Happle [ Conradi-Hünermann-Happle syndrome, which recognizes all three individuals who helped to define this disorder. Prevalence is unknown and incidence is estimated at 1:100,000 to 1:200,000 births. • Individuals with CDPX2 may also have bilateral or unilateral clubfoot [ • Hydronephrosis has been seen in several affected females [ • Hypoglycemia in the neonatal period has been reported [ • Conradi-Hünermann syndrome, named after • Happle syndrome, named after Rudolph Happle [ • Conradi-Hünermann-Happle syndrome, which recognizes all three individuals who helped to define this disorder. ## Clinical Description Approximately 90% of individuals have asymmetric (or occasionally symmetric) shortening of limbs involving mostly the femur, humerus, and other tubular bones [ Moderate-to-severe kyphoscoliosis is common and can present in infancy or early childhood. Lung disease may develop secondary to progressive kyphoscoliosis and can lead to death [ Hair findings include scarring alopecia in patches, sparse eyelashes and eyebrows, and coarse, lusterless hair. Minor nail findings include flattening and splitting of the nail plates [ Individuals with CDPX2 may also have bilateral or unilateral clubfoot [ Hydronephrosis has been seen in several affected females [ Hypoglycemia in the neonatal period has been reported [ • Individuals with CDPX2 may also have bilateral or unilateral clubfoot [ • Hydronephrosis has been seen in several affected females [ • Hypoglycemia in the neonatal period has been reported [ ## Clinical Findings Associated with Classic CDPX2 Approximately 90% of individuals have asymmetric (or occasionally symmetric) shortening of limbs involving mostly the femur, humerus, and other tubular bones [ Moderate-to-severe kyphoscoliosis is common and can present in infancy or early childhood. Lung disease may develop secondary to progressive kyphoscoliosis and can lead to death [ Hair findings include scarring alopecia in patches, sparse eyelashes and eyebrows, and coarse, lusterless hair. Minor nail findings include flattening and splitting of the nail plates [ Individuals with CDPX2 may also have bilateral or unilateral clubfoot [ Hydronephrosis has been seen in several affected females [ Hypoglycemia in the neonatal period has been reported [ • Individuals with CDPX2 may also have bilateral or unilateral clubfoot [ • Hydronephrosis has been seen in several affected females [ • Hypoglycemia in the neonatal period has been reported [ ## Genotype-Phenotype Correlations Null Hypomorphic hemizygous ## Penetrance A few clinically unaffected females with molecularly confirmed CDPX2 have been reported [ ## Nomenclature CDPX2 has also been referred to as: Conradi-Hünermann syndrome, named after Happle syndrome, named after Rudolph Happle [ Conradi-Hünermann-Happle syndrome, which recognizes all three individuals who helped to define this disorder. • Conradi-Hünermann syndrome, named after • Happle syndrome, named after Rudolph Happle [ • Conradi-Hünermann-Happle syndrome, which recognizes all three individuals who helped to define this disorder. ## Prevalence Prevalence is unknown and incidence is estimated at 1:100,000 to 1:200,000 births. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Several disorders demonstrate features similar to those of X-linked chondrodysplasia punctata 2 (CDPX2) and/or manifest stippling on radiographs and various combinations of limb asymmetry, short stature, intellectual disability, cataracts, and skin changes. The key radiologic finding of chondrodysplasia punctata occurs in various metabolic disorders, skeletal dysplasias, chromosome abnormalities, and teratogenic exposures. Disorders and Genes of Interest in the Differential Diagnosis of Chondrodysplasia Punctata 2, X-Linked Affected males have short stature & short limbs Cataracts & cutaneous features are rare. Brachytelephalangy & nasomaxillary hypoplasia are characteristic. Delayed cognitive development has been reported. CDP is usually symmetric. Asymmetric skeletal abnormalities incl CDP, rhizomelia, polydactyly, vertebral anomalies, scoliosis/kyphoscoliosis Pathognomonic abnormalities in plasma or tissue sterol levels Male lethal Normal intelligence Strict midline demarcation & striking unilaterality of skin findings that persist rather than improve over time. More severe limb reduction defects that are usually ipsilateral to skin findings Ipsilateral organ abnormalities No cataracts Prenatally lethal & more severe skeletal abnormalities CDP has a characteristic "moth-eaten" appearance. Rhizomelic shortening of limbs, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities (CDP), vertebral abnormalities (notching but not commonly CDP) Cataracts (usually present at birth or appear in 1st few months of life) Birth size often in lower range of normal, but postnatal growth deficiency is profound, ID severe, & seizures common. Skeletal findings in RCDP are more symmetric & less widespread than in CDPX2. There are few calcifications in the spine in RCDP. Cataracts are more symmetric. Most children w/RCDP do not survive 1st decade of life & a substantial % die in neonatal period. RCDP1 is most common. Significant phenotypic overlap w/MEND syndrome No CDP No CDP or skeletal asymmetry Other features incl craniosynostosis, midface hypoplasia, joint contractures, & DD No CDP or skeletal asymmetry ID Brain & visceral anomalies ID & neuronal migration abnormalities Allelic to CHILD syndrome, but no overlapping features AR = autosomal recessive; CDP = chondrodysplasia punctata; CDPX2 = chondrodysplasia punctata 2, X-linked; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Classification of differential diagnoses is presented according to the most recent Nosology and Classification of Skeletal Disorders [ Contiguous gene deletions involving CHILD syndrome is caused by pathogenic variants in Individuals with CHILD syndrome have increased levels of 4-methyl- and carboxysterols in cultured lymphoblasts, but only occasionally in plasma, whereas those with CDPX2 have increased levels of 8(9)-cholestenol and 8-dehydrocholeterol. In cultured lymphoblasts, both disorders manifest a paradoxic increase in the distal sterol metabolite lathosterol, including hemizygous males with an See • Cataracts & cutaneous features are rare. • Brachytelephalangy & nasomaxillary hypoplasia are characteristic. • Delayed cognitive development has been reported. • CDP is usually symmetric. • Asymmetric skeletal abnormalities incl CDP, rhizomelia, polydactyly, vertebral anomalies, scoliosis/kyphoscoliosis • Pathognomonic abnormalities in plasma or tissue sterol levels • Male lethal • Normal intelligence • Strict midline demarcation & striking unilaterality of skin findings that persist rather than improve over time. • More severe limb reduction defects that are usually ipsilateral to skin findings • Ipsilateral organ abnormalities • No cataracts • Prenatally lethal & more severe skeletal abnormalities • CDP has a characteristic "moth-eaten" appearance. • Rhizomelic shortening of limbs, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities (CDP), vertebral abnormalities (notching but not commonly CDP) • Cataracts (usually present at birth or appear in 1st few months of life) • Birth size often in lower range of normal, but postnatal growth deficiency is profound, ID severe, & seizures common. • Skeletal findings in RCDP are more symmetric & less widespread than in CDPX2. • There are few calcifications in the spine in RCDP. • Cataracts are more symmetric. • Most children w/RCDP do not survive 1st decade of life & a substantial % die in neonatal period. • RCDP1 is most common. • Significant phenotypic overlap w/MEND syndrome • No CDP • No CDP or skeletal asymmetry • Other features incl craniosynostosis, midface hypoplasia, joint contractures, & DD • No CDP or skeletal asymmetry • ID • Brain & visceral anomalies • ID & neuronal migration abnormalities • Allelic to CHILD syndrome, but no overlapping features ## Genetic Disorders Disorders and Genes of Interest in the Differential Diagnosis of Chondrodysplasia Punctata 2, X-Linked Affected males have short stature & short limbs Cataracts & cutaneous features are rare. Brachytelephalangy & nasomaxillary hypoplasia are characteristic. Delayed cognitive development has been reported. CDP is usually symmetric. Asymmetric skeletal abnormalities incl CDP, rhizomelia, polydactyly, vertebral anomalies, scoliosis/kyphoscoliosis Pathognomonic abnormalities in plasma or tissue sterol levels Male lethal Normal intelligence Strict midline demarcation & striking unilaterality of skin findings that persist rather than improve over time. More severe limb reduction defects that are usually ipsilateral to skin findings Ipsilateral organ abnormalities No cataracts Prenatally lethal & more severe skeletal abnormalities CDP has a characteristic "moth-eaten" appearance. Rhizomelic shortening of limbs, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities (CDP), vertebral abnormalities (notching but not commonly CDP) Cataracts (usually present at birth or appear in 1st few months of life) Birth size often in lower range of normal, but postnatal growth deficiency is profound, ID severe, & seizures common. Skeletal findings in RCDP are more symmetric & less widespread than in CDPX2. There are few calcifications in the spine in RCDP. Cataracts are more symmetric. Most children w/RCDP do not survive 1st decade of life & a substantial % die in neonatal period. RCDP1 is most common. Significant phenotypic overlap w/MEND syndrome No CDP No CDP or skeletal asymmetry Other features incl craniosynostosis, midface hypoplasia, joint contractures, & DD No CDP or skeletal asymmetry ID Brain & visceral anomalies ID & neuronal migration abnormalities Allelic to CHILD syndrome, but no overlapping features AR = autosomal recessive; CDP = chondrodysplasia punctata; CDPX2 = chondrodysplasia punctata 2, X-linked; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Classification of differential diagnoses is presented according to the most recent Nosology and Classification of Skeletal Disorders [ Contiguous gene deletions involving CHILD syndrome is caused by pathogenic variants in Individuals with CHILD syndrome have increased levels of 4-methyl- and carboxysterols in cultured lymphoblasts, but only occasionally in plasma, whereas those with CDPX2 have increased levels of 8(9)-cholestenol and 8-dehydrocholeterol. In cultured lymphoblasts, both disorders manifest a paradoxic increase in the distal sterol metabolite lathosterol, including hemizygous males with an See • Cataracts & cutaneous features are rare. • Brachytelephalangy & nasomaxillary hypoplasia are characteristic. • Delayed cognitive development has been reported. • CDP is usually symmetric. • Asymmetric skeletal abnormalities incl CDP, rhizomelia, polydactyly, vertebral anomalies, scoliosis/kyphoscoliosis • Pathognomonic abnormalities in plasma or tissue sterol levels • Male lethal • Normal intelligence • Strict midline demarcation & striking unilaterality of skin findings that persist rather than improve over time. • More severe limb reduction defects that are usually ipsilateral to skin findings • Ipsilateral organ abnormalities • No cataracts • Prenatally lethal & more severe skeletal abnormalities • CDP has a characteristic "moth-eaten" appearance. • Rhizomelic shortening of limbs, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities (CDP), vertebral abnormalities (notching but not commonly CDP) • Cataracts (usually present at birth or appear in 1st few months of life) • Birth size often in lower range of normal, but postnatal growth deficiency is profound, ID severe, & seizures common. • Skeletal findings in RCDP are more symmetric & less widespread than in CDPX2. • There are few calcifications in the spine in RCDP. • Cataracts are more symmetric. • Most children w/RCDP do not survive 1st decade of life & a substantial % die in neonatal period. • RCDP1 is most common. • Significant phenotypic overlap w/MEND syndrome • No CDP • No CDP or skeletal asymmetry • Other features incl craniosynostosis, midface hypoplasia, joint contractures, & DD • No CDP or skeletal asymmetry • ID • Brain & visceral anomalies • ID & neuronal migration abnormalities • Allelic to CHILD syndrome, but no overlapping features ## Teratogen Exposures ## Management No published guidelines exist to establish the extent of disease or proper management in an individual with X-linked chondrodysplasia punctata 2 (CDPX2). The following recommendations are based on current literature and the authors' experience. To establish the extent of disease and needs in an individual diagnosed with CDPX2, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Chondrodysplasia Punctata 2, X-Linked Treatment is symptomatic and should be tailored to the individual. Treatment of Manifestations in Individuals with Chondrodysplasia Punctata 2, X-Linked Cataract extraction Standard treatment(s) per ophthalmologist Standard treatment per otolaryngologist Management per nephrologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. Recommended Surveillance for Individuals with Chondrodysplasia Punctata 2, X-Linked Frequency per orthopedist to monitor kyphoscoliosis or joint problems & assess linear growth & any leg length discrepancy Scoliosis can progress rapidly. Adequate sun protection is recommended for individuals with ichthyosis, who are at risk of dehydration secondary to overheating during prolonged sun exposure. Furthermore, care must be taken with use of emollients (which are oil based) and direct sun exposure, which can lead to sunburn. See Search • Cataract extraction • Standard treatment(s) per ophthalmologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • Frequency per orthopedist to monitor kyphoscoliosis or joint problems & assess linear growth & any leg length discrepancy • Scoliosis can progress rapidly. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CDPX2, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Chondrodysplasia Punctata 2, X-Linked ## Treatment of Manifestations Treatment is symptomatic and should be tailored to the individual. Treatment of Manifestations in Individuals with Chondrodysplasia Punctata 2, X-Linked Cataract extraction Standard treatment(s) per ophthalmologist Standard treatment per otolaryngologist Management per nephrologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. • Cataract extraction • Standard treatment(s) per ophthalmologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. ## Surveillance Recommended Surveillance for Individuals with Chondrodysplasia Punctata 2, X-Linked Frequency per orthopedist to monitor kyphoscoliosis or joint problems & assess linear growth & any leg length discrepancy Scoliosis can progress rapidly. • Frequency per orthopedist to monitor kyphoscoliosis or joint problems & assess linear growth & any leg length discrepancy • Scoliosis can progress rapidly. ## Agents/Circumstances to Avoid Adequate sun protection is recommended for individuals with ichthyosis, who are at risk of dehydration secondary to overheating during prolonged sun exposure. Furthermore, care must be taken with use of emollients (which are oil based) and direct sun exposure, which can lead to sunburn. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling X-linked chondrodysplasia punctata 2 (CDPX2) is inherited in an X-linked manner with typical, but not absolute, male lethality. A female proband may have inherited the The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can help to determine if the pathogenic variant was inherited. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Because almost all males with classic CDPX2 are mosaic for a pathogenic variant in In rare families, the mother of an affected male may be heterozygous or may have germline mosaicism. To date, only one family has been reported in which a male had nonlethal CDPX2 as the result of a constitutional In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the The father of an affected male will not have the disorder nor will he be hemizygous for the The risk to sibs of a female proband depends on the genetic status of the parents. The risk to sibs of a male proband is presumed to be low, as the majority of males with CDPX2 have the disorder as the result of a postzygotic mosaic pathogenic variant. If the mother of the proband has an Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see If the father of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Women with a CDPX2-causing pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see Males with mosaic Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see Affected males transmit the pathogenic variant to all of their daughters and none of their sons. To the authors' knowledge, no affected males with constitutional CDPX2-causing pathogenic variants have been reported to reproduce. Some reported males with mosaic Note: Molecular genetic testing may be able to identify the family member in whom a The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have the pathogenic variant, or are at risk of having the pathogenic variant. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • A female proband may have inherited the • The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. • If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). • The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. • If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can help to determine if the pathogenic variant was inherited. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. • If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). • Because almost all males with classic CDPX2 are mosaic for a pathogenic variant in • In rare families, the mother of an affected male may be heterozygous or may have germline mosaicism. To date, only one family has been reported in which a male had nonlethal CDPX2 as the result of a constitutional • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • The father of an affected male will not have the disorder nor will he be hemizygous for the • The risk to sibs of a female proband depends on the genetic status of the parents. • The risk to sibs of a male proband is presumed to be low, as the majority of males with CDPX2 have the disorder as the result of a postzygotic mosaic pathogenic variant. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • If the father of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Women with a CDPX2-causing pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see • Males with mosaic • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see • Males with mosaic • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Affected males transmit the pathogenic variant to all of their daughters and none of their sons. To the authors' knowledge, no affected males with constitutional CDPX2-causing pathogenic variants have been reported to reproduce. Some reported males with mosaic • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see • Males with mosaic • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have the pathogenic variant, or are at risk of having the pathogenic variant. ## Mode of Inheritance X-linked chondrodysplasia punctata 2 (CDPX2) is inherited in an X-linked manner with typical, but not absolute, male lethality. ## Risk to Family Members A female proband may have inherited the The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can help to determine if the pathogenic variant was inherited. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Because almost all males with classic CDPX2 are mosaic for a pathogenic variant in In rare families, the mother of an affected male may be heterozygous or may have germline mosaicism. To date, only one family has been reported in which a male had nonlethal CDPX2 as the result of a constitutional In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the The father of an affected male will not have the disorder nor will he be hemizygous for the The risk to sibs of a female proband depends on the genetic status of the parents. The risk to sibs of a male proband is presumed to be low, as the majority of males with CDPX2 have the disorder as the result of a postzygotic mosaic pathogenic variant. If the mother of the proband has an Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see If the father of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Women with a CDPX2-causing pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see Males with mosaic Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see Affected males transmit the pathogenic variant to all of their daughters and none of their sons. To the authors' knowledge, no affected males with constitutional CDPX2-causing pathogenic variants have been reported to reproduce. Some reported males with mosaic Note: Molecular genetic testing may be able to identify the family member in whom a • A female proband may have inherited the • The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. • If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). • The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. • If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can help to determine if the pathogenic variant was inherited. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • The mother of a proband may be so mildly affected that she is identified only after having had a child with more severe features in whom CDPX2 was diagnosed. • If the proband’s father is asymptomatic, it is possible (though not likely) that he has the pathogenic variant in some cells of his body (somatic and germline mosaicism). • Because almost all males with classic CDPX2 are mosaic for a pathogenic variant in • In rare families, the mother of an affected male may be heterozygous or may have germline mosaicism. To date, only one family has been reported in which a male had nonlethal CDPX2 as the result of a constitutional • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • The father of an affected male will not have the disorder nor will he be hemizygous for the • The risk to sibs of a female proband depends on the genetic status of the parents. • The risk to sibs of a male proband is presumed to be low, as the majority of males with CDPX2 have the disorder as the result of a postzygotic mosaic pathogenic variant. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • If the father of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality, although a small number of males with constitutional CDPX2-causing pathogenic variants have been reported. • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Women with a CDPX2-causing pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see • Males with mosaic • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see • Males with mosaic • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see • Affected males transmit the pathogenic variant to all of their daughters and none of their sons. To the authors' knowledge, no affected males with constitutional CDPX2-causing pathogenic variants have been reported to reproduce. Some reported males with mosaic • Males who inherit the pathogenic variant will be affected. CDPX2 is associated with early gestational male lethality; males with inherited non-mosaic hypomorphic pathogenic variants who survive have MEND syndrome (see • Males with mosaic • Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have the pathogenic variant, or are at risk of having the pathogenic variant. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have the pathogenic variant, or are at risk of having the pathogenic variant. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics Chondrodysplasia Punctata 2, X-Linked: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Chondrodysplasia Punctata 2, X-Linked ( X-linked chondrodysplasia punctata 2 (CDPX2) is caused by a deficiency of 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase or "sterol-Δ8-isomerase," which is encoded by Variability in phenotypes among females with CDPX2 is likely attributable to variability in X-chromosome inactivation. ## Molecular Pathogenesis X-linked chondrodysplasia punctata 2 (CDPX2) is caused by a deficiency of 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase or "sterol-Δ8-isomerase," which is encoded by Variability in phenotypes among females with CDPX2 is likely attributable to variability in X-chromosome inactivation. ## Chapter Notes Melissa A Dempsey, MS, CGC; University of Chicago (2011-2020)Gail E Herman, MD, PhD; Ohio State University (2011-2020)Smitha Kumble, MBBS (2020-present)Ravi Savarirayan, MBBS, MD, FRACP, ARCPA (Hon) (2020-present)Christopher Tan, MS, CGC; University of Chicago (2011-2020) 9 January 2020 (sw) Comprehensive update posted live 31 May 2011 (me) Review posted live 13 July 2009 (md) Original submission • 9 January 2020 (sw) Comprehensive update posted live • 31 May 2011 (me) Review posted live • 13 July 2009 (md) Original submission ## Author History Melissa A Dempsey, MS, CGC; University of Chicago (2011-2020)Gail E Herman, MD, PhD; Ohio State University (2011-2020)Smitha Kumble, MBBS (2020-present)Ravi Savarirayan, MBBS, MD, FRACP, ARCPA (Hon) (2020-present)Christopher Tan, MS, CGC; University of Chicago (2011-2020) ## Revision History 9 January 2020 (sw) Comprehensive update posted live 31 May 2011 (me) Review posted live 13 July 2009 (md) Original submission • 9 January 2020 (sw) Comprehensive update posted live • 31 May 2011 (me) Review posted live • 13 July 2009 (md) Original submission ## References ## Literature Cited Radiographs from a female infant with CDPX2 demonstrating epiphyseal stippling (also called chondrodysplasia punctata; punctate epiphyseal dysplasia) Radiograph originally published in A. Typical skin findings of CDPX2 at birth, including scaling and an erythematous eruption that follows lines of Blaschko B. Later hyperpigmentation over the back in a two-month-old female Photographs originally published in Scarring, patchy alopecia in a female with CDPX2 Photograph originally published in	[]	31/5/2011	9/1/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
x-hed	x-hed	[ "Anhidrotic Ectodermal Dysplasia", "Christ-Siemens-Touraine Syndrome", "Anhidrotic Ectodermal Dysplasia", "Christ-Siemens-Touraine Syndrome", "Mild Hypohidrotic Ectodermal Dysplasia", "Classic Hypohidrotic Ectodermal Dysplasia", "Ectodysplasin-A", "Ectodysplasin-A receptor-associated adapter protein", "Protein Wnt-10a", "Tumor necrosis factor receptor superfamily member EDAR", "EDA", "EDAR", "EDARADD", "WNT10A", "Hypohidrotic Ectodermal Dysplasia" ]	Hypohidrotic Ectodermal Dysplasia	J Timothy Wright, Dorothy K Grange, Mary Fete	Summary Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features. Classic HED can be diagnosed after infancy based on physical features in most affected individuals. Identification of a hemizygous The diagnosis of mild HED is established in a female by identification of a heterozygous Once the	Classic hypohidrotic ectodermal dysplasia Mild hypohidrotic ectodermal dysplasia For synonyms and outdated names see • Classic hypohidrotic ectodermal dysplasia • Mild hypohidrotic ectodermal dysplasia ## Diagnosis No guidelines regarding diagnostic criteria for hypohidrotic ectodermal dysplasia (HED) have been developed. HED The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. Note: Anthropometric variations (measurements of facial form and tooth size) in HED are subtle and have not proven clinically useful; however, 3D facial recognition has shown promise [ Because females with X-linked HED show mosaic patterns of sweat pore function and distribution, use of an iodine solution to assess sweat gland function or impression materials to assess number and distribution of sweat pores is particularly useful. Between 60% and 80% of females with X-linked HED display some degree of hypodontia [ Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of If molecular genetic testing of For an introduction to multigene panels click Molecular Genetic Testing Used in Hypohidrotic Ectodermal Dysplasia NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ A deletion of at least exon 4 was detected in one individual [ An exon 4 deletion in To date, no large intragenic To date, there are limited reports of individuals with features of HED and pathogenic variants in • The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. • The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. • While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ • The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. • The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. • While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ • An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ • Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. • Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. • An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ • Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. • Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. • The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. • The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. • While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ • An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ • Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. • Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. • Because females with X-linked HED show mosaic patterns of sweat pore function and distribution, use of an iodine solution to assess sweat gland function or impression materials to assess number and distribution of sweat pores is particularly useful. • Between 60% and 80% of females with X-linked HED display some degree of hypodontia [ • The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of • The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of • If molecular genetic testing of • The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of • The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of • For an introduction to multigene panels click • The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of • The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of ## Suggestive Findings HED The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. Note: Anthropometric variations (measurements of facial form and tooth size) in HED are subtle and have not proven clinically useful; however, 3D facial recognition has shown promise [ Because females with X-linked HED show mosaic patterns of sweat pore function and distribution, use of an iodine solution to assess sweat gland function or impression materials to assess number and distribution of sweat pores is particularly useful. Between 60% and 80% of females with X-linked HED display some degree of hypodontia [ • The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. • The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. • While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ • The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. • The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. • While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ • An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ • Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. • Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. • An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ • Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. • Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. • The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating. • The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists. • While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [ • An average of nine permanent teeth, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [ • Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns. • Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals. • Because females with X-linked HED show mosaic patterns of sweat pore function and distribution, use of an iodine solution to assess sweat gland function or impression materials to assess number and distribution of sweat pores is particularly useful. • Between 60% and 80% of females with X-linked HED display some degree of hypodontia [ ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of If molecular genetic testing of For an introduction to multigene panels click Molecular Genetic Testing Used in Hypohidrotic Ectodermal Dysplasia NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ A deletion of at least exon 4 was detected in one individual [ An exon 4 deletion in To date, no large intragenic To date, there are limited reports of individuals with features of HED and pathogenic variants in • The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of • The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of • If molecular genetic testing of • The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of • The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of • For an introduction to multigene panels click • The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of • The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of ## Clinical Characteristics Males with X-linked hypohidrotic ectodermal dysplasia (HED) and males and females with autosomal recessive HED caused by The cardinal features of HED become obvious during Diminished and asymmetric development of the alveolar ridge Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter Depressed nasal bridge that is obvious by early childhood Decreased sebaceous secretions Dry eye symptoms due to abnormal meibomian glands [ Fragile-appearing skin Lack of dermal ridges Periorbital hyperpigmentation that persists Recurrent pneumonia and asthma-like symptoms related to abnormal bronchial glands [ Raspy voice Midface hypoplasia Physical growth and psychomotor development are otherwise within normal limits. Females with X-linked HED and males and females with autosomal dominant HED typically have mild HED. Females with X-linked HED may exhibit mild manifestations of any or all the cardinal features: some sparseness of the hair, patchy distribution of sweat dysfunction, and a few small or missing teeth [ Individuals with autosomal dominant HED exhibit mild manifestations as described for females with X-linked HED, without the patchy distribution of sweat dysfunction. Variable phenotypes are reported in individuals with pathogenic variants in Penetrance is not well described for most ectodermal dysplasias. Historically, the term "anhidrotic" has been defined as the inability to perspire; "hypohidrotic" suggests impairment in the ability to perspire. Because most individuals with HED have at least a limited ability to perspire, the term "hypohidrotic" more accurately reflects the condition. • Diminished and asymmetric development of the alveolar ridge • Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter • Depressed nasal bridge that is obvious by early childhood • Decreased sebaceous secretions • Dry eye symptoms due to abnormal meibomian glands [ • Fragile-appearing skin • Lack of dermal ridges • Periorbital hyperpigmentation that persists • Recurrent pneumonia and asthma-like symptoms related to abnormal bronchial glands [ • Raspy voice • Midface hypoplasia ## Clinical Description Males with X-linked hypohidrotic ectodermal dysplasia (HED) and males and females with autosomal recessive HED caused by The cardinal features of HED become obvious during Diminished and asymmetric development of the alveolar ridge Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter Depressed nasal bridge that is obvious by early childhood Decreased sebaceous secretions Dry eye symptoms due to abnormal meibomian glands [ Fragile-appearing skin Lack of dermal ridges Periorbital hyperpigmentation that persists Recurrent pneumonia and asthma-like symptoms related to abnormal bronchial glands [ Raspy voice Midface hypoplasia Physical growth and psychomotor development are otherwise within normal limits. Females with X-linked HED and males and females with autosomal dominant HED typically have mild HED. Females with X-linked HED may exhibit mild manifestations of any or all the cardinal features: some sparseness of the hair, patchy distribution of sweat dysfunction, and a few small or missing teeth [ Individuals with autosomal dominant HED exhibit mild manifestations as described for females with X-linked HED, without the patchy distribution of sweat dysfunction. Variable phenotypes are reported in individuals with pathogenic variants in • Diminished and asymmetric development of the alveolar ridge • Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter • Depressed nasal bridge that is obvious by early childhood • Decreased sebaceous secretions • Dry eye symptoms due to abnormal meibomian glands [ • Fragile-appearing skin • Lack of dermal ridges • Periorbital hyperpigmentation that persists • Recurrent pneumonia and asthma-like symptoms related to abnormal bronchial glands [ • Raspy voice • Midface hypoplasia ## Classic Hypohidrotic Ectodermal Dysplasia Males with X-linked hypohidrotic ectodermal dysplasia (HED) and males and females with autosomal recessive HED caused by The cardinal features of HED become obvious during Diminished and asymmetric development of the alveolar ridge Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter Depressed nasal bridge that is obvious by early childhood Decreased sebaceous secretions Dry eye symptoms due to abnormal meibomian glands [ Fragile-appearing skin Lack of dermal ridges Periorbital hyperpigmentation that persists Recurrent pneumonia and asthma-like symptoms related to abnormal bronchial glands [ Raspy voice Midface hypoplasia Physical growth and psychomotor development are otherwise within normal limits. • Diminished and asymmetric development of the alveolar ridge • Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter • Depressed nasal bridge that is obvious by early childhood • Decreased sebaceous secretions • Dry eye symptoms due to abnormal meibomian glands [ • Fragile-appearing skin • Lack of dermal ridges • Periorbital hyperpigmentation that persists • Recurrent pneumonia and asthma-like symptoms related to abnormal bronchial glands [ • Raspy voice • Midface hypoplasia ## Mild Hypohidrotic Ectodermal Dysplasia Females with X-linked HED and males and females with autosomal dominant HED typically have mild HED. Females with X-linked HED may exhibit mild manifestations of any or all the cardinal features: some sparseness of the hair, patchy distribution of sweat dysfunction, and a few small or missing teeth [ Individuals with autosomal dominant HED exhibit mild manifestations as described for females with X-linked HED, without the patchy distribution of sweat dysfunction. Variable phenotypes are reported in individuals with pathogenic variants in ## Genotype-Phenotype Correlations ## Penetrance Penetrance is not well described for most ectodermal dysplasias. ## Nomenclature Historically, the term "anhidrotic" has been defined as the inability to perspire; "hypohidrotic" suggests impairment in the ability to perspire. Because most individuals with HED have at least a limited ability to perspire, the term "hypohidrotic" more accurately reflects the condition. ## Prevalence ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders Schopf-Schulz-Passarge syndrome and odonto-onycho-dermal dysplasia syndrome (both associated with additional and/or more severe features) represent the most severe end of the ## Differential Diagnosis Numerous types of ectodermal dysplasia exist [ The presence of onychodysplasia (inherent abnormalities of nail development) and other developmental abnormalities favor diagnoses other than hypohidrotic ectodermal dysplasia (HED). Ectodermal dysplasias that need to be considered in the differential diagnosis of HED are summarized in Ectodermal Dysplasias in the Differential Diagnosis of Hypohidrotic Ectodermal Dysplasia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NR = not reported; XL = X-linked Incontinentia pigmenti manifests in stages that evolve sequentially: stage I (bullous), stage II (verrucous), stage III (hyperpigmentation), and stage IV (atretic). The onset and duration of each stage vary among individuals, and not all individuals experience all four stages. ## Management To establish the extent of disease and needs in an individual diagnosed with hypohidrotic ectodermal dysplasia (HED), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypohidrotic Ectodermal Dysplasia HED = hypohidrotic ectodermal dysplasia; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Management of affected individuals targets the three cardinal features of HED (hypotrichosis, hypohidrosis, and hypodontia) and is directed at optimizing psychosocial development, establishing optimal oral function, and preventing hyperthermia (see Treatment of Manifestations in Individuals with Hypohidrotic Ectodermal Dysplasia During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) Dental treatment, ranging from simple restorations to dentures, should begin at early age. Treatments incl restorations, bonding of conical teeth, dental implants, &/or dentures. Orthodontics may be necessary. Dietary counseling for those persons who have trouble chewing & swallowing despite adequate dental care Bonding of conical teeth improves aesthetics & chewing ability. Dental implants in anterior portion of mandibular arch have proven successful only in children age ≥7 yrs. Children w/HED typically need dental prostheses replaced every 2.5 yrs. Dental implants in adults can support aesthetic & functional dentition. Therapeutics (e.g., saliva substitutes) directed at maintaining oral lubrication & to ↓ risk of dental caries Fluoride treatments as recommended by dentist Consider other dental caries preventive approaches such as pit & fissure sealants. Mgmt per ENT physician Removal of nasal & aural concretions w/suction devices or forceps Humidification of ambient air to prevent their formation Mgmt of recurrent respiratory infections & asthma per primary care provider Referral to allergist &/or pulmonologist as needed for more significant respiratory manifestations Affected individuals learn to control their exposure to heat and to minimize its consequences, but special situations may arise in which intervention by physicians and families is helpful. For example, a physician may have to prescribe an air conditioner before a school district complies, or parents may have to advocate for children who need to carry liquids into areas where they are prohibited. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Recommended Surveillance for Individuals with Hypohidrotic Ectodermal Dysplasia Individuals with severe hypohidrosis can have marked heat intolerance; care should be taken to prevent exposure to extreme heat and the potential for febrile seizures. It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and treatment and, importantly, measures to avoid hyperthermia. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Targeted history, physical examination, and dental examination for the features of HED if the pathogenic variant(s) in the family are not known. Testing for hypohidrosis (see See Optimal prenatal nutrition is recommended for mothers who are unaffected heterozygotes or are affected with HED. Affected women at risk for hyperthermia should take extra care not to become overheated during pregnancy. There are no other special recommendations for pregnancy management. Some women may have difficulty breastfeeding their infants because of hypoplasia of the mammary glands. A Phase II clinical trial was conducted at several US and European medical centers to investigate the use of EDI200, developed by Edimer Pharmaceuticals, Inc [ Subsequently, an open-label, prospective, genotype-match controlled non-randomized, multicenter, international Phase II clinical trial has begun recruiting to investigate the efficacy and safety of ER004 (previously known as EDI200) administered intra-amniotically as a prenatal treatment for males with X-linked HED. The aim of the trial is to confirm the efficacy and safety of ER004 administered intra-amniotically in a larger cohort. The target population will consist of male fetuses diagnosed with X-linked HED based on identification of a heterozygous Search • During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) • Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) • Dental treatment, ranging from simple restorations to dentures, should begin at early age. • Treatments incl restorations, bonding of conical teeth, dental implants, &/or dentures. • Orthodontics may be necessary. • Dietary counseling for those persons who have trouble chewing & swallowing despite adequate dental care • Bonding of conical teeth improves aesthetics & chewing ability. • Dental implants in anterior portion of mandibular arch have proven successful only in children age ≥7 yrs. • Children w/HED typically need dental prostheses replaced every 2.5 yrs. • Dental implants in adults can support aesthetic & functional dentition. • Therapeutics (e.g., saliva substitutes) directed at maintaining oral lubrication & to ↓ risk of dental caries • Fluoride treatments as recommended by dentist • Consider other dental caries preventive approaches such as pit & fissure sealants. • Mgmt per ENT physician • Removal of nasal & aural concretions w/suction devices or forceps • Humidification of ambient air to prevent their formation • Mgmt of recurrent respiratory infections & asthma per primary care provider • Referral to allergist &/or pulmonologist as needed for more significant respiratory manifestations • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Targeted history, physical examination, and dental examination for the features of HED if the pathogenic variant(s) in the family are not known. Testing for hypohidrosis (see ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hypohidrotic ectodermal dysplasia (HED), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypohidrotic Ectodermal Dysplasia HED = hypohidrotic ectodermal dysplasia; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations Management of affected individuals targets the three cardinal features of HED (hypotrichosis, hypohidrosis, and hypodontia) and is directed at optimizing psychosocial development, establishing optimal oral function, and preventing hyperthermia (see Treatment of Manifestations in Individuals with Hypohidrotic Ectodermal Dysplasia During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) Dental treatment, ranging from simple restorations to dentures, should begin at early age. Treatments incl restorations, bonding of conical teeth, dental implants, &/or dentures. Orthodontics may be necessary. Dietary counseling for those persons who have trouble chewing & swallowing despite adequate dental care Bonding of conical teeth improves aesthetics & chewing ability. Dental implants in anterior portion of mandibular arch have proven successful only in children age ≥7 yrs. Children w/HED typically need dental prostheses replaced every 2.5 yrs. Dental implants in adults can support aesthetic & functional dentition. Therapeutics (e.g., saliva substitutes) directed at maintaining oral lubrication & to ↓ risk of dental caries Fluoride treatments as recommended by dentist Consider other dental caries preventive approaches such as pit & fissure sealants. Mgmt per ENT physician Removal of nasal & aural concretions w/suction devices or forceps Humidification of ambient air to prevent their formation Mgmt of recurrent respiratory infections & asthma per primary care provider Referral to allergist &/or pulmonologist as needed for more significant respiratory manifestations Affected individuals learn to control their exposure to heat and to minimize its consequences, but special situations may arise in which intervention by physicians and families is helpful. For example, a physician may have to prescribe an air conditioner before a school district complies, or parents may have to advocate for children who need to carry liquids into areas where they are prohibited. • During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) • Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) • Dental treatment, ranging from simple restorations to dentures, should begin at early age. • Treatments incl restorations, bonding of conical teeth, dental implants, &/or dentures. • Orthodontics may be necessary. • Dietary counseling for those persons who have trouble chewing & swallowing despite adequate dental care • Bonding of conical teeth improves aesthetics & chewing ability. • Dental implants in anterior portion of mandibular arch have proven successful only in children age ≥7 yrs. • Children w/HED typically need dental prostheses replaced every 2.5 yrs. • Dental implants in adults can support aesthetic & functional dentition. • Therapeutics (e.g., saliva substitutes) directed at maintaining oral lubrication & to ↓ risk of dental caries • Fluoride treatments as recommended by dentist • Consider other dental caries preventive approaches such as pit & fissure sealants. • Mgmt per ENT physician • Removal of nasal & aural concretions w/suction devices or forceps • Humidification of ambient air to prevent their formation • Mgmt of recurrent respiratory infections & asthma per primary care provider • Referral to allergist &/or pulmonologist as needed for more significant respiratory manifestations ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Recommended Surveillance for Individuals with Hypohidrotic Ectodermal Dysplasia ## Agents/Circumstances to Avoid Individuals with severe hypohidrosis can have marked heat intolerance; care should be taken to prevent exposure to extreme heat and the potential for febrile seizures. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and treatment and, importantly, measures to avoid hyperthermia. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Targeted history, physical examination, and dental examination for the features of HED if the pathogenic variant(s) in the family are not known. Testing for hypohidrosis (see See • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Targeted history, physical examination, and dental examination for the features of HED if the pathogenic variant(s) in the family are not known. Testing for hypohidrosis (see ## Pregnancy Management Optimal prenatal nutrition is recommended for mothers who are unaffected heterozygotes or are affected with HED. Affected women at risk for hyperthermia should take extra care not to become overheated during pregnancy. There are no other special recommendations for pregnancy management. Some women may have difficulty breastfeeding their infants because of hypoplasia of the mammary glands. ## Therapies Under Investigation A Phase II clinical trial was conducted at several US and European medical centers to investigate the use of EDI200, developed by Edimer Pharmaceuticals, Inc [ Subsequently, an open-label, prospective, genotype-match controlled non-randomized, multicenter, international Phase II clinical trial has begun recruiting to investigate the efficacy and safety of ER004 (previously known as EDI200) administered intra-amniotically as a prenatal treatment for males with X-linked HED. The aim of the trial is to confirm the efficacy and safety of ER004 administered intra-amniotically in a larger cohort. The target population will consist of male fetuses diagnosed with X-linked HED based on identification of a heterozygous Search ## Genetic Counseling Hypohidrotic ectodermal dysplasia (HED) caused by pathogenic variants in The father of an affected male will not have the disorder, nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Clinical examination may detect manifestations of X-linked HED in the mother; manifestations in heterozygous females are typically milder than those seen in affected males (see Clinical Description, Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. A female proband may have inherited the Clinical examination may clarify the status of the parents. Molecular genetic testing of both parents is recommended to confirm their genetic status and to allow reliable recurrence risk assessment. If the mother is heterozygous for an If the proband represents a simplex case and the If the mother of the proband has an If the father of the proband has an If the proband represents a simplex case and if the Detection of heterozygotes based on clinical findings is often imprecise. If sweat distribution is patchy or many teeth are absent, establishing genetic status is relatively easy. Otherwise, mild manifestations in females with X-linked HED overlap with features in the general population. Hypodontia, for instance, is relatively common in the general population, and absence of one or two teeth in the mother of an affected male may be coincidental. Furthermore, there are no useful standards to judge hair density, and reports of sweat dysfunction, often judged by heat intolerance, can be inaccurate. Computerized facial recognition appears to be relatively insensitive in heterozygote detection as well. The parents of a child with autosomal recessive HED are presumed to be heterozygous for a pathogenic variant in If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes may have mild features of the disorder (see Clinical Description, If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes may have mild features of the disorder (see Clinical Description, Some individuals diagnosed with autosomal dominant HED have an affected parent. An individual diagnosed with autosomal dominant HED may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with autosomal dominant HED may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Clinical examination may detect manifestations of X-linked HED in the mother; manifestations in heterozygous females are typically milder than those seen in affected males (see Clinical Description, • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • A female proband may have inherited the • Clinical examination may clarify the status of the parents. Molecular genetic testing of both parents is recommended to confirm their genetic status and to allow reliable recurrence risk assessment. • If the mother is heterozygous for an • If the proband represents a simplex case and the • If the mother of the proband has an • If the father of the proband has an • If the proband represents a simplex case and if the • The parents of a child with autosomal recessive HED are presumed to be heterozygous for a pathogenic variant in • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes may have mild features of the disorder (see Clinical Description, • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygotes may have mild features of the disorder (see Clinical Description, • Some individuals diagnosed with autosomal dominant HED have an affected parent. • An individual diagnosed with autosomal dominant HED may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with autosomal dominant HED may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance Hypohidrotic ectodermal dysplasia (HED) caused by pathogenic variants in ## X-Linked HED – Risk to Family Members The father of an affected male will not have the disorder, nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Clinical examination may detect manifestations of X-linked HED in the mother; manifestations in heterozygous females are typically milder than those seen in affected males (see Clinical Description, Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. A female proband may have inherited the Clinical examination may clarify the status of the parents. Molecular genetic testing of both parents is recommended to confirm their genetic status and to allow reliable recurrence risk assessment. If the mother is heterozygous for an If the proband represents a simplex case and the If the mother of the proband has an If the father of the proband has an If the proband represents a simplex case and if the Detection of heterozygotes based on clinical findings is often imprecise. If sweat distribution is patchy or many teeth are absent, establishing genetic status is relatively easy. Otherwise, mild manifestations in females with X-linked HED overlap with features in the general population. Hypodontia, for instance, is relatively common in the general population, and absence of one or two teeth in the mother of an affected male may be coincidental. Furthermore, there are no useful standards to judge hair density, and reports of sweat dysfunction, often judged by heat intolerance, can be inaccurate. Computerized facial recognition appears to be relatively insensitive in heterozygote detection as well. • The father of an affected male will not have the disorder, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Clinical examination may detect manifestations of X-linked HED in the mother; manifestations in heterozygous females are typically milder than those seen in affected males (see Clinical Description, • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • A female proband may have inherited the • Clinical examination may clarify the status of the parents. Molecular genetic testing of both parents is recommended to confirm their genetic status and to allow reliable recurrence risk assessment. • If the mother is heterozygous for an • If the proband represents a simplex case and the • If the mother of the proband has an • If the father of the proband has an • If the proband represents a simplex case and if the ## Autosomal Recessive HED – Risk to Family Members The parents of a child with autosomal recessive HED are presumed to be heterozygous for a pathogenic variant in If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes may have mild features of the disorder (see Clinical Description, If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes may have mild features of the disorder (see Clinical Description, • The parents of a child with autosomal recessive HED are presumed to be heterozygous for a pathogenic variant in • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes may have mild features of the disorder (see Clinical Description, • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygotes may have mild features of the disorder (see Clinical Description, ## Autosomal Dominant HED – Risk to Family Members Some individuals diagnosed with autosomal dominant HED have an affected parent. An individual diagnosed with autosomal dominant HED may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with autosomal dominant HED may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the • Some individuals diagnosed with autosomal dominant HED have an affected parent. • An individual diagnosed with autosomal dominant HED may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with autosomal dominant HED may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Germany • • United Kingdom • • • • • • • • Germany • • • ## Molecular Genetics Hypohidrotic Ectodermal Dysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hypohidrotic Ectodermal Dysplasia ( EDAR contains a single transmembrane domain with type 1 membrane topology. The protein probably functions as a multimeric receptor and is related to the TNFR family. Mutated EDAR is unable to bind with ectodysplasin. The protein encoded by Hypohidrotic Ectodermal Dysplasia: Notable Pathogenic Variants by Gene HED = hypohidrotic ectodermal dysplasia Variants listed in the table have been provided by the authors. Genes from Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis EDAR contains a single transmembrane domain with type 1 membrane topology. The protein probably functions as a multimeric receptor and is related to the TNFR family. Mutated EDAR is unable to bind with ectodysplasin. The protein encoded by Hypohidrotic Ectodermal Dysplasia: Notable Pathogenic Variants by Gene HED = hypohidrotic ectodermal dysplasia Variants listed in the table have been provided by the authors. Genes from Variant designation that does not conform to current naming conventions ## Chapter Notes J Timothy Wright DDS, MS Dorothy K Grange, MD Mary FeteNational Foundation Ectodermal Dysplasias Thanks to the National Foundation for Ectodermal Dysplasias (Mary Fete, Executive Director). Mary Fete, MSN, RN, CCM (2017-present)Dorothy K Grange, MD (2006-present)Ronald J Jorgenson, DDS, PhD; former President, Applied Genetics, Austin, Texas (2002-2006)Mary K Richter; National Foundation for Ectodermal Dysplasias (2006-2017)J Timothy Wright, DDS, MS (2006-present) 20 March 2025 (ma) Revision: prevalence data updated 27 October 2022 (sw) Comprehensive update posted live 1 June 2017 (sw) Comprehensive update posted live 15 May 2014 (me) Comprehensive update posted live 29 December 2011 (me) Comprehensive update posted live 23 July 2009 (me) Comprehensive update posted live 16 November 2006 (me) Comprehensive update posted live 28 April 2003 (me) Review posted live 23 October 2002 (rj) Original submission • 20 March 2025 (ma) Revision: prevalence data updated • 27 October 2022 (sw) Comprehensive update posted live • 1 June 2017 (sw) Comprehensive update posted live • 15 May 2014 (me) Comprehensive update posted live • 29 December 2011 (me) Comprehensive update posted live • 23 July 2009 (me) Comprehensive update posted live • 16 November 2006 (me) Comprehensive update posted live • 28 April 2003 (me) Review posted live • 23 October 2002 (rj) Original submission ## Author Notes J Timothy Wright DDS, MS Dorothy K Grange, MD Mary FeteNational Foundation Ectodermal Dysplasias ## Acknowledgments Thanks to the National Foundation for Ectodermal Dysplasias (Mary Fete, Executive Director). ## Author History Mary Fete, MSN, RN, CCM (2017-present)Dorothy K Grange, MD (2006-present)Ronald J Jorgenson, DDS, PhD; former President, Applied Genetics, Austin, Texas (2002-2006)Mary K Richter; National Foundation for Ectodermal Dysplasias (2006-2017)J Timothy Wright, DDS, MS (2006-present) ## Revision History 20 March 2025 (ma) Revision: prevalence data updated 27 October 2022 (sw) Comprehensive update posted live 1 June 2017 (sw) Comprehensive update posted live 15 May 2014 (me) Comprehensive update posted live 29 December 2011 (me) Comprehensive update posted live 23 July 2009 (me) Comprehensive update posted live 16 November 2006 (me) Comprehensive update posted live 28 April 2003 (me) Review posted live 23 October 2002 (rj) Original submission • 20 March 2025 (ma) Revision: prevalence data updated • 27 October 2022 (sw) Comprehensive update posted live • 1 June 2017 (sw) Comprehensive update posted live • 15 May 2014 (me) Comprehensive update posted live • 29 December 2011 (me) Comprehensive update posted live • 23 July 2009 (me) Comprehensive update posted live • 16 November 2006 (me) Comprehensive update posted live • 28 April 2003 (me) Review posted live • 23 October 2002 (rj) Original submission ## References ## Literature Cited	[]	28/4/2003	27/10/2022	20/3/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
x-lpd	x-lpd	[ "E3 ubiquitin-protein ligase XIAP", "SH2 domain-containing protein 1A", "SH2D1A", "XIAP", "X-Linked Lymphoproliferative Disease" ]	X-Linked Lymphoproliferative Disease	Lauren Meyer, Melissa Hines, Kejian Zhang, Kim E Nichols	Summary X-linked lymphoproliferative disease (XLP) in general is characterized by an inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, dysgammaglobulinemia, and lymphoproliferative disease (malignant lymphoma). The condition primarily affects males. XLP has two recognizable subtypes, XLP1 (due to pathogenic variants in Heterozygous females rarely have symptoms. There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation favoring the X chromosome with the pathogenic variant who develop HLH, inflammatory bowel disease, and erythema nodosum. The diagnosis of XLP1 or XLP2 can be established in a male proband who has a hemizygous germline pathogenic variant in XLP is inherited in an X-linked manner. The risk to the sibs of a male proband depends on the genetic status of the mother: if the mother is heterozygous for an	## Diagnosis For the purposes of this No consensus clinical diagnostic criteria for X-linked lymphoproliferative disease (XLP) have been published. XLP has traditionally been separated into two recognizable subtypes: XLP1, due to pathogenic variants in XLP Lymphoma, most often B-cell non-Hodgkin lymphoma of the Burkitt subtype, with or without a prior history of Epstein-Barr virus (EBV) infection Vasculitis of the central nervous system or lungs in individuals with or without a prior history of EBV infection Inflammatory bowel disease, often resembling Crohn disease Recurrent splenomegaly, with or without concurrent fever Uveitis Skin abscesses and other skin disorders Arthritis Liver disease Autoimmune disorders Laboratory evidence of hemophagocytic lymphohistiocytosis (HLH): Bi- or trilineage cytopenias Hyperferritinemia Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) Hypertriglyceridemia Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia Inverted CD4:CD8 ratio in peripheral blood Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) Laboratory evidence of an acute Epstein-Barr virus (EBV) infection, such as EBV detection by polymerase chain reaction (PCR) (the preferred method) or positive heterophile antibodies or monospot testing Decreased levels of one or more immunoglobulin subclasses (dysgammaglobulinemia), most frequently manifested by low serum concentration of immunoglobulin G (IgG), with variable serum concentrations of IgM and/or IgA that may also sometimes be abnormally increased Low or absent SAP protein expression by flow cytometry Absent or greatly reduced invariant natural killer T (iNKT) cells [ Impaired 2B4-mediated cytotoxicity of CD8 Reduced levels of CD27 Decreased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T cell receptor (also known as decreased T cell restimulated cell death) Low or absent XIAP protein expression by flow cytometry Increased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T-cell receptor (also known as increased T cell restimulated cell death) Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. A hemizygous germline pathogenic (or likely pathogenic) variant in A hemizygous germline pathogenic (or likely pathogenic) variant in Note: (1) Because bone marrow transplantation becomes an option for affected males if an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in the clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of XLP, molecular genetic testing approaches can include In males with low or absent SAP expression by flow cytometry, sequence analysis of In males with low or absent XIAP expression by flow cytometry, sequence analysis of For symptomatic female probands in whom XLP is considered to be likely, sequencing of In females who have been found to have a heterozygous pathogenic variant in For an introduction to multigene panels click When a person has atypical phenotypic features but XLP remains a consideration, comprehensive genomic testing may be performed. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Lymphoproliferative Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Sequence analysis of the entire coding region and exon/intron boundaries identifies pathogenic variants in approximately 75% of obligate carrier females [ 21% of all reported pathogenic variants are predicted to have deletion of one or more exons or the entire gene [ 19% of all reported pathogenic variants are predicted to have deletion of one or more exons or the entire gene [ • Lymphoma, most often B-cell non-Hodgkin lymphoma of the Burkitt subtype, with or without a prior history of Epstein-Barr virus (EBV) infection • Vasculitis of the central nervous system or lungs in individuals with or without a prior history of EBV infection • Inflammatory bowel disease, often resembling Crohn disease • Recurrent splenomegaly, with or without concurrent fever • Uveitis • Skin abscesses and other skin disorders • Arthritis • Liver disease • Autoimmune disorders • Laboratory evidence of hemophagocytic lymphohistiocytosis (HLH): • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Laboratory evidence of an acute Epstein-Barr virus (EBV) infection, such as EBV detection by polymerase chain reaction (PCR) (the preferred method) or positive heterophile antibodies or monospot testing • Decreased levels of one or more immunoglobulin subclasses (dysgammaglobulinemia), most frequently manifested by low serum concentration of immunoglobulin G (IgG), with variable serum concentrations of IgM and/or IgA that may also sometimes be abnormally increased • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Low or absent SAP protein expression by flow cytometry • Absent or greatly reduced invariant natural killer T (iNKT) cells [ • Impaired 2B4-mediated cytotoxicity of CD8 • Reduced levels of CD27 • Decreased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T cell receptor (also known as decreased T cell restimulated cell death) • Low or absent XIAP protein expression by flow cytometry • Increased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T-cell receptor (also known as increased T cell restimulated cell death) • A hemizygous germline pathogenic (or likely pathogenic) variant in • A hemizygous germline pathogenic (or likely pathogenic) variant in • In males with low or absent SAP expression by flow cytometry, sequence analysis of • In males with low or absent XIAP expression by flow cytometry, sequence analysis of • For symptomatic female probands in whom XLP is considered to be likely, sequencing of • In females who have been found to have a heterozygous pathogenic variant in ## Suggestive Findings XLP Lymphoma, most often B-cell non-Hodgkin lymphoma of the Burkitt subtype, with or without a prior history of Epstein-Barr virus (EBV) infection Vasculitis of the central nervous system or lungs in individuals with or without a prior history of EBV infection Inflammatory bowel disease, often resembling Crohn disease Recurrent splenomegaly, with or without concurrent fever Uveitis Skin abscesses and other skin disorders Arthritis Liver disease Autoimmune disorders Laboratory evidence of hemophagocytic lymphohistiocytosis (HLH): Bi- or trilineage cytopenias Hyperferritinemia Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) Hypertriglyceridemia Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia Inverted CD4:CD8 ratio in peripheral blood Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) Laboratory evidence of an acute Epstein-Barr virus (EBV) infection, such as EBV detection by polymerase chain reaction (PCR) (the preferred method) or positive heterophile antibodies or monospot testing Decreased levels of one or more immunoglobulin subclasses (dysgammaglobulinemia), most frequently manifested by low serum concentration of immunoglobulin G (IgG), with variable serum concentrations of IgM and/or IgA that may also sometimes be abnormally increased Low or absent SAP protein expression by flow cytometry Absent or greatly reduced invariant natural killer T (iNKT) cells [ Impaired 2B4-mediated cytotoxicity of CD8 Reduced levels of CD27 Decreased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T cell receptor (also known as decreased T cell restimulated cell death) Low or absent XIAP protein expression by flow cytometry Increased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T-cell receptor (also known as increased T cell restimulated cell death) Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. • Lymphoma, most often B-cell non-Hodgkin lymphoma of the Burkitt subtype, with or without a prior history of Epstein-Barr virus (EBV) infection • Vasculitis of the central nervous system or lungs in individuals with or without a prior history of EBV infection • Inflammatory bowel disease, often resembling Crohn disease • Recurrent splenomegaly, with or without concurrent fever • Uveitis • Skin abscesses and other skin disorders • Arthritis • Liver disease • Autoimmune disorders • Laboratory evidence of hemophagocytic lymphohistiocytosis (HLH): • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Laboratory evidence of an acute Epstein-Barr virus (EBV) infection, such as EBV detection by polymerase chain reaction (PCR) (the preferred method) or positive heterophile antibodies or monospot testing • Decreased levels of one or more immunoglobulin subclasses (dysgammaglobulinemia), most frequently manifested by low serum concentration of immunoglobulin G (IgG), with variable serum concentrations of IgM and/or IgA that may also sometimes be abnormally increased • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Low or absent SAP protein expression by flow cytometry • Absent or greatly reduced invariant natural killer T (iNKT) cells [ • Impaired 2B4-mediated cytotoxicity of CD8 • Reduced levels of CD27 • Decreased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T cell receptor (also known as decreased T cell restimulated cell death) • Low or absent XIAP protein expression by flow cytometry • Increased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T-cell receptor (also known as increased T cell restimulated cell death) ## Clinical Findings Lymphoma, most often B-cell non-Hodgkin lymphoma of the Burkitt subtype, with or without a prior history of Epstein-Barr virus (EBV) infection Vasculitis of the central nervous system or lungs in individuals with or without a prior history of EBV infection Inflammatory bowel disease, often resembling Crohn disease Recurrent splenomegaly, with or without concurrent fever Uveitis Skin abscesses and other skin disorders Arthritis Liver disease Autoimmune disorders • Lymphoma, most often B-cell non-Hodgkin lymphoma of the Burkitt subtype, with or without a prior history of Epstein-Barr virus (EBV) infection • Vasculitis of the central nervous system or lungs in individuals with or without a prior history of EBV infection • Inflammatory bowel disease, often resembling Crohn disease • Recurrent splenomegaly, with or without concurrent fever • Uveitis • Skin abscesses and other skin disorders • Arthritis • Liver disease • Autoimmune disorders ## Laboratory Findings Laboratory evidence of hemophagocytic lymphohistiocytosis (HLH): Bi- or trilineage cytopenias Hyperferritinemia Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) Hypertriglyceridemia Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia Inverted CD4:CD8 ratio in peripheral blood Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) Laboratory evidence of an acute Epstein-Barr virus (EBV) infection, such as EBV detection by polymerase chain reaction (PCR) (the preferred method) or positive heterophile antibodies or monospot testing Decreased levels of one or more immunoglobulin subclasses (dysgammaglobulinemia), most frequently manifested by low serum concentration of immunoglobulin G (IgG), with variable serum concentrations of IgM and/or IgA that may also sometimes be abnormally increased Low or absent SAP protein expression by flow cytometry Absent or greatly reduced invariant natural killer T (iNKT) cells [ Impaired 2B4-mediated cytotoxicity of CD8 Reduced levels of CD27 Decreased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T cell receptor (also known as decreased T cell restimulated cell death) Low or absent XIAP protein expression by flow cytometry Increased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T-cell receptor (also known as increased T cell restimulated cell death) • Laboratory evidence of hemophagocytic lymphohistiocytosis (HLH): • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Laboratory evidence of an acute Epstein-Barr virus (EBV) infection, such as EBV detection by polymerase chain reaction (PCR) (the preferred method) or positive heterophile antibodies or monospot testing • Decreased levels of one or more immunoglobulin subclasses (dysgammaglobulinemia), most frequently manifested by low serum concentration of immunoglobulin G (IgG), with variable serum concentrations of IgM and/or IgA that may also sometimes be abnormally increased • Bi- or trilineage cytopenias • Hyperferritinemia • Elevated levels of soluble interleukin-2 receptor alpha (IL2RA CD25) • Hypertriglyceridemia • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinogenemia • Inverted CD4:CD8 ratio in peripheral blood • Hemophagocytosis in the bone marrow, spleen, lymph node, or cerebral spinal fluid • Elevated levels of pro-inflammatory cytokines, such as interferon-gamma (IFNG), chemokine ligand 9 (CXCL9; in XLP1), or interleukin-18 (IL-18; in XLP2 plasma IL-18 levels may remain elevated between HLH episodes) • Low or absent SAP protein expression by flow cytometry • Absent or greatly reduced invariant natural killer T (iNKT) cells [ • Impaired 2B4-mediated cytotoxicity of CD8 • Reduced levels of CD27 • Decreased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T cell receptor (also known as decreased T cell restimulated cell death) • Low or absent XIAP protein expression by flow cytometry • Increased apoptosis of T lymphocytes in response to stimulation of the cell death receptors FAS/CD95 or TRAIL-R, or when activated via the T-cell receptor (also known as increased T cell restimulated cell death) ## Family History Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis A hemizygous germline pathogenic (or likely pathogenic) variant in A hemizygous germline pathogenic (or likely pathogenic) variant in Note: (1) Because bone marrow transplantation becomes an option for affected males if an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in the clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of XLP, molecular genetic testing approaches can include In males with low or absent SAP expression by flow cytometry, sequence analysis of In males with low or absent XIAP expression by flow cytometry, sequence analysis of For symptomatic female probands in whom XLP is considered to be likely, sequencing of In females who have been found to have a heterozygous pathogenic variant in For an introduction to multigene panels click When a person has atypical phenotypic features but XLP remains a consideration, comprehensive genomic testing may be performed. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Lymphoproliferative Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Sequence analysis of the entire coding region and exon/intron boundaries identifies pathogenic variants in approximately 75% of obligate carrier females [ 21% of all reported pathogenic variants are predicted to have deletion of one or more exons or the entire gene [ 19% of all reported pathogenic variants are predicted to have deletion of one or more exons or the entire gene [ • A hemizygous germline pathogenic (or likely pathogenic) variant in • A hemizygous germline pathogenic (or likely pathogenic) variant in • In males with low or absent SAP expression by flow cytometry, sequence analysis of • In males with low or absent XIAP expression by flow cytometry, sequence analysis of • For symptomatic female probands in whom XLP is considered to be likely, sequencing of • In females who have been found to have a heterozygous pathogenic variant in ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of XLP, molecular genetic testing approaches can include In males with low or absent SAP expression by flow cytometry, sequence analysis of In males with low or absent XIAP expression by flow cytometry, sequence analysis of For symptomatic female probands in whom XLP is considered to be likely, sequencing of In females who have been found to have a heterozygous pathogenic variant in For an introduction to multigene panels click • In males with low or absent SAP expression by flow cytometry, sequence analysis of • In males with low or absent XIAP expression by flow cytometry, sequence analysis of • For symptomatic female probands in whom XLP is considered to be likely, sequencing of • In females who have been found to have a heterozygous pathogenic variant in ## Option 2 When a person has atypical phenotypic features but XLP remains a consideration, comprehensive genomic testing may be performed. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Lymphoproliferative Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Sequence analysis of the entire coding region and exon/intron boundaries identifies pathogenic variants in approximately 75% of obligate carrier females [ 21% of all reported pathogenic variants are predicted to have deletion of one or more exons or the entire gene [ 19% of all reported pathogenic variants are predicted to have deletion of one or more exons or the entire gene [ ## Clinical Characteristics X-linked lymphoproliferative disease (XLP) in general is characterized by an inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, dysgammaglobulinemia, and lymphoproliferative disease (malignant lymphoma). The condition primarily affects males, although females rarely may have symptoms. Prior to EBV infection, most males appear healthy and do not exhibit any characteristic clinical findings. Clinical findings vary among individuals with XLP, even in the same family. Rarely, males may be asymptomatic; however, they generally develop one or more clinical findings over the course of their life [ There is no way to reliably predict which clinical findings will develop in an individual with XLP. XLP has two recognizable subtypes, XLP1 (due to pathogenic variants in Clinical Phenotypes of Rash and lymphadenopathy are less common but may also occur. Individuals may exhibit liver dysfunction and neurologic abnormalities. Death is generally secondary to liver failure or multisystem organ dysfunction (see Laboratory/pathology findings in HLH may include the following: Hemophagocytosis (phagocytosis identified by microscopy revealing intact or partially degraded blood cells) in the bone marrow, liver, spleen, lymph nodes, and/or cerebral spinal fluid (CSF) Pleiocytosis with increased numbers of mononuclear cells and elevated protein levels in the CSF Hypogammaglobulinemia of one or more immunoglobulin subclasses may be diagnosed prior to EBV infection or in survivors of EBV infection. Some of these affected males were previously considered to have common variable immunodeficiency (see The prognosis for males with dys- or hypogammaglobulinemia is more favorable when managed with regular intravenous immunoglobulin (IVIG) infusions (see Hypogammaglobulinemia is usually progressive in XLP1. Lymphomas can be histologically classified as Burkitt lymphoma (53% of all B-cell lymphomas), immunoblastic lymphomas (12% of all lymphomas), small cleaved or mixed-cell lymphomas (12%), and unclassifiable lymphomas (5%). Hodgkin and T-cell lymphomas have also rarely been reported. Remission may follow treatment with chemotherapy; however, relapse or development of a second primary lymphoma or other clinical manifestation of XLP1 may occur [ It is most often observed in the CNS but can also occur in the lungs or other organs. Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. Retinal involvement can lead to visual disturbances and blindness. Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. Males with Clinical Phenotypes of The prevalence of HLH is 37%-90% in individuals with XLP2 [ Unlike XLP1, recurrence of HLH in individuals with XLP2 is common; repeated episodes may be seen in 67%-83% of affected individuals, often within a year of onset of the initial HLH episode [ HLH poses a significant risk for mortality to males with XLP2. Of the originally described XLP2 cohort, 33% died from HLH between ages six months and 40 years [ Enterocolitis resembles and is often misdiagnosed as Crohn disease. Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. Enterocolitis can lead to gastrointestinal hemorrhage and has a mortality rate of 10%-60% [ Enterocolitis has been reported to resolve following allogenic hematopoietic stem cell transplant (HSCT) [ Rarely, individuals with XLP2 and inflammatory bowel disease have also been reported to develop inflammatory liver disease, which can progress to fatal liver failure [ Advances in the recognition, diagnosis, and management of XLP1 and XLP2 have led to improved outcomes, although mortality rates still remain high. In one of the largest series to date, Survival was greater for those who underwent allogeneic HSCT (81.4%) vs those who did not (62.5%). Regardless of whether affected individuals underwent allogeneic HSCT or not, survival was lowest for individuals with XLP1 who developed HLH. Combined data from this and other reports reveal an overall mortality rate of 29%-66% for individuals with XLP1 [ A large study of 167 individuals with XLP2 revealed that for individuals reaching adulthood who did not undergo allogeneic HSCT, survival probabilities were 86% at age 30 years and 37% at age 52 years, with poorer outcomes for those who developed disease features before age five years or with new disease features as adults [ Enterocolitis appears to have the highest risk for mortality in XLP2. As in many X-linked disorders, females rarely have symptoms. There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation toward the X chromosome with the pathogenic variant in No strong correlation exists between the In the past, the following terms were used to describe XLP: Epstein-Barr virus infection, familial fatal EBV susceptibility (EBVS) X-linked progressive combined variable immunodeficiency 5 Purtilo syndrome Duncan disease The estimated prevalence of XLP1 is one in every one to two million males. The prevalence of XLP2 is less well characterized but believed to be less than XLP1. These frequencies may be an underestimate given the severity and often rapidly fatal initial presentation, variable expression, and clinical overlap with other immunologic disorders [ • Prior to EBV infection, most males appear healthy and do not exhibit any characteristic clinical findings. • Clinical findings vary among individuals with XLP, even in the same family. • Rarely, males may be asymptomatic; however, they generally develop one or more clinical findings over the course of their life [ • There is no way to reliably predict which clinical findings will develop in an individual with XLP. • Rash and lymphadenopathy are less common but may also occur. • Individuals may exhibit liver dysfunction and neurologic abnormalities. • Death is generally secondary to liver failure or multisystem organ dysfunction (see • Hemophagocytosis (phagocytosis identified by microscopy revealing intact or partially degraded blood cells) in the bone marrow, liver, spleen, lymph nodes, and/or cerebral spinal fluid (CSF) • Pleiocytosis with increased numbers of mononuclear cells and elevated protein levels in the CSF • Hypogammaglobulinemia of one or more immunoglobulin subclasses may be diagnosed prior to EBV infection or in survivors of EBV infection. • Some of these affected males were previously considered to have common variable immunodeficiency (see • The prognosis for males with dys- or hypogammaglobulinemia is more favorable when managed with regular intravenous immunoglobulin (IVIG) infusions (see • Hypogammaglobulinemia is usually progressive in XLP1. • Lymphomas can be histologically classified as Burkitt lymphoma (53% of all B-cell lymphomas), immunoblastic lymphomas (12% of all lymphomas), small cleaved or mixed-cell lymphomas (12%), and unclassifiable lymphomas (5%). • Hodgkin and T-cell lymphomas have also rarely been reported. • Remission may follow treatment with chemotherapy; however, relapse or development of a second primary lymphoma or other clinical manifestation of XLP1 may occur [ • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • The prevalence of HLH is 37%-90% in individuals with XLP2 [ • Unlike XLP1, recurrence of HLH in individuals with XLP2 is common; repeated episodes may be seen in 67%-83% of affected individuals, often within a year of onset of the initial HLH episode [ • HLH poses a significant risk for mortality to males with XLP2. Of the originally described XLP2 cohort, 33% died from HLH between ages six months and 40 years [ • Enterocolitis resembles and is often misdiagnosed as Crohn disease. • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • Enterocolitis can lead to gastrointestinal hemorrhage and has a mortality rate of 10%-60% [ • Enterocolitis has been reported to resolve following allogenic hematopoietic stem cell transplant (HSCT) [ • Rarely, individuals with XLP2 and inflammatory bowel disease have also been reported to develop inflammatory liver disease, which can progress to fatal liver failure [ • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • In one of the largest series to date, • Survival was greater for those who underwent allogeneic HSCT (81.4%) vs those who did not (62.5%). • Regardless of whether affected individuals underwent allogeneic HSCT or not, survival was lowest for individuals with XLP1 who developed HLH. • Combined data from this and other reports reveal an overall mortality rate of 29%-66% for individuals with XLP1 [ • A large study of 167 individuals with XLP2 revealed that for individuals reaching adulthood who did not undergo allogeneic HSCT, survival probabilities were 86% at age 30 years and 37% at age 52 years, with poorer outcomes for those who developed disease features before age five years or with new disease features as adults [ • Enterocolitis appears to have the highest risk for mortality in XLP2. • Epstein-Barr virus infection, familial fatal • EBV susceptibility (EBVS) • X-linked progressive combined variable immunodeficiency 5 • Purtilo syndrome • Duncan disease ## Clinical Description X-linked lymphoproliferative disease (XLP) in general is characterized by an inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, dysgammaglobulinemia, and lymphoproliferative disease (malignant lymphoma). The condition primarily affects males, although females rarely may have symptoms. Prior to EBV infection, most males appear healthy and do not exhibit any characteristic clinical findings. Clinical findings vary among individuals with XLP, even in the same family. Rarely, males may be asymptomatic; however, they generally develop one or more clinical findings over the course of their life [ There is no way to reliably predict which clinical findings will develop in an individual with XLP. XLP has two recognizable subtypes, XLP1 (due to pathogenic variants in Clinical Phenotypes of Rash and lymphadenopathy are less common but may also occur. Individuals may exhibit liver dysfunction and neurologic abnormalities. Death is generally secondary to liver failure or multisystem organ dysfunction (see Laboratory/pathology findings in HLH may include the following: Hemophagocytosis (phagocytosis identified by microscopy revealing intact or partially degraded blood cells) in the bone marrow, liver, spleen, lymph nodes, and/or cerebral spinal fluid (CSF) Pleiocytosis with increased numbers of mononuclear cells and elevated protein levels in the CSF Hypogammaglobulinemia of one or more immunoglobulin subclasses may be diagnosed prior to EBV infection or in survivors of EBV infection. Some of these affected males were previously considered to have common variable immunodeficiency (see The prognosis for males with dys- or hypogammaglobulinemia is more favorable when managed with regular intravenous immunoglobulin (IVIG) infusions (see Hypogammaglobulinemia is usually progressive in XLP1. Lymphomas can be histologically classified as Burkitt lymphoma (53% of all B-cell lymphomas), immunoblastic lymphomas (12% of all lymphomas), small cleaved or mixed-cell lymphomas (12%), and unclassifiable lymphomas (5%). Hodgkin and T-cell lymphomas have also rarely been reported. Remission may follow treatment with chemotherapy; however, relapse or development of a second primary lymphoma or other clinical manifestation of XLP1 may occur [ It is most often observed in the CNS but can also occur in the lungs or other organs. Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. Retinal involvement can lead to visual disturbances and blindness. Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. Males with Clinical Phenotypes of The prevalence of HLH is 37%-90% in individuals with XLP2 [ Unlike XLP1, recurrence of HLH in individuals with XLP2 is common; repeated episodes may be seen in 67%-83% of affected individuals, often within a year of onset of the initial HLH episode [ HLH poses a significant risk for mortality to males with XLP2. Of the originally described XLP2 cohort, 33% died from HLH between ages six months and 40 years [ Enterocolitis resembles and is often misdiagnosed as Crohn disease. Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. Enterocolitis can lead to gastrointestinal hemorrhage and has a mortality rate of 10%-60% [ Enterocolitis has been reported to resolve following allogenic hematopoietic stem cell transplant (HSCT) [ Rarely, individuals with XLP2 and inflammatory bowel disease have also been reported to develop inflammatory liver disease, which can progress to fatal liver failure [ Advances in the recognition, diagnosis, and management of XLP1 and XLP2 have led to improved outcomes, although mortality rates still remain high. In one of the largest series to date, Survival was greater for those who underwent allogeneic HSCT (81.4%) vs those who did not (62.5%). Regardless of whether affected individuals underwent allogeneic HSCT or not, survival was lowest for individuals with XLP1 who developed HLH. Combined data from this and other reports reveal an overall mortality rate of 29%-66% for individuals with XLP1 [ A large study of 167 individuals with XLP2 revealed that for individuals reaching adulthood who did not undergo allogeneic HSCT, survival probabilities were 86% at age 30 years and 37% at age 52 years, with poorer outcomes for those who developed disease features before age five years or with new disease features as adults [ Enterocolitis appears to have the highest risk for mortality in XLP2. As in many X-linked disorders, females rarely have symptoms. There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation toward the X chromosome with the pathogenic variant in • Prior to EBV infection, most males appear healthy and do not exhibit any characteristic clinical findings. • Clinical findings vary among individuals with XLP, even in the same family. • Rarely, males may be asymptomatic; however, they generally develop one or more clinical findings over the course of their life [ • There is no way to reliably predict which clinical findings will develop in an individual with XLP. • Rash and lymphadenopathy are less common but may also occur. • Individuals may exhibit liver dysfunction and neurologic abnormalities. • Death is generally secondary to liver failure or multisystem organ dysfunction (see • Hemophagocytosis (phagocytosis identified by microscopy revealing intact or partially degraded blood cells) in the bone marrow, liver, spleen, lymph nodes, and/or cerebral spinal fluid (CSF) • Pleiocytosis with increased numbers of mononuclear cells and elevated protein levels in the CSF • Hypogammaglobulinemia of one or more immunoglobulin subclasses may be diagnosed prior to EBV infection or in survivors of EBV infection. • Some of these affected males were previously considered to have common variable immunodeficiency (see • The prognosis for males with dys- or hypogammaglobulinemia is more favorable when managed with regular intravenous immunoglobulin (IVIG) infusions (see • Hypogammaglobulinemia is usually progressive in XLP1. • Lymphomas can be histologically classified as Burkitt lymphoma (53% of all B-cell lymphomas), immunoblastic lymphomas (12% of all lymphomas), small cleaved or mixed-cell lymphomas (12%), and unclassifiable lymphomas (5%). • Hodgkin and T-cell lymphomas have also rarely been reported. • Remission may follow treatment with chemotherapy; however, relapse or development of a second primary lymphoma or other clinical manifestation of XLP1 may occur [ • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • The prevalence of HLH is 37%-90% in individuals with XLP2 [ • Unlike XLP1, recurrence of HLH in individuals with XLP2 is common; repeated episodes may be seen in 67%-83% of affected individuals, often within a year of onset of the initial HLH episode [ • HLH poses a significant risk for mortality to males with XLP2. Of the originally described XLP2 cohort, 33% died from HLH between ages six months and 40 years [ • Enterocolitis resembles and is often misdiagnosed as Crohn disease. • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • Enterocolitis can lead to gastrointestinal hemorrhage and has a mortality rate of 10%-60% [ • Enterocolitis has been reported to resolve following allogenic hematopoietic stem cell transplant (HSCT) [ • Rarely, individuals with XLP2 and inflammatory bowel disease have also been reported to develop inflammatory liver disease, which can progress to fatal liver failure [ • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • In one of the largest series to date, • Survival was greater for those who underwent allogeneic HSCT (81.4%) vs those who did not (62.5%). • Regardless of whether affected individuals underwent allogeneic HSCT or not, survival was lowest for individuals with XLP1 who developed HLH. • Combined data from this and other reports reveal an overall mortality rate of 29%-66% for individuals with XLP1 [ • A large study of 167 individuals with XLP2 revealed that for individuals reaching adulthood who did not undergo allogeneic HSCT, survival probabilities were 86% at age 30 years and 37% at age 52 years, with poorer outcomes for those who developed disease features before age five years or with new disease features as adults [ • Enterocolitis appears to have the highest risk for mortality in XLP2. ## XLP1 Clinical Phenotypes of Rash and lymphadenopathy are less common but may also occur. Individuals may exhibit liver dysfunction and neurologic abnormalities. Death is generally secondary to liver failure or multisystem organ dysfunction (see Laboratory/pathology findings in HLH may include the following: Hemophagocytosis (phagocytosis identified by microscopy revealing intact or partially degraded blood cells) in the bone marrow, liver, spleen, lymph nodes, and/or cerebral spinal fluid (CSF) Pleiocytosis with increased numbers of mononuclear cells and elevated protein levels in the CSF Hypogammaglobulinemia of one or more immunoglobulin subclasses may be diagnosed prior to EBV infection or in survivors of EBV infection. Some of these affected males were previously considered to have common variable immunodeficiency (see The prognosis for males with dys- or hypogammaglobulinemia is more favorable when managed with regular intravenous immunoglobulin (IVIG) infusions (see Hypogammaglobulinemia is usually progressive in XLP1. Lymphomas can be histologically classified as Burkitt lymphoma (53% of all B-cell lymphomas), immunoblastic lymphomas (12% of all lymphomas), small cleaved or mixed-cell lymphomas (12%), and unclassifiable lymphomas (5%). Hodgkin and T-cell lymphomas have also rarely been reported. Remission may follow treatment with chemotherapy; however, relapse or development of a second primary lymphoma or other clinical manifestation of XLP1 may occur [ It is most often observed in the CNS but can also occur in the lungs or other organs. Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. Retinal involvement can lead to visual disturbances and blindness. Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • Rash and lymphadenopathy are less common but may also occur. • Individuals may exhibit liver dysfunction and neurologic abnormalities. • Death is generally secondary to liver failure or multisystem organ dysfunction (see • Hemophagocytosis (phagocytosis identified by microscopy revealing intact or partially degraded blood cells) in the bone marrow, liver, spleen, lymph nodes, and/or cerebral spinal fluid (CSF) • Pleiocytosis with increased numbers of mononuclear cells and elevated protein levels in the CSF • Hypogammaglobulinemia of one or more immunoglobulin subclasses may be diagnosed prior to EBV infection or in survivors of EBV infection. • Some of these affected males were previously considered to have common variable immunodeficiency (see • The prognosis for males with dys- or hypogammaglobulinemia is more favorable when managed with regular intravenous immunoglobulin (IVIG) infusions (see • Hypogammaglobulinemia is usually progressive in XLP1. • Lymphomas can be histologically classified as Burkitt lymphoma (53% of all B-cell lymphomas), immunoblastic lymphomas (12% of all lymphomas), small cleaved or mixed-cell lymphomas (12%), and unclassifiable lymphomas (5%). • Hodgkin and T-cell lymphomas have also rarely been reported. • Remission may follow treatment with chemotherapy; however, relapse or development of a second primary lymphoma or other clinical manifestation of XLP1 may occur [ • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. • It is most often observed in the CNS but can also occur in the lungs or other organs. • Symptoms of CNS vasculitis include headaches, disorientation, seizures, focal deficits, memory problems, stroke, and hemorrhage. • Retinal involvement can lead to visual disturbances and blindness. • Pathology of CNS vasculitis reveals clonal or non-clonal T-cell infiltration of vessel walls. ## XLP2 Males with Clinical Phenotypes of The prevalence of HLH is 37%-90% in individuals with XLP2 [ Unlike XLP1, recurrence of HLH in individuals with XLP2 is common; repeated episodes may be seen in 67%-83% of affected individuals, often within a year of onset of the initial HLH episode [ HLH poses a significant risk for mortality to males with XLP2. Of the originally described XLP2 cohort, 33% died from HLH between ages six months and 40 years [ Enterocolitis resembles and is often misdiagnosed as Crohn disease. Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. Enterocolitis can lead to gastrointestinal hemorrhage and has a mortality rate of 10%-60% [ Enterocolitis has been reported to resolve following allogenic hematopoietic stem cell transplant (HSCT) [ Rarely, individuals with XLP2 and inflammatory bowel disease have also been reported to develop inflammatory liver disease, which can progress to fatal liver failure [ • The prevalence of HLH is 37%-90% in individuals with XLP2 [ • Unlike XLP1, recurrence of HLH in individuals with XLP2 is common; repeated episodes may be seen in 67%-83% of affected individuals, often within a year of onset of the initial HLH episode [ • HLH poses a significant risk for mortality to males with XLP2. Of the originally described XLP2 cohort, 33% died from HLH between ages six months and 40 years [ • Enterocolitis resembles and is often misdiagnosed as Crohn disease. • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. • Enterocolitis can lead to gastrointestinal hemorrhage and has a mortality rate of 10%-60% [ • Enterocolitis has been reported to resolve following allogenic hematopoietic stem cell transplant (HSCT) [ • Rarely, individuals with XLP2 and inflammatory bowel disease have also been reported to develop inflammatory liver disease, which can progress to fatal liver failure [ • Approximately 5% of individuals with signs and symptoms of inflammatory bowel disease are ultimately diagnosed with XLP2. • Pathologic examination of the colon reveals inflammatory infiltrates in the lamina propria with ulceration, apoptotic crypt cells, and crypt abscesses. ## Prognosis Advances in the recognition, diagnosis, and management of XLP1 and XLP2 have led to improved outcomes, although mortality rates still remain high. In one of the largest series to date, Survival was greater for those who underwent allogeneic HSCT (81.4%) vs those who did not (62.5%). Regardless of whether affected individuals underwent allogeneic HSCT or not, survival was lowest for individuals with XLP1 who developed HLH. Combined data from this and other reports reveal an overall mortality rate of 29%-66% for individuals with XLP1 [ A large study of 167 individuals with XLP2 revealed that for individuals reaching adulthood who did not undergo allogeneic HSCT, survival probabilities were 86% at age 30 years and 37% at age 52 years, with poorer outcomes for those who developed disease features before age five years or with new disease features as adults [ Enterocolitis appears to have the highest risk for mortality in XLP2. • In one of the largest series to date, • Survival was greater for those who underwent allogeneic HSCT (81.4%) vs those who did not (62.5%). • Regardless of whether affected individuals underwent allogeneic HSCT or not, survival was lowest for individuals with XLP1 who developed HLH. • Combined data from this and other reports reveal an overall mortality rate of 29%-66% for individuals with XLP1 [ • A large study of 167 individuals with XLP2 revealed that for individuals reaching adulthood who did not undergo allogeneic HSCT, survival probabilities were 86% at age 30 years and 37% at age 52 years, with poorer outcomes for those who developed disease features before age five years or with new disease features as adults [ • Enterocolitis appears to have the highest risk for mortality in XLP2. ## Heterozygous Females As in many X-linked disorders, females rarely have symptoms. There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation toward the X chromosome with the pathogenic variant in ## Genotype-Phenotype Correlations No strong correlation exists between the ## Nomenclature In the past, the following terms were used to describe XLP: Epstein-Barr virus infection, familial fatal EBV susceptibility (EBVS) X-linked progressive combined variable immunodeficiency 5 Purtilo syndrome Duncan disease • Epstein-Barr virus infection, familial fatal • EBV susceptibility (EBVS) • X-linked progressive combined variable immunodeficiency 5 • Purtilo syndrome • Duncan disease ## Prevalence The estimated prevalence of XLP1 is one in every one to two million males. The prevalence of XLP2 is less well characterized but believed to be less than XLP1. These frequencies may be an underestimate given the severity and often rapidly fatal initial presentation, variable expression, and clinical overlap with other immunologic disorders [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Although ## Differential Diagnosis The differential diagnosis of X-linked lymphoproliferative disease (XLP) includes the following hereditary and acquired disorders: Genes of Interest in the Differential Diagnosis of X-Linked Lymphoproliferative Disease Humoral immune deficiency w/age of onset most commonly between 16 & 20 yrs resulting in ↑ susceptibility to infections & ↓ responses to protein & polysaccharide vaccines The most common infections are sinopulmonary. Overall prevalence is approximately one in 20,000 to 50,000 live births. Occurs equally in males & females. The genetic etiology of most CVID is currently unknown. XLP should be considered in males w/CVID & hypogammaglobulinemia identified during 1st decade of life, particularly in presence of other signs or positive family history. Persons w/CVID occasionally present with HLH-like phenotype. Partial oculocutaneous albinism, a mild bleeding tendency, & severe immunodeficiency ~85% of persons w/classic CHS develop HLH. Excessive immune activation w/uncontrolled T lymphocyte & macrophage activation Familial HLH may also be triggered by EBV infection Familial HLH is lethal in childhood unless treated w/HSCT. Disorder of cytotoxic T lymphocytes Usually assoc w/ neurologic abnormalities in addition to partial albinism w/fair skin & silvery-gray hair Many persons w/GS2 develop HLH. AD = autosomal dominant; ALPS = autoimmune lymphoproliferative syndrome; AR = autosomal recessive; CVID = common variable immunodeficiency; EBV = Epstein-Barr virus; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplant; Ig = immunoglobulin; MOI = mode of inheritance; XL = X-linked; XLP = X-linked lymphoproliferative disease ALPS-FAS refers to autoimmune lymphoproliferative syndrome (ALPS) associated with biallelic or heterozygous germline pathogenic variants in In most individuals with ALPS-FAS and some individuals with ALPS-FASLG, inheritance is autosomal dominant. In most individuals with ALPS-FASLG and individuals with severe ALPS associated with biallelic Autosomal dominant inheritance of • Humoral immune deficiency w/age of onset most commonly between 16 & 20 yrs resulting in ↑ susceptibility to infections & ↓ responses to protein & polysaccharide vaccines • The most common infections are sinopulmonary. • Overall prevalence is approximately one in 20,000 to 50,000 live births. • Occurs equally in males & females. • The genetic etiology of most CVID is currently unknown. • XLP should be considered in males w/CVID & hypogammaglobulinemia identified during 1st decade of life, particularly in presence of other signs or positive family history. • Persons w/CVID occasionally present with HLH-like phenotype. • Partial oculocutaneous albinism, a mild bleeding tendency, & severe immunodeficiency • ~85% of persons w/classic CHS develop HLH. • Excessive immune activation w/uncontrolled T lymphocyte & macrophage activation • Familial HLH may also be triggered by EBV infection • Familial HLH is lethal in childhood unless treated w/HSCT. • Disorder of cytotoxic T lymphocytes • Usually assoc w/ neurologic abnormalities in addition to partial albinism w/fair skin & silvery-gray hair • Many persons w/GS2 develop HLH. ## Management No clinical practice guidelines for X-linked lymphoproliferative disease (XLP) have been published. To establish the extent of disease and needs in an individual diagnosed with XLP, the evaluations summarized in X-Linked Proliferative Disease: Recommended Evaluations Following Initial Diagnosis Consider liver imaging if there is hepatomegaly w/abnormal serum transaminases or bilirubin. Consider MR cholangiopancreatography if there is concern for cholangitis in those w/XLP2 ( Splenomegaly can be seen in setting of HLH or incomplete HLH (fever & cytopenias only). Splenomegaly & lymphadenopathy should prompt further investigation for lymphoma in those w/XLP1 ( In persons w/XLP2, transient splenomegaly can be seen after vaccinations. To evaluate for history of recurrent bacterial infections to aid in decisions for Ig replacement therapy, if needed To evaluate for history of previous viral infections, such as EBV Identification of possible active infections (esp viral infection or reactivation such as EBV, CMV, HSV, adenovirus, HHV6) that would require specific treatment Eval of infection status of EBV & other infections If abnormal neurologic exam or symptoms: evaluate CSF cell count w/differential, glucose, protein, culture (& meningitis PCR panel if available), & cytology. Consider CNS imaging w/MRI of brain w/ & w/o contrast (± MR angiography if concern for vasculitis). Elevation of CSF mononuclear cells, often w/assoc elevation of protein, is sufficient to determine CNS involvement of HLH w/o need to demonstrate hemophagocytosis. CNS lymphoma & vasculitis can be seen in persons w/XLP1. Community or Social work involvement for parental support Home nursing referral CBC = complete blood count; CMV = cytomegalovirus; CNS = central nervous system; CSF = cerebrospinal fluid; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; HHV6 = human herpes virus 6; HSV = herpes simplex virus; Ig = immunoglobulin; IL2RA = interleukin-2 receptor alpha; MOI = mode of inheritance; MR = magnetic resonance; PCR = polymerase chain reaction; PTT = partial thromboplastin time; XLP = X-linked lymphoproliferative disease Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2. Those with XLP1 generally do not develop cholitis. Consider evaluation of CMV, HSV, varicella, hepatitis B virus, and hepatitis C virus infection status. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The only known curative therapy for XLP1 ( X-Linked Proliferative Disease: Targeted Therapy Should be strongly considered in all males as early in life as is feasible, particularly in those who have not yet developed symptoms. In those who have developed HLH, HSCT should be pursued as soon as the person is clinically stable & HLH has been adequately controlled (i.e., remission). HSCT is not recommended for asymptomatic heterozygous females. Those w/XLP2 appear to experience more complications following allogeneic HSCT, incl ↑ rates of acute & chronic graft-vs-host disease. High mortality has been observed when using myeloablative conditioning regimens in persons w/XLP2. Those w/XLP2 who develop HLH have better outcomes if their HLH is in remission prior to HSCT. There are reports of improvement of enterocolitis following HSCT. HLH = hemophagocytic lymphohistiocytosis Successful outcomes have been reported with the use of matched-sib donors and marrow or umbilical cord blood from unrelated donors [ Overall survival is approximately 70%-80% [ Survival of affected individuals who received a transplant may be increased if they were transplanted prior to developing HLH or other symptoms of disease [ Early evidence suggests that reduced-intensity conditioning regimens are effective and should be considered due to very poor early experience with myeloablative preparative regimens [ Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see X-Linked Proliferative Disease: Treatment of Manifestations IVIG therapy should be considered in affected persons w/hypogammaglobinemia. IVIG replacement should be strongly considered in persons w/hypogammaglobulinemia & recurrent respiratory infections or evidence of impaired vaccine response. Decision to start Ig replacement is supported by presence of low Ig levels (IgG) &/or if there is a history of recurrent respiratory infections. If it is unclear if a person needs IgG replacement therapy, vaccine response can be tested. Etoposide & steroids Consideration of rituximab (anti-CD20 antibody) if person has active EBV infection Consideration of IVIG therapy Other therapies to consider incl cytokine-directed therapy, such emapalumab & ruxolitinib. Persons w/XLP2 may benefit from anakinra (IL-1 beta antagonist) or IL-18 binding agents due to inflammasomapathy. Once HLH is controlled, those w/XLP1 should quickly proceed to allogeneic HCST (see Those w/XLP2 who develop HLH should undergo careful consideration to determine if HSCT is needed (see Symptomatic therapy, which typically incl immunosuppression, such as 5-amino salicylic acid, azathioprine, steroids, cyclosporine, & infliximab (anti-TNF therapies) HSCT can be curative for severe colitis & should be considered on a case-by-case basis. Supportive care w/transfusions as needed Antimicrobial prophylaxis if neutropenic or lymphopenic Consider HSCT. There is no definitive immunosuppressive therapy for vasculitis, & it is often difficult to treat. Agents that have been reported incl steroids, IVIG, & rituximab. If unresponsive to immunosuppression, HSCT can be considered. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Assess health care decisions in the context of the best interest of the affected person & values & preferences of the family. For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams. CNS = central nervous system; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplant; Ig = immunoglobulin; IL = interleukin; IVIG = intravenous immunoglobulins; TNF = tumor necrosis factor; XLP = X-linked lymphoproliferative disease Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2. It is recommended that males with known or suspected XLP and hypogammaglobulinemia receive regular intravenous IgG replacement therapy every three to four weeks until definitive treatment can be provided. There is limited data available for anti-cytokine therapy in individuals with XLP1 or XLP2 [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in X-Linked Proliferative Disease: Recommended Surveillance CBC = complete blood count; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; Ig = immunoglobulin; IL2RA = interleukin-2 receptor alpha; PCR = polymerase chain reaction; PTT = partial thromboplastin time Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs and other maternal male relatives of an affected individual in order to identify as early as possible those who would benefit from medical management and consideration of presymptomatic bone marrow transplantation in males [ Targeted molecular genetic testing if the pathogenic variant in the family is known; Flow cytometry to measure SAP and XIAP protein expression if the pathogenic variant in the family is not known. See The following therapies are under investigation for XLP: Search • Consider liver imaging if there is hepatomegaly w/abnormal serum transaminases or bilirubin. • Consider MR cholangiopancreatography if there is concern for cholangitis in those w/XLP2 ( • Splenomegaly can be seen in setting of HLH or incomplete HLH (fever & cytopenias only). • Splenomegaly & lymphadenopathy should prompt further investigation for lymphoma in those w/XLP1 ( • In persons w/XLP2, transient splenomegaly can be seen after vaccinations. • To evaluate for history of recurrent bacterial infections to aid in decisions for Ig replacement therapy, if needed • To evaluate for history of previous viral infections, such as EBV • Identification of possible active infections (esp viral infection or reactivation such as EBV, CMV, HSV, adenovirus, HHV6) that would require specific treatment • Eval of infection status of EBV & other infections • If abnormal neurologic exam or symptoms: evaluate CSF cell count w/differential, glucose, protein, culture (& meningitis PCR panel if available), & cytology. Consider CNS imaging w/MRI of brain w/ & w/o contrast (± MR angiography if concern for vasculitis). • Elevation of CSF mononuclear cells, often w/assoc elevation of protein, is sufficient to determine CNS involvement of HLH w/o need to demonstrate hemophagocytosis. • CNS lymphoma & vasculitis can be seen in persons w/XLP1. • Community or • Social work involvement for parental support • Home nursing referral • Should be strongly considered in all males as early in life as is feasible, particularly in those who have not yet developed symptoms. • In those who have developed HLH, HSCT should be pursued as soon as the person is clinically stable & HLH has been adequately controlled (i.e., remission). • HSCT is not recommended for asymptomatic heterozygous females. • Those w/XLP2 appear to experience more complications following allogeneic HSCT, incl ↑ rates of acute & chronic graft-vs-host disease. • High mortality has been observed when using myeloablative conditioning regimens in persons w/XLP2. • Those w/XLP2 who develop HLH have better outcomes if their HLH is in remission prior to HSCT. • There are reports of improvement of enterocolitis following HSCT. • IVIG therapy should be considered in affected persons w/hypogammaglobinemia. • IVIG replacement should be strongly considered in persons w/hypogammaglobulinemia & recurrent respiratory infections or evidence of impaired vaccine response. • Decision to start Ig replacement is supported by presence of low Ig levels (IgG) &/or if there is a history of recurrent respiratory infections. • If it is unclear if a person needs IgG replacement therapy, vaccine response can be tested. • Etoposide & steroids • Consideration of rituximab (anti-CD20 antibody) if person has active EBV infection • Consideration of IVIG therapy • Other therapies to consider incl cytokine-directed therapy, such emapalumab & ruxolitinib. • Persons w/XLP2 may benefit from anakinra (IL-1 beta antagonist) or IL-18 binding agents due to inflammasomapathy. • Once HLH is controlled, those w/XLP1 should quickly proceed to allogeneic HCST (see • Those w/XLP2 who develop HLH should undergo careful consideration to determine if HSCT is needed (see • Symptomatic therapy, which typically incl immunosuppression, such as 5-amino salicylic acid, azathioprine, steroids, cyclosporine, & infliximab (anti-TNF therapies) • HSCT can be curative for severe colitis & should be considered on a case-by-case basis. • Supportive care w/transfusions as needed • Antimicrobial prophylaxis if neutropenic or lymphopenic • Consider HSCT. • There is no definitive immunosuppressive therapy for vasculitis, & it is often difficult to treat. Agents that have been reported incl steroids, IVIG, & rituximab. • If unresponsive to immunosuppression, HSCT can be considered. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Assess health care decisions in the context of the best interest of the affected person & values & preferences of the family. • For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams. • Targeted molecular genetic testing if the pathogenic variant in the family is known; • Flow cytometry to measure SAP and XIAP protein expression if the pathogenic variant in the family is not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with XLP, the evaluations summarized in X-Linked Proliferative Disease: Recommended Evaluations Following Initial Diagnosis Consider liver imaging if there is hepatomegaly w/abnormal serum transaminases or bilirubin. Consider MR cholangiopancreatography if there is concern for cholangitis in those w/XLP2 ( Splenomegaly can be seen in setting of HLH or incomplete HLH (fever & cytopenias only). Splenomegaly & lymphadenopathy should prompt further investigation for lymphoma in those w/XLP1 ( In persons w/XLP2, transient splenomegaly can be seen after vaccinations. To evaluate for history of recurrent bacterial infections to aid in decisions for Ig replacement therapy, if needed To evaluate for history of previous viral infections, such as EBV Identification of possible active infections (esp viral infection or reactivation such as EBV, CMV, HSV, adenovirus, HHV6) that would require specific treatment Eval of infection status of EBV & other infections If abnormal neurologic exam or symptoms: evaluate CSF cell count w/differential, glucose, protein, culture (& meningitis PCR panel if available), & cytology. Consider CNS imaging w/MRI of brain w/ & w/o contrast (± MR angiography if concern for vasculitis). Elevation of CSF mononuclear cells, often w/assoc elevation of protein, is sufficient to determine CNS involvement of HLH w/o need to demonstrate hemophagocytosis. CNS lymphoma & vasculitis can be seen in persons w/XLP1. Community or Social work involvement for parental support Home nursing referral CBC = complete blood count; CMV = cytomegalovirus; CNS = central nervous system; CSF = cerebrospinal fluid; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; HHV6 = human herpes virus 6; HSV = herpes simplex virus; Ig = immunoglobulin; IL2RA = interleukin-2 receptor alpha; MOI = mode of inheritance; MR = magnetic resonance; PCR = polymerase chain reaction; PTT = partial thromboplastin time; XLP = X-linked lymphoproliferative disease Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2. Those with XLP1 generally do not develop cholitis. Consider evaluation of CMV, HSV, varicella, hepatitis B virus, and hepatitis C virus infection status. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Consider liver imaging if there is hepatomegaly w/abnormal serum transaminases or bilirubin. • Consider MR cholangiopancreatography if there is concern for cholangitis in those w/XLP2 ( • Splenomegaly can be seen in setting of HLH or incomplete HLH (fever & cytopenias only). • Splenomegaly & lymphadenopathy should prompt further investigation for lymphoma in those w/XLP1 ( • In persons w/XLP2, transient splenomegaly can be seen after vaccinations. • To evaluate for history of recurrent bacterial infections to aid in decisions for Ig replacement therapy, if needed • To evaluate for history of previous viral infections, such as EBV • Identification of possible active infections (esp viral infection or reactivation such as EBV, CMV, HSV, adenovirus, HHV6) that would require specific treatment • Eval of infection status of EBV & other infections • If abnormal neurologic exam or symptoms: evaluate CSF cell count w/differential, glucose, protein, culture (& meningitis PCR panel if available), & cytology. Consider CNS imaging w/MRI of brain w/ & w/o contrast (± MR angiography if concern for vasculitis). • Elevation of CSF mononuclear cells, often w/assoc elevation of protein, is sufficient to determine CNS involvement of HLH w/o need to demonstrate hemophagocytosis. • CNS lymphoma & vasculitis can be seen in persons w/XLP1. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations The only known curative therapy for XLP1 ( X-Linked Proliferative Disease: Targeted Therapy Should be strongly considered in all males as early in life as is feasible, particularly in those who have not yet developed symptoms. In those who have developed HLH, HSCT should be pursued as soon as the person is clinically stable & HLH has been adequately controlled (i.e., remission). HSCT is not recommended for asymptomatic heterozygous females. Those w/XLP2 appear to experience more complications following allogeneic HSCT, incl ↑ rates of acute & chronic graft-vs-host disease. High mortality has been observed when using myeloablative conditioning regimens in persons w/XLP2. Those w/XLP2 who develop HLH have better outcomes if their HLH is in remission prior to HSCT. There are reports of improvement of enterocolitis following HSCT. HLH = hemophagocytic lymphohistiocytosis Successful outcomes have been reported with the use of matched-sib donors and marrow or umbilical cord blood from unrelated donors [ Overall survival is approximately 70%-80% [ Survival of affected individuals who received a transplant may be increased if they were transplanted prior to developing HLH or other symptoms of disease [ Early evidence suggests that reduced-intensity conditioning regimens are effective and should be considered due to very poor early experience with myeloablative preparative regimens [ Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see X-Linked Proliferative Disease: Treatment of Manifestations IVIG therapy should be considered in affected persons w/hypogammaglobinemia. IVIG replacement should be strongly considered in persons w/hypogammaglobulinemia & recurrent respiratory infections or evidence of impaired vaccine response. Decision to start Ig replacement is supported by presence of low Ig levels (IgG) &/or if there is a history of recurrent respiratory infections. If it is unclear if a person needs IgG replacement therapy, vaccine response can be tested. Etoposide & steroids Consideration of rituximab (anti-CD20 antibody) if person has active EBV infection Consideration of IVIG therapy Other therapies to consider incl cytokine-directed therapy, such emapalumab & ruxolitinib. Persons w/XLP2 may benefit from anakinra (IL-1 beta antagonist) or IL-18 binding agents due to inflammasomapathy. Once HLH is controlled, those w/XLP1 should quickly proceed to allogeneic HCST (see Those w/XLP2 who develop HLH should undergo careful consideration to determine if HSCT is needed (see Symptomatic therapy, which typically incl immunosuppression, such as 5-amino salicylic acid, azathioprine, steroids, cyclosporine, & infliximab (anti-TNF therapies) HSCT can be curative for severe colitis & should be considered on a case-by-case basis. Supportive care w/transfusions as needed Antimicrobial prophylaxis if neutropenic or lymphopenic Consider HSCT. There is no definitive immunosuppressive therapy for vasculitis, & it is often difficult to treat. Agents that have been reported incl steroids, IVIG, & rituximab. If unresponsive to immunosuppression, HSCT can be considered. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Assess health care decisions in the context of the best interest of the affected person & values & preferences of the family. For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams. CNS = central nervous system; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplant; Ig = immunoglobulin; IL = interleukin; IVIG = intravenous immunoglobulins; TNF = tumor necrosis factor; XLP = X-linked lymphoproliferative disease Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2. It is recommended that males with known or suspected XLP and hypogammaglobulinemia receive regular intravenous IgG replacement therapy every three to four weeks until definitive treatment can be provided. There is limited data available for anti-cytokine therapy in individuals with XLP1 or XLP2 [ • Should be strongly considered in all males as early in life as is feasible, particularly in those who have not yet developed symptoms. • In those who have developed HLH, HSCT should be pursued as soon as the person is clinically stable & HLH has been adequately controlled (i.e., remission). • HSCT is not recommended for asymptomatic heterozygous females. • Those w/XLP2 appear to experience more complications following allogeneic HSCT, incl ↑ rates of acute & chronic graft-vs-host disease. • High mortality has been observed when using myeloablative conditioning regimens in persons w/XLP2. • Those w/XLP2 who develop HLH have better outcomes if their HLH is in remission prior to HSCT. • There are reports of improvement of enterocolitis following HSCT. • IVIG therapy should be considered in affected persons w/hypogammaglobinemia. • IVIG replacement should be strongly considered in persons w/hypogammaglobulinemia & recurrent respiratory infections or evidence of impaired vaccine response. • Decision to start Ig replacement is supported by presence of low Ig levels (IgG) &/or if there is a history of recurrent respiratory infections. • If it is unclear if a person needs IgG replacement therapy, vaccine response can be tested. • Etoposide & steroids • Consideration of rituximab (anti-CD20 antibody) if person has active EBV infection • Consideration of IVIG therapy • Other therapies to consider incl cytokine-directed therapy, such emapalumab & ruxolitinib. • Persons w/XLP2 may benefit from anakinra (IL-1 beta antagonist) or IL-18 binding agents due to inflammasomapathy. • Once HLH is controlled, those w/XLP1 should quickly proceed to allogeneic HCST (see • Those w/XLP2 who develop HLH should undergo careful consideration to determine if HSCT is needed (see • Symptomatic therapy, which typically incl immunosuppression, such as 5-amino salicylic acid, azathioprine, steroids, cyclosporine, & infliximab (anti-TNF therapies) • HSCT can be curative for severe colitis & should be considered on a case-by-case basis. • Supportive care w/transfusions as needed • Antimicrobial prophylaxis if neutropenic or lymphopenic • Consider HSCT. • There is no definitive immunosuppressive therapy for vasculitis, & it is often difficult to treat. Agents that have been reported incl steroids, IVIG, & rituximab. • If unresponsive to immunosuppression, HSCT can be considered. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Assess health care decisions in the context of the best interest of the affected person & values & preferences of the family. • For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams. ## Targeted Therapy The only known curative therapy for XLP1 ( X-Linked Proliferative Disease: Targeted Therapy Should be strongly considered in all males as early in life as is feasible, particularly in those who have not yet developed symptoms. In those who have developed HLH, HSCT should be pursued as soon as the person is clinically stable & HLH has been adequately controlled (i.e., remission). HSCT is not recommended for asymptomatic heterozygous females. Those w/XLP2 appear to experience more complications following allogeneic HSCT, incl ↑ rates of acute & chronic graft-vs-host disease. High mortality has been observed when using myeloablative conditioning regimens in persons w/XLP2. Those w/XLP2 who develop HLH have better outcomes if their HLH is in remission prior to HSCT. There are reports of improvement of enterocolitis following HSCT. HLH = hemophagocytic lymphohistiocytosis Successful outcomes have been reported with the use of matched-sib donors and marrow or umbilical cord blood from unrelated donors [ Overall survival is approximately 70%-80% [ Survival of affected individuals who received a transplant may be increased if they were transplanted prior to developing HLH or other symptoms of disease [ Early evidence suggests that reduced-intensity conditioning regimens are effective and should be considered due to very poor early experience with myeloablative preparative regimens [ • Should be strongly considered in all males as early in life as is feasible, particularly in those who have not yet developed symptoms. • In those who have developed HLH, HSCT should be pursued as soon as the person is clinically stable & HLH has been adequately controlled (i.e., remission). • HSCT is not recommended for asymptomatic heterozygous females. • Those w/XLP2 appear to experience more complications following allogeneic HSCT, incl ↑ rates of acute & chronic graft-vs-host disease. • High mortality has been observed when using myeloablative conditioning regimens in persons w/XLP2. • Those w/XLP2 who develop HLH have better outcomes if their HLH is in remission prior to HSCT. • There are reports of improvement of enterocolitis following HSCT. ## Supportive Care Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see X-Linked Proliferative Disease: Treatment of Manifestations IVIG therapy should be considered in affected persons w/hypogammaglobinemia. IVIG replacement should be strongly considered in persons w/hypogammaglobulinemia & recurrent respiratory infections or evidence of impaired vaccine response. Decision to start Ig replacement is supported by presence of low Ig levels (IgG) &/or if there is a history of recurrent respiratory infections. If it is unclear if a person needs IgG replacement therapy, vaccine response can be tested. Etoposide & steroids Consideration of rituximab (anti-CD20 antibody) if person has active EBV infection Consideration of IVIG therapy Other therapies to consider incl cytokine-directed therapy, such emapalumab & ruxolitinib. Persons w/XLP2 may benefit from anakinra (IL-1 beta antagonist) or IL-18 binding agents due to inflammasomapathy. Once HLH is controlled, those w/XLP1 should quickly proceed to allogeneic HCST (see Those w/XLP2 who develop HLH should undergo careful consideration to determine if HSCT is needed (see Symptomatic therapy, which typically incl immunosuppression, such as 5-amino salicylic acid, azathioprine, steroids, cyclosporine, & infliximab (anti-TNF therapies) HSCT can be curative for severe colitis & should be considered on a case-by-case basis. Supportive care w/transfusions as needed Antimicrobial prophylaxis if neutropenic or lymphopenic Consider HSCT. There is no definitive immunosuppressive therapy for vasculitis, & it is often difficult to treat. Agents that have been reported incl steroids, IVIG, & rituximab. If unresponsive to immunosuppression, HSCT can be considered. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Assess health care decisions in the context of the best interest of the affected person & values & preferences of the family. For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams. CNS = central nervous system; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplant; Ig = immunoglobulin; IL = interleukin; IVIG = intravenous immunoglobulins; TNF = tumor necrosis factor; XLP = X-linked lymphoproliferative disease Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2. It is recommended that males with known or suspected XLP and hypogammaglobulinemia receive regular intravenous IgG replacement therapy every three to four weeks until definitive treatment can be provided. There is limited data available for anti-cytokine therapy in individuals with XLP1 or XLP2 [ • IVIG therapy should be considered in affected persons w/hypogammaglobinemia. • IVIG replacement should be strongly considered in persons w/hypogammaglobulinemia & recurrent respiratory infections or evidence of impaired vaccine response. • Decision to start Ig replacement is supported by presence of low Ig levels (IgG) &/or if there is a history of recurrent respiratory infections. • If it is unclear if a person needs IgG replacement therapy, vaccine response can be tested. • Etoposide & steroids • Consideration of rituximab (anti-CD20 antibody) if person has active EBV infection • Consideration of IVIG therapy • Other therapies to consider incl cytokine-directed therapy, such emapalumab & ruxolitinib. • Persons w/XLP2 may benefit from anakinra (IL-1 beta antagonist) or IL-18 binding agents due to inflammasomapathy. • Once HLH is controlled, those w/XLP1 should quickly proceed to allogeneic HCST (see • Those w/XLP2 who develop HLH should undergo careful consideration to determine if HSCT is needed (see • Symptomatic therapy, which typically incl immunosuppression, such as 5-amino salicylic acid, azathioprine, steroids, cyclosporine, & infliximab (anti-TNF therapies) • HSCT can be curative for severe colitis & should be considered on a case-by-case basis. • Supportive care w/transfusions as needed • Antimicrobial prophylaxis if neutropenic or lymphopenic • Consider HSCT. • There is no definitive immunosuppressive therapy for vasculitis, & it is often difficult to treat. Agents that have been reported incl steroids, IVIG, & rituximab. • If unresponsive to immunosuppression, HSCT can be considered. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Assess health care decisions in the context of the best interest of the affected person & values & preferences of the family. • For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in X-Linked Proliferative Disease: Recommended Surveillance CBC = complete blood count; EBV = Epstein-Barr virus; FIM = fulminant infectious mononucleosis; HLH = hemophagocytic lymphohistiocytosis; Ig = immunoglobulin; IL2RA = interleukin-2 receptor alpha; PCR = polymerase chain reaction; PTT = partial thromboplastin time Unless otherwise specified, all recommendations listed in this table pertain to individuals diagnosed with either XLP1 or XLP2. ## Agents/Circumstances to Avoid ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs and other maternal male relatives of an affected individual in order to identify as early as possible those who would benefit from medical management and consideration of presymptomatic bone marrow transplantation in males [ Targeted molecular genetic testing if the pathogenic variant in the family is known; Flow cytometry to measure SAP and XIAP protein expression if the pathogenic variant in the family is not known. See • Targeted molecular genetic testing if the pathogenic variant in the family is known; • Flow cytometry to measure SAP and XIAP protein expression if the pathogenic variant in the family is not known. ## Therapies Under Investigation The following therapies are under investigation for XLP: Search ## Genetic Counseling X-linked lymphoproliferative disease (XLP) is inherited in an X-linked manner. XLP primarily affects males, although females rarely may have symptoms. The father of an affected male will not have XLP, nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Females who are heterozygous for an If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote; The affected male may have a The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism (maternal germline mosaicism has been reported [ Historically, affected males have not been known to reproduce owing to poor survival. However, survival outcomes for affected males are improving, resulting in larger numbers of affected individuals surviving into adulthood [ Affected males would transmit the All of their daughters, who would be heterozygotes (see Clinical Description, None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Identification of female heterozygotes requires either prior identification of the XLP-related pathogenic variant in the family or, if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the Note: Females who are heterozygous for an See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the XLP-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. In pregnancies where the fetus is found to be unaffected, prenatal identification of an HLA-matched potential stem cell donor for an affected sib may be considered. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have XLP, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Females who are heterozygous for an • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, • If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism (maternal germline mosaicism has been reported [ • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, • Historically, affected males have not been known to reproduce owing to poor survival. However, survival outcomes for affected males are improving, resulting in larger numbers of affected individuals surviving into adulthood [ • Affected males would transmit the • All of their daughters, who would be heterozygotes (see Clinical Description, • None of their sons. • All of their daughters, who would be heterozygotes (see Clinical Description, • None of their sons. • All of their daughters, who would be heterozygotes (see Clinical Description, • None of their sons. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance X-linked lymphoproliferative disease (XLP) is inherited in an X-linked manner. XLP primarily affects males, although females rarely may have symptoms. ## Risk to Family Members The father of an affected male will not have XLP, nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Females who are heterozygous for an If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote; The affected male may have a The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism (maternal germline mosaicism has been reported [ Historically, affected males have not been known to reproduce owing to poor survival. However, survival outcomes for affected males are improving, resulting in larger numbers of affected individuals surviving into adulthood [ Affected males would transmit the All of their daughters, who would be heterozygotes (see Clinical Description, None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have XLP, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Females who are heterozygous for an • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported [ • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, • If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism (maternal germline mosaicism has been reported [ • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Females rarely have symptoms; however, there are increasing numbers of reports of affected females with skewed X-chromosome inactivation who develop HLH, inflammatory bowel disease, and erythema nodosum (see Clinical Description, • Historically, affected males have not been known to reproduce owing to poor survival. However, survival outcomes for affected males are improving, resulting in larger numbers of affected individuals surviving into adulthood [ • Affected males would transmit the • All of their daughters, who would be heterozygotes (see Clinical Description, • None of their sons. • All of their daughters, who would be heterozygotes (see Clinical Description, • None of their sons. • All of their daughters, who would be heterozygotes (see Clinical Description, • None of their sons. ## Heterozygote Detection Identification of female heterozygotes requires either prior identification of the XLP-related pathogenic variant in the family or, if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the Note: Females who are heterozygous for an ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the XLP-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. In pregnancies where the fetus is found to be unaffected, prenatal identification of an HLA-matched potential stem cell donor for an affected sib may be considered. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics X-Linked Lymphoproliferative Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Lymphoproliferative Disease ( The majority of X-Linked Lymphoproliferative Disease: Gene-Specific Laboratory Considerations Genes from ## Molecular Pathogenesis The majority of X-Linked Lymphoproliferative Disease: Gene-Specific Laboratory Considerations Genes from ## Chapter Notes Pediatric oncologist with clinical and research interest in hereditary predisposition to cancer and primary immunodeficiencies, including XLP1 ( Web page: Department of OncologySt Jude Children's Research Hospital262 Danny Thomas PlaceMemphis, TN, 38105901-595-8385 (office)901-595-6086 (fax)Email: Alexandra Filipovich, MD; Cincinnati Children's Hospital Medical Center (2004-2016)Melissa Hines, MD (2024-present)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2004-2016)Rebecca Marsh, MD; Cincinnati Children’s Hospital Medical Center (2009-2024)Lauren Meyer, MD, PhD (2024-present)Kim E Nichols, MD (2024-present)Janos Sumegi, MD, PhD; Cincinnati Children's Hospital Medical Center (2004-2011)Emily Wakefield, MS; Cincinnati Children’s Hospital Medical Center (2016-2024)Kejian Zhang, MD, MBA (2004-present) 16 May 2024 (ma) Comprehensive update posted live 30 June 2016 (sw) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 10 November 2011 (me) Comprehensive update posted live 18 June 2009 (me) Comprehensive update posted live 3 August 2006 (me) Comprehensive update posted live 27 February 2004 (me) Review posted live 10 August 2003 (js) Original submission • 16 May 2024 (ma) Comprehensive update posted live • 30 June 2016 (sw) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 10 November 2011 (me) Comprehensive update posted live • 18 June 2009 (me) Comprehensive update posted live • 3 August 2006 (me) Comprehensive update posted live • 27 February 2004 (me) Review posted live • 10 August 2003 (js) Original submission ## Author Notes Pediatric oncologist with clinical and research interest in hereditary predisposition to cancer and primary immunodeficiencies, including XLP1 ( Web page: Department of OncologySt Jude Children's Research Hospital262 Danny Thomas PlaceMemphis, TN, 38105901-595-8385 (office)901-595-6086 (fax)Email: ## Acknowledgments ## Author History Alexandra Filipovich, MD; Cincinnati Children's Hospital Medical Center (2004-2016)Melissa Hines, MD (2024-present)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2004-2016)Rebecca Marsh, MD; Cincinnati Children’s Hospital Medical Center (2009-2024)Lauren Meyer, MD, PhD (2024-present)Kim E Nichols, MD (2024-present)Janos Sumegi, MD, PhD; Cincinnati Children's Hospital Medical Center (2004-2011)Emily Wakefield, MS; Cincinnati Children’s Hospital Medical Center (2016-2024)Kejian Zhang, MD, MBA (2004-present) ## Revision History 16 May 2024 (ma) Comprehensive update posted live 30 June 2016 (sw) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 10 November 2011 (me) Comprehensive update posted live 18 June 2009 (me) Comprehensive update posted live 3 August 2006 (me) Comprehensive update posted live 27 February 2004 (me) Review posted live 10 August 2003 (js) Original submission • 16 May 2024 (ma) Comprehensive update posted live • 30 June 2016 (sw) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 10 November 2011 (me) Comprehensive update posted live • 18 June 2009 (me) Comprehensive update posted live • 3 August 2006 (me) Comprehensive update posted live • 27 February 2004 (me) Review posted live • 10 August 2003 (js) Original submission ## Key Sections in this ## References ## Literature Cited	[]	27/2/2004	16/5/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
x-oa	x-oa	[ "Nettleship-Falls Ocular Albinism", "OA1", "Ocular Albinism Type 1", "XLOA", "Nettleship-Falls Ocular Albinism", "OA1", "Ocular Albinism Type 1", "XLOA", "G-protein coupled receptor 143", "GPR143", "Ocular Albinism, X-Linked" ]	Ocular Albinism, X-Linked – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Richard Alan Lewis	Summary X-linked ocular albinism (XLOA) is a disorder of melanosome biogenesis leading to minor cutaneous and adnexal manifestations and congenital and persistent visual impairment in affected males. XLOA is characterized by infantile nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. XLOA is a non-progressive disorder and the visual acuity remains stable throughout life, often slowly improving into the mid-teens. A diagnosis of ocular albinism (OA) is probable in the presence of infantile nystagmus, iris translucency, substantial hypopigmentation of the ocular fundus periphery in males with mildly hypopigmented skin (most notably when compared to unaffected sibs), foveal hypoplasia, reduced visual acuity, and aberrant optic pathway projection as demonstrated by crossed asymmetry of the cortical responses on visual evoked potential testing. X-linked inheritance is documented by either a family history consistent with X-linked inheritance or the presence of typical carrier signs (irregular retinal pigmentation and mild iris transillumination) in an obligate carrier female. Molecular genetic testing of XLOA is inherited in an X-linked manner. An affected male transmits the pathogenic variant to all of his daughters and none of his sons. The risk to the sibs of a male proband depends on the carrier status of the mother. If the mother is a carrier, the chance of transmitting the	## Diagnosis X-linked ocular albinism (XLOA) Nystagmus amplitude and/or frequency often varies with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance. Note: None of the above findings is either specific or obligate for X-linked ocular albinism, and the diagnosis may be difficult in blond northern European males with only minimally reduced central visual acuity. Maternal male relatives with ocular albinism The most consistent clinical diagnostic clue for XLOA: presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers Depending on overall ethnic and racial skin and adnexal pigmentation, heterozygous females may show iris transillumination and a coarse pattern of blotchy hypo-and hyperpigmentation of the retinal pigment epithelium that becomes more dramatic outside the vascular arcades. Some carriers have isolated patches of hypopigmented skin that does not tan to the same degree as uninvolved skin. Rarely, heterozygous females are affected, showing infantile nystagmus, foveal hypoplasia, reduced visual acuity, and diffuse hypopigmentation of the ocular structures. The diagnosis of XLOA For an introduction to multigene panels click Molecular Genetic Testing Used in X-Linked Ocular Albinism See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by deletion/duplication analysis. Due to the high prevalence of deletions in this X-linked gene, attempts at sequence analysis may detect amplification failure resulting in an apparent detection rate of ~90% in affected males [Personal communications, Baylor Miraca Genetics Laboratory, Houston, TX]. Standard clinical laboratory practice does not consider assay failure to be diagnostic; therefore, deletion/duplication analysis would be necessary to confirm a diagnosis. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Nystagmus amplitude and/or frequency often varies with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance. • Maternal male relatives with ocular albinism • The most consistent clinical diagnostic clue for XLOA: presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers • For an introduction to multigene panels click ## Suggestive Findings X-linked ocular albinism (XLOA) Nystagmus amplitude and/or frequency often varies with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance. Note: None of the above findings is either specific or obligate for X-linked ocular albinism, and the diagnosis may be difficult in blond northern European males with only minimally reduced central visual acuity. Maternal male relatives with ocular albinism The most consistent clinical diagnostic clue for XLOA: presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers Depending on overall ethnic and racial skin and adnexal pigmentation, heterozygous females may show iris transillumination and a coarse pattern of blotchy hypo-and hyperpigmentation of the retinal pigment epithelium that becomes more dramatic outside the vascular arcades. Some carriers have isolated patches of hypopigmented skin that does not tan to the same degree as uninvolved skin. Rarely, heterozygous females are affected, showing infantile nystagmus, foveal hypoplasia, reduced visual acuity, and diffuse hypopigmentation of the ocular structures. • Nystagmus amplitude and/or frequency often varies with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance. • Maternal male relatives with ocular albinism • The most consistent clinical diagnostic clue for XLOA: presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers ## Males X-linked ocular albinism (XLOA) Nystagmus amplitude and/or frequency often varies with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance. Note: None of the above findings is either specific or obligate for X-linked ocular albinism, and the diagnosis may be difficult in blond northern European males with only minimally reduced central visual acuity. Maternal male relatives with ocular albinism The most consistent clinical diagnostic clue for XLOA: presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers • Nystagmus amplitude and/or frequency often varies with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance. • Maternal male relatives with ocular albinism • The most consistent clinical diagnostic clue for XLOA: presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers ## Heterozygous Females Depending on overall ethnic and racial skin and adnexal pigmentation, heterozygous females may show iris transillumination and a coarse pattern of blotchy hypo-and hyperpigmentation of the retinal pigment epithelium that becomes more dramatic outside the vascular arcades. Some carriers have isolated patches of hypopigmented skin that does not tan to the same degree as uninvolved skin. Rarely, heterozygous females are affected, showing infantile nystagmus, foveal hypoplasia, reduced visual acuity, and diffuse hypopigmentation of the ocular structures. ## Establishing the Diagnosis The diagnosis of XLOA For an introduction to multigene panels click Molecular Genetic Testing Used in X-Linked Ocular Albinism See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by deletion/duplication analysis. Due to the high prevalence of deletions in this X-linked gene, attempts at sequence analysis may detect amplification failure resulting in an apparent detection rate of ~90% in affected males [Personal communications, Baylor Miraca Genetics Laboratory, Houston, TX]. Standard clinical laboratory practice does not consider assay failure to be diagnostic; therefore, deletion/duplication analysis would be necessary to confirm a diagnosis. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Clinical Characteristics X-linked ocular albinism (XLOA) is a disorder of melanosome biogenesis leading to congenital and persistent visual impairment and mild to moderate skin changes in affected males. Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom. Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia or compound myopic astigmatism may occur in some affected individuals. Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [ Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [ Heterozygous females may be considered mosaic with respect to the Most heterozygous females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks, more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA. On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a No genotype-phenotype correlations have been identified [ Even in the same family, the cutaneous and adnexal coloration and the visual acuities may vary widely [ A minimum birth prevalence of one male in 60,000 live born children has been reported in a Danish cohort [ • Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom. • Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia or compound myopic astigmatism may occur in some affected individuals. • Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [ • Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [ • Most heterozygous females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks, more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA. • On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a ## Clinical Description X-linked ocular albinism (XLOA) is a disorder of melanosome biogenesis leading to congenital and persistent visual impairment and mild to moderate skin changes in affected males. Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom. Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia or compound myopic astigmatism may occur in some affected individuals. Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [ Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [ Heterozygous females may be considered mosaic with respect to the Most heterozygous females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks, more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA. On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a • Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom. • Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia or compound myopic astigmatism may occur in some affected individuals. • Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [ • Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [ • Most heterozygous females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks, more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA. • On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a ## Affected Males Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom. Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia or compound myopic astigmatism may occur in some affected individuals. Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [ Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [ • Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom. • Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia or compound myopic astigmatism may occur in some affected individuals. • Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [ • Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [ ## Heterozygous Females Heterozygous females may be considered mosaic with respect to the Most heterozygous females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks, more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA. On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a • Most heterozygous females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks, more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA. • On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified [ Even in the same family, the cutaneous and adnexal coloration and the visual acuities may vary widely [ ## Prevalence A minimum birth prevalence of one male in 60,000 live born children has been reported in a Danish cohort [ ## Genetically Related (Allelic) Disorders With the exception of contiguous gene syndromes, no phenotypes other than those discussed in this ## Differential Diagnosis A family history of X-linked inheritance for similarly affected individuals along with typical clinical findings supports the diagnosis of XLOA and further testing may not be indicated. However, when the family history is negative, XLOA must be distinguished from other forms of albinism and from X-linked disorders associated with infantile nystagmus. The Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in Oculocutaneous albinism type 2 (OCA2) (OMIM Oculocutaneous albinism type 3 (OCA3) (OMIM Two common molecular defects are associated with this phenotype [ Failure to detect a pathogenic variant in • Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in • Oculocutaneous albinism type 2 (OCA2) (OMIM • Oculocutaneous albinism type 3 (OCA3) (OMIM ## Management To establish the extent of disease and needs in an individual diagnosed with X-linked ocular albinism (XLOA), the following evaluations are recommended: Medical history and physical examination, including a careful evaluation of pigmentation status at birth and later to distinguish between oculocutaneous and ocular albinism A complete ophthalmologic evaluation Dilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier state Dermatologic consultation for sun-protective lotion and sun-protective clothing and avoidance of associated cumulative solar damage Consultation with a clinical geneticist and/or genetic counselor Refractive errors should be treated with appropriate spectacle correction as early as possible. Photodysphoria can be relieved by sunglasses, transition lenses, or special filter glasses, although many prefer not to wear them because of the reduction in vision from the dark lenses when indoors. Abnormal head posture with dampening of the nystagmus in a null point may be modified with prismatic spectacle correction. Strabismus surgery is usually not required but may be performed for cosmetic purposes, particularly if the strabismus or the face turn is marked or fixed. The need for vision aids and the educational needs of the visually impaired should be addressed. Dermatologic counseling for age-appropriate sun-protective lotions and clothing should be sought. Appropriate education for sun-protective lotions and clothing (preferably by an informed dermatologic consultant) is indicated to moderate the cumulative lifelong effects of solar radiation. Children younger than age 16 years with ocular albinism should have an annual ophthalmologic examination (including assessment of refractive error and the need for filter glasses) and psychosocial and educational support. In adults, ophthalmologic examinations should be undertaken when needed, typically every two to three years. Although no formal trials exist, standard care avoids use or application of sun-sensitizing drugs or agents. See Search Nystagmus dampening has been achieved by bilateral horizontal rectus recession surgery in some centers, but this is not a generally accepted treatment nor is there evidence from a comparative clinical trial that such intervention improves the final visual outcome. • Medical history and physical examination, including a careful evaluation of pigmentation status at birth and later to distinguish between oculocutaneous and ocular albinism • A complete ophthalmologic evaluation • Dilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier state • Dermatologic consultation for sun-protective lotion and sun-protective clothing and avoidance of associated cumulative solar damage • Consultation with a clinical geneticist and/or genetic counselor ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with X-linked ocular albinism (XLOA), the following evaluations are recommended: Medical history and physical examination, including a careful evaluation of pigmentation status at birth and later to distinguish between oculocutaneous and ocular albinism A complete ophthalmologic evaluation Dilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier state Dermatologic consultation for sun-protective lotion and sun-protective clothing and avoidance of associated cumulative solar damage Consultation with a clinical geneticist and/or genetic counselor • Medical history and physical examination, including a careful evaluation of pigmentation status at birth and later to distinguish between oculocutaneous and ocular albinism • A complete ophthalmologic evaluation • Dilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier state • Dermatologic consultation for sun-protective lotion and sun-protective clothing and avoidance of associated cumulative solar damage • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Refractive errors should be treated with appropriate spectacle correction as early as possible. Photodysphoria can be relieved by sunglasses, transition lenses, or special filter glasses, although many prefer not to wear them because of the reduction in vision from the dark lenses when indoors. Abnormal head posture with dampening of the nystagmus in a null point may be modified with prismatic spectacle correction. Strabismus surgery is usually not required but may be performed for cosmetic purposes, particularly if the strabismus or the face turn is marked or fixed. The need for vision aids and the educational needs of the visually impaired should be addressed. Dermatologic counseling for age-appropriate sun-protective lotions and clothing should be sought. ## Prevention of Secondary Complications Appropriate education for sun-protective lotions and clothing (preferably by an informed dermatologic consultant) is indicated to moderate the cumulative lifelong effects of solar radiation. ## Surveillance Children younger than age 16 years with ocular albinism should have an annual ophthalmologic examination (including assessment of refractive error and the need for filter glasses) and psychosocial and educational support. In adults, ophthalmologic examinations should be undertaken when needed, typically every two to three years. ## Agents/Circumstances to Avoid Although no formal trials exist, standard care avoids use or application of sun-sensitizing drugs or agents. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Other Nystagmus dampening has been achieved by bilateral horizontal rectus recession surgery in some centers, but this is not a generally accepted treatment nor is there evidence from a comparative clinical trial that such intervention improves the final visual outcome. ## Genetic Counseling X-linked ocular albinism is inherited in an X-linked manner. The father of an affected male will not have ocular albinism nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child with the same pathogenic variant and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. If pedigree analysis reveals that the proband is the only affected family member, it is appropriate to examine the retina of the mother for evidence of classic mosaic pigmentation of the retinal pigment epithelium. Alternatively, if the The proband has a The proband's mother has a a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. The risk to sibs depends on the genetic status of the mother. If the If the proband represents a simplex case (i.e., a single occurrence in a family) and the If the pathogenic variant is not known but the mother of a single affected male has normal fundus pigmentation, the risk to the sibs of a proband appears to be low but is likely to be greater than that of the general population because of the possibility of maternal germline mosaicism. All his daughters, who will be heterozygotes and will usually not be affected (see Clinical Description, None of his sons. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have ocular albinism nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child with the same pathogenic variant and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. • If pedigree analysis reveals that the proband is the only affected family member, it is appropriate to examine the retina of the mother for evidence of classic mosaic pigmentation of the retinal pigment epithelium. Alternatively, if the • The proband has a • The proband's mother has a • a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or • b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. • Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. • The proband has a • The proband's mother has a • a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or • b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. • Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. • The proband has a • The proband's mother has a • a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or • b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. • Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. • The risk to sibs depends on the genetic status of the mother. • If the • If the proband represents a simplex case (i.e., a single occurrence in a family) and the • If the pathogenic variant is not known but the mother of a single affected male has normal fundus pigmentation, the risk to the sibs of a proband appears to be low but is likely to be greater than that of the general population because of the possibility of maternal germline mosaicism. • All his daughters, who will be heterozygotes and will usually not be affected (see Clinical Description, • None of his sons. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance X-linked ocular albinism is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have ocular albinism nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child with the same pathogenic variant and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. If pedigree analysis reveals that the proband is the only affected family member, it is appropriate to examine the retina of the mother for evidence of classic mosaic pigmentation of the retinal pigment epithelium. Alternatively, if the The proband has a The proband's mother has a a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. The risk to sibs depends on the genetic status of the mother. If the If the proband represents a simplex case (i.e., a single occurrence in a family) and the If the pathogenic variant is not known but the mother of a single affected male has normal fundus pigmentation, the risk to the sibs of a proband appears to be low but is likely to be greater than that of the general population because of the possibility of maternal germline mosaicism. All his daughters, who will be heterozygotes and will usually not be affected (see Clinical Description, None of his sons. • The father of an affected male will not have ocular albinism nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child with the same pathogenic variant and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. • If pedigree analysis reveals that the proband is the only affected family member, it is appropriate to examine the retina of the mother for evidence of classic mosaic pigmentation of the retinal pigment epithelium. Alternatively, if the • The proband has a • The proband's mother has a • a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or • b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. • Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. • The proband has a • The proband's mother has a • a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or • b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. • Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. • The proband has a • The proband's mother has a • a. A germline pathogenic variant that was present at the time of her conception, is present in every cell of her body, and can be detected in DNA extracted from her leukocytes; or • b. A pathogenic variant that is present only in her ovaries (termed "germline mosaicism") and cannot be detected in DNA extracted from leukocytes. Germline mosaicism has not been reported in XLOA, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. • Note: In both a and b above, all offspring of the proband's mother are at risk of inheriting the pathogenic variant, whereas the sibs of the proband's mother are not. • The risk to sibs depends on the genetic status of the mother. • If the • If the proband represents a simplex case (i.e., a single occurrence in a family) and the • If the pathogenic variant is not known but the mother of a single affected male has normal fundus pigmentation, the risk to the sibs of a proband appears to be low but is likely to be greater than that of the general population because of the possibility of maternal germline mosaicism. • All his daughters, who will be heterozygotes and will usually not be affected (see Clinical Description, • None of his sons. ## Heterozygote (Carrier) Detection Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources PO Box 959 East Hampstead NH 03826-0959 11975 El Camino Real Suite 104 San Diego CA 92130 • • • • • • PO Box 959 • East Hampstead NH 03826-0959 • • • • • 11975 El Camino Real • Suite 104 • San Diego CA 92130 • • • ## Molecular Genetics Ocular Albinism, X-Linked: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ocular Albinism, X-Linked ( When expressed in COS7 cells that lack melanosomes, GPCR-143 displays a considerable and spontaneous capacity to activate heterotrimeric G proteins and the associated signaling cascade. These findings indicate that heterologously expressed GPCR-143 exhibits two fundamental properties of GPCRs: being capable of activating heterotrimeric G proteins and providing proof that GPCR-143 can actually function as a canonic GPCR in mammalian cells [ ## Chapter Notes Richard Alan Lewis, MD, MS (2011-present)Thomas Rosenberg, MD; National Eye Clinic for the Visually Impaired, Hellerup (2003-2011)Marianne Schwartz, PhD; Rigshospitalet, Copenhagen (2003-2011) 10 November 2021 (ma) Chapter retired: outdated; qualified authors not available for update 19 November 2015 (me) Comprehensive update posted live 5 April 2011 (me) Comprehensive update posted live 22 May 2006 (me) Comprehensive update posted live 12 March 2004 (me) Review posted live 30 September 2003 (tr) Original submission • 10 November 2021 (ma) Chapter retired: outdated; qualified authors not available for update • 19 November 2015 (me) Comprehensive update posted live • 5 April 2011 (me) Comprehensive update posted live • 22 May 2006 (me) Comprehensive update posted live • 12 March 2004 (me) Review posted live • 30 September 2003 (tr) Original submission ## Author History Richard Alan Lewis, MD, MS (2011-present)Thomas Rosenberg, MD; National Eye Clinic for the Visually Impaired, Hellerup (2003-2011)Marianne Schwartz, PhD; Rigshospitalet, Copenhagen (2003-2011) ## Revision History 10 November 2021 (ma) Chapter retired: outdated; qualified authors not available for update 19 November 2015 (me) Comprehensive update posted live 5 April 2011 (me) Comprehensive update posted live 22 May 2006 (me) Comprehensive update posted live 12 March 2004 (me) Review posted live 30 September 2003 (tr) Original submission • 10 November 2021 (ma) Chapter retired: outdated; qualified authors not available for update • 19 November 2015 (me) Comprehensive update posted live • 5 April 2011 (me) Comprehensive update posted live • 22 May 2006 (me) Comprehensive update posted live • 12 March 2004 (me) Review posted live • 30 September 2003 (tr) Original submission ## References ## Literature Cited	[ "MT Bassi, AA Bergen, P Bitoun, SJ Charles, M Clementi, R Gosselin, J Hurst, RA Lewis, B Lorenz, T Meitinger, L Messiaen, RS Ramesar, A Ballabio, MV Schiaffino. 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Screening of TYR, OCA2, GPR143, and MC1R in patients with congenital nystagmus, macular hypoplasia, and fundus hypopigmentation indicating albinism.. Mol Vis 2011;17:939-48", "M Preising, JP Op de Laak, B Lorenz. Deletion in the OA1 gene in a family with congenital X linked nystagmus.. Br J Ophthalmol 2001;85:1098-103", "T Rosenberg, M Schwartz. X-linked ocular albinism: prevalence and mutations--a national study.. Eur J Hum Genet 1998;6:570-7", "MV Schiaffino, C Baschirotto, G Pellegrini, S Montalti, C Tacchetti, M De Luca, A Ballabio. The ocular albinism type 1 gene product is a membrane glycoprotein localized to melanosomes.. Proc Natl Acad Sci U S A 1996;93:9055-60", "MV Schiaffino, MT Bassi, L Galli, A Renieri, M Bruttini, F De Nigris, AA Bergen, SJ Charles, JR Yates, A Meindl. Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism.. 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x-pvh	x-pvh	[ "Bilateral Periventricular Nodular Heterotopia (BPNH)", "X-Linked Periventricular Heterotopia", "Isolated X-Linked Cardiac Valvular Dysplasia", "FLNA-Related Periventricular Nodular Heterotopia (FLNA-Related PVNH; Huttenlocher Syndrome)", "FLNA-Related Isolated Gastrointestinal Manifestations", "FLNA-Related Isolated Macrothrombocytopenia", "Filamin-A", "FLNA", "FLNA Deficiency" ]	FLNA Deficiency	Ming Hui Chen, Christopher A Walsh	Summary FLNA deficiency is associated with a phenotypic spectrum that includes The diagnosis of FLNA deficiency is established in a proband by identification of a heterozygous FLNA deficiency is inherited in an X-linked manner. The condition is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. About 50% of affected females inherit the pathogenic variant from their mother and at least 50% have a	Isolated X-linked cardiac valvular dysplasia Isolated gastrointestinal manifestations Isolated macrothrombocytopenia For synonyms and outdated names see For other genetic causes of these phenotypes, see • Isolated X-linked cardiac valvular dysplasia • Isolated gastrointestinal manifestations • Isolated macrothrombocytopenia ## Diagnosis FLNA deficiency Seizure disorder Cardiovascular findings: dilated aortic root or thoracic ascending aorta, valvular heart disease, structural heart disease Pulmonary findings: pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis Gastrointestinal manifestations: feeding difficulties, constipation, progressive weight loss, congenital short bowel, chronic intestinal pseudo-obstruction Joint hypermobility On brain MRI, bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) lining the lateral ventricles beneath an otherwise normal-appearing cortex; occasionally, mild abnormalities of cerebral cortical gyri are present. Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT imaging. Thinning of the corpus callosum and malformations of the posterior fossa (e.g., mild cerebellar hypoplasia, enlarged cisterna magna) in some individuals (See Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in FLNA Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Seizure disorder • Cardiovascular findings: dilated aortic root or thoracic ascending aorta, valvular heart disease, structural heart disease • Pulmonary findings: pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis • Gastrointestinal manifestations: feeding difficulties, constipation, progressive weight loss, congenital short bowel, chronic intestinal pseudo-obstruction • Joint hypermobility • On brain MRI, bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) lining the lateral ventricles beneath an otherwise normal-appearing cortex; occasionally, mild abnormalities of cerebral cortical gyri are present. • Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT imaging. • Thinning of the corpus callosum and malformations of the posterior fossa (e.g., mild cerebellar hypoplasia, enlarged cisterna magna) in some individuals (See • For an introduction to multigene panels click ## Suggestive Findings FLNA deficiency Seizure disorder Cardiovascular findings: dilated aortic root or thoracic ascending aorta, valvular heart disease, structural heart disease Pulmonary findings: pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis Gastrointestinal manifestations: feeding difficulties, constipation, progressive weight loss, congenital short bowel, chronic intestinal pseudo-obstruction Joint hypermobility On brain MRI, bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) lining the lateral ventricles beneath an otherwise normal-appearing cortex; occasionally, mild abnormalities of cerebral cortical gyri are present. Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT imaging. Thinning of the corpus callosum and malformations of the posterior fossa (e.g., mild cerebellar hypoplasia, enlarged cisterna magna) in some individuals (See • Seizure disorder • Cardiovascular findings: dilated aortic root or thoracic ascending aorta, valvular heart disease, structural heart disease • Pulmonary findings: pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis • Gastrointestinal manifestations: feeding difficulties, constipation, progressive weight loss, congenital short bowel, chronic intestinal pseudo-obstruction • Joint hypermobility • On brain MRI, bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) lining the lateral ventricles beneath an otherwise normal-appearing cortex; occasionally, mild abnormalities of cerebral cortical gyri are present. • Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT imaging. • Thinning of the corpus callosum and malformations of the posterior fossa (e.g., mild cerebellar hypoplasia, enlarged cisterna magna) in some individuals (See ## Establishing the Diagnosis Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in FLNA Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Clinical Characteristics FLNA deficiency is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. To date, more than 100 individuals (both males and females) have been identified with loss-of-function variants in FLNA Deficiency: Frequency of Select Features (Males and Females) No correlation exists between the extent and severity of the nodular heterotopia seen radiographically and the clinical manifestations, though early seizure onset correlates with poorer developmental outcome [ Almost 20% of individuals reported by Males with Immune compromise with recurrent infection was reported in two individuals Overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development was reported in one male [ Bilateral inguinal hernia has been reported in affected males [ All individuals with known deleterious loss-of-function The authors suggest the term Huttenlocher syndrome for individuals with FLNA deficiency and multisystem involvement. The prevalence of FLNA deficiency is difficult to assess because individuals with the mild phenotype may never seek medical evaluation. • Immune compromise with recurrent infection was reported in two individuals • Overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development was reported in one male [ • Bilateral inguinal hernia has been reported in affected males [ ## Clinical Description FLNA deficiency is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. To date, more than 100 individuals (both males and females) have been identified with loss-of-function variants in FLNA Deficiency: Frequency of Select Features (Males and Females) No correlation exists between the extent and severity of the nodular heterotopia seen radiographically and the clinical manifestations, though early seizure onset correlates with poorer developmental outcome [ Almost 20% of individuals reported by Males with Immune compromise with recurrent infection was reported in two individuals Overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development was reported in one male [ Bilateral inguinal hernia has been reported in affected males [ • Immune compromise with recurrent infection was reported in two individuals • Overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development was reported in one male [ • Bilateral inguinal hernia has been reported in affected males [ ## Genotype-Phenotype Correlations ## Penetrance All individuals with known deleterious loss-of-function ## Nomenclature The authors suggest the term Huttenlocher syndrome for individuals with FLNA deficiency and multisystem involvement. ## Prevalence The prevalence of FLNA deficiency is difficult to assess because individuals with the mild phenotype may never seek medical evaluation. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Disorders That May Be Associated with Periventricular Nodular Heterotopia (PVNH) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Other Periventricular Nodular Heterotopia (PVNH) Phenotypes chr = chromosome; ID = intellectual disability ## Management No clinical practice guidelines for FLNA deficiency have been published. To establish the extent of disease and needs in an individual diagnosed with FLNA deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with FLNA Deficiency Eval by neurologist Eval by epileptologist if seizures are present Assess for pulmonary symptoms, pulmonary hypertension, & interstitial lung disease. Pulmonary consultation if needed Eval for constipation/motility issues Gastrointestinal consultation as needed To incl motor, adaptive, cognitive, & speech-language eval for dyslexia Eval for early intervention if needed Family history assessment by genetics professional, Consider brain MRI & echocardiogram for the mother. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; MRA = magnetic resonance angiography; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Management of individuals with FLNA deficiency is directed toward symptomatic treatment. Treatment of Manifestations in Individuals with FLNA Deficiency Treatment of structural heart disease & valvular dysplasia per cardiologist Because of risk for aortic or carotid dissection, ensure good blood pressure control. Treat any symptoms that may worsen pulmonary function. Good pulmonary toilet to preserve lung function Sildenafil & medical management for pulmonary hypertension if present Stool softeners, prokinetics, osmotic agents, or laxatives as needed Treat GERD if present. ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy Recommended Surveillance for Individuals with FLNA Deficiency Cardiology eval Echocardiogram Stress testing & cardiac MRI as needed Serial echocardiographic follow up per cardiologist, as severity of valve disease & aortic dilatation can evolve w/time Consider cardiac MRI if difficult acoustic windows, & for periodic visualization of ascending aorta & aortic arch. Monitor for signs/symptoms of bleeding diathesis. CBC w/platelets Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to clarify the genetic status of older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from echocardiogram and MRI/MRA to screen for See Ideally, women should seek information prior to conception regarding risks to the fetus associated with taking an anti-seizure medication during pregnancy so that changes in the anti-seizure medication regimen (if needed) can be made prior to conception. If not done prior to conception, discussion of the risks and benefits of anti-seizure medication use during pregnancy should occur as soon as the pregnancy is recognized. The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus. Women with FLNA deficiency may have an increased incidence of pregnancy loss as a result of spontaneous abortion of affected male pregnancies. Currently no guidelines exist on the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy in women with PVNH. See Search Surgical resection has been attempted but has not proven beneficial [ • Eval by neurologist • Eval by epileptologist if seizures are present • Assess for pulmonary symptoms, pulmonary hypertension, & interstitial lung disease. • Pulmonary consultation if needed • Eval for constipation/motility issues • Gastrointestinal consultation as needed • To incl motor, adaptive, cognitive, & speech-language eval for dyslexia • Eval for early intervention if needed • Family history assessment by genetics professional, • Consider brain MRI & echocardiogram for the mother. • Community or • Social work involvement for parental support; • Home nursing referral. • Treatment of structural heart disease & valvular dysplasia per cardiologist • Because of risk for aortic or carotid dissection, ensure good blood pressure control. • Treat any symptoms that may worsen pulmonary function. • Good pulmonary toilet to preserve lung function • Sildenafil & medical management for pulmonary hypertension if present • Stool softeners, prokinetics, osmotic agents, or laxatives as needed • Treat GERD if present. • Cardiology eval • Echocardiogram • Stress testing & cardiac MRI as needed • Serial echocardiographic follow up per cardiologist, as severity of valve disease & aortic dilatation can evolve w/time • Consider cardiac MRI if difficult acoustic windows, & for periodic visualization of ascending aorta & aortic arch. • Monitor for signs/symptoms of bleeding diathesis. • CBC w/platelets ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with FLNA deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with FLNA Deficiency Eval by neurologist Eval by epileptologist if seizures are present Assess for pulmonary symptoms, pulmonary hypertension, & interstitial lung disease. Pulmonary consultation if needed Eval for constipation/motility issues Gastrointestinal consultation as needed To incl motor, adaptive, cognitive, & speech-language eval for dyslexia Eval for early intervention if needed Family history assessment by genetics professional, Consider brain MRI & echocardiogram for the mother. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; MRA = magnetic resonance angiography; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Eval by neurologist • Eval by epileptologist if seizures are present • Assess for pulmonary symptoms, pulmonary hypertension, & interstitial lung disease. • Pulmonary consultation if needed • Eval for constipation/motility issues • Gastrointestinal consultation as needed • To incl motor, adaptive, cognitive, & speech-language eval for dyslexia • Eval for early intervention if needed • Family history assessment by genetics professional, • Consider brain MRI & echocardiogram for the mother. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Management of individuals with FLNA deficiency is directed toward symptomatic treatment. Treatment of Manifestations in Individuals with FLNA Deficiency Treatment of structural heart disease & valvular dysplasia per cardiologist Because of risk for aortic or carotid dissection, ensure good blood pressure control. Treat any symptoms that may worsen pulmonary function. Good pulmonary toilet to preserve lung function Sildenafil & medical management for pulmonary hypertension if present Stool softeners, prokinetics, osmotic agents, or laxatives as needed Treat GERD if present. ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy • Treatment of structural heart disease & valvular dysplasia per cardiologist • Because of risk for aortic or carotid dissection, ensure good blood pressure control. • Treat any symptoms that may worsen pulmonary function. • Good pulmonary toilet to preserve lung function • Sildenafil & medical management for pulmonary hypertension if present • Stool softeners, prokinetics, osmotic agents, or laxatives as needed • Treat GERD if present. ## Surveillance Recommended Surveillance for Individuals with FLNA Deficiency Cardiology eval Echocardiogram Stress testing & cardiac MRI as needed Serial echocardiographic follow up per cardiologist, as severity of valve disease & aortic dilatation can evolve w/time Consider cardiac MRI if difficult acoustic windows, & for periodic visualization of ascending aorta & aortic arch. Monitor for signs/symptoms of bleeding diathesis. CBC w/platelets • Cardiology eval • Echocardiogram • Stress testing & cardiac MRI as needed • Serial echocardiographic follow up per cardiologist, as severity of valve disease & aortic dilatation can evolve w/time • Consider cardiac MRI if difficult acoustic windows, & for periodic visualization of ascending aorta & aortic arch. • Monitor for signs/symptoms of bleeding diathesis. • CBC w/platelets ## Evaluation of Relatives at Risk Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to clarify the genetic status of older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from echocardiogram and MRI/MRA to screen for See ## Pregnancy Management Ideally, women should seek information prior to conception regarding risks to the fetus associated with taking an anti-seizure medication during pregnancy so that changes in the anti-seizure medication regimen (if needed) can be made prior to conception. If not done prior to conception, discussion of the risks and benefits of anti-seizure medication use during pregnancy should occur as soon as the pregnancy is recognized. The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus. Women with FLNA deficiency may have an increased incidence of pregnancy loss as a result of spontaneous abortion of affected male pregnancies. Currently no guidelines exist on the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy in women with PVNH. See ## Therapies Under Investigation Search ## Other Surgical resection has been attempted but has not proven beneficial [ ## Genetic Counseling FLNA deficiency is inherited in an X-linked manner. About 50% of females with About 50% of females with In a family with more than one affected individual, the parent of an affected child will typically be heterozygous (or hemizygous) for the pathogenic variant. Note: If the proband has an affected sib and no other affected relatives and if the pathogenic variant cannot be detected in either parent’s leukocyte DNA, a parent most likely has somatic/germline mosaicism. If there is only one affected family member (i.e., a simplex case), a parent may be heterozygous (or hemizygous) for the pathogenic variant, the proband may have a Molecular genetic testing of the mother (and possibly, or subsequently, the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. The father of an affected male will not have the disorder nor will he be hemizygous for the Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Female sibs who inherit the Most males who inherit an Theoretically, if the father of the proband is hemizygous for an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Each child of a female proband with Hemizygous males with Note: Molecular genetic testing may be able to identify the family member in whom a A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a Most males with XCVD inherited an To date, all males with Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. If the father of the proband has an If the proband represents a simplex case and the Women with an Males with an Note: Molecular genetic testing may be able to identify the family member in whom a See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have an Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • About 50% of females with • About 50% of females with • In a family with more than one affected individual, the parent of an affected child will typically be heterozygous (or hemizygous) for the pathogenic variant. Note: If the proband has an affected sib and no other affected relatives and if the pathogenic variant cannot be detected in either parent’s leukocyte DNA, a parent most likely has somatic/germline mosaicism. • If there is only one affected family member (i.e., a simplex case), a parent may be heterozygous (or hemizygous) for the pathogenic variant, the proband may have a • Molecular genetic testing of the mother (and possibly, or subsequently, the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. • The father of an affected male will not have the disorder nor will he be hemizygous for the • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has an • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • Each child of a female proband with • Hemizygous males with • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a • Most males with XCVD inherited an • To date, all males with • Most males with XCVD inherited an • To date, all males with • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • Most males with XCVD inherited an • To date, all males with • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • If the father of the proband has an • If the proband represents a simplex case and the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • Women with an • Males with an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have an ## Mode of Inheritance FLNA deficiency is inherited in an X-linked manner. ## Risk to Family Members About 50% of females with About 50% of females with In a family with more than one affected individual, the parent of an affected child will typically be heterozygous (or hemizygous) for the pathogenic variant. Note: If the proband has an affected sib and no other affected relatives and if the pathogenic variant cannot be detected in either parent’s leukocyte DNA, a parent most likely has somatic/germline mosaicism. If there is only one affected family member (i.e., a simplex case), a parent may be heterozygous (or hemizygous) for the pathogenic variant, the proband may have a Molecular genetic testing of the mother (and possibly, or subsequently, the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. The father of an affected male will not have the disorder nor will he be hemizygous for the Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Female sibs who inherit the Most males who inherit an Theoretically, if the father of the proband is hemizygous for an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Each child of a female proband with Hemizygous males with Note: Molecular genetic testing may be able to identify the family member in whom a A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a Most males with XCVD inherited an To date, all males with Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. If the father of the proband has an If the proband represents a simplex case and the Women with an Males with an Note: Molecular genetic testing may be able to identify the family member in whom a • About 50% of females with • About 50% of females with • In a family with more than one affected individual, the parent of an affected child will typically be heterozygous (or hemizygous) for the pathogenic variant. Note: If the proband has an affected sib and no other affected relatives and if the pathogenic variant cannot be detected in either parent’s leukocyte DNA, a parent most likely has somatic/germline mosaicism. • If there is only one affected family member (i.e., a simplex case), a parent may be heterozygous (or hemizygous) for the pathogenic variant, the proband may have a • Molecular genetic testing of the mother (and possibly, or subsequently, the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. • The father of an affected male will not have the disorder nor will he be hemizygous for the • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has an • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • Each child of a female proband with • Hemizygous males with • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a • Most males with XCVD inherited an • To date, all males with • Most males with XCVD inherited an • To date, all males with • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • Most males with XCVD inherited an • To date, all males with • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • If the father of the proband has an • If the proband represents a simplex case and the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • Women with an • Males with an About 50% of females with About 50% of females with In a family with more than one affected individual, the parent of an affected child will typically be heterozygous (or hemizygous) for the pathogenic variant. Note: If the proband has an affected sib and no other affected relatives and if the pathogenic variant cannot be detected in either parent’s leukocyte DNA, a parent most likely has somatic/germline mosaicism. If there is only one affected family member (i.e., a simplex case), a parent may be heterozygous (or hemizygous) for the pathogenic variant, the proband may have a Molecular genetic testing of the mother (and possibly, or subsequently, the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. The father of an affected male will not have the disorder nor will he be hemizygous for the Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Female sibs who inherit the Most males who inherit an Theoretically, if the father of the proband is hemizygous for an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Each child of a female proband with Hemizygous males with Note: Molecular genetic testing may be able to identify the family member in whom a • About 50% of females with • About 50% of females with • In a family with more than one affected individual, the parent of an affected child will typically be heterozygous (or hemizygous) for the pathogenic variant. Note: If the proband has an affected sib and no other affected relatives and if the pathogenic variant cannot be detected in either parent’s leukocyte DNA, a parent most likely has somatic/germline mosaicism. • If there is only one affected family member (i.e., a simplex case), a parent may be heterozygous (or hemizygous) for the pathogenic variant, the proband may have a • Molecular genetic testing of the mother (and possibly, or subsequently, the father) is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. • The father of an affected male will not have the disorder nor will he be hemizygous for the • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has an • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Female sibs who inherit the • Most males who inherit an • Theoretically, if the father of the proband is hemizygous for an • Each child of a female proband with • Hemizygous males with ## XCVD, A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a Most males with XCVD inherited an To date, all males with Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. If the father of the proband has an If the proband represents a simplex case and the Women with an Males with an Note: Molecular genetic testing may be able to identify the family member in whom a • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a • Most males with XCVD inherited an • To date, all males with • Most males with XCVD inherited an • To date, all males with • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • Most males with XCVD inherited an • To date, all males with • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • If the father of the proband has an • If the proband represents a simplex case and the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have manifestations of the disorder. • Women with an • Males with an ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have an ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada • • • • Canada • • • • • ## Molecular Genetics FLNA Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for FLNA Deficiency ( The filamin class of actin-binding proteins is known to regulate cell stability, protrusion, motility, cell-cell communication, and response to stress across various biologic systems [ Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The filamin class of actin-binding proteins is known to regulate cell stability, protrusion, motility, cell-cell communication, and response to stress across various biologic systems [ Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Ming Hui Chen, MD, MMSc is an Associate Professor of Pediatrics at Harvard Medical School in the Departments of Cardiology and Pediatrics, and the Division of Genetics and Genomics at Boston Children's Hospital, Boston, MA. Dr Chen is an expert in cardiovascular and medical manifestations of Dr Chen has worked very closely over the last two decades with Dr Christopher A Walsh, MD, PhD, who is the Chief of Genetics and Genomics at Boston Children's Hospital, and the Bullard Professor of Pediatrics and Neurology at Harvard Medical School. The Walsh lab has worked on genetic disorders affecting the human cerebral cortex for more than twenty years, publishing twenty papers on PVNH, We are grateful to patients with PVNH and other brain disorders, their physicians, and to many colleagues present and past for collaborating with us to understand the genetic basis of these conditions, and for the patient support groups that we have allied with to help understand and develop better therapies. Research on PVNH in the Chen group and the Walsh lab has been supported by grant funding from the NIH and the NINDS (R01 NS 35129). CAW is an Investigator of the Howard Hughes Medical Institute. Adria Bodell, MS, CGC; Beth Israel Deaconess Medical Center (2007-2015)Ming Hui Chen, MD, MMSc (2015-present)Volney L Sheen, MD, PhD; Harvard Medical School (2007-2015)Christopher A Walsh, MD, PhD (2007-present) 30 September 2021 (sw) Comprehensive update posted live 17 September 2015 (me) Comprehensive update posted live 10 April 2007 (me) Comprehensive update posted live 4 August 2004 (me) Comprehensive update posted live 8 October 2002 (me) Review posted live 29 April 2002 (cw) Original submission • 30 September 2021 (sw) Comprehensive update posted live • 17 September 2015 (me) Comprehensive update posted live • 10 April 2007 (me) Comprehensive update posted live • 4 August 2004 (me) Comprehensive update posted live • 8 October 2002 (me) Review posted live • 29 April 2002 (cw) Original submission ## Author Notes Ming Hui Chen, MD, MMSc is an Associate Professor of Pediatrics at Harvard Medical School in the Departments of Cardiology and Pediatrics, and the Division of Genetics and Genomics at Boston Children's Hospital, Boston, MA. Dr Chen is an expert in cardiovascular and medical manifestations of Dr Chen has worked very closely over the last two decades with Dr Christopher A Walsh, MD, PhD, who is the Chief of Genetics and Genomics at Boston Children's Hospital, and the Bullard Professor of Pediatrics and Neurology at Harvard Medical School. The Walsh lab has worked on genetic disorders affecting the human cerebral cortex for more than twenty years, publishing twenty papers on PVNH, ## Acknowledgments We are grateful to patients with PVNH and other brain disorders, their physicians, and to many colleagues present and past for collaborating with us to understand the genetic basis of these conditions, and for the patient support groups that we have allied with to help understand and develop better therapies. Research on PVNH in the Chen group and the Walsh lab has been supported by grant funding from the NIH and the NINDS (R01 NS 35129). CAW is an Investigator of the Howard Hughes Medical Institute. ## Author History Adria Bodell, MS, CGC; Beth Israel Deaconess Medical Center (2007-2015)Ming Hui Chen, MD, MMSc (2015-present)Volney L Sheen, MD, PhD; Harvard Medical School (2007-2015)Christopher A Walsh, MD, PhD (2007-present) ## Revision History 30 September 2021 (sw) Comprehensive update posted live 17 September 2015 (me) Comprehensive update posted live 10 April 2007 (me) Comprehensive update posted live 4 August 2004 (me) Comprehensive update posted live 8 October 2002 (me) Review posted live 29 April 2002 (cw) Original submission • 30 September 2021 (sw) Comprehensive update posted live • 17 September 2015 (me) Comprehensive update posted live • 10 April 2007 (me) Comprehensive update posted live • 4 August 2004 (me) Comprehensive update posted live • 8 October 2002 (me) Review posted live • 29 April 2002 (cw) Original submission ## References ## Literature Cited Anatomic phenotype of PVNH in an individual with a heterozygous pathogenic variant in A. MRI of the head demonstrating characteristic periventricular nodular heterotopia B. MRI of the head demonstrating thin corpus callosum and hypoplastic cerebellum	[]	8/10/2002	30/9/2021	4/6/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
x-scid	x-scid	[ "SCID-X1", "X-Linked SCID (X-SCID)", "SCID-X1", "X-Linked SCID (X-SCID)", "Typical X-SCID", "Atypical X-SCID", "Cytokine receptor common subunit gamma", "IL2RG", "X-Linked Severe Combined Immunodeficiency" ]	X-Linked Severe Combined Immunodeficiency	Eric J Allenspach, David J Rawlings, Aleksandra Petrovic, Karin Chen	Summary The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity). The diagnosis of typical and atypical X-SCID X-SCID is inherited in an X-linked manner. The chance that a female who is heterozygous (i.e., a carrier) for the familial	Typical X-SCID Atypical X-SCID For synonyms and outdated names see For other genetic causes of severe combined immunodeficiency, see • Typical X-SCID • Atypical X-SCID ## Diagnosis The Primary Immune Deficiency Treatment Consortium (PIDTC) has established laboratory-based definitions for SCID [ There are two scenarios in which X-SCID may be considered: an abnormal SCID newborn screening and a symptomatic male with suggestive findings. Both scenarios warrant immediate subspecialty immunologic evaluation and steps taken to ensure the safety of the baby or older child pending the establishment of the diagnosis and treatment. As of December 10, 2018, all newborns in the US, including all 50 states, the District of Columbia, and the Navajo Nation, are screened for a group of conditions characterized by severe combined immunodeficiency (SCID), (adapted from the PIDTC criteria [ SCID newborn screening uses a blood spot to measure T-cell receptor excision circles (TRECs) to detect T-cell lymphopenia [ Newborns with an abnormal NBS Note: This chapter specifically focuses on X-linked severe combined immunodeficiency (X-SCID), one genetic cause of SCID. For other genetic causes of an abnormal NBS possibly indicating SCID, see Breast-feeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T Naïve CD45RA Absence of antibody responses to vaccines and infectious agents Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies X-Linked Severe Combined Immunodeficiency (X-SCID): Lymphocyte Subset Counts in Infants Adapted from B cells that are present are generally dysfunctional Two individuals with low B cells (44 and 50 cells/μL) were considered to have X-SCID based on family history [ Age <2 years: 300 to 1000/µL Age 2-4 years: <800/μL Age >4 years <600/μL Note: T- and NK-cell counts may even be nearly normal depending on the functionality of the See The diagnosis of X-SCID Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Severe Combined Immunodeficiency (X-SCID) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, five large deletions in • Breast-feeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL • Note: T- and NK-cell counts may even be nearly normal depending on the functionality of the • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL ## Suggestive Findings There are two scenarios in which X-SCID may be considered: an abnormal SCID newborn screening and a symptomatic male with suggestive findings. Both scenarios warrant immediate subspecialty immunologic evaluation and steps taken to ensure the safety of the baby or older child pending the establishment of the diagnosis and treatment. As of December 10, 2018, all newborns in the US, including all 50 states, the District of Columbia, and the Navajo Nation, are screened for a group of conditions characterized by severe combined immunodeficiency (SCID), (adapted from the PIDTC criteria [ SCID newborn screening uses a blood spot to measure T-cell receptor excision circles (TRECs) to detect T-cell lymphopenia [ Newborns with an abnormal NBS Note: This chapter specifically focuses on X-linked severe combined immunodeficiency (X-SCID), one genetic cause of SCID. For other genetic causes of an abnormal NBS possibly indicating SCID, see Breast-feeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T Naïve CD45RA Absence of antibody responses to vaccines and infectious agents Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies X-Linked Severe Combined Immunodeficiency (X-SCID): Lymphocyte Subset Counts in Infants Adapted from B cells that are present are generally dysfunctional Two individuals with low B cells (44 and 50 cells/μL) were considered to have X-SCID based on family history [ Age <2 years: 300 to 1000/µL Age 2-4 years: <800/μL Age >4 years <600/μL Note: T- and NK-cell counts may even be nearly normal depending on the functionality of the See • Breast-feeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL • Note: T- and NK-cell counts may even be nearly normal depending on the functionality of the • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL ## Scenario 1: Abnormal SCID Newborn Screening (NBS) – Typical X-SCID As of December 10, 2018, all newborns in the US, including all 50 states, the District of Columbia, and the Navajo Nation, are screened for a group of conditions characterized by severe combined immunodeficiency (SCID), (adapted from the PIDTC criteria [ SCID newborn screening uses a blood spot to measure T-cell receptor excision circles (TRECs) to detect T-cell lymphopenia [ Newborns with an abnormal NBS Note: This chapter specifically focuses on X-linked severe combined immunodeficiency (X-SCID), one genetic cause of SCID. For other genetic causes of an abnormal NBS possibly indicating SCID, see Breast-feeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T Naïve CD45RA Absence of antibody responses to vaccines and infectious agents Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies X-Linked Severe Combined Immunodeficiency (X-SCID): Lymphocyte Subset Counts in Infants Adapted from B cells that are present are generally dysfunctional Two individuals with low B cells (44 and 50 cells/μL) were considered to have X-SCID based on family history [ • Breast-feeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies • Low numbers of T and NK lymphocyte subsets compared to age-matched normal controls (designated T • Naïve CD45RA • Absence of antibody responses to vaccines and infectious agents • Absence of T-cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen PHA having excluded maternal engraftment) and/or anti-CD3 antibodies ## Scenario 2: Symptomatic Males with Findings Suggestive of X-SCID Age <2 years: 300 to 1000/µL Age 2-4 years: <800/μL Age >4 years <600/μL Note: T- and NK-cell counts may even be nearly normal depending on the functionality of the See • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL • Note: T- and NK-cell counts may even be nearly normal depending on the functionality of the • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL • Age <2 years: 300 to 1000/µL • Age 2-4 years: <800/μL • Age >4 years <600/μL ## Establishing the Diagnosis The diagnosis of X-SCID Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Severe Combined Immunodeficiency (X-SCID) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, five large deletions in ## Clinical Characteristics X-linked severe combined immunodeficiency (X-SCID) comprises a phenotypic spectrum ranging from typical X-SCID (early-onset disease that is fatal if not treated with HSCT) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity). Affected males appear normal at birth. However, as the concentrations of transplacentally transferred maternal serum antibodies decline, infants with X-SCID are increasingly prone to infection. Prior to universal newborn screening for SCID, most infants with X-SCID came to medical attention between ages three and six months; presentation with life-threatening infection prior to age three months also occurred. With universal newborn screening for SCID, the common presentation has become an asymptomatic, healthy-appearing infant. Delayed diagnosis of X-SCID can lead to complications such as failure to thrive, oral/diaper candidiasis, recurrent infections, persistent infections, and infections with opportunistic organisms such as Infections that initially appear ordinary such as oral thrush, otitis media, respiratory viral infections (e.g., RSV, parainfluenza, adenovirus, influenza), and gastrointestinal diseases resulting in diarrhea may cause concern only when they persist or do not respond to usual medical management. Less common features can include the following: Disseminated infections (salmonella, varicella, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, Calmette-Guérin bacillus, and vaccine strain [live] polio virus) Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition that causes graft-vs-host disease (GVHD) characterized by erythematous skin rashes, hepatomegaly, and lymphadenopathy [ Recurrent bacterial meningitis In rare instances, neurologic features such as opisthotonus, infantile spasms, and hypsarrhythmia Clinical phenotypes can include the following: Recurrent upper and lower respiratory tract infections with bronchiectasis Omenn syndrome, a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE and/or increased eosinophils. The immunophenotype is CD3+ T cells >300 cells/μL in the absence of maternal engraftment. X-SCID combined immunodeficiency, including rare instances of somatic reversion (in which an inherited Immune dysregulation and autoimmunity associated with arthritis, rashes, gastrointestinal malabsorption, and/or short stature Epstein-Barr virus-related lymphoproliferative complications including lymphoma or severe verrucous lesions Of note, within a family, affected males have been reported with different atypical X-SCID clinical phenotypes. For example, One exception is the Newborn screening in 11 programs in the United States identified the incidence of SCID of all genetic causes to be 1:58,000 infants (95% CI 1/46,000-1/80,000) over an approximately 5.5-year observation period [ • Disseminated infections (salmonella, varicella, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, Calmette-Guérin bacillus, and vaccine strain [live] polio virus) • Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition that causes graft-vs-host disease (GVHD) characterized by erythematous skin rashes, hepatomegaly, and lymphadenopathy [ • Recurrent bacterial meningitis • In rare instances, neurologic features such as opisthotonus, infantile spasms, and hypsarrhythmia • Recurrent upper and lower respiratory tract infections with bronchiectasis • Omenn syndrome, a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE and/or increased eosinophils. The immunophenotype is CD3+ T cells >300 cells/μL in the absence of maternal engraftment. • X-SCID combined immunodeficiency, including rare instances of somatic reversion (in which an inherited • Immune dysregulation and autoimmunity associated with arthritis, rashes, gastrointestinal malabsorption, and/or short stature • Epstein-Barr virus-related lymphoproliferative complications including lymphoma or severe verrucous lesions ## Clinical Description X-linked severe combined immunodeficiency (X-SCID) comprises a phenotypic spectrum ranging from typical X-SCID (early-onset disease that is fatal if not treated with HSCT) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity). Affected males appear normal at birth. However, as the concentrations of transplacentally transferred maternal serum antibodies decline, infants with X-SCID are increasingly prone to infection. Prior to universal newborn screening for SCID, most infants with X-SCID came to medical attention between ages three and six months; presentation with life-threatening infection prior to age three months also occurred. With universal newborn screening for SCID, the common presentation has become an asymptomatic, healthy-appearing infant. Delayed diagnosis of X-SCID can lead to complications such as failure to thrive, oral/diaper candidiasis, recurrent infections, persistent infections, and infections with opportunistic organisms such as Infections that initially appear ordinary such as oral thrush, otitis media, respiratory viral infections (e.g., RSV, parainfluenza, adenovirus, influenza), and gastrointestinal diseases resulting in diarrhea may cause concern only when they persist or do not respond to usual medical management. Less common features can include the following: Disseminated infections (salmonella, varicella, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, Calmette-Guérin bacillus, and vaccine strain [live] polio virus) Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition that causes graft-vs-host disease (GVHD) characterized by erythematous skin rashes, hepatomegaly, and lymphadenopathy [ Recurrent bacterial meningitis In rare instances, neurologic features such as opisthotonus, infantile spasms, and hypsarrhythmia Clinical phenotypes can include the following: Recurrent upper and lower respiratory tract infections with bronchiectasis Omenn syndrome, a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE and/or increased eosinophils. The immunophenotype is CD3+ T cells >300 cells/μL in the absence of maternal engraftment. X-SCID combined immunodeficiency, including rare instances of somatic reversion (in which an inherited Immune dysregulation and autoimmunity associated with arthritis, rashes, gastrointestinal malabsorption, and/or short stature Epstein-Barr virus-related lymphoproliferative complications including lymphoma or severe verrucous lesions Of note, within a family, affected males have been reported with different atypical X-SCID clinical phenotypes. For example, • Disseminated infections (salmonella, varicella, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, Calmette-Guérin bacillus, and vaccine strain [live] polio virus) • Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition that causes graft-vs-host disease (GVHD) characterized by erythematous skin rashes, hepatomegaly, and lymphadenopathy [ • Recurrent bacterial meningitis • In rare instances, neurologic features such as opisthotonus, infantile spasms, and hypsarrhythmia • Recurrent upper and lower respiratory tract infections with bronchiectasis • Omenn syndrome, a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE and/or increased eosinophils. The immunophenotype is CD3+ T cells >300 cells/μL in the absence of maternal engraftment. • X-SCID combined immunodeficiency, including rare instances of somatic reversion (in which an inherited • Immune dysregulation and autoimmunity associated with arthritis, rashes, gastrointestinal malabsorption, and/or short stature • Epstein-Barr virus-related lymphoproliferative complications including lymphoma or severe verrucous lesions ## Typical X-SCID Clinical Phenotype Affected males appear normal at birth. However, as the concentrations of transplacentally transferred maternal serum antibodies decline, infants with X-SCID are increasingly prone to infection. Prior to universal newborn screening for SCID, most infants with X-SCID came to medical attention between ages three and six months; presentation with life-threatening infection prior to age three months also occurred. With universal newborn screening for SCID, the common presentation has become an asymptomatic, healthy-appearing infant. Delayed diagnosis of X-SCID can lead to complications such as failure to thrive, oral/diaper candidiasis, recurrent infections, persistent infections, and infections with opportunistic organisms such as Infections that initially appear ordinary such as oral thrush, otitis media, respiratory viral infections (e.g., RSV, parainfluenza, adenovirus, influenza), and gastrointestinal diseases resulting in diarrhea may cause concern only when they persist or do not respond to usual medical management. Less common features can include the following: Disseminated infections (salmonella, varicella, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, Calmette-Guérin bacillus, and vaccine strain [live] polio virus) Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition that causes graft-vs-host disease (GVHD) characterized by erythematous skin rashes, hepatomegaly, and lymphadenopathy [ Recurrent bacterial meningitis In rare instances, neurologic features such as opisthotonus, infantile spasms, and hypsarrhythmia • Disseminated infections (salmonella, varicella, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, Calmette-Guérin bacillus, and vaccine strain [live] polio virus) • Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition that causes graft-vs-host disease (GVHD) characterized by erythematous skin rashes, hepatomegaly, and lymphadenopathy [ • Recurrent bacterial meningitis • In rare instances, neurologic features such as opisthotonus, infantile spasms, and hypsarrhythmia ## Atypical X-SCID Clinical Phenotypes Clinical phenotypes can include the following: Recurrent upper and lower respiratory tract infections with bronchiectasis Omenn syndrome, a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE and/or increased eosinophils. The immunophenotype is CD3+ T cells >300 cells/μL in the absence of maternal engraftment. X-SCID combined immunodeficiency, including rare instances of somatic reversion (in which an inherited Immune dysregulation and autoimmunity associated with arthritis, rashes, gastrointestinal malabsorption, and/or short stature Epstein-Barr virus-related lymphoproliferative complications including lymphoma or severe verrucous lesions Of note, within a family, affected males have been reported with different atypical X-SCID clinical phenotypes. For example, • Recurrent upper and lower respiratory tract infections with bronchiectasis • Omenn syndrome, a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE and/or increased eosinophils. The immunophenotype is CD3+ T cells >300 cells/μL in the absence of maternal engraftment. • X-SCID combined immunodeficiency, including rare instances of somatic reversion (in which an inherited • Immune dysregulation and autoimmunity associated with arthritis, rashes, gastrointestinal malabsorption, and/or short stature • Epstein-Barr virus-related lymphoproliferative complications including lymphoma or severe verrucous lesions ## Nomenclature ## Genotype-Phenotype Correlations One exception is the ## Prevalence Newborn screening in 11 programs in the United States identified the incidence of SCID of all genetic causes to be 1:58,000 infants (95% CI 1/46,000-1/80,000) over an approximately 5.5-year observation period [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Since the implementation of newborn screening the incidence of each genetic type of typical severe combined immunodeficiency (SCID) has become clearer. X-SCID has remained one of the most common forms of typical SCID [ Typical Severe Combined Immunodeficiency (SCID): Genetic Causes Molecular causes of SCID based on the International Union of Immunological Societies expert committee for primary immunodeficiency = lymphocyte subclass is present; – = lymphocyte subclass is absent; ADA = adenosine deaminase; AR = autosomal recessive; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked For immunophenotype information, see Omenn syndrome is a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE, and/or increased eosinophils. The immunophenotype is CD3+ T cells >300 cells/μL in the absence of maternal engraftment. Delayed-onset ADA deficiency will be missed by NBS. Increasingly detected w/ newborn screening [ Note: A growing list of rare causes of SCID-like phenotypes include pathogenic variants in the following additional genes: ## Management Management is discussed in three subsections: issues relating to Clinical practices and protocols for typical X-linked severe combined immunodeficiency (X-SCID) can vary depending on the center; however, many aspects overlap in an effort to minimize infection and maximize pre-hematopoietic stem cell transplantation (HSCT) management in infants with abnormal newborn screening results. The following outlines management based on the Primary Immune Deficiency Treatment Consortium (PIDTC) analysis [ The following evaluations are indicated: Screen for respiratory viral PCR, urine CMV by PCR and blood viral PCR in all individuals meeting X-SCID criteria. Consider additional testing if symptomatic. Maternal engraftment studies with multiple samples including (1) a buccal swab or brush from the child; (2) a peripheral blood sample from the biological mother; and (3) a peripheral blood sample collected from the child. Cells isolated from the blood sample will be genotyped for comparison to the child’s and biological mother’s baseline genotypes. Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of X-SCID in order to facilitate medical and personal decision making For evaluation of a male with a positive newborn screen for SCID to establish the genetic diagnosis and initiate the search for an HSCT donor, see Suggestive Findings, The current goals of treatment include ensuring the safety of the infant/child, prophylaxis for infections, and preemptive hematopoietic stem cell transplantation (HSCT) prior to the development of symptoms. The general experience is that HLA-matched HSCT restores T-cell immunity in more than 90% of unconditioned individuals or individuals with SCID, although B-cell reconstitution occurs preferentially in a subset of these individuals who have NK Although many centers have expertise in performing HSCT in individuals with malignancy, the following special issues arising in HSCT for X-SCID require involvement of immunodeficiency specialists for an optimal outcome. Individuals with X-SCID (who have no immune system or at best an immune system minimally capable of rejecting the graft) do not typically require myeloablative-conditioning regimens. Rather, "reduced-intensity conditioning (RIC)" regimens are preferred as they employ agents at doses that do not result in long-lasting marrow aplasia. HLA-matched HSCT from a relative is preferred; however, 70% of affected individuals lack a matched related donor [ In the 100 transplants performed for individuals with SCID (including 33 with X-SCID) from 2010 to 2014, no statistically significant difference was observed between donor types; therefore, unrelated donors and umbilical cord grafts present viable options [ For infants who do not have a matched related donor, haploidentical parental bone marrow or mobilized peripheral blood that has been depleted of T cells can be used [ In both retrospective and prospective SCID cohorts since 2000, fewer than 30% of individuals received myeloablative-conditioning regimen, with 35%-65% of individuals receiving no conditioning or only immunosuppression (serotherapy). Note that conditioning regimens are typically used when grafts from unrelated donors are used [ The best timing for HSCT is shortly after birth, as young infants are less likely than older infants to have had serious infections or failure to thrive. In 25 centers, the prospective analysis performed by the PIDTC [ Over the last decade significantly better outcomes (>90% survival) in children without prior infections who received transplantation in early infancy (age <3.5 months) even with use of alternative donor grafts (i.e., donor not a matched sib, but rather a haploidentical individual, mismatched individual, or cord blood). Presence of active infections was the main factor affecting overall survival, with nine of 11 deaths occurring in children who had infections prior to transplantation. Younger infants in whom no conditioning is used also have more rapid engraftment, fewer post-transplantation infections, less GVHD with TCD grafts, and shorter hospitalizations. In contrast, in very young infants who require conditioning, there is a fine balance between risk of acquiring infection versus short- and long-term toxicities associated with use of conditioning. While it is expected that universal newborn screening will lead to a decrease of pre-transplantation infections and even better survival rates, optimal timing of transplantation and intensity of conditioning regimens (when required) still need to be defined in the era of universal newborn screening for SCID. Complications following HSCT can include GVHD, graft failure, failure to produce adequate antibodies requiring long-term immunoglobulin replacement therapy, inadequate and declining T cells associated with late graft failure (presumably due to declining numbers of engrafted hematopoietic stem cells), chronic warts, lymphocyte dysregulation leading to post-transplant autoimmunity, and (rarely) secondary malignancy. Post-transplantation all individuals have some degree of immunodeficiency, especially in the first six to 12 months, during which time the following are necessary: Prophylaxis for Consideration of IVIG prophylaxis to maintain serum IgG levels above 600 mg/dL Prompt evaluation of illnesses until immunocompetence is achieved Individuals with primary immunodeficiency post-transplantation need to meet criteria for immunocompetence (adequate CD4 and CD19 counts, PHA lymphocyte proliferation, and freedom from immunoglobulin supplementation) before starting vaccinations. Gene therapy performed with no conditioning regimen using autologous bone marrow stem/progenitor cells transduced with gamma-retroviral vectors expressing a therapeutic gene resulted in significant T-cell reconstitution in the majority of young infants with X-SCID. B-cell reconstitution was less consistent; only about 50% of infants were able to discontinue gamma-globulin replacement therapy. Unfortunately, two to 14 years after treatment in two independent trials using gamma-retroviral vectors, six of 20 individuals developed T-cell acute lymphoblastic leukemia, which was fatal in one. Data revealed that retroviral insertional activation of cellular-growth regulatory genes led to the malignant transformation [ A subsequent clinical trial that utilized gamma-retroviral vectors with improved safety design (utilizing self-inactivating [SIN] vectors) demonstrated safety and partial efficacy in nine individuals over three years post transplantation: efficacy in T-cell reconstitution, no adverse events, and significantly fewer insertions in genes implicated in lymphoproliferation [ Due to the risk for insertional mutagenesis inherent with use of gamma-retroviral vectors, investigators developed next-generation lentiviral vectors that can transverse the nuclear membrane and transduce both mitotic and non-mitotic hematopoietic stem cells [ After successful HSCT, routine evaluation of affected males every six to 12 months is indicated to monitor lineage specific donor cell engraftment, growth, immune and lung function, and gastrointestinal and dermatologic issues. If conditioning chemotherapy was used, long-term monitoring of vital organ function and neurodevelopmental progress is also warranted. Because the clinical phenotypes of atypical X-SCID vary widely, the diagnosis of X-SCID is often delayed until later in childhood or even young adulthood. Treatment depends on the degree of infectious complications and the presence of immune dysregulation and/or autoimmunity, and requires subspecialty immunologic care to assist in the diagnosis and choice of antimicrobial and immune-suppressive therapies. The following evaluations are indicated: Medical history including growth and development and localized and generalized infectious processes (e.g., diarrhea, failure to thrive, pneumonia, sepsis, viral and fungal infections) Referral to an immunology specialty center to determine immediate and long-term management and surveillance. Immunophenotyping can be performed in consultation with an immunologist. Determine the immunophenotype (see Treatment of atypical X-SCID varies depending on the degree of immune deficiency and should be evaluated on an individual basis. To ensure the safety of the infant/older individual pending definitive treatment to achieve immunocompetence, parents and other care providers need to avoid the following: Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure When the pathogenic variant causing X-SCID in the family is known, prenatal testing of at-risk male fetuses may be performed to help prepare for optimal management of an affected infant at birth (i.e., identification of a center with expertise in SCID treatment protocols that can help initiate the search for a bone marrow donor and explain ways to ensure the safety of the infant while awaiting HSCT) (see If prenatal testing has not been performed, an at-risk newborn male should immediately be placed in an appropriate environment (see See The following investigations are under way: Second-generation gene replacement strategies based on self-inactivating (SIN) gamma-retroviral (RV) and lentiviral (LV) vectors lacking the LTR enhancers with high insertional genotoxicity have been assessed in Phase I/II clinical trials (see St Jude Children's Research Hospital, Seattle Children's Hospital, and University of California San Francisco (UCSF) are enrolling infants with X-SCID and the NIH is enrolling older males who had prior transplantation in SIN LV (self-inactivating lentivirus) clinical trials using low dose busulfan conditioning. The initial results of both Phase I/II trials were reported [ PIDTC "CSIDE" (Conditioning SCID Infants Diagnoised Early), a randomized trial of low vs moderate exposure to busulfan for infants with SCID receiving TCRαβ/CD19 Pre-clinical efficacy showed that gene correction in human long-term hematopoietic stem cells (LT-HSCs) is feasible for X-SCID using a CRISPR-Cas9/AAV6-based strategy [ Search • Screen for respiratory viral PCR, urine CMV by PCR and blood viral PCR in all individuals meeting X-SCID criteria. Consider additional testing if symptomatic. • Maternal engraftment studies with multiple samples including (1) a buccal swab or brush from the child; (2) a peripheral blood sample from the biological mother; and (3) a peripheral blood sample collected from the child. Cells isolated from the blood sample will be genotyped for comparison to the child’s and biological mother’s baseline genotypes. • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of X-SCID in order to facilitate medical and personal decision making • HLA-matched HSCT from a relative is preferred; however, 70% of affected individuals lack a matched related donor [ • In the 100 transplants performed for individuals with SCID (including 33 with X-SCID) from 2010 to 2014, no statistically significant difference was observed between donor types; therefore, unrelated donors and umbilical cord grafts present viable options [ • For infants who do not have a matched related donor, haploidentical parental bone marrow or mobilized peripheral blood that has been depleted of T cells can be used [ • In both retrospective and prospective SCID cohorts since 2000, fewer than 30% of individuals received myeloablative-conditioning regimen, with 35%-65% of individuals receiving no conditioning or only immunosuppression (serotherapy). Note that conditioning regimens are typically used when grafts from unrelated donors are used [ • Over the last decade significantly better outcomes (>90% survival) in children without prior infections who received transplantation in early infancy (age <3.5 months) even with use of alternative donor grafts (i.e., donor not a matched sib, but rather a haploidentical individual, mismatched individual, or cord blood). • Presence of active infections was the main factor affecting overall survival, with nine of 11 deaths occurring in children who had infections prior to transplantation. • Younger infants in whom no conditioning is used also have more rapid engraftment, fewer post-transplantation infections, less GVHD with TCD grafts, and shorter hospitalizations. In contrast, in very young infants who require conditioning, there is a fine balance between risk of acquiring infection versus short- and long-term toxicities associated with use of conditioning. • Prophylaxis for • Consideration of IVIG prophylaxis to maintain serum IgG levels above 600 mg/dL • Prompt evaluation of illnesses until immunocompetence is achieved • Medical history including growth and development and localized and generalized infectious processes (e.g., diarrhea, failure to thrive, pneumonia, sepsis, viral and fungal infections) • Referral to an immunology specialty center to determine immediate and long-term management and surveillance. Immunophenotyping can be performed in consultation with an immunologist. • Determine the immunophenotype (see • Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure • Second-generation gene replacement strategies based on self-inactivating (SIN) gamma-retroviral (RV) and lentiviral (LV) vectors lacking the LTR enhancers with high insertional genotoxicity have been assessed in Phase I/II clinical trials (see • St Jude Children's Research Hospital, Seattle Children's Hospital, and University of California San Francisco (UCSF) are enrolling infants with X-SCID and the NIH is enrolling older males who had prior transplantation in SIN LV (self-inactivating lentivirus) clinical trials using low dose busulfan conditioning. The initial results of both Phase I/II trials were reported [ • PIDTC "CSIDE" (Conditioning SCID Infants Diagnoised Early), a randomized trial of low vs moderate exposure to busulfan for infants with SCID receiving TCRαβ/CD19 • Pre-clinical efficacy showed that gene correction in human long-term hematopoietic stem cells (LT-HSCs) is feasible for X-SCID using a CRISPR-Cas9/AAV6-based strategy [ ## Typical X-SCID Clinical Phenotype Clinical practices and protocols for typical X-linked severe combined immunodeficiency (X-SCID) can vary depending on the center; however, many aspects overlap in an effort to minimize infection and maximize pre-hematopoietic stem cell transplantation (HSCT) management in infants with abnormal newborn screening results. The following outlines management based on the Primary Immune Deficiency Treatment Consortium (PIDTC) analysis [ The following evaluations are indicated: Screen for respiratory viral PCR, urine CMV by PCR and blood viral PCR in all individuals meeting X-SCID criteria. Consider additional testing if symptomatic. Maternal engraftment studies with multiple samples including (1) a buccal swab or brush from the child; (2) a peripheral blood sample from the biological mother; and (3) a peripheral blood sample collected from the child. Cells isolated from the blood sample will be genotyped for comparison to the child’s and biological mother’s baseline genotypes. Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of X-SCID in order to facilitate medical and personal decision making For evaluation of a male with a positive newborn screen for SCID to establish the genetic diagnosis and initiate the search for an HSCT donor, see Suggestive Findings, The current goals of treatment include ensuring the safety of the infant/child, prophylaxis for infections, and preemptive hematopoietic stem cell transplantation (HSCT) prior to the development of symptoms. The general experience is that HLA-matched HSCT restores T-cell immunity in more than 90% of unconditioned individuals or individuals with SCID, although B-cell reconstitution occurs preferentially in a subset of these individuals who have NK Although many centers have expertise in performing HSCT in individuals with malignancy, the following special issues arising in HSCT for X-SCID require involvement of immunodeficiency specialists for an optimal outcome. Individuals with X-SCID (who have no immune system or at best an immune system minimally capable of rejecting the graft) do not typically require myeloablative-conditioning regimens. Rather, "reduced-intensity conditioning (RIC)" regimens are preferred as they employ agents at doses that do not result in long-lasting marrow aplasia. HLA-matched HSCT from a relative is preferred; however, 70% of affected individuals lack a matched related donor [ In the 100 transplants performed for individuals with SCID (including 33 with X-SCID) from 2010 to 2014, no statistically significant difference was observed between donor types; therefore, unrelated donors and umbilical cord grafts present viable options [ For infants who do not have a matched related donor, haploidentical parental bone marrow or mobilized peripheral blood that has been depleted of T cells can be used [ In both retrospective and prospective SCID cohorts since 2000, fewer than 30% of individuals received myeloablative-conditioning regimen, with 35%-65% of individuals receiving no conditioning or only immunosuppression (serotherapy). Note that conditioning regimens are typically used when grafts from unrelated donors are used [ The best timing for HSCT is shortly after birth, as young infants are less likely than older infants to have had serious infections or failure to thrive. In 25 centers, the prospective analysis performed by the PIDTC [ Over the last decade significantly better outcomes (>90% survival) in children without prior infections who received transplantation in early infancy (age <3.5 months) even with use of alternative donor grafts (i.e., donor not a matched sib, but rather a haploidentical individual, mismatched individual, or cord blood). Presence of active infections was the main factor affecting overall survival, with nine of 11 deaths occurring in children who had infections prior to transplantation. Younger infants in whom no conditioning is used also have more rapid engraftment, fewer post-transplantation infections, less GVHD with TCD grafts, and shorter hospitalizations. In contrast, in very young infants who require conditioning, there is a fine balance between risk of acquiring infection versus short- and long-term toxicities associated with use of conditioning. While it is expected that universal newborn screening will lead to a decrease of pre-transplantation infections and even better survival rates, optimal timing of transplantation and intensity of conditioning regimens (when required) still need to be defined in the era of universal newborn screening for SCID. Complications following HSCT can include GVHD, graft failure, failure to produce adequate antibodies requiring long-term immunoglobulin replacement therapy, inadequate and declining T cells associated with late graft failure (presumably due to declining numbers of engrafted hematopoietic stem cells), chronic warts, lymphocyte dysregulation leading to post-transplant autoimmunity, and (rarely) secondary malignancy. Post-transplantation all individuals have some degree of immunodeficiency, especially in the first six to 12 months, during which time the following are necessary: Prophylaxis for Consideration of IVIG prophylaxis to maintain serum IgG levels above 600 mg/dL Prompt evaluation of illnesses until immunocompetence is achieved Individuals with primary immunodeficiency post-transplantation need to meet criteria for immunocompetence (adequate CD4 and CD19 counts, PHA lymphocyte proliferation, and freedom from immunoglobulin supplementation) before starting vaccinations. Gene therapy performed with no conditioning regimen using autologous bone marrow stem/progenitor cells transduced with gamma-retroviral vectors expressing a therapeutic gene resulted in significant T-cell reconstitution in the majority of young infants with X-SCID. B-cell reconstitution was less consistent; only about 50% of infants were able to discontinue gamma-globulin replacement therapy. Unfortunately, two to 14 years after treatment in two independent trials using gamma-retroviral vectors, six of 20 individuals developed T-cell acute lymphoblastic leukemia, which was fatal in one. Data revealed that retroviral insertional activation of cellular-growth regulatory genes led to the malignant transformation [ A subsequent clinical trial that utilized gamma-retroviral vectors with improved safety design (utilizing self-inactivating [SIN] vectors) demonstrated safety and partial efficacy in nine individuals over three years post transplantation: efficacy in T-cell reconstitution, no adverse events, and significantly fewer insertions in genes implicated in lymphoproliferation [ Due to the risk for insertional mutagenesis inherent with use of gamma-retroviral vectors, investigators developed next-generation lentiviral vectors that can transverse the nuclear membrane and transduce both mitotic and non-mitotic hematopoietic stem cells [ After successful HSCT, routine evaluation of affected males every six to 12 months is indicated to monitor lineage specific donor cell engraftment, growth, immune and lung function, and gastrointestinal and dermatologic issues. If conditioning chemotherapy was used, long-term monitoring of vital organ function and neurodevelopmental progress is also warranted. • Screen for respiratory viral PCR, urine CMV by PCR and blood viral PCR in all individuals meeting X-SCID criteria. Consider additional testing if symptomatic. • Maternal engraftment studies with multiple samples including (1) a buccal swab or brush from the child; (2) a peripheral blood sample from the biological mother; and (3) a peripheral blood sample collected from the child. Cells isolated from the blood sample will be genotyped for comparison to the child’s and biological mother’s baseline genotypes. • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of X-SCID in order to facilitate medical and personal decision making • HLA-matched HSCT from a relative is preferred; however, 70% of affected individuals lack a matched related donor [ • In the 100 transplants performed for individuals with SCID (including 33 with X-SCID) from 2010 to 2014, no statistically significant difference was observed between donor types; therefore, unrelated donors and umbilical cord grafts present viable options [ • For infants who do not have a matched related donor, haploidentical parental bone marrow or mobilized peripheral blood that has been depleted of T cells can be used [ • In both retrospective and prospective SCID cohorts since 2000, fewer than 30% of individuals received myeloablative-conditioning regimen, with 35%-65% of individuals receiving no conditioning or only immunosuppression (serotherapy). Note that conditioning regimens are typically used when grafts from unrelated donors are used [ • Over the last decade significantly better outcomes (>90% survival) in children without prior infections who received transplantation in early infancy (age <3.5 months) even with use of alternative donor grafts (i.e., donor not a matched sib, but rather a haploidentical individual, mismatched individual, or cord blood). • Presence of active infections was the main factor affecting overall survival, with nine of 11 deaths occurring in children who had infections prior to transplantation. • Younger infants in whom no conditioning is used also have more rapid engraftment, fewer post-transplantation infections, less GVHD with TCD grafts, and shorter hospitalizations. In contrast, in very young infants who require conditioning, there is a fine balance between risk of acquiring infection versus short- and long-term toxicities associated with use of conditioning. • Prophylaxis for • Consideration of IVIG prophylaxis to maintain serum IgG levels above 600 mg/dL • Prompt evaluation of illnesses until immunocompetence is achieved ## Evaluations Following Initial Diagnosis The following evaluations are indicated: Screen for respiratory viral PCR, urine CMV by PCR and blood viral PCR in all individuals meeting X-SCID criteria. Consider additional testing if symptomatic. Maternal engraftment studies with multiple samples including (1) a buccal swab or brush from the child; (2) a peripheral blood sample from the biological mother; and (3) a peripheral blood sample collected from the child. Cells isolated from the blood sample will be genotyped for comparison to the child’s and biological mother’s baseline genotypes. Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of X-SCID in order to facilitate medical and personal decision making For evaluation of a male with a positive newborn screen for SCID to establish the genetic diagnosis and initiate the search for an HSCT donor, see Suggestive Findings, • Screen for respiratory viral PCR, urine CMV by PCR and blood viral PCR in all individuals meeting X-SCID criteria. Consider additional testing if symptomatic. • Maternal engraftment studies with multiple samples including (1) a buccal swab or brush from the child; (2) a peripheral blood sample from the biological mother; and (3) a peripheral blood sample collected from the child. Cells isolated from the blood sample will be genotyped for comparison to the child’s and biological mother’s baseline genotypes. • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of X-SCID in order to facilitate medical and personal decision making ## Treatment of Manifestations The current goals of treatment include ensuring the safety of the infant/child, prophylaxis for infections, and preemptive hematopoietic stem cell transplantation (HSCT) prior to the development of symptoms. The general experience is that HLA-matched HSCT restores T-cell immunity in more than 90% of unconditioned individuals or individuals with SCID, although B-cell reconstitution occurs preferentially in a subset of these individuals who have NK Although many centers have expertise in performing HSCT in individuals with malignancy, the following special issues arising in HSCT for X-SCID require involvement of immunodeficiency specialists for an optimal outcome. Individuals with X-SCID (who have no immune system or at best an immune system minimally capable of rejecting the graft) do not typically require myeloablative-conditioning regimens. Rather, "reduced-intensity conditioning (RIC)" regimens are preferred as they employ agents at doses that do not result in long-lasting marrow aplasia. HLA-matched HSCT from a relative is preferred; however, 70% of affected individuals lack a matched related donor [ In the 100 transplants performed for individuals with SCID (including 33 with X-SCID) from 2010 to 2014, no statistically significant difference was observed between donor types; therefore, unrelated donors and umbilical cord grafts present viable options [ For infants who do not have a matched related donor, haploidentical parental bone marrow or mobilized peripheral blood that has been depleted of T cells can be used [ In both retrospective and prospective SCID cohorts since 2000, fewer than 30% of individuals received myeloablative-conditioning regimen, with 35%-65% of individuals receiving no conditioning or only immunosuppression (serotherapy). Note that conditioning regimens are typically used when grafts from unrelated donors are used [ The best timing for HSCT is shortly after birth, as young infants are less likely than older infants to have had serious infections or failure to thrive. In 25 centers, the prospective analysis performed by the PIDTC [ Over the last decade significantly better outcomes (>90% survival) in children without prior infections who received transplantation in early infancy (age <3.5 months) even with use of alternative donor grafts (i.e., donor not a matched sib, but rather a haploidentical individual, mismatched individual, or cord blood). Presence of active infections was the main factor affecting overall survival, with nine of 11 deaths occurring in children who had infections prior to transplantation. Younger infants in whom no conditioning is used also have more rapid engraftment, fewer post-transplantation infections, less GVHD with TCD grafts, and shorter hospitalizations. In contrast, in very young infants who require conditioning, there is a fine balance between risk of acquiring infection versus short- and long-term toxicities associated with use of conditioning. While it is expected that universal newborn screening will lead to a decrease of pre-transplantation infections and even better survival rates, optimal timing of transplantation and intensity of conditioning regimens (when required) still need to be defined in the era of universal newborn screening for SCID. Complications following HSCT can include GVHD, graft failure, failure to produce adequate antibodies requiring long-term immunoglobulin replacement therapy, inadequate and declining T cells associated with late graft failure (presumably due to declining numbers of engrafted hematopoietic stem cells), chronic warts, lymphocyte dysregulation leading to post-transplant autoimmunity, and (rarely) secondary malignancy. Post-transplantation all individuals have some degree of immunodeficiency, especially in the first six to 12 months, during which time the following are necessary: Prophylaxis for Consideration of IVIG prophylaxis to maintain serum IgG levels above 600 mg/dL Prompt evaluation of illnesses until immunocompetence is achieved Individuals with primary immunodeficiency post-transplantation need to meet criteria for immunocompetence (adequate CD4 and CD19 counts, PHA lymphocyte proliferation, and freedom from immunoglobulin supplementation) before starting vaccinations. Gene therapy performed with no conditioning regimen using autologous bone marrow stem/progenitor cells transduced with gamma-retroviral vectors expressing a therapeutic gene resulted in significant T-cell reconstitution in the majority of young infants with X-SCID. B-cell reconstitution was less consistent; only about 50% of infants were able to discontinue gamma-globulin replacement therapy. Unfortunately, two to 14 years after treatment in two independent trials using gamma-retroviral vectors, six of 20 individuals developed T-cell acute lymphoblastic leukemia, which was fatal in one. Data revealed that retroviral insertional activation of cellular-growth regulatory genes led to the malignant transformation [ A subsequent clinical trial that utilized gamma-retroviral vectors with improved safety design (utilizing self-inactivating [SIN] vectors) demonstrated safety and partial efficacy in nine individuals over three years post transplantation: efficacy in T-cell reconstitution, no adverse events, and significantly fewer insertions in genes implicated in lymphoproliferation [ Due to the risk for insertional mutagenesis inherent with use of gamma-retroviral vectors, investigators developed next-generation lentiviral vectors that can transverse the nuclear membrane and transduce both mitotic and non-mitotic hematopoietic stem cells [ • HLA-matched HSCT from a relative is preferred; however, 70% of affected individuals lack a matched related donor [ • In the 100 transplants performed for individuals with SCID (including 33 with X-SCID) from 2010 to 2014, no statistically significant difference was observed between donor types; therefore, unrelated donors and umbilical cord grafts present viable options [ • For infants who do not have a matched related donor, haploidentical parental bone marrow or mobilized peripheral blood that has been depleted of T cells can be used [ • In both retrospective and prospective SCID cohorts since 2000, fewer than 30% of individuals received myeloablative-conditioning regimen, with 35%-65% of individuals receiving no conditioning or only immunosuppression (serotherapy). Note that conditioning regimens are typically used when grafts from unrelated donors are used [ • Over the last decade significantly better outcomes (>90% survival) in children without prior infections who received transplantation in early infancy (age <3.5 months) even with use of alternative donor grafts (i.e., donor not a matched sib, but rather a haploidentical individual, mismatched individual, or cord blood). • Presence of active infections was the main factor affecting overall survival, with nine of 11 deaths occurring in children who had infections prior to transplantation. • Younger infants in whom no conditioning is used also have more rapid engraftment, fewer post-transplantation infections, less GVHD with TCD grafts, and shorter hospitalizations. In contrast, in very young infants who require conditioning, there is a fine balance between risk of acquiring infection versus short- and long-term toxicities associated with use of conditioning. • Prophylaxis for • Consideration of IVIG prophylaxis to maintain serum IgG levels above 600 mg/dL • Prompt evaluation of illnesses until immunocompetence is achieved ## Surveillance After successful HSCT, routine evaluation of affected males every six to 12 months is indicated to monitor lineage specific donor cell engraftment, growth, immune and lung function, and gastrointestinal and dermatologic issues. If conditioning chemotherapy was used, long-term monitoring of vital organ function and neurodevelopmental progress is also warranted. ## Atypical X-SCID Clinical Phenotypes Because the clinical phenotypes of atypical X-SCID vary widely, the diagnosis of X-SCID is often delayed until later in childhood or even young adulthood. Treatment depends on the degree of infectious complications and the presence of immune dysregulation and/or autoimmunity, and requires subspecialty immunologic care to assist in the diagnosis and choice of antimicrobial and immune-suppressive therapies. The following evaluations are indicated: Medical history including growth and development and localized and generalized infectious processes (e.g., diarrhea, failure to thrive, pneumonia, sepsis, viral and fungal infections) Referral to an immunology specialty center to determine immediate and long-term management and surveillance. Immunophenotyping can be performed in consultation with an immunologist. Determine the immunophenotype (see Treatment of atypical X-SCID varies depending on the degree of immune deficiency and should be evaluated on an individual basis. • Medical history including growth and development and localized and generalized infectious processes (e.g., diarrhea, failure to thrive, pneumonia, sepsis, viral and fungal infections) • Referral to an immunology specialty center to determine immediate and long-term management and surveillance. Immunophenotyping can be performed in consultation with an immunologist. • Determine the immunophenotype (see ## Evaluations Following Initial Diagnosis The following evaluations are indicated: Medical history including growth and development and localized and generalized infectious processes (e.g., diarrhea, failure to thrive, pneumonia, sepsis, viral and fungal infections) Referral to an immunology specialty center to determine immediate and long-term management and surveillance. Immunophenotyping can be performed in consultation with an immunologist. Determine the immunophenotype (see • Medical history including growth and development and localized and generalized infectious processes (e.g., diarrhea, failure to thrive, pneumonia, sepsis, viral and fungal infections) • Referral to an immunology specialty center to determine immediate and long-term management and surveillance. Immunophenotyping can be performed in consultation with an immunologist. • Determine the immunophenotype (see ## Treatment of Manifestations Treatment of atypical X-SCID varies depending on the degree of immune deficiency and should be evaluated on an individual basis. ## Both Typical and Atypical X-SCID Clinical Phenotypes To ensure the safety of the infant/older individual pending definitive treatment to achieve immunocompetence, parents and other care providers need to avoid the following: Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure When the pathogenic variant causing X-SCID in the family is known, prenatal testing of at-risk male fetuses may be performed to help prepare for optimal management of an affected infant at birth (i.e., identification of a center with expertise in SCID treatment protocols that can help initiate the search for a bone marrow donor and explain ways to ensure the safety of the infant while awaiting HSCT) (see If prenatal testing has not been performed, an at-risk newborn male should immediately be placed in an appropriate environment (see See The following investigations are under way: Second-generation gene replacement strategies based on self-inactivating (SIN) gamma-retroviral (RV) and lentiviral (LV) vectors lacking the LTR enhancers with high insertional genotoxicity have been assessed in Phase I/II clinical trials (see St Jude Children's Research Hospital, Seattle Children's Hospital, and University of California San Francisco (UCSF) are enrolling infants with X-SCID and the NIH is enrolling older males who had prior transplantation in SIN LV (self-inactivating lentivirus) clinical trials using low dose busulfan conditioning. The initial results of both Phase I/II trials were reported [ PIDTC "CSIDE" (Conditioning SCID Infants Diagnoised Early), a randomized trial of low vs moderate exposure to busulfan for infants with SCID receiving TCRαβ/CD19 Pre-clinical efficacy showed that gene correction in human long-term hematopoietic stem cells (LT-HSCs) is feasible for X-SCID using a CRISPR-Cas9/AAV6-based strategy [ Search • Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure • Second-generation gene replacement strategies based on self-inactivating (SIN) gamma-retroviral (RV) and lentiviral (LV) vectors lacking the LTR enhancers with high insertional genotoxicity have been assessed in Phase I/II clinical trials (see • St Jude Children's Research Hospital, Seattle Children's Hospital, and University of California San Francisco (UCSF) are enrolling infants with X-SCID and the NIH is enrolling older males who had prior transplantation in SIN LV (self-inactivating lentivirus) clinical trials using low dose busulfan conditioning. The initial results of both Phase I/II trials were reported [ • PIDTC "CSIDE" (Conditioning SCID Infants Diagnoised Early), a randomized trial of low vs moderate exposure to busulfan for infants with SCID receiving TCRαβ/CD19 • Pre-clinical efficacy showed that gene correction in human long-term hematopoietic stem cells (LT-HSCs) is feasible for X-SCID using a CRISPR-Cas9/AAV6-based strategy [ ## Agents/Circumstances to Avoid To ensure the safety of the infant/older individual pending definitive treatment to achieve immunocompetence, parents and other care providers need to avoid the following: Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure • Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure ## Evaluation of Relatives at Risk When the pathogenic variant causing X-SCID in the family is known, prenatal testing of at-risk male fetuses may be performed to help prepare for optimal management of an affected infant at birth (i.e., identification of a center with expertise in SCID treatment protocols that can help initiate the search for a bone marrow donor and explain ways to ensure the safety of the infant while awaiting HSCT) (see If prenatal testing has not been performed, an at-risk newborn male should immediately be placed in an appropriate environment (see See ## Therapies Under Investigation The following investigations are under way: Second-generation gene replacement strategies based on self-inactivating (SIN) gamma-retroviral (RV) and lentiviral (LV) vectors lacking the LTR enhancers with high insertional genotoxicity have been assessed in Phase I/II clinical trials (see St Jude Children's Research Hospital, Seattle Children's Hospital, and University of California San Francisco (UCSF) are enrolling infants with X-SCID and the NIH is enrolling older males who had prior transplantation in SIN LV (self-inactivating lentivirus) clinical trials using low dose busulfan conditioning. The initial results of both Phase I/II trials were reported [ PIDTC "CSIDE" (Conditioning SCID Infants Diagnoised Early), a randomized trial of low vs moderate exposure to busulfan for infants with SCID receiving TCRαβ/CD19 Pre-clinical efficacy showed that gene correction in human long-term hematopoietic stem cells (LT-HSCs) is feasible for X-SCID using a CRISPR-Cas9/AAV6-based strategy [ Search • Second-generation gene replacement strategies based on self-inactivating (SIN) gamma-retroviral (RV) and lentiviral (LV) vectors lacking the LTR enhancers with high insertional genotoxicity have been assessed in Phase I/II clinical trials (see • St Jude Children's Research Hospital, Seattle Children's Hospital, and University of California San Francisco (UCSF) are enrolling infants with X-SCID and the NIH is enrolling older males who had prior transplantation in SIN LV (self-inactivating lentivirus) clinical trials using low dose busulfan conditioning. The initial results of both Phase I/II trials were reported [ • PIDTC "CSIDE" (Conditioning SCID Infants Diagnoised Early), a randomized trial of low vs moderate exposure to busulfan for infants with SCID receiving TCRαβ/CD19 • Pre-clinical efficacy showed that gene correction in human long-term hematopoietic stem cells (LT-HSCs) is feasible for X-SCID using a CRISPR-Cas9/AAV6-based strategy [ ## Genetic Counseling By definition, X-linked severe combined immunodeficiency (X-SCID) is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected son and the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Maternal germline mosaicism has been documented in X-SCID [ If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a More than half of affected males have no family history of early deaths in maternally related affected males [ Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. If the proband represents a simplex case and if the Note: Molecular genetic testing may be able to identify the family member in whom a Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygotes for this X-linked disorder are carriers and are clinically asymptomatic secondary to skewed X-chromosome inactivation. See The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers or affected. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected son and the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Maternal germline mosaicism has been documented in X-SCID [ • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a • More than half of affected males have no family history of early deaths in maternally related affected males [ • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers or affected. ## Mode of Inheritance By definition, X-linked severe combined immunodeficiency (X-SCID) is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected son and the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Maternal germline mosaicism has been documented in X-SCID [ If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a More than half of affected males have no family history of early deaths in maternally related affected males [ Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. If the proband represents a simplex case and if the Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected son and the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Maternal germline mosaicism has been documented in X-SCID [ • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a • More than half of affected males have no family history of early deaths in maternally related affected males [ • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic secondary to skewed X-chromosome inactivation. ## Carrier Detection Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygotes for this X-linked disorder are carriers and are clinically asymptomatic secondary to skewed X-chromosome inactivation. ## Related Genetic Counseling Issues See The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers or affected. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers or affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada United Kingdom Health Resources & Services Administration • • • • • • Canada • • • United Kingdom • • • • • • • • • Health Resources & Services Administration • • • • • • • ## Molecular Genetics X-Linked Severe Combined Immunodeficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Severe Combined Immunodeficiency ( Complete loss-of-function Identification of the functional consequences of pathogenic Rare instances of somatic reversion (in which an inherited Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Complete loss-of-function Identification of the functional consequences of pathogenic Rare instances of somatic reversion (in which an inherited Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Eric J Allenspach, MD, PhD (2013-present) Karin Chen, MD (2021-present) Joie Davis, APRN, BC, APNG; National Institutes of Health (2003-2013) Aleksandra Petrovic, MD (2021-present) Jennifer M Puck, MD; University of California, San Francisco (2003-2013) David J Rawlings, MD (2013-present) Andrew Scharenberg, MD; University of Washington (2013-2021) 5 August 2021 (bp) Comprehensive update posted live 14 April 2016 (sw) Comprehensive update posted live 30 July 2015 (ea/ams) Revision: 24 January 2013 (me) Comprehensive update posted live 12 December 2005 (me) Comprehensive update posted live 26 August 2003 (me) Review posted live 23 April 2003 (jd) Original submission • 5 August 2021 (bp) Comprehensive update posted live • 14 April 2016 (sw) Comprehensive update posted live • 30 July 2015 (ea/ams) Revision: • 24 January 2013 (me) Comprehensive update posted live • 12 December 2005 (me) Comprehensive update posted live • 26 August 2003 (me) Review posted live • 23 April 2003 (jd) Original submission ## Author History Eric J Allenspach, MD, PhD (2013-present) Karin Chen, MD (2021-present) Joie Davis, APRN, BC, APNG; National Institutes of Health (2003-2013) Aleksandra Petrovic, MD (2021-present) Jennifer M Puck, MD; University of California, San Francisco (2003-2013) David J Rawlings, MD (2013-present) Andrew Scharenberg, MD; University of Washington (2013-2021) ## Revision History 5 August 2021 (bp) Comprehensive update posted live 14 April 2016 (sw) Comprehensive update posted live 30 July 2015 (ea/ams) Revision: 24 January 2013 (me) Comprehensive update posted live 12 December 2005 (me) Comprehensive update posted live 26 August 2003 (me) Review posted live 23 April 2003 (jd) Original submission • 5 August 2021 (bp) Comprehensive update posted live • 14 April 2016 (sw) Comprehensive update posted live • 30 July 2015 (ea/ams) Revision: • 24 January 2013 (me) Comprehensive update posted live • 12 December 2005 (me) Comprehensive update posted live • 26 August 2003 (me) Review posted live • 23 April 2003 (jd) Original submission ## References Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available ## Published Guidelines / Consensus Statements Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available ## Literature Cited	[]	26/8/2003	5/8/2021	30/7/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
xdp	xdp	[ "DYT3", "DYT-TAF1", "Lubag", "DYT3", "Lubag", "DYT-TAF1", "Transcription initiation factor TFIID subunit 1", "TAF1", "X-Linked Dystonia-Parkinsonism" ]	X-Linked Dystonia-Parkinsonism	Virgilio Gerald H Evidente	Summary Individuals with X-linked dystonia-parkinsonism (XDP) have dystonia of varying severity and parkinsonism. XDP afflicts primarily Filipino men and, rarely, women. The mean age of onset in men is 39 years; the clinical course is highly variable with parkinsonism as the initial presenting sign, overshadowed by dystonia as the disease progresses. Features of parkinsonism include resting tremor, bradykinesia, rigidity, postural instability, and severe shuffling gait. The dystonia develops focally, most commonly in the jaw, neck, trunk, and eyes, and less commonly in the limbs, tongue, pharynx, and larynx, the most characteristic being jaw dystonia often progressing to neck dystonia. Individuals with pure parkinsonism have non-disabling symptoms that are only slowly progressive; those who develop a combination of parkinsonism and dystonia can develop multifocal or generalized symptoms within a few years and die prematurely from pneumonia or intercurrent infections. Female carriers are mostly asymptomatic, though a small minority may manifest dystonia, parkinsonism, or chorea. The diagnosis of XDP is suspected in a male with typical clinical findings, family history consistent with X-linked inheritance, and maternal ancestral roots from the Panay Islands in the Philippines. Molecular genetic testing for variants that tag a disease-associated haplotype of the multilocus transcript system termed XDP is inherited in an X-linked manner. Approximately 94% of affected individuals have a known family history of the condition.	## Diagnosis The diagnosis of X-linked dystonia-parkinsonism (XDP) Dystonia of varying severity, ranging from focal to generalized typically starting in early adulthood Parkinsonism Family history consistent with X-linked inheritance Maternal ancestral roots from the Panay Islands in the Philippines where XDP originated as a genetic founder effect. All known affected individuals to date are of Filipino descent. As genetic testing is often not available in the endemic rural areas in the Philippines, olfactory testing may support the diagnosis in symptomatic (and possibly presymptomatic) individuals with XDP, though this possibility needs to be studied further. Note: (1) Although detection of c.94C>T (p.Arg32Cys) in a symptomatic individual is considered diagnostic, this is an indirect finding. Variants at this locus not previously associated with XDP cannot be interpreted as disease associated (see For an introduction to multigene panels click Molecular Genetic Testing Used in X-Linked Dystonia-Parkinsonism See See A variety of molecular methods may be used to detect a specific variant. If sequence analysis is performed, variants other than the c.94C>T (p.Arg32Cys) may be detected. For issues to consider in interpretation of sequence analysis results, click The common c.94C>T (p.Arg32Cys) variant (historically known as disease-specific single-nucleotide change 3 (DSC3) is the only DSC embedded in a predicted coding region; see • Dystonia of varying severity, ranging from focal to generalized typically starting in early adulthood • Parkinsonism • Family history consistent with X-linked inheritance • Maternal ancestral roots from the Panay Islands in the Philippines where XDP originated as a genetic founder effect. All known affected individuals to date are of Filipino descent. • As genetic testing is often not available in the endemic rural areas in the Philippines, olfactory testing may support the diagnosis in symptomatic (and possibly presymptomatic) individuals with XDP, though this possibility needs to be studied further. • Note: (1) Although detection of c.94C>T (p.Arg32Cys) in a symptomatic individual is considered diagnostic, this is an indirect finding. Variants at this locus not previously associated with XDP cannot be interpreted as disease associated (see • For an introduction to multigene panels click ## Clinical Diagnosis The diagnosis of X-linked dystonia-parkinsonism (XDP) Dystonia of varying severity, ranging from focal to generalized typically starting in early adulthood Parkinsonism Family history consistent with X-linked inheritance Maternal ancestral roots from the Panay Islands in the Philippines where XDP originated as a genetic founder effect. All known affected individuals to date are of Filipino descent. As genetic testing is often not available in the endemic rural areas in the Philippines, olfactory testing may support the diagnosis in symptomatic (and possibly presymptomatic) individuals with XDP, though this possibility needs to be studied further. • Dystonia of varying severity, ranging from focal to generalized typically starting in early adulthood • Parkinsonism • Family history consistent with X-linked inheritance • Maternal ancestral roots from the Panay Islands in the Philippines where XDP originated as a genetic founder effect. All known affected individuals to date are of Filipino descent. • As genetic testing is often not available in the endemic rural areas in the Philippines, olfactory testing may support the diagnosis in symptomatic (and possibly presymptomatic) individuals with XDP, though this possibility needs to be studied further. ## Establishing the Diagnosis Note: (1) Although detection of c.94C>T (p.Arg32Cys) in a symptomatic individual is considered diagnostic, this is an indirect finding. Variants at this locus not previously associated with XDP cannot be interpreted as disease associated (see For an introduction to multigene panels click Molecular Genetic Testing Used in X-Linked Dystonia-Parkinsonism See See A variety of molecular methods may be used to detect a specific variant. If sequence analysis is performed, variants other than the c.94C>T (p.Arg32Cys) may be detected. For issues to consider in interpretation of sequence analysis results, click The common c.94C>T (p.Arg32Cys) variant (historically known as disease-specific single-nucleotide change 3 (DSC3) is the only DSC embedded in a predicted coding region; see • Note: (1) Although detection of c.94C>T (p.Arg32Cys) in a symptomatic individual is considered diagnostic, this is an indirect finding. Variants at this locus not previously associated with XDP cannot be interpreted as disease associated (see • For an introduction to multigene panels click ## Clinical Characteristics X-linked dystonia-parkinsonism (XDP) or The clinical course in men with XDP is highly variable. Although the presenting finding was traditionally thought to be dystonia in most cases [ Some individuals may have pure parkinsonism and no dystonia for many years [ Some individuals with XDP (both male and female) may have all the cardinal features of parkinsonism, asymmetric findings, and levodopa responsiveness. These individuals may initially be misdiagnosed as having Parkinson disease [ The most characteristic dystonia seen in males with XDP is jaw dystonia, more commonly presenting as more difficulty with jaw opening than jaw closing. Jaw dystonia often progresses to neck dystonia, with retrocollis being more common than torticollis. Retrocollis can be so severe that the neck is extended more than 90 degrees, and the trunk is hyperextended. Cervical dystonia may be accompanied by a dystonic head tremor. Extension dystonia of the trunk is far more common than flexion or lateral dystonia of the trunk. Blepharospasm is only rarely the initial symptom of XDP. It tends to be more common as the disease progresses. It can coexist with mid- or lower-facial dystonia. Limb dystonia, rarely an initial presenting finding, is more commonly seen as disease advances. It affects the upper limbs as often as the lower limbs and is usually bilateral, although severity can be greater on one side of the body than the other. Unlike DYT1 torsion dystonia, XDP only rarely presents with dystonia of the foot. Tongue dystonia may also be seen, manifesting as either involuntary tongue protrusion or limitation in tongue protrusion. Pharyngeal dystonia, manifesting as difficulty swallowing, usually affects those with orolingual dystonia. Pharyngeal dystonia often leads to significant weight loss, aspiration pneumonia, and early death. Laryngeal dystonia leading to stridor (a rare finding) can also lead to sudden death. Individuals with orolingual, pharyngeal, or laryngeal dystonia may present with respiratory sounds [ Sensory tricks (improvement in dystonia by touching certain areas) have been observed in individuals with XDP with dystonia, particularly those with cervical dystonia. Electrophysiologic studies show muscle bursts ≤50-100 milliseconds in duration. Back-averaging may show a jerk-locked pre-movement surface-positive cortical electroencephalographic potential in the contralateral sensorimotor area, supporting the cortical origin of the myoclonus. Those who develop a combination of parkinsonism and orobuccolingual dystonia and cervical dystonia in the first year or two of the disease have the worst prognosis. Such individuals develop multifocal or generalized symptoms from the second to fifth year after onset, rapidly become bedridden, and die prematurely from aspiration pneumonia, laryngeal stridor, and/or intercurrent infections resulting from immobility. Other manifestations in women include chorea (which can be in a hemi-distribution), focal tremor (usually limb), or parkinsonism. The parkinsonism is usually mild, non-progressive, and non-disabling. Rarely, levodopa-responsive parkinsonism very similar to Parkinson disease can be observed. Normal findings on CT and brain MRI in the majority of patients, although generalized cerebral atrophy (usually mild) may be seen in some individuals and caudate atrophy in more advanced disease [Evidente, personal observation] Evidence for strong involvement of the white matter and putamen based on diffusion-weighted imaging [ Evidence of both postsynaptic [ Putaminal abnormalities on fluorodeoxyglucose (FDG) PET scan in affected men with early or mild symptomatic Results on presynaptic single-photon emission computed tomography (SPECT) studies using either [ Functional decline of postsynaptic dopaminergic transmission related to disease duration and ongoing degeneration function on [ Hyperechogenicity of the substantia nigra in 79% and of the lenticular nuclei in 81% of individuals with XDP on transcranial brain sonography studies [ Thus, it appears that by functional imaging, individuals with XDP may have one of the following: The earliest neuropathology report on XDP, from one Filipino male with dystonia-parkinsonism, showed neuronal loss and a multifocal mosaic pattern of astrocytosis in the caudate and lateral putamen [ Neuropathologic examination on an individual with severe generalized dystonia and parkinsonism confirmed the mosaic pattern of striatal gliosis as reported earlier, but also noted that the gliotic patches showed gradients that were dorsal to ventral, rostral to caudal, and medial to lateral [ Postmortem analyses of the basal ganglia based on striatal compartments (i.e., the striosomes and the matrix compartment) showed that in the neostriatum of individuals with XDP, the striosomes are severely depleted while the matrix component is relatively spared [ Neuropathologic studies have shown a neostriatal defect of the neuropeptide Y system in individuals with XDP, suggesting that the neuropeptide Y system may play a role in the progressive loss of striatal neurons [ All symptomatic individuals have the same disease-associated Recently, Anticipation is not observed in XDP. XDP was first described by In the local Filipino dialect, The first epidemiologic study was by The prevalence in the general population in the Philippines is estimated at 0.34:100,000. Although maternal ancestry can be traced to the Panay Islands in most cases, some individuals have no such traceable ancestry. • Electrophysiologic studies show muscle bursts ≤50-100 milliseconds in duration. Back-averaging may show a jerk-locked pre-movement surface-positive cortical electroencephalographic potential in the contralateral sensorimotor area, supporting the cortical origin of the myoclonus. • Normal findings on CT and brain MRI in the majority of patients, although generalized cerebral atrophy (usually mild) may be seen in some individuals and caudate atrophy in more advanced disease [Evidente, personal observation] • Evidence for strong involvement of the white matter and putamen based on diffusion-weighted imaging [ • Evidence of both postsynaptic [ • Putaminal abnormalities on fluorodeoxyglucose (FDG) PET scan in affected men with early or mild symptomatic • Results on presynaptic single-photon emission computed tomography (SPECT) studies using either [ • Functional decline of postsynaptic dopaminergic transmission related to disease duration and ongoing degeneration function on [ • Hyperechogenicity of the substantia nigra in 79% and of the lenticular nuclei in 81% of individuals with XDP on transcranial brain sonography studies [ ## Clinical Description X-linked dystonia-parkinsonism (XDP) or The clinical course in men with XDP is highly variable. Although the presenting finding was traditionally thought to be dystonia in most cases [ Some individuals may have pure parkinsonism and no dystonia for many years [ Some individuals with XDP (both male and female) may have all the cardinal features of parkinsonism, asymmetric findings, and levodopa responsiveness. These individuals may initially be misdiagnosed as having Parkinson disease [ The most characteristic dystonia seen in males with XDP is jaw dystonia, more commonly presenting as more difficulty with jaw opening than jaw closing. Jaw dystonia often progresses to neck dystonia, with retrocollis being more common than torticollis. Retrocollis can be so severe that the neck is extended more than 90 degrees, and the trunk is hyperextended. Cervical dystonia may be accompanied by a dystonic head tremor. Extension dystonia of the trunk is far more common than flexion or lateral dystonia of the trunk. Blepharospasm is only rarely the initial symptom of XDP. It tends to be more common as the disease progresses. It can coexist with mid- or lower-facial dystonia. Limb dystonia, rarely an initial presenting finding, is more commonly seen as disease advances. It affects the upper limbs as often as the lower limbs and is usually bilateral, although severity can be greater on one side of the body than the other. Unlike DYT1 torsion dystonia, XDP only rarely presents with dystonia of the foot. Tongue dystonia may also be seen, manifesting as either involuntary tongue protrusion or limitation in tongue protrusion. Pharyngeal dystonia, manifesting as difficulty swallowing, usually affects those with orolingual dystonia. Pharyngeal dystonia often leads to significant weight loss, aspiration pneumonia, and early death. Laryngeal dystonia leading to stridor (a rare finding) can also lead to sudden death. Individuals with orolingual, pharyngeal, or laryngeal dystonia may present with respiratory sounds [ Sensory tricks (improvement in dystonia by touching certain areas) have been observed in individuals with XDP with dystonia, particularly those with cervical dystonia. Electrophysiologic studies show muscle bursts ≤50-100 milliseconds in duration. Back-averaging may show a jerk-locked pre-movement surface-positive cortical electroencephalographic potential in the contralateral sensorimotor area, supporting the cortical origin of the myoclonus. Those who develop a combination of parkinsonism and orobuccolingual dystonia and cervical dystonia in the first year or two of the disease have the worst prognosis. Such individuals develop multifocal or generalized symptoms from the second to fifth year after onset, rapidly become bedridden, and die prematurely from aspiration pneumonia, laryngeal stridor, and/or intercurrent infections resulting from immobility. Other manifestations in women include chorea (which can be in a hemi-distribution), focal tremor (usually limb), or parkinsonism. The parkinsonism is usually mild, non-progressive, and non-disabling. Rarely, levodopa-responsive parkinsonism very similar to Parkinson disease can be observed. Normal findings on CT and brain MRI in the majority of patients, although generalized cerebral atrophy (usually mild) may be seen in some individuals and caudate atrophy in more advanced disease [Evidente, personal observation] Evidence for strong involvement of the white matter and putamen based on diffusion-weighted imaging [ Evidence of both postsynaptic [ Putaminal abnormalities on fluorodeoxyglucose (FDG) PET scan in affected men with early or mild symptomatic Results on presynaptic single-photon emission computed tomography (SPECT) studies using either [ Functional decline of postsynaptic dopaminergic transmission related to disease duration and ongoing degeneration function on [ Hyperechogenicity of the substantia nigra in 79% and of the lenticular nuclei in 81% of individuals with XDP on transcranial brain sonography studies [ Thus, it appears that by functional imaging, individuals with XDP may have one of the following: The earliest neuropathology report on XDP, from one Filipino male with dystonia-parkinsonism, showed neuronal loss and a multifocal mosaic pattern of astrocytosis in the caudate and lateral putamen [ Neuropathologic examination on an individual with severe generalized dystonia and parkinsonism confirmed the mosaic pattern of striatal gliosis as reported earlier, but also noted that the gliotic patches showed gradients that were dorsal to ventral, rostral to caudal, and medial to lateral [ Postmortem analyses of the basal ganglia based on striatal compartments (i.e., the striosomes and the matrix compartment) showed that in the neostriatum of individuals with XDP, the striosomes are severely depleted while the matrix component is relatively spared [ Neuropathologic studies have shown a neostriatal defect of the neuropeptide Y system in individuals with XDP, suggesting that the neuropeptide Y system may play a role in the progressive loss of striatal neurons [ • Electrophysiologic studies show muscle bursts ≤50-100 milliseconds in duration. Back-averaging may show a jerk-locked pre-movement surface-positive cortical electroencephalographic potential in the contralateral sensorimotor area, supporting the cortical origin of the myoclonus. • Normal findings on CT and brain MRI in the majority of patients, although generalized cerebral atrophy (usually mild) may be seen in some individuals and caudate atrophy in more advanced disease [Evidente, personal observation] • Evidence for strong involvement of the white matter and putamen based on diffusion-weighted imaging [ • Evidence of both postsynaptic [ • Putaminal abnormalities on fluorodeoxyglucose (FDG) PET scan in affected men with early or mild symptomatic • Results on presynaptic single-photon emission computed tomography (SPECT) studies using either [ • Functional decline of postsynaptic dopaminergic transmission related to disease duration and ongoing degeneration function on [ • Hyperechogenicity of the substantia nigra in 79% and of the lenticular nuclei in 81% of individuals with XDP on transcranial brain sonography studies [ ## Genotype-Phenotype Correlations All symptomatic individuals have the same disease-associated Recently, ## Anticipation Anticipation is not observed in XDP. ## Nomenclature XDP was first described by In the local Filipino dialect, ## Prevalence The first epidemiologic study was by The prevalence in the general population in the Philippines is estimated at 0.34:100,000. Although maternal ancestry can be traced to the Panay Islands in most cases, some individuals have no such traceable ancestry. ## Genetically Related (Allelic) Disorders Hemizygous, usually ## Differential Diagnosis See Individuals with X-linked dystonia-parkinsonism (XDP) with tremor can be misdiagnosed as having ## Management To establish the extent of disease and needs in an individual diagnosed with X-linked dystonia-parkinsonism (XDP) syndrome, the following evaluations are recommended if they have not already been completed: Neurologic examination Assessment of speech Assessment of swallowing Nutritional assessment Surface electromyography study Consultation with a clinical geneticist and/or genetic counselor The two most commonly prescribed anticholinergic drugs are trihexyphenidyl (Artane™) and biperiden (Akineton™). Trihexyphenidyl appears to have a more consistent and beneficial effect than biperiden, especially in the moderate-to-advanced stages. The benzodiazepine associated with the best response is clonazepam. Even greater improvement in dystonia is noted when anticholinergic drugs are combined with clonazepam. Zolpidem is particularly useful in individuals with a predominantly phasic type of generalized dystonic movements and no contractures. In such cases dramatic improvement can occur: some individuals experience nearly 100% improvement of dystonia for a few hours. The clinical effect of zolpidem may last six to eight hours per 10-mg dose in the first few weeks. Subsequently, the effect becomes progressively shorter, decreasing to two to three hours. Zolpidem was previously reported to have modest effects on parkinsonism in some individuals with progressive supranuclear palsy (PSP) [ Individuals with XDP who take frequent doses of zolpidem either overcome its soporific effects rapidly or develop tolerable daytime sleepiness. Haloperidol is often used by primary care physicians who see individuals with XDP Risperidone appears less effective than haloperidol in controlling dystonia. At doses of 6 mg/day or higher, risperidone may also be associated with EPS including tardive dyskinesias and parkinsonism. Of the atypical neuroleptics, clozapine has the greatest potential to be effective, at least for a limited period. However, its clinical use is limited by its potential to cause aplastic anemia and the need to do frequent complete blood counts, which is impractical in the rural areas of the Panay Islands where XDP is most prevalent. DBS has been done so far primarily on individuals with more advanced dystonia, either multifocal or generalized. However, a Filipino male age 45 years with only three years of relatively mild symptoms of unilateral big toe extension dystonia, mild jaw-opening dystonia, mild parkinsonism, and dysarthria underwent bilateral pallidal GPi DBS, with significant improvement of his symptoms immediately post-op [Evidente, unpublished data]. As of latest follow up 18 months after DBS, his symptoms remain well controlled with no further spread of dystonia to other parts of the body. This individual is the earliest known with XDP to have undergone DBS during the initial stages of the disease. Long-term follow up as well as identification of other cases treated early in the course of the disease may help determine if performing DBS early in the stages of XDP may have a disease-modifying effect. Although dystonia uniformly improves in individuals with XDP undergoing bilateral pallidal DBS, the parkinsonism may be less responsive [ See The secondary complications of significant dysphagia and immobility are usually related to progression of dystonia. Swallowing evaluation, especially in those with subjective dysphagia, can guide diet modification and use of swallowing techniques that minimize the risk for aspiration pneumonia. Physical therapy, coupled with maximal medical and surgical therapy, may help delay the bedridden state and its complications. Although traditional neuroleptics may initially help focal or segmental dystonia, they may eventually exacerbate the underlying parkinsonism in individuals with XDP and also lead to tardive dystonia with chronic use. Thus, it may be difficult to determine with chronic therapy if traditional neuroleptics actually help or worsen dystonia in individuals with XDP. Presymptomatic males known to have the disease-associated haplotype may need yearly clinical evaluations after age 30 years to identify the onset of symptoms in order to institute appropriate therapy as early as possible. Once an individual is symptomatic, biannual follow ups are recommended in order to adjust medications to assure best management of dystonia and/or parkinsonism. Periodic swallowing evaluation, especially in those with subjective dysphagia, is appropriate. See Search Other sleep medications such as zaleplon (Sonata™) have had no beneficial effect on dystonia in individuals with XDP. Drugs that have been used anecdotally with poor or inconsistent effects on dystonia in individuals with XDP include gabapentin, topiramate, baclofen, and tizanidine. Brain surgeries for advanced dystonia in individuals with XDP that have failed in the past include four thalamotomies, two pallidotomies, and one cerebellar implantation [ • Neurologic examination • Assessment of speech • Assessment of swallowing • Nutritional assessment • Surface electromyography study • Consultation with a clinical geneticist and/or genetic counselor • The two most commonly prescribed anticholinergic drugs are trihexyphenidyl (Artane™) and biperiden (Akineton™). Trihexyphenidyl appears to have a more consistent and beneficial effect than biperiden, especially in the moderate-to-advanced stages. • The benzodiazepine associated with the best response is clonazepam. • Even greater improvement in dystonia is noted when anticholinergic drugs are combined with clonazepam. • The clinical effect of zolpidem may last six to eight hours per 10-mg dose in the first few weeks. Subsequently, the effect becomes progressively shorter, decreasing to two to three hours. • Zolpidem was previously reported to have modest effects on parkinsonism in some individuals with progressive supranuclear palsy (PSP) [ • Individuals with XDP who take frequent doses of zolpidem either overcome its soporific effects rapidly or develop tolerable daytime sleepiness. • Haloperidol is often used by primary care physicians who see individuals with XDP • Risperidone appears less effective than haloperidol in controlling dystonia. At doses of 6 mg/day or higher, risperidone may also be associated with EPS including tardive dyskinesias and parkinsonism. • Of the atypical neuroleptics, clozapine has the greatest potential to be effective, at least for a limited period. However, its clinical use is limited by its potential to cause aplastic anemia and the need to do frequent complete blood counts, which is impractical in the rural areas of the Panay Islands where XDP is most prevalent. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with X-linked dystonia-parkinsonism (XDP) syndrome, the following evaluations are recommended if they have not already been completed: Neurologic examination Assessment of speech Assessment of swallowing Nutritional assessment Surface electromyography study Consultation with a clinical geneticist and/or genetic counselor • Neurologic examination • Assessment of speech • Assessment of swallowing • Nutritional assessment • Surface electromyography study • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations The two most commonly prescribed anticholinergic drugs are trihexyphenidyl (Artane™) and biperiden (Akineton™). Trihexyphenidyl appears to have a more consistent and beneficial effect than biperiden, especially in the moderate-to-advanced stages. The benzodiazepine associated with the best response is clonazepam. Even greater improvement in dystonia is noted when anticholinergic drugs are combined with clonazepam. Zolpidem is particularly useful in individuals with a predominantly phasic type of generalized dystonic movements and no contractures. In such cases dramatic improvement can occur: some individuals experience nearly 100% improvement of dystonia for a few hours. The clinical effect of zolpidem may last six to eight hours per 10-mg dose in the first few weeks. Subsequently, the effect becomes progressively shorter, decreasing to two to three hours. Zolpidem was previously reported to have modest effects on parkinsonism in some individuals with progressive supranuclear palsy (PSP) [ Individuals with XDP who take frequent doses of zolpidem either overcome its soporific effects rapidly or develop tolerable daytime sleepiness. Haloperidol is often used by primary care physicians who see individuals with XDP Risperidone appears less effective than haloperidol in controlling dystonia. At doses of 6 mg/day or higher, risperidone may also be associated with EPS including tardive dyskinesias and parkinsonism. Of the atypical neuroleptics, clozapine has the greatest potential to be effective, at least for a limited period. However, its clinical use is limited by its potential to cause aplastic anemia and the need to do frequent complete blood counts, which is impractical in the rural areas of the Panay Islands where XDP is most prevalent. DBS has been done so far primarily on individuals with more advanced dystonia, either multifocal or generalized. However, a Filipino male age 45 years with only three years of relatively mild symptoms of unilateral big toe extension dystonia, mild jaw-opening dystonia, mild parkinsonism, and dysarthria underwent bilateral pallidal GPi DBS, with significant improvement of his symptoms immediately post-op [Evidente, unpublished data]. As of latest follow up 18 months after DBS, his symptoms remain well controlled with no further spread of dystonia to other parts of the body. This individual is the earliest known with XDP to have undergone DBS during the initial stages of the disease. Long-term follow up as well as identification of other cases treated early in the course of the disease may help determine if performing DBS early in the stages of XDP may have a disease-modifying effect. Although dystonia uniformly improves in individuals with XDP undergoing bilateral pallidal DBS, the parkinsonism may be less responsive [ • The two most commonly prescribed anticholinergic drugs are trihexyphenidyl (Artane™) and biperiden (Akineton™). Trihexyphenidyl appears to have a more consistent and beneficial effect than biperiden, especially in the moderate-to-advanced stages. • The benzodiazepine associated with the best response is clonazepam. • Even greater improvement in dystonia is noted when anticholinergic drugs are combined with clonazepam. • The clinical effect of zolpidem may last six to eight hours per 10-mg dose in the first few weeks. Subsequently, the effect becomes progressively shorter, decreasing to two to three hours. • Zolpidem was previously reported to have modest effects on parkinsonism in some individuals with progressive supranuclear palsy (PSP) [ • Individuals with XDP who take frequent doses of zolpidem either overcome its soporific effects rapidly or develop tolerable daytime sleepiness. • Haloperidol is often used by primary care physicians who see individuals with XDP • Risperidone appears less effective than haloperidol in controlling dystonia. At doses of 6 mg/day or higher, risperidone may also be associated with EPS including tardive dyskinesias and parkinsonism. • Of the atypical neuroleptics, clozapine has the greatest potential to be effective, at least for a limited period. However, its clinical use is limited by its potential to cause aplastic anemia and the need to do frequent complete blood counts, which is impractical in the rural areas of the Panay Islands where XDP is most prevalent. ## Pharmacologic Treatment of Dystonia The two most commonly prescribed anticholinergic drugs are trihexyphenidyl (Artane™) and biperiden (Akineton™). Trihexyphenidyl appears to have a more consistent and beneficial effect than biperiden, especially in the moderate-to-advanced stages. The benzodiazepine associated with the best response is clonazepam. Even greater improvement in dystonia is noted when anticholinergic drugs are combined with clonazepam. Zolpidem is particularly useful in individuals with a predominantly phasic type of generalized dystonic movements and no contractures. In such cases dramatic improvement can occur: some individuals experience nearly 100% improvement of dystonia for a few hours. The clinical effect of zolpidem may last six to eight hours per 10-mg dose in the first few weeks. Subsequently, the effect becomes progressively shorter, decreasing to two to three hours. Zolpidem was previously reported to have modest effects on parkinsonism in some individuals with progressive supranuclear palsy (PSP) [ Individuals with XDP who take frequent doses of zolpidem either overcome its soporific effects rapidly or develop tolerable daytime sleepiness. Haloperidol is often used by primary care physicians who see individuals with XDP Risperidone appears less effective than haloperidol in controlling dystonia. At doses of 6 mg/day or higher, risperidone may also be associated with EPS including tardive dyskinesias and parkinsonism. Of the atypical neuroleptics, clozapine has the greatest potential to be effective, at least for a limited period. However, its clinical use is limited by its potential to cause aplastic anemia and the need to do frequent complete blood counts, which is impractical in the rural areas of the Panay Islands where XDP is most prevalent. • The two most commonly prescribed anticholinergic drugs are trihexyphenidyl (Artane™) and biperiden (Akineton™). Trihexyphenidyl appears to have a more consistent and beneficial effect than biperiden, especially in the moderate-to-advanced stages. • The benzodiazepine associated with the best response is clonazepam. • Even greater improvement in dystonia is noted when anticholinergic drugs are combined with clonazepam. • The clinical effect of zolpidem may last six to eight hours per 10-mg dose in the first few weeks. Subsequently, the effect becomes progressively shorter, decreasing to two to three hours. • Zolpidem was previously reported to have modest effects on parkinsonism in some individuals with progressive supranuclear palsy (PSP) [ • Individuals with XDP who take frequent doses of zolpidem either overcome its soporific effects rapidly or develop tolerable daytime sleepiness. • Haloperidol is often used by primary care physicians who see individuals with XDP • Risperidone appears less effective than haloperidol in controlling dystonia. At doses of 6 mg/day or higher, risperidone may also be associated with EPS including tardive dyskinesias and parkinsonism. • Of the atypical neuroleptics, clozapine has the greatest potential to be effective, at least for a limited period. However, its clinical use is limited by its potential to cause aplastic anemia and the need to do frequent complete blood counts, which is impractical in the rural areas of the Panay Islands where XDP is most prevalent. ## Pharmacologic Treatment of Parkinsonism ## Surgical Treatment of Dystonia and Parkinsonism DBS has been done so far primarily on individuals with more advanced dystonia, either multifocal or generalized. However, a Filipino male age 45 years with only three years of relatively mild symptoms of unilateral big toe extension dystonia, mild jaw-opening dystonia, mild parkinsonism, and dysarthria underwent bilateral pallidal GPi DBS, with significant improvement of his symptoms immediately post-op [Evidente, unpublished data]. As of latest follow up 18 months after DBS, his symptoms remain well controlled with no further spread of dystonia to other parts of the body. This individual is the earliest known with XDP to have undergone DBS during the initial stages of the disease. Long-term follow up as well as identification of other cases treated early in the course of the disease may help determine if performing DBS early in the stages of XDP may have a disease-modifying effect. Although dystonia uniformly improves in individuals with XDP undergoing bilateral pallidal DBS, the parkinsonism may be less responsive [ ## Prevention of Primary Manifestations See ## Prevention of Secondary Complications The secondary complications of significant dysphagia and immobility are usually related to progression of dystonia. Swallowing evaluation, especially in those with subjective dysphagia, can guide diet modification and use of swallowing techniques that minimize the risk for aspiration pneumonia. Physical therapy, coupled with maximal medical and surgical therapy, may help delay the bedridden state and its complications. Although traditional neuroleptics may initially help focal or segmental dystonia, they may eventually exacerbate the underlying parkinsonism in individuals with XDP and also lead to tardive dystonia with chronic use. Thus, it may be difficult to determine with chronic therapy if traditional neuroleptics actually help or worsen dystonia in individuals with XDP. ## Surveillance Presymptomatic males known to have the disease-associated haplotype may need yearly clinical evaluations after age 30 years to identify the onset of symptoms in order to institute appropriate therapy as early as possible. Once an individual is symptomatic, biannual follow ups are recommended in order to adjust medications to assure best management of dystonia and/or parkinsonism. Periodic swallowing evaluation, especially in those with subjective dysphagia, is appropriate. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Other Other sleep medications such as zaleplon (Sonata™) have had no beneficial effect on dystonia in individuals with XDP. Drugs that have been used anecdotally with poor or inconsistent effects on dystonia in individuals with XDP include gabapentin, topiramate, baclofen, and tizanidine. Brain surgeries for advanced dystonia in individuals with XDP that have failed in the past include four thalamotomies, two pallidotomies, and one cerebellar implantation [ ## Genetic Counseling X-linked dystonia-parkinsonism (XDP) is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be a carrier of the In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Approximately 94% of affected individuals have a known family history of the condition. When an affected male is the only affected individual in the family (i.e., a simplex case), it is likely that his mother has the Most often, the mother of the proband is a carrier and the chance of transmitting the There is no evidence to date of Carrier evaluation of at-risk female relatives is possible if the Predictive testing for at-risk male relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, there is concern as to the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of XDP, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Note: Caution should be exercised in interpreting the results of prenatal testing as the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disease nor will he be a carrier of the • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. • Approximately 94% of affected individuals have a known family history of the condition. • When an affected male is the only affected individual in the family (i.e., a simplex case), it is likely that his mother has the • Most often, the mother of the proband is a carrier and the chance of transmitting the • There is no evidence to date of • Predictive testing for at-risk male relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, there is concern as to the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance X-linked dystonia-parkinsonism (XDP) is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disease nor will he be a carrier of the In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Approximately 94% of affected individuals have a known family history of the condition. When an affected male is the only affected individual in the family (i.e., a simplex case), it is likely that his mother has the Most often, the mother of the proband is a carrier and the chance of transmitting the There is no evidence to date of • The father of an affected male will not have the disease nor will he be a carrier of the • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. • Approximately 94% of affected individuals have a known family history of the condition. • When an affected male is the only affected individual in the family (i.e., a simplex case), it is likely that his mother has the • Most often, the mother of the proband is a carrier and the chance of transmitting the • There is no evidence to date of ## Carrier (Heterozygote) Detection Carrier evaluation of at-risk female relatives is possible if the ## Related Genetic Counseling Issues Predictive testing for at-risk male relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, there is concern as to the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of XDP, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Predictive testing for at-risk male relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, there is concern as to the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Note: Caution should be exercised in interpreting the results of prenatal testing as the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • ## Molecular Genetics X-Linked Dystonia-Parkinsonism Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Dystonia-Parkinsonism Syndrome ( Though first described in 1976, it was only in 1990 that X-linked dystonia-parkinsonism (XDP) was formally shown through segregation and biochemical analyses to be inherited as an X-linked trait [ The locus identified with It is difficult to predict cellular pathways which are affected in XDP cells. Vaine and colleagues assayed expression of defined gene sets in XDP versus control fibroblasts to identify networks of functionally related transcripts which may be dysregulated in XDP cells [ None of the DSCs was located within a structural or regulatory region of a known gene. Rather, most changes occurred within repetitive DNA: DSC1 is located within an Alu repeat, DSC2 within a LINE2 repeat, and DSC10 within a LIMB2 repeat in intron 32 of Only DSC3 ( Using genomic sequencing analysis followed by expression analysis of XDP in brain tissues, Selected Variants within the XDP Critical Region Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions The variant c.94C>T (p.Arg32Cys) is named on the reference sequence for The loss of one X chromosome in a subset of cells or X-chromosome monosomy (45,X / 46,XX) has also been noted in a female with XDP and a phenotype similar to Turner syndrome [ Although the individual or combined roles of DSC3, the other DSCs, and the SVA retrotransposon in pathogenesis of XDP remain to be determined, more recent work by Ito and colleagues generated XDP and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with XDP [ • DSC1 is located within an Alu repeat, DSC2 within a LINE2 repeat, and DSC10 within a LIMB2 repeat in intron 32 of • Only DSC3 ( ## Molecular Pathogenesis Though first described in 1976, it was only in 1990 that X-linked dystonia-parkinsonism (XDP) was formally shown through segregation and biochemical analyses to be inherited as an X-linked trait [ The locus identified with It is difficult to predict cellular pathways which are affected in XDP cells. Vaine and colleagues assayed expression of defined gene sets in XDP versus control fibroblasts to identify networks of functionally related transcripts which may be dysregulated in XDP cells [ None of the DSCs was located within a structural or regulatory region of a known gene. Rather, most changes occurred within repetitive DNA: DSC1 is located within an Alu repeat, DSC2 within a LINE2 repeat, and DSC10 within a LIMB2 repeat in intron 32 of Only DSC3 ( Using genomic sequencing analysis followed by expression analysis of XDP in brain tissues, Selected Variants within the XDP Critical Region Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions The variant c.94C>T (p.Arg32Cys) is named on the reference sequence for The loss of one X chromosome in a subset of cells or X-chromosome monosomy (45,X / 46,XX) has also been noted in a female with XDP and a phenotype similar to Turner syndrome [ Although the individual or combined roles of DSC3, the other DSCs, and the SVA retrotransposon in pathogenesis of XDP remain to be determined, more recent work by Ito and colleagues generated XDP and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with XDP [ • DSC1 is located within an Alu repeat, DSC2 within a LINE2 repeat, and DSC10 within a LIMB2 repeat in intron 32 of • Only DSC3 ( ## XDP Critical Region The locus identified with It is difficult to predict cellular pathways which are affected in XDP cells. Vaine and colleagues assayed expression of defined gene sets in XDP versus control fibroblasts to identify networks of functionally related transcripts which may be dysregulated in XDP cells [ None of the DSCs was located within a structural or regulatory region of a known gene. Rather, most changes occurred within repetitive DNA: DSC1 is located within an Alu repeat, DSC2 within a LINE2 repeat, and DSC10 within a LIMB2 repeat in intron 32 of Only DSC3 ( Using genomic sequencing analysis followed by expression analysis of XDP in brain tissues, Selected Variants within the XDP Critical Region Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions The variant c.94C>T (p.Arg32Cys) is named on the reference sequence for The loss of one X chromosome in a subset of cells or X-chromosome monosomy (45,X / 46,XX) has also been noted in a female with XDP and a phenotype similar to Turner syndrome [ Although the individual or combined roles of DSC3, the other DSCs, and the SVA retrotransposon in pathogenesis of XDP remain to be determined, more recent work by Ito and colleagues generated XDP and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with XDP [ • DSC1 is located within an Alu repeat, DSC2 within a LINE2 repeat, and DSC10 within a LIMB2 repeat in intron 32 of • Only DSC3 ( ## References ## Literature Cited ## Chapter Notes Dr Evidente has received research support from the Udall PD Research Center of Excellence Grant #P50 NS40256, Mayo Clinic Foundation, and St Luke's Medical Center Research & Biotechnology Division (Philippines). 15 February 2018 (ha) Comprehensive update posted live 23 April 2015 (me) Comprehensive update posted live 18 October 2012 (me) Comprehensive update posted live 22 June 2010 (cd) Revision: prenatal testing available 27 April 2010 (me) Comprehensive update posted live 6 January 2009 (me) Comprehensive update posted live 13 December 2005 (me) Review posted live 8 March 2005 (vge) Original submission • 15 February 2018 (ha) Comprehensive update posted live • 23 April 2015 (me) Comprehensive update posted live • 18 October 2012 (me) Comprehensive update posted live • 22 June 2010 (cd) Revision: prenatal testing available • 27 April 2010 (me) Comprehensive update posted live • 6 January 2009 (me) Comprehensive update posted live • 13 December 2005 (me) Review posted live • 8 March 2005 (vge) Original submission ## Acknowledgments Dr Evidente has received research support from the Udall PD Research Center of Excellence Grant #P50 NS40256, Mayo Clinic Foundation, and St Luke's Medical Center Research & Biotechnology Division (Philippines). ## Revision History 15 February 2018 (ha) Comprehensive update posted live 23 April 2015 (me) Comprehensive update posted live 18 October 2012 (me) Comprehensive update posted live 22 June 2010 (cd) Revision: prenatal testing available 27 April 2010 (me) Comprehensive update posted live 6 January 2009 (me) Comprehensive update posted live 13 December 2005 (me) Review posted live 8 March 2005 (vge) Original submission • 15 February 2018 (ha) Comprehensive update posted live • 23 April 2015 (me) Comprehensive update posted live • 18 October 2012 (me) Comprehensive update posted live • 22 June 2010 (cd) Revision: prenatal testing available • 27 April 2010 (me) Comprehensive update posted live • 6 January 2009 (me) Comprehensive update posted live • 13 December 2005 (me) Review posted live • 8 March 2005 (vge) Original submission	[ "JA Aguilar, TS Vesagas, RD Jamora, RA Teleg, L Ledesma, RL Rosales, HH Fernandez, HV Lee. 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Functional anatomy of the basal ganglia in x-linked recessive dystonia-parkinsonism.. Ann Neurol 2005;58:7-17", "S Goto, T Kawarai, R Morigaki, S Okita, H Koizumi, S Nagahiro, EL Munoz, LV Lee, R Kaji. Defects in the striatal neuropeptide Y system in X-linked dystonia-parkinsonism.. Brain 2013;136:1555-67", "T Herzfeld, D Nolte, U Müller. Structural and functional analysis of the human TAF1/DYT3 multiple transcript system.. Mamm Genome 2007;18:787-95", "T Herzfeld, D Nolte, M Grznarova, A Hofmann, J Schultze, U Muller. X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism.. Hum Mol Genet 2013;22:941-51", "N Ito, WT Hendriks, J Dhakal, CA Vaine, C Liu, D Shin, K Shin, N Wakabayashi-Ito, M Dy, T Multhaupt-Buell, N Sharma, XO Breakefield, DC Bragg. Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells.. Dis Model Mech. 2016;9:451-62", "KG Kupke, LV Lee, U Muller. Assignment of the X-linked recessive torsion dystonia gene to Xq21 by linkage analysis.. Neurology 1990a;40:1438-42", "KG Kupke, LV Lee, GH Viterbo, J Arancillo, T Donlon, U Muller. X-linked recessive torsion dystonia in the Philippines.. Am J Med Genet 1990b;36:237-42", "LV Lee, E Maranon, C Demaisip, O Peralta, R Borres-Icasiano, J Arancillo, C Rivera, E Munoz, K Tan, MT Reyes. The natural history of sex-linked recessive dystonia parkinsonism of Panay, Philippines (XDP).. Parkinsonism Relat Disord 2002;9:29-38", "LV Lee, FM Pascasio, FD Fuentes, GH Viterbo. Torsion dystonia in Panay, Philippines.. Adv Neurol 1976;14:137-51", "LV Lee, C Rivera, RA Teleg, MB Dantes, PMD Pasco, RDG Jamora, J Arancill, RF Villareal-Jordan, RL Rosales, C Demaisip, E Maranon, O Peralta, R Borres, C Tolentino, MR Monding, S Sarcia. The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DT3, \"Lubag\").. 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Am J Hum Genet 2007;81:415-7", "D Nolte, S Niemann, U Muller. Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.. Proc Natl Acad Sci USA 2003;100:10347-52", "G Oyama, HH Fernandez, KD Foote, P Zeilman, N Hwynn, CE Jacobson, IA Malaty, RL Rodriguez, MS Okun. Differential response of dystonia and parkinsonism following globus pallidus internus deep brain stimulation in X-linked dystonia-parkinsonism (Lubag).. Stereotact Funct Neurosurg 2010;88:329-33", "PM Pasco, CV Ison, EL Muñoz, NS Magpusao, AE Cheng, KT Tan, RW Lo, RA Teleg, MB Dantes, R Borres, E Maranon, C Demaisip, MV Reyes, LV Lee. Understanding XDP through imaging, pathology, and genetics.. Int J Neurosci. 2011;121:12-7", "AJ Patel, AI Sarwar, J Jankovic, A Viswanathan. Bilateral pallidal deep brain stimulation for X-linked dystonia-parkinsonism.. World Neurosurg 2014;82:241.e1-4", "AN Piano, LC Tan. Impulse control disorder in a patient with X-linked dystonia-parkinsonism after bilateral pallidal deep brain stimulation.. Parkinsonism Relat Disord 2013;19:1069-70", "RL Rosales, AR Ng, MM Santos, HH Fernandez. The broadening application of chemodenervation in X-linked dystonia-parkinsonism (Part II): an open-label experience with botulinum toxin-A (Dysport®) injections for oromandibular, lingual, and truncal-axial dystonias.. Int J Neurosci. 2011;121:44-56", "B Tackenberg, A Metz, M Unger, N Schimke, S Passow. Nigrostriatal dysfunction in X-linked dystonia-parkinsonism.. Mov Disord. 2007;22:900-2", "G Tamiya, S Makino, R Kaji. TAF1 as the most plausible disease gene for XDP/DYT3.. Am J Hum Genet. 2007;81:417-8", "CA Vaine, D Shin, C Liu, WT Hendriks, J Dhakal, K Shin, N Sharma, DC Bragg. X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B.. Neurobiol Dis. 2017;100:108-18", "PM Wadia, SY Lim, AM Lozano, JR Adams, YY Poon, CV Torres Diaz, E Moro. Bilateral pallidal stimulation for x-linked dystonia parkinsonism.. Arch Neurol. 2010;67:1012-5", "U Walter, R Rosales, A Rocco, A Westenberger, A Domingo, CL Go, N Brüggemann, C Klein, LV Lee, D Dressler. Sonographic alteration of substantia nigra isrelated to parkinsonism-predominant course of X-linked dystonia-parkinsonism.. Parkinsonism Relat Disord. 2017;37:43-9", "CH Waters, H Takahashi, KC Wilhelmsen, R Shubin, BJ Snow, TG Nygaard, CB Moskowitz, S Fahn, DB Calne. Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women.. Neurology 1993;43:1555-8", "A Westenberger, RL Rosales, S Heinitz, K Freimann, LV Lee, RD Jamora, AR Ng, A Domingo, K Lohmann, U Walter, U Golnit, A Rolfs, I Nagel, G Gillessen-Kaesbach, R Siebert, D Dressler, C Klein. X-linked dystonia-parkinsonism manifesting in a female patient due to atypical Turner syndrome.. Mov Disord 2013;28:675-8" ]	13/12/2005	15/2/2018	22/6/2010	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
xia-gibbs	xia-gibbs	[ "Transcription factor Gibbin", "AHDC1", "Xia-Gibbs Syndrome" ]	Xia-Gibbs Syndrome	Varuna Chander, Michael Wangler, Richard Gibbs, David Murdock	Summary The main features of Xia-Gibbs syndrome (XGS), present in a majority of affected individuals, include delayed motor milestones, speech delay with severely limited or absent speech, moderate-to-severe cognitive impairment, hypotonia, structural brain anomalies, and nonspecific dysmorphic features. Other features may include sleep apnea, movement disorders (ataxia, tremors, and bradykinesias) that often become apparent in childhood or adolescence, short stature, seizures, eye anomalies, behavioral concerns, autism spectrum disorder, scoliosis, and laryngomalacia. The diagnosis of XGS is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in XGS is an autosomal dominant disorder typically caused by a	## Diagnosis No consensus clinical diagnostic criteria for Xia-Gibbs syndrome (XGS) have been published. XGS Neurologic issues, including: Generalized hypotonia of infancy Epilepsy Ataxia Nystagmus Developmental issues, including: Delayed motor milestones Speech delay Autism spectrum disorder (ASD) Respiratory issues, including: Obstructive sleep apnea Tracheomalacia Laryngomalacia Scoliosis Short stature Strabismus Dysmorphic features (See Thinning of the corpus callosum Posterior fossa cyst Delayed myelination The diagnosis of XGS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Xia-Gibbs Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click From Most individuals so far reported have pathogenic truncating or missense variants in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. There have been reports of large deletions of 1p36.11 that include Deletions have been reported in the DECIPHER database, but the reported deletions are large and involve many genes, and there is not sufficient evidence to narrow down the cause to a single gene [ • Neurologic issues, including: • Generalized hypotonia of infancy • Epilepsy • Ataxia • Nystagmus • Generalized hypotonia of infancy • Epilepsy • Ataxia • Nystagmus • Developmental issues, including: • Delayed motor milestones • Speech delay • Autism spectrum disorder (ASD) • Delayed motor milestones • Speech delay • Autism spectrum disorder (ASD) • Respiratory issues, including: • Obstructive sleep apnea • Tracheomalacia • Laryngomalacia • Obstructive sleep apnea • Tracheomalacia • Laryngomalacia • Scoliosis • Short stature • Strabismus • Dysmorphic features (See • Generalized hypotonia of infancy • Epilepsy • Ataxia • Nystagmus • Delayed motor milestones • Speech delay • Autism spectrum disorder (ASD) • Obstructive sleep apnea • Tracheomalacia • Laryngomalacia • Thinning of the corpus callosum • Posterior fossa cyst • Delayed myelination • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings XGS Neurologic issues, including: Generalized hypotonia of infancy Epilepsy Ataxia Nystagmus Developmental issues, including: Delayed motor milestones Speech delay Autism spectrum disorder (ASD) Respiratory issues, including: Obstructive sleep apnea Tracheomalacia Laryngomalacia Scoliosis Short stature Strabismus Dysmorphic features (See Thinning of the corpus callosum Posterior fossa cyst Delayed myelination • Neurologic issues, including: • Generalized hypotonia of infancy • Epilepsy • Ataxia • Nystagmus • Generalized hypotonia of infancy • Epilepsy • Ataxia • Nystagmus • Developmental issues, including: • Delayed motor milestones • Speech delay • Autism spectrum disorder (ASD) • Delayed motor milestones • Speech delay • Autism spectrum disorder (ASD) • Respiratory issues, including: • Obstructive sleep apnea • Tracheomalacia • Laryngomalacia • Obstructive sleep apnea • Tracheomalacia • Laryngomalacia • Scoliosis • Short stature • Strabismus • Dysmorphic features (See • Generalized hypotonia of infancy • Epilepsy • Ataxia • Nystagmus • Delayed motor milestones • Speech delay • Autism spectrum disorder (ASD) • Obstructive sleep apnea • Tracheomalacia • Laryngomalacia • Thinning of the corpus callosum • Posterior fossa cyst • Delayed myelination ## Establishing the Diagnosis The diagnosis of XGS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Xia-Gibbs Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click From Most individuals so far reported have pathogenic truncating or missense variants in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. There have been reports of large deletions of 1p36.11 that include Deletions have been reported in the DECIPHER database, but the reported deletions are large and involve many genes, and there is not sufficient evidence to narrow down the cause to a single gene [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, approximately 280 individuals have been identified with a pathogenic variant in Select Features of Xia-Gibbs Syndrome ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability Motor development delay is usually accompanied by poor coordination and gait disturbances, typically starting in early childhood. The median age when walking begins is 2.5 years (range ~1.5-6 years) [ The majority of affected individuals function in the moderate-to-severe range of intellectual disability, although individuals with mild intellectual disability have also been reported [ In one study the average age of using a first word was 2.75 years and the median age for using two words together was 3.5 years [ Language delay was more pronounced in males than females, with one small study of 20 affected individuals demonstrating that affected males were statistically significantly more likely to be nonverbal compared to affected females (p<.01) [ Impulsiveness Anxiety Poor social interaction Sleep disturbances Attention-deficit/hyperactivity disorder (ADHD) Behavioral issues in affected individuals is an ongoing active area of study. The degree of manifestation of these behavioral features is variable among individuals with XGS, and not all affected individuals will display these features. The median age of seizure onset is four years (range 9 months to ~12 years) [ Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. Seizures typically respond to standard anti-seizure medication. Most affected individuals have a normal birth weight but have poor postnatal growth due to feeding issues during infancy. Specific feeding problems may include difficulties with suck and swallowing, recurrent vomiting, and gastroesophageal reflux disease [ Growth hormone deficiency was revealed as the cause for short stature in two affected individuals, who eventually responded well to growth hormone replacement therapy [ Broad forehead Horizontal eyebrows Widely spaced eyes Downslanted or upslanted palpebral fissures Mild ptosis Depressed nasal bridge Low-set ears Thin vermilion of the upper lip Micrognathia Transverse palmar crease Sleep disturbance is also a common finding with some affected individuals reported to have abnormal breathing patterns, breath-holding episodes, and irregular breathing patterns at night. Many use respiratory support. CPAP, BiPAP, and supplementary oxygen have been used during sleep at night. Some affected individuals also have structural airway issues, including laryngomalacia and tracheomalacia. Surgical intervention may be pursued in some cases. These occurrences suggest the need for close monitoring of airway function and consideration of referral to pulmonology (see About one fifth of affected individuals who participated in a XGS registry had scoliosis (at ages 10~21 years) [ Some individuals have required surgery for scoliosis In a male age 55 years with XGS and loose soft skin, scoliosis was ascribed to connective tissue abnormalities [ Timely identification, intervention, and management of scoliosis is recommended to prevent life-threatening complications [ Some affected individuals have nystagmus, myopia, hyperopia, and/or ptosis. The severity of eye anomalies varies among individuals with XGS, with visual problems requiring correction and many affected individuals wearing glasses. Truncating pathogenic variants that arise near the N terminus of the protein have been associated with a statistically significant higher risk of developing seizures and scoliosis [ Similarly, truncating pathogenic variants at the C terminus of the protein are less likely to be associated with the development of seizures or scoliosis. The prevalence of XGS in the general population is estimated to be more than one in 80,000 live births with more than 270 individuals reported worldwide. Since many individuals with XGS may go undiagnosed due to lack of genomic testing (particularly in developing countries), the incidence may be greater than the current estimate. • Motor development delay is usually accompanied by poor coordination and gait disturbances, typically starting in early childhood. • The median age when walking begins is 2.5 years (range ~1.5-6 years) [ • The majority of affected individuals function in the moderate-to-severe range of intellectual disability, although individuals with mild intellectual disability have also been reported [ • In one study the average age of using a first word was 2.75 years and the median age for using two words together was 3.5 years [ • Language delay was more pronounced in males than females, with one small study of 20 affected individuals demonstrating that affected males were statistically significantly more likely to be nonverbal compared to affected females (p<.01) [ • Impulsiveness • Anxiety • Poor social interaction • Sleep disturbances • Attention-deficit/hyperactivity disorder (ADHD) • The median age of seizure onset is four years (range 9 months to ~12 years) [ • Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. • Seizures typically respond to standard anti-seizure medication. • The median age of seizure onset is four years (range 9 months to ~12 years) [ • Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. • Seizures typically respond to standard anti-seizure medication. • The median age of seizure onset is four years (range 9 months to ~12 years) [ • Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. • Seizures typically respond to standard anti-seizure medication. • Most affected individuals have a normal birth weight but have poor postnatal growth due to feeding issues during infancy. • Specific feeding problems may include difficulties with suck and swallowing, recurrent vomiting, and gastroesophageal reflux disease [ • Growth hormone deficiency was revealed as the cause for short stature in two affected individuals, who eventually responded well to growth hormone replacement therapy [ • Broad forehead • Horizontal eyebrows • Widely spaced eyes • Downslanted or upslanted palpebral fissures • Mild ptosis • Depressed nasal bridge • Low-set ears • Thin vermilion of the upper lip • Micrognathia • Transverse palmar crease • Sleep disturbance is also a common finding with some affected individuals reported to have abnormal breathing patterns, breath-holding episodes, and irregular breathing patterns at night. • Many use respiratory support. CPAP, BiPAP, and supplementary oxygen have been used during sleep at night. • Some affected individuals also have structural airway issues, including laryngomalacia and tracheomalacia. Surgical intervention may be pursued in some cases. • These occurrences suggest the need for close monitoring of airway function and consideration of referral to pulmonology (see • About one fifth of affected individuals who participated in a XGS registry had scoliosis (at ages 10~21 years) [ • Some individuals have required surgery for scoliosis • In a male age 55 years with XGS and loose soft skin, scoliosis was ascribed to connective tissue abnormalities [ • Timely identification, intervention, and management of scoliosis is recommended to prevent life-threatening complications [ • Some affected individuals have nystagmus, myopia, hyperopia, and/or ptosis. • The severity of eye anomalies varies among individuals with XGS, with visual problems requiring correction and many affected individuals wearing glasses. • Truncating pathogenic variants that arise near the N terminus of the protein have been associated with a statistically significant higher risk of developing seizures and scoliosis [ • Similarly, truncating pathogenic variants at the C terminus of the protein are less likely to be associated with the development of seizures or scoliosis. ## Clinical Description To date, approximately 280 individuals have been identified with a pathogenic variant in Select Features of Xia-Gibbs Syndrome ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability Motor development delay is usually accompanied by poor coordination and gait disturbances, typically starting in early childhood. The median age when walking begins is 2.5 years (range ~1.5-6 years) [ The majority of affected individuals function in the moderate-to-severe range of intellectual disability, although individuals with mild intellectual disability have also been reported [ In one study the average age of using a first word was 2.75 years and the median age for using two words together was 3.5 years [ Language delay was more pronounced in males than females, with one small study of 20 affected individuals demonstrating that affected males were statistically significantly more likely to be nonverbal compared to affected females (p<.01) [ Impulsiveness Anxiety Poor social interaction Sleep disturbances Attention-deficit/hyperactivity disorder (ADHD) Behavioral issues in affected individuals is an ongoing active area of study. The degree of manifestation of these behavioral features is variable among individuals with XGS, and not all affected individuals will display these features. The median age of seizure onset is four years (range 9 months to ~12 years) [ Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. Seizures typically respond to standard anti-seizure medication. Most affected individuals have a normal birth weight but have poor postnatal growth due to feeding issues during infancy. Specific feeding problems may include difficulties with suck and swallowing, recurrent vomiting, and gastroesophageal reflux disease [ Growth hormone deficiency was revealed as the cause for short stature in two affected individuals, who eventually responded well to growth hormone replacement therapy [ Broad forehead Horizontal eyebrows Widely spaced eyes Downslanted or upslanted palpebral fissures Mild ptosis Depressed nasal bridge Low-set ears Thin vermilion of the upper lip Micrognathia Transverse palmar crease Sleep disturbance is also a common finding with some affected individuals reported to have abnormal breathing patterns, breath-holding episodes, and irregular breathing patterns at night. Many use respiratory support. CPAP, BiPAP, and supplementary oxygen have been used during sleep at night. Some affected individuals also have structural airway issues, including laryngomalacia and tracheomalacia. Surgical intervention may be pursued in some cases. These occurrences suggest the need for close monitoring of airway function and consideration of referral to pulmonology (see About one fifth of affected individuals who participated in a XGS registry had scoliosis (at ages 10~21 years) [ Some individuals have required surgery for scoliosis In a male age 55 years with XGS and loose soft skin, scoliosis was ascribed to connective tissue abnormalities [ Timely identification, intervention, and management of scoliosis is recommended to prevent life-threatening complications [ Some affected individuals have nystagmus, myopia, hyperopia, and/or ptosis. The severity of eye anomalies varies among individuals with XGS, with visual problems requiring correction and many affected individuals wearing glasses. • Motor development delay is usually accompanied by poor coordination and gait disturbances, typically starting in early childhood. • The median age when walking begins is 2.5 years (range ~1.5-6 years) [ • The majority of affected individuals function in the moderate-to-severe range of intellectual disability, although individuals with mild intellectual disability have also been reported [ • In one study the average age of using a first word was 2.75 years and the median age for using two words together was 3.5 years [ • Language delay was more pronounced in males than females, with one small study of 20 affected individuals demonstrating that affected males were statistically significantly more likely to be nonverbal compared to affected females (p<.01) [ • Impulsiveness • Anxiety • Poor social interaction • Sleep disturbances • Attention-deficit/hyperactivity disorder (ADHD) • The median age of seizure onset is four years (range 9 months to ~12 years) [ • Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. • Seizures typically respond to standard anti-seizure medication. • The median age of seizure onset is four years (range 9 months to ~12 years) [ • Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. • Seizures typically respond to standard anti-seizure medication. • The median age of seizure onset is four years (range 9 months to ~12 years) [ • Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities. • Seizures typically respond to standard anti-seizure medication. • Most affected individuals have a normal birth weight but have poor postnatal growth due to feeding issues during infancy. • Specific feeding problems may include difficulties with suck and swallowing, recurrent vomiting, and gastroesophageal reflux disease [ • Growth hormone deficiency was revealed as the cause for short stature in two affected individuals, who eventually responded well to growth hormone replacement therapy [ • Broad forehead • Horizontal eyebrows • Widely spaced eyes • Downslanted or upslanted palpebral fissures • Mild ptosis • Depressed nasal bridge • Low-set ears • Thin vermilion of the upper lip • Micrognathia • Transverse palmar crease • Sleep disturbance is also a common finding with some affected individuals reported to have abnormal breathing patterns, breath-holding episodes, and irregular breathing patterns at night. • Many use respiratory support. CPAP, BiPAP, and supplementary oxygen have been used during sleep at night. • Some affected individuals also have structural airway issues, including laryngomalacia and tracheomalacia. Surgical intervention may be pursued in some cases. • These occurrences suggest the need for close monitoring of airway function and consideration of referral to pulmonology (see • About one fifth of affected individuals who participated in a XGS registry had scoliosis (at ages 10~21 years) [ • Some individuals have required surgery for scoliosis • In a male age 55 years with XGS and loose soft skin, scoliosis was ascribed to connective tissue abnormalities [ • Timely identification, intervention, and management of scoliosis is recommended to prevent life-threatening complications [ • Some affected individuals have nystagmus, myopia, hyperopia, and/or ptosis. • The severity of eye anomalies varies among individuals with XGS, with visual problems requiring correction and many affected individuals wearing glasses. ## Genotype-Phenotype Correlations Truncating pathogenic variants that arise near the N terminus of the protein have been associated with a statistically significant higher risk of developing seizures and scoliosis [ Similarly, truncating pathogenic variants at the C terminus of the protein are less likely to be associated with the development of seizures or scoliosis. • Truncating pathogenic variants that arise near the N terminus of the protein have been associated with a statistically significant higher risk of developing seizures and scoliosis [ • Similarly, truncating pathogenic variants at the C terminus of the protein are less likely to be associated with the development of seizures or scoliosis. ## Prevalence The prevalence of XGS in the general population is estimated to be more than one in 80,000 live births with more than 270 individuals reported worldwide. Since many individuals with XGS may go undiagnosed due to lack of genomic testing (particularly in developing countries), the incidence may be greater than the current estimate. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Because the clinical presentation of Xia-Gibbs syndrome (XGS) is typically nonspecific developmental delay (DD) and intellectual disability (ID), the phenotypic features alone are not sufficient to diagnose this condition. XGS should be considered as a differential diagnosis for individuals presenting with unexplained ID and DDs. All disorders associated with ID without other distinctive findings and childhood onset behavior disorder (particularly when associated with mild dysmorphic features, sleep apnea, seizures, or scoliosis) should be considered in the differential diagnosis. See ## Management To establish the extent of disease and needs in an individual diagnosed with Xia-Gibbs syndrome (XGS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Xia-Gibbs Syndrome To assess for growth deficiency & short stature Consider targeted assessment for growth hormone deficiency in those w/poor growth velocity. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl consideration of brain MRI if clinically indicated EEG if seizures suspected Eval of aspiration risk & nutritional status History of constipation & GERD Consider need for gastric tube placement. Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; XGS = Xia-Gibbs syndrome Although hearing loss is not commonly described in association with this condition, screening for occult hearing loss is often recommended in those who have developmental delay / intellectual disability that includes speech delay. Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Xia-Gibbs Syndrome Provide specialized instruction, OT, PT, & speech/behavioral therapies if indicated. Standard treatment for ADHD (may incl medication) Psychiatric consultation & therapy for those w/anxiety Many ASMs may be effective; none has been demonstrated effective specifically for XGS. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ABA = applied behavioral therapy; ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; CPAP = continuous positive airway pressure; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Xia-Gibbs Syndrome Eval of nutritional status & safety of oral intake Assess for signs & symptoms of GERD GERD = gastroesophageal reflux disease See Search • To assess for growth deficiency & short stature • Consider targeted assessment for growth hormone deficiency in those w/poor growth velocity. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl consideration of brain MRI if clinically indicated • EEG if seizures suspected • Eval of aspiration risk & nutritional status • History of constipation & GERD • Consider need for gastric tube placement. • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. • Provide specialized instruction, OT, PT, & speech/behavioral therapies if indicated. • Standard treatment for ADHD (may incl medication) • Psychiatric consultation & therapy for those w/anxiety • Many ASMs may be effective; none has been demonstrated effective specifically for XGS. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Eval of nutritional status & safety of oral intake • Assess for signs & symptoms of GERD ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Xia-Gibbs syndrome (XGS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Xia-Gibbs Syndrome To assess for growth deficiency & short stature Consider targeted assessment for growth hormone deficiency in those w/poor growth velocity. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl consideration of brain MRI if clinically indicated EEG if seizures suspected Eval of aspiration risk & nutritional status History of constipation & GERD Consider need for gastric tube placement. Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; XGS = Xia-Gibbs syndrome Although hearing loss is not commonly described in association with this condition, screening for occult hearing loss is often recommended in those who have developmental delay / intellectual disability that includes speech delay. Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To assess for growth deficiency & short stature • Consider targeted assessment for growth hormone deficiency in those w/poor growth velocity. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl consideration of brain MRI if clinically indicated • EEG if seizures suspected • Eval of aspiration risk & nutritional status • History of constipation & GERD • Consider need for gastric tube placement. • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Xia-Gibbs Syndrome Provide specialized instruction, OT, PT, & speech/behavioral therapies if indicated. Standard treatment for ADHD (may incl medication) Psychiatric consultation & therapy for those w/anxiety Many ASMs may be effective; none has been demonstrated effective specifically for XGS. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ABA = applied behavioral therapy; ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; CPAP = continuous positive airway pressure; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Provide specialized instruction, OT, PT, & speech/behavioral therapies if indicated. • Standard treatment for ADHD (may incl medication) • Psychiatric consultation & therapy for those w/anxiety • Many ASMs may be effective; none has been demonstrated effective specifically for XGS. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Xia-Gibbs Syndrome Eval of nutritional status & safety of oral intake Assess for signs & symptoms of GERD GERD = gastroesophageal reflux disease • Eval of nutritional status & safety of oral intake • Assess for signs & symptoms of GERD ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Xia-Gibbs syndrome (XGS) is an autosomal dominant disorder typically caused by a Most probands reported to date with XGS whose parents have undergone molecular genetic testing have the disorder as a result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to assess risk of recurrence. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ If a parent of the proband is known to have the If the Each child of an individual with XGS has a 50% chance of inheriting the Individuals with XGS are generally not known to reproduce; however, most are not yet of reproductive age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most probands reported to date with XGS whose parents have undergone molecular genetic testing have the disorder as a result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to assess risk of recurrence. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • If a parent of the proband is known to have the • If the • Each child of an individual with XGS has a 50% chance of inheriting the • Individuals with XGS are generally not known to reproduce; however, most are not yet of reproductive age. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance Xia-Gibbs syndrome (XGS) is an autosomal dominant disorder typically caused by a ## Risk to Family Members Most probands reported to date with XGS whose parents have undergone molecular genetic testing have the disorder as a result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to assess risk of recurrence. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ If a parent of the proband is known to have the If the Each child of an individual with XGS has a 50% chance of inheriting the Individuals with XGS are generally not known to reproduce; however, most are not yet of reproductive age. • Most probands reported to date with XGS whose parents have undergone molecular genetic testing have the disorder as a result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to assess risk of recurrence. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • If a parent of the proband is known to have the • If the • Each child of an individual with XGS has a 50% chance of inheriting the • Individuals with XGS are generally not known to reproduce; however, most are not yet of reproductive age. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 13402 Scenic Glade Drive Houston TX 77059 • • • 13402 Scenic Glade Drive • Houston TX 77059 • ## Molecular Genetics Xia-Gibbs Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Xia-Gibbs Syndrome ( Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Varuna Chander, MSPhD candidate, Molecular and Human GeneticsBaylor College of [email protected] Michael F Wangler, MDAssistant Professor, Molecular and Human GeneticsBaylor College of [email protected] page: Richard A Gibbs, PhDWofford Cain Chair and Professor, Molecular and Human GeneticsDirector, Human Genome Sequencing CenterBaylor College of Medicine [email protected] page: David Murdock, MD, FACMGAssistant Professor, Molecular and Human GeneticsAssistant Director, Human Genome Sequencing Center Clinical LaboratoryBaylor College of [email protected] page: We would like to thank all the family members participating in the 9 December 2021 (ma) Review posted live 21 June 2021 (dm) Original submission • 9 December 2021 (ma) Review posted live • 21 June 2021 (dm) Original submission ## Author Notes Varuna Chander, MSPhD candidate, Molecular and Human GeneticsBaylor College of [email protected] Michael F Wangler, MDAssistant Professor, Molecular and Human GeneticsBaylor College of [email protected] page: Richard A Gibbs, PhDWofford Cain Chair and Professor, Molecular and Human GeneticsDirector, Human Genome Sequencing CenterBaylor College of Medicine [email protected] page: David Murdock, MD, FACMGAssistant Professor, Molecular and Human GeneticsAssistant Director, Human Genome Sequencing Center Clinical LaboratoryBaylor College of [email protected] page: ## Acknowledgments We would like to thank all the family members participating in the ## Revision History 9 December 2021 (ma) Review posted live 21 June 2021 (dm) Original submission • 9 December 2021 (ma) Review posted live • 21 June 2021 (dm) Original submission ## References ## Literature Cited	[ "AC Cardoso-Dos-Santos, T Oliveira Silva, A Silveira Faccini, T Woycinck Kowalski, A Bertoli-Avella, JA Morales Saute, L Schuler-Faccini, F de Oliveira Poswar. Novel AHDC1 gene mutation in a Brazilian individual: implications of Xia-Gibbs syndrome.. Mol Syndromol. 2020;11:24-9", "X Cheng, F Tang, X Hu, H Li, M Li, Y Fu, L Yan, Z Li, P Gou, N Su, C Gong, W He, R Xiang, D Bu, Y. Shen. Two Chinese Xia-Gibbs syndrome patients with partial growth hormone deficiency.. Mol Genet Genomic Med. 2019;7", "S Della Vecchia, R Milone, R Cagiano, S Calderoni, E Santocchi, R Pasquariello, R Battini, F Muratori. Focusing on autism spectrum disorder in Xia-Gibbs syndrome: description of a female with high functioning autism and literature review.. Children (Basel) 2021;8:450", "L Díaz-Ordoñez, D Ramirez-Montaño, E Candelo, S Cruz, H Pachajoa. Syndromic intellectual disability caused by a novel truncating variant in AHDC1: a case report.. 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Rare mutations in AHDC1 in patients with obstructive sleep apnea.. Biomed Res Int. 2019;2019" ]	9/12/2021			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
xl-nystag	xl-nystag	[ "NYS1", "X-Linked Idiopathic Infantile Nystagmus", "NYS1", "X-Linked Idiopathic Infantile Nystagmus", "FERM domain-containing protein 7", "FRMD7", "FRMD7-Related Infantile Nystagmus" ]		Mervyn G Thomas, Gail Maconachie, Michael Hisaund, Irene Gottlob	Summary The diagnosis is based on clinical findings (including, when possible, ocular motility recordings). Identification of a hemizygous (in a male proband) or heterozygous (in a female proband) pathogenic variant in FIN is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Women who are carriers have a 50% chance of transmitting the pathogenic variant in each pregnancy. Carrier testing for at-risk female relatives and prenatal testing for a pregnancy at increased risk are possible once the pathogenic variant has been identified in the family.	## Diagnosis Currently there are no formal diagnostic clinical criteria for The diagnosis of Onset of nystagmus during infancy (age ≤6 months) Horizontal and conjugate nystagmus oscillations Visual acuity that is typically better than 0.3 LogMAR (Snellen equivalent 6/12) Good binocular vision and normal color vision Family history of nystagmus consistent with X-linked inheritance In some individuals: dampening of the nystagmus by convergence Less common findings: anomalous head posture (15% of affected individuals) and strabismus (8% of affected individuals) Affected individuals typically exhibit a pendular or jerk-related waveform with horizontal and conjugate oscillations. In the jerk waveform, the slow phase has an increasing velocity. Amplitude of nystagmus can be gaze dependent (i.e., small amplitude on central gaze when compared to left and right gaze). Amplitude and direction of the quick phase may be time dependent (periodic alternating nystagmus) [ Slit-lamp biomicroscopy (normal iris pigmentation with no iris transillumination) Fundoscopy Cranial MRI Electroretinogram Visual evoked potentials Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FIN is broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of FIN molecular genetic testing approaches can include Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For an introduction to multigene panels click When the diagnosis of FIN is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Includes males and heterozygous females Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Onset of nystagmus during infancy (age ≤6 months) • Horizontal and conjugate nystagmus oscillations • Visual acuity that is typically better than 0.3 LogMAR (Snellen equivalent 6/12) • Good binocular vision and normal color vision • Family history of nystagmus consistent with X-linked inheritance • In some individuals: dampening of the nystagmus by convergence • Less common findings: anomalous head posture (15% of affected individuals) and strabismus (8% of affected individuals) • Affected individuals typically exhibit a pendular or jerk-related waveform with horizontal and conjugate oscillations. In the jerk waveform, the slow phase has an increasing velocity. • Amplitude of nystagmus can be gaze dependent (i.e., small amplitude on central gaze when compared to left and right gaze). • Amplitude and direction of the quick phase may be time dependent (periodic alternating nystagmus) [ • Slit-lamp biomicroscopy (normal iris pigmentation with no iris transillumination) • Fundoscopy • Cranial MRI • Electroretinogram • Visual evoked potentials • Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For an introduction to multigene panels click ## Suggestive Findings The diagnosis of Onset of nystagmus during infancy (age ≤6 months) Horizontal and conjugate nystagmus oscillations Visual acuity that is typically better than 0.3 LogMAR (Snellen equivalent 6/12) Good binocular vision and normal color vision Family history of nystagmus consistent with X-linked inheritance In some individuals: dampening of the nystagmus by convergence Less common findings: anomalous head posture (15% of affected individuals) and strabismus (8% of affected individuals) Affected individuals typically exhibit a pendular or jerk-related waveform with horizontal and conjugate oscillations. In the jerk waveform, the slow phase has an increasing velocity. Amplitude of nystagmus can be gaze dependent (i.e., small amplitude on central gaze when compared to left and right gaze). Amplitude and direction of the quick phase may be time dependent (periodic alternating nystagmus) [ Slit-lamp biomicroscopy (normal iris pigmentation with no iris transillumination) Fundoscopy Cranial MRI Electroretinogram Visual evoked potentials • Onset of nystagmus during infancy (age ≤6 months) • Horizontal and conjugate nystagmus oscillations • Visual acuity that is typically better than 0.3 LogMAR (Snellen equivalent 6/12) • Good binocular vision and normal color vision • Family history of nystagmus consistent with X-linked inheritance • In some individuals: dampening of the nystagmus by convergence • Less common findings: anomalous head posture (15% of affected individuals) and strabismus (8% of affected individuals) • Affected individuals typically exhibit a pendular or jerk-related waveform with horizontal and conjugate oscillations. In the jerk waveform, the slow phase has an increasing velocity. • Amplitude of nystagmus can be gaze dependent (i.e., small amplitude on central gaze when compared to left and right gaze). • Amplitude and direction of the quick phase may be time dependent (periodic alternating nystagmus) [ • Slit-lamp biomicroscopy (normal iris pigmentation with no iris transillumination) • Fundoscopy • Cranial MRI • Electroretinogram • Visual evoked potentials ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FIN is broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of FIN molecular genetic testing approaches can include Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For an introduction to multigene panels click When the diagnosis of FIN is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Includes males and heterozygous females Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of FIN molecular genetic testing approaches can include Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For an introduction to multigene panels click • Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For an introduction to multigene panels click ## Option 2 When the diagnosis of FIN is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Includes males and heterozygous females Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Affected individuals usually develop nystagmus within the first six months of life; the mean age of onset is two months. Nystagmus can be gaze-dependent oscillations or time-dependent oscillations (periodic alternating nystagmus) [ Nystagmus waveform characteristics are established by eye movement recordings that assess the following (see Conjugacy Plane of oscillations (horizontal, vertical, and torsional) Pattern of oscillations (pendular, jerk, or bidirectional waveforms) Direction of oscillations (quick phase) Quantitative features of the waveform, including: Frequency Amplitude Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) Null point width (range of eye eccentricities in which the nystagmus is quietest) Note: The quantitative features of the waveform can only be evaluated using eye movement recordings. The above measurements also help in assessing the clinical severity of the nystagmus. Conventionally, intensity (product of amplitude and frequency) is measured in order to describe the severity of nystagmus; however, foveation correlates best with visual function scores. Foveation takes into account both the retinal image velocity and position of the image in relation to the fovea. An example of the measure of foveation is the NAFX (e Measuring intensity, foveation characteristics, and null point width before and after treatment provides an objective measure of the therapeutic response. Numerous studies have shown that the predominant waveform changes with age (see At the onset, large-amplitude, low-frequency horizontal eye movements (described as triangular eye movements) are seen. This waveform pattern is followed by a smaller-amplitude pendular or jerk waveform and development of foveation. Another study reported that the predominant waveform during the first six months was asymmetric pendular and jerk with extended foveation [ How the Infantile Nystagmus Waveform Evolves: An Example The infant was initially part of another study looking at normal visual development. In adults, a pendular waveform is more commonly associated with Individuals with FIN report good visual acuity (typically >6/12) because the nystagmus waveform is interrupted by a foveation period and, in contrast to other forms of infantile nystagmus, FIN is not the result of sensory abnormalities (e.g., reduced visual acuity resulting from foveal hypoplasia) (see An abnormal head posture is seen in approximately 15% of affected individuals. Affected individuals may assume an anomalous head posture if they have an eccentric null zone. Titubation of the head is observed in some individuals. However, affected individuals do not report any tremor of the limbs or trunk or any balance or coordination issues. Oscillopsia, the illusion of movement in one's surroundings, is very rarely reported in FIN. This may result in part from the presence of foveation periods during the waveform. However, an affected individual may complain of oscillopsia when looking at a position of gaze in which the nystagmus is more pronounced or when the individual is tired. Affected females report slightly better visual acuity than affected males. However, no notable differences in amplitude, frequency, and waveform of nystagmus are observed between males and females. The optokinetic response (OKR) is abnormal, with either low gains or reversal patterns described [ Optical coherence tomography studies have shown either normal fovea morphology or grade 1 foveal hypoplasia [ Studies have shown extensive intra- and interfamilial variability in the phenotype [ FIN with periodic alternating nystagmus is predominantly associated with Penetrance of Idiopathic infantile nystagmus (IIN) is a term used to describe nystagmus which presents at birth or infancy. There are no associated afferent or brain defects and IIN is characterized by normal electroretinograms and visual evoked potentials. If an Congenital motor nystagmus is an outdated term for IIN. Infantile nystagmus syndrome (INS) is an umbrella term used to describe different forms of infantile nystagmus (with or without sensory defects) characterized by an increasing slow phase velocity. The prevalence of IIN is estimated at 2:10,000 [ • Conjugacy • Plane of oscillations (horizontal, vertical, and torsional) • Pattern of oscillations (pendular, jerk, or bidirectional waveforms) • Direction of oscillations (quick phase) • Quantitative features of the waveform, including: • Frequency • Amplitude • Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) • Null point width (range of eye eccentricities in which the nystagmus is quietest) • Frequency • Amplitude • Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) • Null point width (range of eye eccentricities in which the nystagmus is quietest) • Frequency • Amplitude • Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) • Null point width (range of eye eccentricities in which the nystagmus is quietest) • Conventionally, intensity (product of amplitude and frequency) is measured in order to describe the severity of nystagmus; however, foveation correlates best with visual function scores. • Foveation takes into account both the retinal image velocity and position of the image in relation to the fovea. An example of the measure of foveation is the NAFX (e ## Clinical Description Affected individuals usually develop nystagmus within the first six months of life; the mean age of onset is two months. Nystagmus can be gaze-dependent oscillations or time-dependent oscillations (periodic alternating nystagmus) [ Nystagmus waveform characteristics are established by eye movement recordings that assess the following (see Conjugacy Plane of oscillations (horizontal, vertical, and torsional) Pattern of oscillations (pendular, jerk, or bidirectional waveforms) Direction of oscillations (quick phase) Quantitative features of the waveform, including: Frequency Amplitude Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) Null point width (range of eye eccentricities in which the nystagmus is quietest) Note: The quantitative features of the waveform can only be evaluated using eye movement recordings. The above measurements also help in assessing the clinical severity of the nystagmus. Conventionally, intensity (product of amplitude and frequency) is measured in order to describe the severity of nystagmus; however, foveation correlates best with visual function scores. Foveation takes into account both the retinal image velocity and position of the image in relation to the fovea. An example of the measure of foveation is the NAFX (e Measuring intensity, foveation characteristics, and null point width before and after treatment provides an objective measure of the therapeutic response. Numerous studies have shown that the predominant waveform changes with age (see At the onset, large-amplitude, low-frequency horizontal eye movements (described as triangular eye movements) are seen. This waveform pattern is followed by a smaller-amplitude pendular or jerk waveform and development of foveation. Another study reported that the predominant waveform during the first six months was asymmetric pendular and jerk with extended foveation [ How the Infantile Nystagmus Waveform Evolves: An Example The infant was initially part of another study looking at normal visual development. In adults, a pendular waveform is more commonly associated with Individuals with FIN report good visual acuity (typically >6/12) because the nystagmus waveform is interrupted by a foveation period and, in contrast to other forms of infantile nystagmus, FIN is not the result of sensory abnormalities (e.g., reduced visual acuity resulting from foveal hypoplasia) (see An abnormal head posture is seen in approximately 15% of affected individuals. Affected individuals may assume an anomalous head posture if they have an eccentric null zone. Titubation of the head is observed in some individuals. However, affected individuals do not report any tremor of the limbs or trunk or any balance or coordination issues. Oscillopsia, the illusion of movement in one's surroundings, is very rarely reported in FIN. This may result in part from the presence of foveation periods during the waveform. However, an affected individual may complain of oscillopsia when looking at a position of gaze in which the nystagmus is more pronounced or when the individual is tired. Affected females report slightly better visual acuity than affected males. However, no notable differences in amplitude, frequency, and waveform of nystagmus are observed between males and females. The optokinetic response (OKR) is abnormal, with either low gains or reversal patterns described [ Optical coherence tomography studies have shown either normal fovea morphology or grade 1 foveal hypoplasia [ • Conjugacy • Plane of oscillations (horizontal, vertical, and torsional) • Pattern of oscillations (pendular, jerk, or bidirectional waveforms) • Direction of oscillations (quick phase) • Quantitative features of the waveform, including: • Frequency • Amplitude • Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) • Null point width (range of eye eccentricities in which the nystagmus is quietest) • Frequency • Amplitude • Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) • Null point width (range of eye eccentricities in which the nystagmus is quietest) • Frequency • Amplitude • Foveation dynamics (foveation is the period during which the eyes remain relatively still and the image is incident on the fovea) • Null point width (range of eye eccentricities in which the nystagmus is quietest) • Conventionally, intensity (product of amplitude and frequency) is measured in order to describe the severity of nystagmus; however, foveation correlates best with visual function scores. • Foveation takes into account both the retinal image velocity and position of the image in relation to the fovea. An example of the measure of foveation is the NAFX (e ## Genotype-Phenotype Correlations Studies have shown extensive intra- and interfamilial variability in the phenotype [ FIN with periodic alternating nystagmus is predominantly associated with ## Penetrance Penetrance of ## Nomenclature Idiopathic infantile nystagmus (IIN) is a term used to describe nystagmus which presents at birth or infancy. There are no associated afferent or brain defects and IIN is characterized by normal electroretinograms and visual evoked potentials. If an Congenital motor nystagmus is an outdated term for IIN. Infantile nystagmus syndrome (INS) is an umbrella term used to describe different forms of infantile nystagmus (with or without sensory defects) characterized by an increasing slow phase velocity. ## Prevalence The prevalence of IIN is estimated at 2:10,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The diagnosis of Affected individuals rarely have a family history of nystagmus; in rare cases autosomal dominant inheritance has been reported [ Disorders to Consider in the Differential Diagnosis of Hypopigmentation of iris pigment epithelium Hypopigmentation of ocular fundus Foveal hypoplasia Misrouting of axons in optic chiasm Much poorer visual acuity (in all forms of albinism) Poor binocular vision; strabismus is common Ocular albinism type 1 (OMIM Infantile nystagmus Normal hair & skin pigmentation X-linked inheritance Partial OCA Immunodeficiency Mild bleeding tendency Neurologic findings during early adulthood ~85% develop the accelerated phase (lymphoproliferative infiltration of bone marrow & reticuloendothelial system) Reduced visual acuity Photophobia Small central scotoma Eccentric fixation Absent/markedly diminished ERG photopic response but normal/mildly abnormal scotopic response Characteristic lesion at the fovea w/outer nuclear layer thinning on optical coherence tomography Reduced visual acuity (but better than in Photophobia Reduced photopic ERG but well-preserved S cone ERG Infantile nystagmus Normal color vision Normal fundus examination Non-progressive retinal findings of reduced visual acuity, defective dark adaptation, refractive error, & strabismus Scotopic ERG shows severely reduced (or absent) b-waves in CSNB1 & reduced but measurable b-waves in CSNB2 (absent b-wave may be referred to as a "negative ERG." Visual acuity rarely >6/12 Oculodigital sign AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked All forms of albinism are characterized by infantile nystagmus. The most common forms of albinism are OCA and X-linked ocular albinism. See When color vision is difficult to test in young children, ERG can be used. Pathogenic variants in at least 17 genes are known to cause LCA (see LCA is a severe dystrophy of the retina typically evident in 1 Because measuring visual acuity in infants can be difficult, ERG is the test of choice for distinguishing between FIN and LCA in infants. • Hypopigmentation of iris pigment epithelium • Hypopigmentation of ocular fundus • Foveal hypoplasia • Misrouting of axons in optic chiasm • Much poorer visual acuity (in all forms of albinism) • Poor binocular vision; strabismus is common • Infantile nystagmus • Normal hair & skin pigmentation • X-linked inheritance • Partial OCA • Immunodeficiency • Mild bleeding tendency • Neurologic findings during early adulthood • ~85% develop the accelerated phase (lymphoproliferative infiltration of bone marrow & reticuloendothelial system) • Reduced visual acuity • Photophobia • Small central scotoma • Eccentric fixation • Absent/markedly diminished ERG photopic response but normal/mildly abnormal scotopic response • Characteristic lesion at the fovea w/outer nuclear layer thinning on optical coherence tomography • Reduced visual acuity (but better than in • Photophobia • Reduced photopic ERG but well-preserved S cone ERG • Infantile nystagmus • Normal color vision • Normal fundus examination • Non-progressive retinal findings of reduced visual acuity, defective dark adaptation, refractive error, & strabismus • Scotopic ERG shows severely reduced (or absent) b-waves in CSNB1 & reduced but measurable b-waves in CSNB2 (absent b-wave may be referred to as a "negative ERG." • Visual acuity rarely >6/12 • Oculodigital sign ## Management To establish the extent of disease in an individual diagnosed with Evaluation of visual acuity at different gaze positions Recording eye movements to evaluate the nystagmus waveform: Amplitude, frequency, and conjugacy Foveation dynamics Null point width determination In individuals with periodic alternating nystagmus, recording of cycle duration and the presence of an alternating head posture Consultation with a clinical geneticist and/or genetic counselor Correction of refractive errors as early as possible using contact lenses or appropriate refractive correction can improve visual acuity appreciably. Previously it was thought that contact lenses also had a role in dampening the intensity of the nystagmus. Although the mechanism is not clear, it has been suggested that dampening of the nystagmus may be exerted through the ophthalmic branch of the trigeminal nerve, which is part of the proprioceptive pathway [ The use of prisms may be helpful in individuals with binocular vision whose nystagmus is dampened by convergence. There are no fixed age groups for which prisms are prescribed; however, prisms are typically used in adults, teenagers, and cooperative children. Clinical trials to assess the role of horizontal rectus tenotomy and its effects on visual function found an improvement in nystagmus waveform and visual function [ Regular follow up, especially during childhood, is necessary to evaluate for development of vision, refractive errors, strabismus, and/or amblyopia. See Search • Evaluation of visual acuity at different gaze positions • Recording eye movements to evaluate the nystagmus waveform: • Amplitude, frequency, and conjugacy • Foveation dynamics • Null point width determination • Amplitude, frequency, and conjugacy • Foveation dynamics • Null point width determination • In individuals with periodic alternating nystagmus, recording of cycle duration and the presence of an alternating head posture • Consultation with a clinical geneticist and/or genetic counselor • Amplitude, frequency, and conjugacy • Foveation dynamics • Null point width determination • Correction of refractive errors as early as possible using contact lenses or appropriate refractive correction can improve visual acuity appreciably. Previously it was thought that contact lenses also had a role in dampening the intensity of the nystagmus. Although the mechanism is not clear, it has been suggested that dampening of the nystagmus may be exerted through the ophthalmic branch of the trigeminal nerve, which is part of the proprioceptive pathway [ • The use of prisms may be helpful in individuals with binocular vision whose nystagmus is dampened by convergence. There are no fixed age groups for which prisms are prescribed; however, prisms are typically used in adults, teenagers, and cooperative children. ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Evaluation of visual acuity at different gaze positions Recording eye movements to evaluate the nystagmus waveform: Amplitude, frequency, and conjugacy Foveation dynamics Null point width determination In individuals with periodic alternating nystagmus, recording of cycle duration and the presence of an alternating head posture Consultation with a clinical geneticist and/or genetic counselor • Evaluation of visual acuity at different gaze positions • Recording eye movements to evaluate the nystagmus waveform: • Amplitude, frequency, and conjugacy • Foveation dynamics • Null point width determination • Amplitude, frequency, and conjugacy • Foveation dynamics • Null point width determination • In individuals with periodic alternating nystagmus, recording of cycle duration and the presence of an alternating head posture • Consultation with a clinical geneticist and/or genetic counselor • Amplitude, frequency, and conjugacy • Foveation dynamics • Null point width determination ## Treatment of Manifestations Correction of refractive errors as early as possible using contact lenses or appropriate refractive correction can improve visual acuity appreciably. Previously it was thought that contact lenses also had a role in dampening the intensity of the nystagmus. Although the mechanism is not clear, it has been suggested that dampening of the nystagmus may be exerted through the ophthalmic branch of the trigeminal nerve, which is part of the proprioceptive pathway [ The use of prisms may be helpful in individuals with binocular vision whose nystagmus is dampened by convergence. There are no fixed age groups for which prisms are prescribed; however, prisms are typically used in adults, teenagers, and cooperative children. Clinical trials to assess the role of horizontal rectus tenotomy and its effects on visual function found an improvement in nystagmus waveform and visual function [ • Correction of refractive errors as early as possible using contact lenses or appropriate refractive correction can improve visual acuity appreciably. Previously it was thought that contact lenses also had a role in dampening the intensity of the nystagmus. Although the mechanism is not clear, it has been suggested that dampening of the nystagmus may be exerted through the ophthalmic branch of the trigeminal nerve, which is part of the proprioceptive pathway [ • The use of prisms may be helpful in individuals with binocular vision whose nystagmus is dampened by convergence. There are no fixed age groups for which prisms are prescribed; however, prisms are typically used in adults, teenagers, and cooperative children. ## Surveillance Regular follow up, especially during childhood, is necessary to evaluate for development of vision, refractive errors, strabismus, and/or amblyopia. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a A female with Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has an If the proband represents a simplex case (i.e., a single occurrence in the family) and if the If the mother of the proband has an If the father of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Affected males will transmit the pathogenic variant to all of their daughters (who will be heterozygotes and may or may not have nystagmus) and none of their sons. Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband. Note: (1) Females who are heterozygous for this X-linked disorder may or may not have nystagmus. (2) Identification of female heterozygotes requires either (a) prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • A female with • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in the family) and if the • If the mother of the proband has an • If the father of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Affected males will transmit the pathogenic variant to all of their daughters (who will be heterozygotes and may or may not have nystagmus) and none of their sons. • Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a A female with Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has an If the proband represents a simplex case (i.e., a single occurrence in the family) and if the If the mother of the proband has an If the father of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Affected males will transmit the pathogenic variant to all of their daughters (who will be heterozygotes and may or may not have nystagmus) and none of their sons. Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • A female with • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in the family) and if the • If the mother of the proband has an • If the father of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Affected males will transmit the pathogenic variant to all of their daughters (who will be heterozygotes and may or may not have nystagmus) and none of their sons. • Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. ## Heterozygote Detection Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband. Note: (1) Females who are heterozygous for this X-linked disorder may or may not have nystagmus. (2) Identification of female heterozygotes requires either (a) prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • United Kingdom • • • ## Molecular Genetics FRMD7-Related Infantile Nystagmus: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for FRMD7-Related Infantile Nystagmus ( ## Chapter Notes The authors would like to acknowledge the Ulverscroft Foundation, Medical Research Council, National Institute of Health Research and Fight for Sight for their support toward research into Irene Gottlob, MD, Univ Doz, FRCOphth (2009-present)Michael Hisaund, BSc (2018-present)Anil Kumar, MRCS, MRCOphth; University of Leicester (2009-2018)Gail Maconachie, BSc, PhD (2018-present)Frank A Proudlock, BSc, MSc, PhD; University of Leicester (2009-2018)Mervyn G Thomas, BSc (Hons), MBChB, PhD (2009-present)Shery Thomas, MRCOphth; University of Leicester (2009-2018) 16 August 2018 (sw) Comprehensive update posted live 29 September 2011 (me) Comprehensive update posted live 12 February 2009 (me) Review posted live 8 October 2008 (ig) Original submission • 16 August 2018 (sw) Comprehensive update posted live • 29 September 2011 (me) Comprehensive update posted live • 12 February 2009 (me) Review posted live • 8 October 2008 (ig) Original submission ## Acknowledgments The authors would like to acknowledge the Ulverscroft Foundation, Medical Research Council, National Institute of Health Research and Fight for Sight for their support toward research into ## Author History Irene Gottlob, MD, Univ Doz, FRCOphth (2009-present)Michael Hisaund, BSc (2018-present)Anil Kumar, MRCS, MRCOphth; University of Leicester (2009-2018)Gail Maconachie, BSc, PhD (2018-present)Frank A Proudlock, BSc, MSc, PhD; University of Leicester (2009-2018)Mervyn G Thomas, BSc (Hons), MBChB, PhD (2009-present)Shery Thomas, MRCOphth; University of Leicester (2009-2018) ## Revision History 16 August 2018 (sw) Comprehensive update posted live 29 September 2011 (me) Comprehensive update posted live 12 February 2009 (me) Review posted live 8 October 2008 (ig) Original submission • 16 August 2018 (sw) Comprehensive update posted live • 29 September 2011 (me) Comprehensive update posted live • 12 February 2009 (me) Review posted live • 8 October 2008 (ig) Original submission ## References ## Literature Cited Eye rotation can occur about three axes (X, Y, Z). Torsional eye movements occur along the line of sight (X); horizontal and vertical eye movements occur along the Z and Y axes, respectively. The oscillations seen in FIN occur only in the horizontal plane. The horizontal eye movement recordings in an individual with FIN (a) Gaze-dependent nystagmus. Note the right-beating pattern on right gaze. (b) Components of a jerk waveform. Note the increasing velocity of the slow phase and the foveation period. (c) The intensity of nystagmus calculated using amplitude and frequency (d) Conjugate oscillations	[ "B AlMoallem, M Bauwens, S Walraedt, P Delbeke, J De Zaeytijd, P Kestelyn, F Meire, S Janssens, C van Cauwenbergh, H Verdin, S Hooghe, P Kumar Thakur, F Coppieters, K De Leeneer, K Devriendt, BP Leroy, E De Baere. Novel FRMD7 mutations and genomic rearrangement expand the molecular pathogenesis of X-linked idiopathic infantile nystagmus.. 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Ophthalmology 2014;121:1827-36", "Y Kaplan, I Vargel, T Kansu, B Akin, E Rohmann, S Kamaci, E Uz, T Ozcelik, B Wollnik, NA Akarsu. Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene.. Br J Ophthalmol 2008;92:135-41", "JB Kerrison, MR Vagefi, MM Barmada, IH Maumenee. Congenital motor nystagmus linked to Xq26-q27.. Am J Hum Genet 1999;64:600-7", "C Klein, P Vieregge, W Heide, B Kemper, M Hagedorn-Greiwe, J Hagenah, C Vollmer, XO Breakefield, D Kompf, L Ozelius. Exclusion of chromosome regions 6p12 and 15q11, but not chromosome region 7p11, in a German family with autosomal dominant congenital nystagmus.. Genomics 1998;54:176-7", "N Li, L Wang, L Cui, L Zhang, S Dai, H Li, X Chen, L Zhu, JF Hejtmancik, K Zhao. Five novel mutations of the FRMD7 gene in Chinese families with X-linked infantile nystagmus.. Mol Vis 2008;14:733-8", "R McLean, F Proudlock, S Thomas, C Degg, I Gottlob. Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin.. Ann Neurol 2007;61:130-8", "J Pu, Y Li, Z Liu, Y Yan, J Tian, S Chen, B Zhang. Expression and localization of FRMD7 in human fetal brain, and a role for F-actin.. Mol Vis. 2011;17:591-7", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "N Sarvananthan, M Surendran, EO Roberts, S Jain, S Thomas, N Shah, FA Proudlock, JR Thompson, RJ McLean, C Degg, G Woodruff, I Gottlob. The prevalence of nystagmus: the Leicestershire nystagmus survey.. Invest Ophthalmol Vis Sci. 2009;50:5201-6", "DF Schorderet, L Tiab, MC Gaillard, B Lorenz, G Klainguti, JB Kerrison, EI Traboulsi, FL Munier. 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Mol Vis 2007;13:2233-41", "P Tarpey, S Thomas, N Sarvananthan, U Mallya, S Lisgo, CJ Talbot, EO Roberts, M Awan, M Surendran, RJ McLean, RD Reinecke, A Langmann, S Lindner, M Koch, S Jain, G Woodruff, RP Gale, C Degg, K Droutsas, I Asproudis, AA Zubcov, C Pieh, CD Veal, RD Machado, OC Backhouse, L Baumber, CS Constantinescu, MC Brodsky, DG Hunter, RW Hertle, RJ Read, S Edkins, S O'Meara, A Parker, C Stevens, J Teague, R Wooster, PA Futreal, RC Trembath, MR Stratton, FL Raymond, I Gottlob. Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.. Nat Genet 2006;38:1242-4", "MG Thomas, M Crosier, S Lindsay, A Kumar, S Thomas, M Araki, CJ Talbot, RJ McLean, M Surendran, K Taylor, BP Leroy, AT Moore, DG Hunter, RW Hertle, P Tarpey, A Langmann, S Lindner, M Brandner, I Gottlob. The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.. 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xla	xla	[ "Bruton's Agammaglobulinemia", "BTK Deficiency", "XLA", "Bruton's Agammaglobulinemia", "XLA", "BTK Deficiency", "Tyrosine-protein kinase BTK", "BTK", "X-Linked Agammaglobulinemia" ]	X-Linked Agammaglobulinemia	CI Edvard Smith, Anna Berglöf	Summary X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. The diagnosis of XLA is established in a male proband with characteristic clinical and laboratory findings and a hemizygous By definition, XLA is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother: if the mother has a	## Diagnosis X-linked agammaglobulinemia (XLA) Recurrent otitis, pneumonitis, sinusitis, and conjunctivitis starting before age five years A severe life-threatening bacterial infection such as sepsis, meningitis, cellulitis, or empyema Paucity of lymphoid tissue (small adenoids, tonsils, and lymph nodes on physical examination) The serum IgG concentration is typically 200 mg/dL. The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: (1) Because approximately 3%-5% of individuals with a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Agammaglobulinemia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays to detect genome-wide large deletions/duplications (including Approximately 3%-5% of individuals (a subset of the 8% detected by gene-targeted deletion/duplication analysis) with a • Recurrent otitis, pneumonitis, sinusitis, and conjunctivitis starting before age five years • A severe life-threatening bacterial infection such as sepsis, meningitis, cellulitis, or empyema • Paucity of lymphoid tissue (small adenoids, tonsils, and lymph nodes on physical examination) • The serum IgG concentration is typically 200 mg/dL. • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. • The serum IgG concentration is typically 200 mg/dL. • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. • The serum IgG concentration is typically 200 mg/dL. • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. ## Suggestive Findings X-linked agammaglobulinemia (XLA) Recurrent otitis, pneumonitis, sinusitis, and conjunctivitis starting before age five years A severe life-threatening bacterial infection such as sepsis, meningitis, cellulitis, or empyema Paucity of lymphoid tissue (small adenoids, tonsils, and lymph nodes on physical examination) The serum IgG concentration is typically 200 mg/dL. The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. • Recurrent otitis, pneumonitis, sinusitis, and conjunctivitis starting before age five years • A severe life-threatening bacterial infection such as sepsis, meningitis, cellulitis, or empyema • Paucity of lymphoid tissue (small adenoids, tonsils, and lymph nodes on physical examination) • The serum IgG concentration is typically 200 mg/dL. • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. • The serum IgG concentration is typically 200 mg/dL. • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. • The serum IgG concentration is typically 200 mg/dL. • The serum concentrations of IgM and IgA are typically <20 mg/dL. Particular attention should be given to serum IgM concentration. Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration, when combined with reduced IgA and IgG, is almost always associated with immunodeficiency. ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: (1) Because approximately 3%-5% of individuals with a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Agammaglobulinemia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays to detect genome-wide large deletions/duplications (including Approximately 3%-5% of individuals (a subset of the 8% detected by gene-targeted deletion/duplication analysis) with a ## Option 1 Note: (1) Because approximately 3%-5% of individuals with a For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Agammaglobulinemia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays to detect genome-wide large deletions/duplications (including Approximately 3%-5% of individuals (a subset of the 8% detected by gene-targeted deletion/duplication analysis) with a ## Clinical Characteristics Males with X-linked agammaglobulinemia (XLA) are usually well for the first few months of life because they are protected by transplacentally acquired maternal immunoglobulin. Typically, affected males develop recurrent bacterial infections in the first two years of life and are recognized as having immunodeficiency before age five years [ Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. Because males with XLA fail to make antibodies to vaccine antigens like tetanus, Individuals with XLA are not vulnerable to the majority of viral infections; however, they are susceptible to severe and chronic enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) [ Like all individuals with antibody deficiencies, persons with XLA are highly susceptible to giardia infection. They may also develop persistent mycoplasma infections. Infections with unusual organisms, like Approximately 10% of males with a hemizygous The prognosis for individuals with XLA has improved markedly in the last 35 years [ No strong correlation is observed between the specific Bruton called the disorder that he first described in 1952 "agammaglobulinemia" (despite low levels of detected immunoglobulins). The X-linked pattern of inheritance was noted shortly after that time. In the 1950s, 1960s, and 1970s, the disorder was sometimes called congenital agammaglobulinemia, familial hypogammaglobulinemia, infantile agammaglobulinemia, or simply agammaglobulinemia. Prevalence of X-linked agammaglobulinemia is approximately 3-6:1,000,000 males in all racial and ethnic groups. ## Clinical Description Males with X-linked agammaglobulinemia (XLA) are usually well for the first few months of life because they are protected by transplacentally acquired maternal immunoglobulin. Typically, affected males develop recurrent bacterial infections in the first two years of life and are recognized as having immunodeficiency before age five years [ Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. Because males with XLA fail to make antibodies to vaccine antigens like tetanus, Individuals with XLA are not vulnerable to the majority of viral infections; however, they are susceptible to severe and chronic enteroviral infections (often manifesting as dermatomyositis or chronic meningoencephalitis) [ Like all individuals with antibody deficiencies, persons with XLA are highly susceptible to giardia infection. They may also develop persistent mycoplasma infections. Infections with unusual organisms, like Approximately 10% of males with a hemizygous The prognosis for individuals with XLA has improved markedly in the last 35 years [ ## Genotype-Phenotype Correlations No strong correlation is observed between the specific ## Nomenclature Bruton called the disorder that he first described in 1952 "agammaglobulinemia" (despite low levels of detected immunoglobulins). The X-linked pattern of inheritance was noted shortly after that time. In the 1950s, 1960s, and 1970s, the disorder was sometimes called congenital agammaglobulinemia, familial hypogammaglobulinemia, infantile agammaglobulinemia, or simply agammaglobulinemia. ## Prevalence Prevalence of X-linked agammaglobulinemia is approximately 3-6:1,000,000 males in all racial and ethnic groups. ## Genetically Related Disorders No phenotypes other than those discussed in this ## Differential Diagnosis X-linked agammaglobulinemia (XLA) is the most common cause of agammaglobulinemia, accounting for approximately 85% of individuals with early onset of infections, panhypogammaglobulinemia, and markedly reduced numbers of B lymphocytes (CD19 The majority of females with an XLA-like phenotype and males with an XLA phenotype who do not have an identifiable The underlying defect remains unknown in a small percentage of individuals with congenital agammaglobulinemia and absent B cells [ X-Linked Agammaglobulinemia: Genes of Interest in the Differential Diagnosis of Congenital Agammaglobulinemia and Absent B Cells AD = autosomal dominant, AR = autosomal recessive; MOI = mode of inheritance At least 30 individuals with more than 20 different pathogenic variants in Low concentrations of serum immunoglobulins can be seen in a variety of conditions, including the following X-linked disorders: CD40 ligand deficiency (See However, individuals with these disorders usually have relatively normal or elevated numbers of B cells. • CD40 ligand deficiency (See • • ## Management No clinical practice guidelines specific for X-linked agammaglobulinemia (XLA) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with XLA, the evaluations summarized in X-Linked Agammaglobulinemia: Recommended Evaluations Following Initial Diagnosis CBC w/differential CRP Quantitative serum immunoglobulins & titers to vaccine antigens as baseline measurements prior to initiation of gammaglobulin substitution therapy CBC = complete blood count; CRP = C-reactive protein; MOI = mode of inheritance; XLA = X-linked agammaglobulinemia Medical geneticist, certified genetic counselor, certified advanced genetic nurse X-Linked Agammaglobulinemia: Targeted Therapy Occasionally, individuals with XLA have a reaction to gammaglobulin, consisting of headaches, chills, backache, or nausea. These reactions are more likely to occur when the individual has an intercurrent viral infection or when the brand of gammaglobulin has been changed. Such reactions may disappear over time. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Individuals with XLA should receive specialty care at a center with expertise in this disorder (see X-Linked Agammaglobulinemia: Treatment of Manifestations For example, an individual w/XLA contracted tick-borne encephalitis and developed severe disease, which might have been avoided by previous vaccination [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in X-Linked Agammaglobulinemia: Recommended Surveillance CBC w/differential Quantitative serum immunoglobulins to monitor gammaglobulin substitution therapy Chest radiographs or chest CT to assess for chronic lung disease Sinus imaging CBC = complete blood count If the individual is stable, the serum IgG does not need to be evaluated with every infusion of gammaglobulin. Live viral vaccines, particularly oral polio vaccine, should be avoided in individuals with XLA. It is appropriate to clarify the genetic status of at-risk male relatives as soon after birth as possible so that gammaglobulin substitution therapy can be initiated promptly in affected individuals and administration of live viral vaccines can be avoided. Note: Additional clinical evaluations can include analysis of the percentage of B cells in the peripheral circulation and physical examination with a focus on lymphoid tissues. Serum immunoglobulins will not be helpful in the evaluation of a newborn or infant because maternal IgG crosses the placenta. See Research studies exploring virus-mediated and oligonucleotide gene therapy for XLA have been conducted in mice [ Search • CBC w/differential • CRP • Quantitative serum immunoglobulins & titers to vaccine antigens as baseline measurements prior to initiation of gammaglobulin substitution therapy • CBC w/differential • Quantitative serum immunoglobulins to monitor gammaglobulin substitution therapy • Chest radiographs or chest CT to assess for chronic lung disease • Sinus imaging ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with XLA, the evaluations summarized in X-Linked Agammaglobulinemia: Recommended Evaluations Following Initial Diagnosis CBC w/differential CRP Quantitative serum immunoglobulins & titers to vaccine antigens as baseline measurements prior to initiation of gammaglobulin substitution therapy CBC = complete blood count; CRP = C-reactive protein; MOI = mode of inheritance; XLA = X-linked agammaglobulinemia Medical geneticist, certified genetic counselor, certified advanced genetic nurse • CBC w/differential • CRP • Quantitative serum immunoglobulins & titers to vaccine antigens as baseline measurements prior to initiation of gammaglobulin substitution therapy ## Treatment of Manifestations X-Linked Agammaglobulinemia: Targeted Therapy Occasionally, individuals with XLA have a reaction to gammaglobulin, consisting of headaches, chills, backache, or nausea. These reactions are more likely to occur when the individual has an intercurrent viral infection or when the brand of gammaglobulin has been changed. Such reactions may disappear over time. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Individuals with XLA should receive specialty care at a center with expertise in this disorder (see X-Linked Agammaglobulinemia: Treatment of Manifestations For example, an individual w/XLA contracted tick-borne encephalitis and developed severe disease, which might have been avoided by previous vaccination [ ## Targeted Therapy X-Linked Agammaglobulinemia: Targeted Therapy Occasionally, individuals with XLA have a reaction to gammaglobulin, consisting of headaches, chills, backache, or nausea. These reactions are more likely to occur when the individual has an intercurrent viral infection or when the brand of gammaglobulin has been changed. Such reactions may disappear over time. ## Supportive Care Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Individuals with XLA should receive specialty care at a center with expertise in this disorder (see X-Linked Agammaglobulinemia: Treatment of Manifestations For example, an individual w/XLA contracted tick-borne encephalitis and developed severe disease, which might have been avoided by previous vaccination [ ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in X-Linked Agammaglobulinemia: Recommended Surveillance CBC w/differential Quantitative serum immunoglobulins to monitor gammaglobulin substitution therapy Chest radiographs or chest CT to assess for chronic lung disease Sinus imaging CBC = complete blood count If the individual is stable, the serum IgG does not need to be evaluated with every infusion of gammaglobulin. • CBC w/differential • Quantitative serum immunoglobulins to monitor gammaglobulin substitution therapy • Chest radiographs or chest CT to assess for chronic lung disease • Sinus imaging ## Agents/Circumstances to Avoid Live viral vaccines, particularly oral polio vaccine, should be avoided in individuals with XLA. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of at-risk male relatives as soon after birth as possible so that gammaglobulin substitution therapy can be initiated promptly in affected individuals and administration of live viral vaccines can be avoided. Note: Additional clinical evaluations can include analysis of the percentage of B cells in the peripheral circulation and physical examination with a focus on lymphoid tissues. Serum immunoglobulins will not be helpful in the evaluation of a newborn or infant because maternal IgG crosses the placenta. See ## Therapies Under Investigation Research studies exploring virus-mediated and oligonucleotide gene therapy for XLA have been conducted in mice [ Search ## Genetic Counseling By definition, X-linked agammaglobulinemia (XLA) is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a female has more than one affected child and no other affected relatives and if the If a male is the only affected family member (50% of affected males represent simplex cases), the mother may be a heterozygote (carrier), the affected male may have a In about 80%-85% of families, the mother of an affected male is heterozygous for a About 15%-20% of affected males have XLA as the result of a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see If the proband represents a simplex case and the All of their daughters, who will be carriers and highly unlikely to be affected; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygous (carriers) for this X-linked disorder are highly unlikely to be affected. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a female has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (50% of affected males represent simplex cases), the mother may be a heterozygote (carrier), the affected male may have a • In about 80%-85% of families, the mother of an affected male is heterozygous for a • About 15%-20% of affected males have XLA as the result of a • In about 80%-85% of families, the mother of an affected male is heterozygous for a • About 15%-20% of affected males have XLA as the result of a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. • In about 80%-85% of families, the mother of an affected male is heterozygous for a • About 15%-20% of affected males have XLA as the result of a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see • If the proband represents a simplex case and the • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see • All of their daughters, who will be carriers and highly unlikely to be affected; • None of their sons. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance By definition, X-linked agammaglobulinemia (XLA) is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a female has more than one affected child and no other affected relatives and if the If a male is the only affected family member (50% of affected males represent simplex cases), the mother may be a heterozygote (carrier), the affected male may have a In about 80%-85% of families, the mother of an affected male is heterozygous for a About 15%-20% of affected males have XLA as the result of a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see If the proband represents a simplex case and the All of their daughters, who will be carriers and highly unlikely to be affected; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a female has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (50% of affected males represent simplex cases), the mother may be a heterozygote (carrier), the affected male may have a • In about 80%-85% of families, the mother of an affected male is heterozygous for a • About 15%-20% of affected males have XLA as the result of a • In about 80%-85% of families, the mother of an affected male is heterozygous for a • About 15%-20% of affected males have XLA as the result of a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. • In about 80%-85% of families, the mother of an affected male is heterozygous for a • About 15%-20% of affected males have XLA as the result of a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see • If the proband represents a simplex case and the • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and are highly unlikely to be affected (see • All of their daughters, who will be carriers and highly unlikely to be affected; • None of their sons. ## Carrier Detection Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygous (carriers) for this X-linked disorder are highly unlikely to be affected. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada • • Canada • • • • • • • ## Molecular Genetics X-Linked Agammaglobulinemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Agammaglobulinemia ( More than 1,000 different pathogenic variants in Several deep intronic pathogenic variants that would not be detected by routine sequence analysis have been reported [ Approximately 3%-5% of affected individuals who have a large deletion that extends through neighboring genes have XLA and ## Molecular Pathogenesis More than 1,000 different pathogenic variants in Several deep intronic pathogenic variants that would not be detected by routine sequence analysis have been reported [ Approximately 3%-5% of affected individuals who have a large deletion that extends through neighboring genes have XLA and ## Chapter Notes We are indebted to Dr Mauno Vihinen, University of Lund, who curates the BTKbase mutation database, and to Dr Peter Bergman, Karolinska Institutet, for clinical advice. This work was supported by the Swedish Cancer Society (CAN2013/389; 22 2361 Pj 01 H), the Swedish Medical Research Council (K2015-68X-11247-21-3) and the Swedish County Council (ALF-project 2012006; FoUI97465), and Center for Innovative Medicine (CIMED). Mary Ellen Conley, MD; St Jude Children’s Research Hospital (2001-2016)Vanessa C Howard, RN, MSN; St Jude Children’s Research Hospital (2001-2016)CI Edvard Smith, MD, PhD (2016-present)Anna Berglöf, PhD (2016-present) 27 June 2024 (sw) Comprehensive update posted live 4 August 2016 (bp) Comprehensive update posted live 17 November 2011 (me) Comprehensive update posted live 30 July 2009 (me) Comprehensive update posted live 21 December 2005 (me) Comprehensive update posted live 3 October 2003 (me) Comprehensive update posted live 5 April 2001 (me) Review posted live December 2000 (mec) Original submission • 27 June 2024 (sw) Comprehensive update posted live • 4 August 2016 (bp) Comprehensive update posted live • 17 November 2011 (me) Comprehensive update posted live • 30 July 2009 (me) Comprehensive update posted live • 21 December 2005 (me) Comprehensive update posted live • 3 October 2003 (me) Comprehensive update posted live • 5 April 2001 (me) Review posted live • December 2000 (mec) Original submission ## Author Notes ## Acknowledgments We are indebted to Dr Mauno Vihinen, University of Lund, who curates the BTKbase mutation database, and to Dr Peter Bergman, Karolinska Institutet, for clinical advice. This work was supported by the Swedish Cancer Society (CAN2013/389; 22 2361 Pj 01 H), the Swedish Medical Research Council (K2015-68X-11247-21-3) and the Swedish County Council (ALF-project 2012006; FoUI97465), and Center for Innovative Medicine (CIMED). ## Author History Mary Ellen Conley, MD; St Jude Children’s Research Hospital (2001-2016)Vanessa C Howard, RN, MSN; St Jude Children’s Research Hospital (2001-2016)CI Edvard Smith, MD, PhD (2016-present)Anna Berglöf, PhD (2016-present) ## Revision History 27 June 2024 (sw) Comprehensive update posted live 4 August 2016 (bp) Comprehensive update posted live 17 November 2011 (me) Comprehensive update posted live 30 July 2009 (me) Comprehensive update posted live 21 December 2005 (me) Comprehensive update posted live 3 October 2003 (me) Comprehensive update posted live 5 April 2001 (me) Review posted live December 2000 (mec) Original submission • 27 June 2024 (sw) Comprehensive update posted live • 4 August 2016 (bp) Comprehensive update posted live • 17 November 2011 (me) Comprehensive update posted live • 30 July 2009 (me) Comprehensive update posted live • 21 December 2005 (me) Comprehensive update posted live • 3 October 2003 (me) Comprehensive update posted live • 5 April 2001 (me) Review posted live • December 2000 (mec) Original submission ## Key Sections in This ## References ## Literature Cited	[]	5/4/2001	27/6/2024	4/11/2004	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
xlhi	xlhi	[ "HIGM1", "X-Linked Hyper-IgM Immunodeficiency (XHIGM)", "HIGM1", "X-Linked Hyper-IgM Immunodeficiency (XHIGM)", "CD40 ligand", "CD40LG", "X-Linked Hyper IgM Syndrome" ]	X-Linked Hyper IgM Syndrome	Clinton P Dunn, M Teresa de la Morena	Summary X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including The diagnosis of X-linked hyper IgM syndrome is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic variant in By definition, X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all their daughters and none of their sons. Women with a	## Diagnosis X-linked hyper IgM syndrome (HIGM1) Absent or low serum concentrations of IgG and IgA Normal or elevated serum concentrations of IgM Normal: Number and distribution of T, B, and NK lymphocyte subsets T-cell proliferation in response to mitogens Decreased expression of CD40L on the surface of activated CD4 cells (not universal) The diagnosis of HIGM1 The diagnosis of HIGM1 is extremely rare in a female, as heterozygous females are typically asymptomatic unless there is skewed X-chromosome inactivation (see Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-linked hyper IgM syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HIGM1 syndrome, molecular genetic testing approaches can include For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by immunodeficiency, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Hyper IgM Syndrome (HIGM1) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L. Note: Infants younger than age six months may not express normal amounts of CD40L protein [ Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells. NOTE: This testing should not be used as the only diagnostic test when HIGM1 is suspected. Up to 32% of individuals with HIGM1 may have normal extracellular domains of CD40L detected by this laboratory measure, which uses CD40L binding; but the intracellular signaling pathway from CD40L is nonfunctional, and thus genetic testing is required for diagnosis [ • Absent or low serum concentrations of IgG and IgA • Normal or elevated serum concentrations of IgM • Normal: • Number and distribution of T, B, and NK lymphocyte subsets • T-cell proliferation in response to mitogens • Number and distribution of T, B, and NK lymphocyte subsets • T-cell proliferation in response to mitogens • Decreased expression of CD40L on the surface of activated CD4 cells (not universal) • Number and distribution of T, B, and NK lymphocyte subsets • T-cell proliferation in response to mitogens • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click • Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L. • Note: Infants younger than age six months may not express normal amounts of CD40L protein [ • Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells. ## Suggestive Findings X-linked hyper IgM syndrome (HIGM1) Absent or low serum concentrations of IgG and IgA Normal or elevated serum concentrations of IgM Normal: Number and distribution of T, B, and NK lymphocyte subsets T-cell proliferation in response to mitogens Decreased expression of CD40L on the surface of activated CD4 cells (not universal) • Absent or low serum concentrations of IgG and IgA • Normal or elevated serum concentrations of IgM • Normal: • Number and distribution of T, B, and NK lymphocyte subsets • T-cell proliferation in response to mitogens • Number and distribution of T, B, and NK lymphocyte subsets • T-cell proliferation in response to mitogens • Decreased expression of CD40L on the surface of activated CD4 cells (not universal) • Number and distribution of T, B, and NK lymphocyte subsets • T-cell proliferation in response to mitogens ## Establishing the Diagnosis The diagnosis of HIGM1 The diagnosis of HIGM1 is extremely rare in a female, as heterozygous females are typically asymptomatic unless there is skewed X-chromosome inactivation (see Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-linked hyper IgM syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HIGM1 syndrome, molecular genetic testing approaches can include For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by immunodeficiency, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Hyper IgM Syndrome (HIGM1) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L. Note: Infants younger than age six months may not express normal amounts of CD40L protein [ Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells. NOTE: This testing should not be used as the only diagnostic test when HIGM1 is suspected. Up to 32% of individuals with HIGM1 may have normal extracellular domains of CD40L detected by this laboratory measure, which uses CD40L binding; but the intracellular signaling pathway from CD40L is nonfunctional, and thus genetic testing is required for diagnosis [ • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click • Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L. • Note: Infants younger than age six months may not express normal amounts of CD40L protein [ • Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells. ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of HIGM1 syndrome, molecular genetic testing approaches can include For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by immunodeficiency, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in X-Linked Hyper IgM Syndrome (HIGM1) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Additional Confirmatory Testing Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L. Note: Infants younger than age six months may not express normal amounts of CD40L protein [ Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells. NOTE: This testing should not be used as the only diagnostic test when HIGM1 is suspected. Up to 32% of individuals with HIGM1 may have normal extracellular domains of CD40L detected by this laboratory measure, which uses CD40L binding; but the intracellular signaling pathway from CD40L is nonfunctional, and thus genetic testing is required for diagnosis [ • Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L. • Note: Infants younger than age six months may not express normal amounts of CD40L protein [ • Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells. ## Clinical Characteristics X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE and normal or elevated serum concentrations of IgM. HIGM1 is due to defects or deficiencies in the CD40L protein that affect T cell communication with B lymphocytes. Mitogen proliferation may be normal but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years [ The presentation of HIGM1 across different ethnic backgrounds and in different countries has been shown to be consistent in the infectious organisms at present across all individuals with HIGM1 but they are also at risk for the pathogens that are endemic to their specific region [ The total number of B cells in circulation is normal, however, there is a marked reduction of class-switched memory B cells [ Histologic examination of lymph nodes shows absence of germinal center formation. Males with HIGM1 are also at increased risk for acute myelogenous leukemia and lymphoma, particularly Hodgkin disease associated with Epstein-Barr virus infection [ Hematopoietic stem cell transplant (HSCT) is the only curative therapy available for HIGM1. In a retrospective series of 130 affected individuals who had undergone HSCT, overall survival, event-free survival, and disease-free survival rates were respectively 78.2%, 58.1%, and 72.3% five years post HSCT [ Typically, heterozygous females are asymptomatic but on immunologic testing have been shown to have reduced expression of CD40L on activation of CD4+ T lymphocytes. Those females with more dramatic reduction in circulating lymphocytes with CD40L due to skewed X-chromosome inactivation can have a presentation similar to HIGM1 or common variable immunodeficiency [ Males with HIGM1 show remarkable variability in clinical symptoms. No specific genotype-phenotype correlations for The estimated prevalence of HIGM is 1:1,000,000 males [ HIGM1 has been reported in families of European, African, and Asian descent; thus, no evidence exists for a racial or ethnic predilection. ## Clinical Description X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE and normal or elevated serum concentrations of IgM. HIGM1 is due to defects or deficiencies in the CD40L protein that affect T cell communication with B lymphocytes. Mitogen proliferation may be normal but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years [ The presentation of HIGM1 across different ethnic backgrounds and in different countries has been shown to be consistent in the infectious organisms at present across all individuals with HIGM1 but they are also at risk for the pathogens that are endemic to their specific region [ The total number of B cells in circulation is normal, however, there is a marked reduction of class-switched memory B cells [ Histologic examination of lymph nodes shows absence of germinal center formation. Males with HIGM1 are also at increased risk for acute myelogenous leukemia and lymphoma, particularly Hodgkin disease associated with Epstein-Barr virus infection [ Hematopoietic stem cell transplant (HSCT) is the only curative therapy available for HIGM1. In a retrospective series of 130 affected individuals who had undergone HSCT, overall survival, event-free survival, and disease-free survival rates were respectively 78.2%, 58.1%, and 72.3% five years post HSCT [ Typically, heterozygous females are asymptomatic but on immunologic testing have been shown to have reduced expression of CD40L on activation of CD4+ T lymphocytes. Those females with more dramatic reduction in circulating lymphocytes with CD40L due to skewed X-chromosome inactivation can have a presentation similar to HIGM1 or common variable immunodeficiency [ ## Males The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years [ The presentation of HIGM1 across different ethnic backgrounds and in different countries has been shown to be consistent in the infectious organisms at present across all individuals with HIGM1 but they are also at risk for the pathogens that are endemic to their specific region [ The total number of B cells in circulation is normal, however, there is a marked reduction of class-switched memory B cells [ Histologic examination of lymph nodes shows absence of germinal center formation. Males with HIGM1 are also at increased risk for acute myelogenous leukemia and lymphoma, particularly Hodgkin disease associated with Epstein-Barr virus infection [ Hematopoietic stem cell transplant (HSCT) is the only curative therapy available for HIGM1. In a retrospective series of 130 affected individuals who had undergone HSCT, overall survival, event-free survival, and disease-free survival rates were respectively 78.2%, 58.1%, and 72.3% five years post HSCT [ ## Heterozygous Females Typically, heterozygous females are asymptomatic but on immunologic testing have been shown to have reduced expression of CD40L on activation of CD4+ T lymphocytes. Those females with more dramatic reduction in circulating lymphocytes with CD40L due to skewed X-chromosome inactivation can have a presentation similar to HIGM1 or common variable immunodeficiency [ ## Genotype-Phenotype Correlations Males with HIGM1 show remarkable variability in clinical symptoms. No specific genotype-phenotype correlations for ## Prevalence The estimated prevalence of HIGM is 1:1,000,000 males [ HIGM1 has been reported in families of European, African, and Asian descent; thus, no evidence exists for a racial or ethnic predilection. ## Genetically Related (Allelic) Disorders Duplication of ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of X-Linked Hyper IgM Syndrome (HIGM1) Opportunistic infections rare Lymphoid hyperplasia common; incl: hepatomegaly, splenomegaly, giant germinal centers, follicular hyperplasia. Autoimmunity w/hemolytic anemia more common Recurrent URTI, LRTI ↓ production of IgG, abnormalities in B cell differentiation No recurrent infections ↑ risk for cancers incl colorectal cancer, hereditary nonpolyposis colon cancer, & endometrial cancer Recurrent infections ↑ or normal IgM w/↓ IgG & IgA Normal B cell counts but ↓ memory B cells Café au lait spots Colorectal adenocarcinoma Recurrent sinopulmonary infections ↓ immunoglobulins incl IgG & IgA CD40LG protein may be ↓. No May be assoc w/↓ number of total T cells or ↓ T-cell function Most forms of SCID present w/absent T-cell function, quantitative abnormalities of T lymphocyte populations, & markedly ↓ mitogen function. Hypomorphic Males w/agammaglobulinemia should be considered in differential of HIGM1. XLA typically presents in 1st yr of life w/recurrent bacterial infections Serious infections, incl opportunistic infections, are a common complication at any age. Variable immunoglobulins from agammaglobulinemia to normal or ↑ IgM, ↓ IgG, & low/↑ IgA w/↓ memory B cells Invasive disease by MRSA & MSSA; osteopetrosis, lymphedema; conical shaped teeth Recurrent infections w/ Chronic lung disease ↑ IgM, ↓/normal IgG/IgA ↓ class-switched memory B cells Lymphoid hyperplasia Lymphopenia, ↓ T/B cell counts Severe response to herpes family virus (EBV, CMV, HSV, VZV) Recurrent URTI/LRTI, malignancy Normal/↑ IgM, normal to ↓ IgG/IgA, normal to ↓ T/B cells Ataxia, telangiectasias, hypotonia, dysarthria, radiosensitivity Lymphopenia, ↑ α-fetoprotein, variable mitogen & antigen response Recurrent URTI/LRTI, malignancy, autoimmune conditions (primarily hemolytic anemia) Variable immunoglobulins w/agammaglobulinemia to ↓ IgG/IgA & normal/↑ IgM Recurrent bacterial infections COPD ↓ IgG & IgA ↓ class-switched memory B cells AD = autosomal dominant; AR = autosomal recessive; COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; An autosomal dominant form of hyper IgM syndrome has been reported in four unrelated families with an identical pathogenic nonsense variant (p.Arg190Ter) in AICDA (reference sequence See Note: A growing list of rare causes of SCID-like phenotypes include pathogenic variants in the following additional genes: The differential diagnosis of HIGM1 also includes the following disorders: • Opportunistic infections rare • Lymphoid hyperplasia common; incl: hepatomegaly, splenomegaly, giant germinal centers, follicular hyperplasia. • Autoimmunity w/hemolytic anemia more common • Recurrent URTI, LRTI • ↓ production of IgG, abnormalities in B cell differentiation • No recurrent infections • ↑ risk for cancers incl colorectal cancer, hereditary nonpolyposis colon cancer, & endometrial cancer • Recurrent infections • ↑ or normal IgM w/↓ IgG & IgA • Normal B cell counts but ↓ memory B cells • Café au lait spots • Colorectal adenocarcinoma • Recurrent sinopulmonary infections • ↓ immunoglobulins incl IgG & IgA • CD40LG protein may be ↓. • No • May be assoc w/↓ number of total T cells or ↓ T-cell function • Most forms of SCID present w/absent T-cell function, quantitative abnormalities of T lymphocyte populations, & markedly ↓ mitogen function. • Hypomorphic • Males w/agammaglobulinemia should be considered in differential of HIGM1. • XLA typically presents in 1st yr of life w/recurrent bacterial infections • Serious infections, incl opportunistic infections, are a common complication at any age. • Variable immunoglobulins from agammaglobulinemia to normal or ↑ IgM, ↓ IgG, & low/↑ IgA w/↓ memory B cells • Invasive disease by MRSA & MSSA; osteopetrosis, lymphedema; conical shaped teeth • Recurrent infections w/ • Chronic lung disease • ↑ IgM, ↓/normal IgG/IgA • ↓ class-switched memory B cells • Lymphoid hyperplasia • Lymphopenia, ↓ T/B cell counts • Severe response to herpes family virus (EBV, CMV, HSV, VZV) • Recurrent URTI/LRTI, malignancy • Normal/↑ IgM, normal to ↓ IgG/IgA, normal to ↓ T/B cells • Ataxia, telangiectasias, hypotonia, dysarthria, radiosensitivity • Lymphopenia, ↑ α-fetoprotein, variable mitogen & antigen response • Recurrent URTI/LRTI, malignancy, autoimmune conditions (primarily hemolytic anemia) • Variable immunoglobulins w/agammaglobulinemia to ↓ IgG/IgA & normal/↑ IgM • Recurrent bacterial infections • COPD • ↓ IgG & IgA • ↓ class-switched memory B cells ## Management To establish the extent of disease and needs in an individual diagnosed with X-linked hyper IgM syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with X-Linked Hyper IgM Syndrome CBC w/differential IgG levels T, B, & NK cell numbers CBC = complete blood count; HLA = human leukocyte antigen; HSCT = hematopoietic stem cell transplant; PCR = polymerase chain reaction For a concise summary of current clinical management practices in this disorder, see Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome Immunoglobulin replacement w/intravenous or subcutaneous immunoglobulin starting at diagnosis Initial dosing for IgG replacement: 0.4-0.6 g/kg every 3-4 wks for IV, or ≥100 mg/kg dose weekly for subcutaneous Ig. Titrate IgG levels as for primary antibody deficiency syndromes. Prophylactic antibiotics against opportunistic infections incl Institute appropriate antimicrobial therapy for acute infections. Aggressively evaluate pulmonary infections (incl use of diagnostic bronchoalveolar lavage) to define specific etiology. Prevention of infections GCSF = granulocyte colony-stimulating factor; HSCT = hematopoietic stem-cell transplantation; The following methods are used to prevent infection: No guidelines have been published for ongoing surveillance in individuals with HIGM1. Recommended Surveillance for Individuals with X-Linked Hyper IgM Syndrome IgG frequency depends on time needed to achieve adequate IgG levels; similar to those w/primary antibody deficiency syndromes. Adults: at least yrly Children: at least every 4-6 mos or if change in clinical status Adults: at least 1-2x/yr or if change in clinical status Monitor growth in children. Measure weight in adolescents & adults at least 2x/yr Children: at every visit; at least every 4-6 mos Adolescents/adults: at least 2x/yr If any change in clinical status Children: at least every 4-6 mos Adolescents/adults: at least 1-2x/yr Low threshold for lymph node biopsy CBC = complete blood count; PCR = polymerase chain reaction Avoid areas that place the individual at risk of contracting Live vaccines (e.g., rotavirus, MMR, varicella, live attenuated polio, and BCG) should not be given to individuals with HIGM1. It is appropriate to clarify the genetic status of newborn at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and prompt initiation of treatment and prevention of infections. See Research into autologous gene corrective therapy is ongoing [ Search • CBC w/differential • IgG levels • T, B, & NK cell numbers • Immunoglobulin replacement w/intravenous or subcutaneous immunoglobulin starting at diagnosis • Initial dosing for IgG replacement: 0.4-0.6 g/kg every 3-4 wks for IV, or ≥100 mg/kg dose weekly for subcutaneous Ig. • Titrate IgG levels as for primary antibody deficiency syndromes. • Prophylactic antibiotics against opportunistic infections incl • Institute appropriate antimicrobial therapy for acute infections. • Aggressively evaluate pulmonary infections (incl use of diagnostic bronchoalveolar lavage) to define specific etiology. • Prevention of infections • IgG frequency depends on time needed to achieve adequate IgG levels; similar to those w/primary antibody deficiency syndromes. • Adults: at least yrly • Children: at least every 4-6 mos or if change in clinical status • Adults: at least 1-2x/yr or if change in clinical status • Monitor growth in children. • Measure weight in adolescents & adults at least 2x/yr • Children: at every visit; at least every 4-6 mos • Adolescents/adults: at least 2x/yr • If any change in clinical status • Children: at least every 4-6 mos • Adolescents/adults: at least 1-2x/yr • Low threshold for lymph node biopsy ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with X-linked hyper IgM syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with X-Linked Hyper IgM Syndrome CBC w/differential IgG levels T, B, & NK cell numbers CBC = complete blood count; HLA = human leukocyte antigen; HSCT = hematopoietic stem cell transplant; PCR = polymerase chain reaction • CBC w/differential • IgG levels • T, B, & NK cell numbers ## Treatment of Manifestations For a concise summary of current clinical management practices in this disorder, see Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome Immunoglobulin replacement w/intravenous or subcutaneous immunoglobulin starting at diagnosis Initial dosing for IgG replacement: 0.4-0.6 g/kg every 3-4 wks for IV, or ≥100 mg/kg dose weekly for subcutaneous Ig. Titrate IgG levels as for primary antibody deficiency syndromes. Prophylactic antibiotics against opportunistic infections incl Institute appropriate antimicrobial therapy for acute infections. Aggressively evaluate pulmonary infections (incl use of diagnostic bronchoalveolar lavage) to define specific etiology. Prevention of infections GCSF = granulocyte colony-stimulating factor; HSCT = hematopoietic stem-cell transplantation; The following methods are used to prevent infection: • Immunoglobulin replacement w/intravenous or subcutaneous immunoglobulin starting at diagnosis • Initial dosing for IgG replacement: 0.4-0.6 g/kg every 3-4 wks for IV, or ≥100 mg/kg dose weekly for subcutaneous Ig. • Titrate IgG levels as for primary antibody deficiency syndromes. • Prophylactic antibiotics against opportunistic infections incl • Institute appropriate antimicrobial therapy for acute infections. • Aggressively evaluate pulmonary infections (incl use of diagnostic bronchoalveolar lavage) to define specific etiology. • Prevention of infections ## Surveillance No guidelines have been published for ongoing surveillance in individuals with HIGM1. Recommended Surveillance for Individuals with X-Linked Hyper IgM Syndrome IgG frequency depends on time needed to achieve adequate IgG levels; similar to those w/primary antibody deficiency syndromes. Adults: at least yrly Children: at least every 4-6 mos or if change in clinical status Adults: at least 1-2x/yr or if change in clinical status Monitor growth in children. Measure weight in adolescents & adults at least 2x/yr Children: at every visit; at least every 4-6 mos Adolescents/adults: at least 2x/yr If any change in clinical status Children: at least every 4-6 mos Adolescents/adults: at least 1-2x/yr Low threshold for lymph node biopsy CBC = complete blood count; PCR = polymerase chain reaction • IgG frequency depends on time needed to achieve adequate IgG levels; similar to those w/primary antibody deficiency syndromes. • Adults: at least yrly • Children: at least every 4-6 mos or if change in clinical status • Adults: at least 1-2x/yr or if change in clinical status • Monitor growth in children. • Measure weight in adolescents & adults at least 2x/yr • Children: at every visit; at least every 4-6 mos • Adolescents/adults: at least 2x/yr • If any change in clinical status • Children: at least every 4-6 mos • Adolescents/adults: at least 1-2x/yr • Low threshold for lymph node biopsy ## Agents/Circumstances to Avoid Avoid areas that place the individual at risk of contracting Live vaccines (e.g., rotavirus, MMR, varicella, live attenuated polio, and BCG) should not be given to individuals with HIGM1. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of newborn at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and prompt initiation of treatment and prevention of infections. See ## Therapies Under Investigation Research into autologous gene corrective therapy is ongoing [ Search ## Genetic Counseling X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner. The father of an affected male will not have HIGM1 nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother is heterozygous for the If the proband represents a simplex case and if the All of their daughters, who will typically be asymptomatic but may have a range of clinical manifestations depending on X-chromosome inactivation (see Clinical Description, None of their sons. A male proband's maternal aunts or other maternal relatives and their offspring may be at risk of being heterozygous for a Note: Molecular genetic testing may be able to identify the family member in whom a Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in an affected male relative. If an affected male is not available for testing, perform molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis. Note: CD40L expression by flow cytometry may be helpful but is not a diagnostic test for the detection of heterozygotes. See Management, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have HIGM1 nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother is heterozygous for the • If the proband represents a simplex case and if the • All of their daughters, who will typically be asymptomatic but may have a range of clinical manifestations depending on X-chromosome inactivation (see Clinical Description, • None of their sons. • A male proband's maternal aunts or other maternal relatives and their offspring may be at risk of being heterozygous for a • Note: Molecular genetic testing may be able to identify the family member in whom a • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance X-linked hyper IgM syndrome (HIGM1) is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have HIGM1 nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother is heterozygous for the If the proband represents a simplex case and if the All of their daughters, who will typically be asymptomatic but may have a range of clinical manifestations depending on X-chromosome inactivation (see Clinical Description, None of their sons. A male proband's maternal aunts or other maternal relatives and their offspring may be at risk of being heterozygous for a Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have HIGM1 nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother is heterozygous for the • If the proband represents a simplex case and if the • All of their daughters, who will typically be asymptomatic but may have a range of clinical manifestations depending on X-chromosome inactivation (see Clinical Description, • None of their sons. • A male proband's maternal aunts or other maternal relatives and their offspring may be at risk of being heterozygous for a • Note: Molecular genetic testing may be able to identify the family member in whom a ## Heterozygote Detection Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in an affected male relative. If an affected male is not available for testing, perform molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis. Note: CD40L expression by flow cytometry may be helpful but is not a diagnostic test for the detection of heterozygotes. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada • • • • • • Canada • • • • • • • ## Molecular Genetics X-Linked Hyper IgM Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Hyper IgM Syndrome ( Pathogenic variants in Flow cytometry using anti-CD40L monoclonal antibodies can confirm the diagnosis of HIGM1 in some affected individuals: Those who produce no CD40L protein on the surface of CD4+ cells due to missense or frameshift variants Those who produce an altered protein structure of CD40L, preventing anti-CD40L antibody binding Anti-CD40L antibody testing will not identify affected individuals with pathogenic variants in the intracellular tail or those producing reduced amounts of normal CD40L. Notable Variants listed in the table have been provided by the authors. • Those who produce no CD40L protein on the surface of CD4+ cells due to missense or frameshift variants • Those who produce an altered protein structure of CD40L, preventing anti-CD40L antibody binding ## Molecular Pathogenesis Pathogenic variants in Flow cytometry using anti-CD40L monoclonal antibodies can confirm the diagnosis of HIGM1 in some affected individuals: Those who produce no CD40L protein on the surface of CD4+ cells due to missense or frameshift variants Those who produce an altered protein structure of CD40L, preventing anti-CD40L antibody binding Anti-CD40L antibody testing will not identify affected individuals with pathogenic variants in the intracellular tail or those producing reduced amounts of normal CD40L. Notable Variants listed in the table have been provided by the authors. • Those who produce no CD40L protein on the surface of CD4+ cells due to missense or frameshift variants • Those who produce an altered protein structure of CD40L, preventing anti-CD40L antibody binding ## Chapter Notes M Teresa de la Morena, MD (2020-present)Clinton P Dunn, MD (2020-present)Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2007-2020)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2007-2020)Kejian Zhang, MD, MBA; Cincinnati Children's Hospital Medical Center (2007-2020) 20 February 2020 (ha) Comprehensive update posted live 24 January 2013 (cd) Revision: deletion/duplication analysis available clinically 21 June 2012 (me) Comprehensive update posted live 2 February 2010 (me) Comprehensive update posted live 31 May 2007 (me) Review posted live 20 February 2007 (jj) Original submission • 20 February 2020 (ha) Comprehensive update posted live • 24 January 2013 (cd) Revision: deletion/duplication analysis available clinically • 21 June 2012 (me) Comprehensive update posted live • 2 February 2010 (me) Comprehensive update posted live • 31 May 2007 (me) Review posted live • 20 February 2007 (jj) Original submission ## Author History M Teresa de la Morena, MD (2020-present)Clinton P Dunn, MD (2020-present)Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2007-2020)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2007-2020)Kejian Zhang, MD, MBA; Cincinnati Children's Hospital Medical Center (2007-2020) ## Revision History 20 February 2020 (ha) Comprehensive update posted live 24 January 2013 (cd) Revision: deletion/duplication analysis available clinically 21 June 2012 (me) Comprehensive update posted live 2 February 2010 (me) Comprehensive update posted live 31 May 2007 (me) Review posted live 20 February 2007 (jj) Original submission • 20 February 2020 (ha) Comprehensive update posted live • 24 January 2013 (cd) Revision: deletion/duplication analysis available clinically • 21 June 2012 (me) Comprehensive update posted live • 2 February 2010 (me) Comprehensive update posted live • 31 May 2007 (me) Review posted live • 20 February 2007 (jj) Original submission ## References ## Literature Cited	[ "JK Abbott, EW Gelfand. 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xlmr	xlmr	[ "ATR-X Syndrome", "ATR-X Syndrome", "Transcriptional regulator ATRX", "ATRX", "Alpha-Thalassemia X-Linked Intellectual Disability Syndrome" ]	Alpha-Thalassemia X-Linked Intellectual Disability Syndrome	Roger E Stevenson	Summary Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants. The diagnosis of ATR-X syndrome is established in a proband with suggestive findings, a 46,XY karyotype, and a hemizygous pathogenic variant in ATR-X syndrome is inherited in an X-linked manner. The mother of a proband may be heterozygous (i.e., a carrier) or the affected individual may have a	## Diagnosis Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome A recognizable pattern of craniofacial findings including small head circumference, upsweep of the frontal hair, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, thick or everted lower lip, and open mouth. Irregular anatomy of the pinnae, widely spaced teeth, and protruding tongue are supplemental findings, the latter two adding to a coarseness of the facial appearance, particularly after the first few years of life. Growth impairment including microcephaly and short stature, usually present at birth Genital anomalies (in an individual with a 46,XY karyotype) that can range from hypospadias and undescended testes to ambiguous genitalia to normal external female genitalia Developmental delay / intellectual disability, typically in the severe-to-profound range The diagnosis of ATR-X syndrome Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ATR-X Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Based on data from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, of note: whole-gene duplications but not deletions have been reported. Breakpoints of large duplications and/or duplication of adjacent genes (e.g., those described by • A recognizable pattern of craniofacial findings including small head circumference, upsweep of the frontal hair, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, thick or everted lower lip, and open mouth. Irregular anatomy of the pinnae, widely spaced teeth, and protruding tongue are supplemental findings, the latter two adding to a coarseness of the facial appearance, particularly after the first few years of life. • Growth impairment including microcephaly and short stature, usually present at birth • Genital anomalies (in an individual with a 46,XY karyotype) that can range from hypospadias and undescended testes to ambiguous genitalia to normal external female genitalia • Developmental delay / intellectual disability, typically in the severe-to-profound range ## Establishing the Diagnosis The diagnosis of ATR-X syndrome Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ATR-X Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Based on data from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, of note: whole-gene duplications but not deletions have been reported. Breakpoints of large duplications and/or duplication of adjacent genes (e.g., those described by ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ATR-X Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Based on data from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, of note: whole-gene duplications but not deletions have been reported. Breakpoints of large duplications and/or duplication of adjacent genes (e.g., those described by ## Other Testing ## Clinical Characteristics A more or less distinctive phenotype is characteristic of alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome. Craniofacial, genital, and developmental manifestations are prominent among the most severely affected individuals [ As additional individuals/families have been evaluated using molecular genetic testing, the range of phenotypic variability has broadened, particularly on the mild end of the spectrum. Affected males may have mild, moderate, or profound intellectual disability (ID), even within the same family. Adults in the family described by Selected Features of Alpha-thalassemia X-linked Intellectual Disability Syndrome Hypertelorism/telecanthus Small nose Tented upper lip Open mouth Prominent lips Severe developmental impairment and intellectual disability are the most important clinical manifestations. From the outset, developmental milestones are globally and markedly delayed. Speech and ambulation occur late in childhood. Some affected individuals never walk independently or develop significant speech. Growth impairment with microcephaly and short stature occurs in most individuals with ATR-X syndrome and is often present at birth. Stature is typically short (>2 SD below the mean in 67% of individuals using standard growth charts; syndrome-specific growth charts are not available). Growth above average is exceptional. Gastrointestinal manifestations, present in the majority of individuals, contribute significantly to morbidity. Approximately three fourths have gastroesophageal reflux and one third have chronic constipation. Gastric pseudo-obstruction can result from abnormal suspension of the stomach and constipation can result from colon hypoganglionosis [ Genital anomalies are often minor, including first-degree hypospadias, undescended testes, and underdevelopment of the scrotum. Although all individuals with ATR-X syndrome have a normal 46,XY karyotype, gonadal dysgenesis resulting in inadequate testosterone production can cause more severe defects that can include second- and third-degree hypospadias, small penis, ambiguous genitalia, or even normal-appearing female external genitalia. Although all individuals with ATR-X syndrome have a normal 46,XY karyotype, occasionally gonadal dysgenesis results in inadequate testosterone production and ambiguous genitalia. Although the spectrum of possible genital anomalies in ATR-X syndrome is broad, the type of genital anomaly appears to be consistent within a family. Hypotonia, a hallmark of ATR-X syndrome, contributes to the facial manifestations, drooling, developmental delay, and possibly to the gastrointestinal manifestations. Seizures of various types occur in about one third of individuals with ATR-X syndrome but are not a defining manifestation of the syndrome [ The Although One individual with two metachronous osteosarcomas, the first (of the tibia) diagnosed and successfully treated at age nine years, and the second (of the humerus) diagnosed and successfully treated ten years later at age 20 years One child, diagnosed with osteosarcoma of the femur with pulmonary nodules at age four years, who succumbed 18 months later Heterozygous females rarely show clinical manifestations. Typically, carrier females have marked skewing of X-chromosome inactivation (>90:10) with preferential inactivation of the X chromosome with the A five-generation pedigree in which three females had signs of ATR-X syndrome [ Moderate ID without other phenotypic features of ATR-X syndrome in a female carrier with random X-chromosome inactivation [ A girl conceived by in vitro fertilization (IVF) who had craniofacial features, growth restriction, and developmental impairment typical of ATR-X syndrome [ Pathogenic variants that affect the ATRX zinc finger domain produce severe psychomotor impairment and urogenital anomalies, whereas pathogenic variants in the helicase domains cause milder phenotypes [ More severe genital anomalies occur with variants in the plant homeodomain-like domain. A nonsense variant in exon 2 ( "Alpha-thalassemia X-linked intellectual disability syndrome" and "ATR-X syndrome" are the preferred designations for this disorder. Note: A family considered to have Juberg-Marsidi syndrome had an Although two families considered to have Smith-Fineman-Myers syndrome have The prevalence is not known. More than 200 affected individuals are known to the laboratories conducting molecular genetic testing; substantial underascertainment, especially of those with milder phenotypes, is probable. No racial or ethnic concentration of individuals has been reported. • Hypertelorism/telecanthus • Small nose • Tented upper lip • Open mouth • Prominent lips • One individual with two metachronous osteosarcomas, the first (of the tibia) diagnosed and successfully treated at age nine years, and the second (of the humerus) diagnosed and successfully treated ten years later at age 20 years • One child, diagnosed with osteosarcoma of the femur with pulmonary nodules at age four years, who succumbed 18 months later • A five-generation pedigree in which three females had signs of ATR-X syndrome [ • Moderate ID without other phenotypic features of ATR-X syndrome in a female carrier with random X-chromosome inactivation [ • A girl conceived by in vitro fertilization (IVF) who had craniofacial features, growth restriction, and developmental impairment typical of ATR-X syndrome [ ## Clinical Description A more or less distinctive phenotype is characteristic of alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome. Craniofacial, genital, and developmental manifestations are prominent among the most severely affected individuals [ As additional individuals/families have been evaluated using molecular genetic testing, the range of phenotypic variability has broadened, particularly on the mild end of the spectrum. Affected males may have mild, moderate, or profound intellectual disability (ID), even within the same family. Adults in the family described by Selected Features of Alpha-thalassemia X-linked Intellectual Disability Syndrome Hypertelorism/telecanthus Small nose Tented upper lip Open mouth Prominent lips Severe developmental impairment and intellectual disability are the most important clinical manifestations. From the outset, developmental milestones are globally and markedly delayed. Speech and ambulation occur late in childhood. Some affected individuals never walk independently or develop significant speech. Growth impairment with microcephaly and short stature occurs in most individuals with ATR-X syndrome and is often present at birth. Stature is typically short (>2 SD below the mean in 67% of individuals using standard growth charts; syndrome-specific growth charts are not available). Growth above average is exceptional. Gastrointestinal manifestations, present in the majority of individuals, contribute significantly to morbidity. Approximately three fourths have gastroesophageal reflux and one third have chronic constipation. Gastric pseudo-obstruction can result from abnormal suspension of the stomach and constipation can result from colon hypoganglionosis [ Genital anomalies are often minor, including first-degree hypospadias, undescended testes, and underdevelopment of the scrotum. Although all individuals with ATR-X syndrome have a normal 46,XY karyotype, gonadal dysgenesis resulting in inadequate testosterone production can cause more severe defects that can include second- and third-degree hypospadias, small penis, ambiguous genitalia, or even normal-appearing female external genitalia. Although all individuals with ATR-X syndrome have a normal 46,XY karyotype, occasionally gonadal dysgenesis results in inadequate testosterone production and ambiguous genitalia. Although the spectrum of possible genital anomalies in ATR-X syndrome is broad, the type of genital anomaly appears to be consistent within a family. Hypotonia, a hallmark of ATR-X syndrome, contributes to the facial manifestations, drooling, developmental delay, and possibly to the gastrointestinal manifestations. Seizures of various types occur in about one third of individuals with ATR-X syndrome but are not a defining manifestation of the syndrome [ The Although One individual with two metachronous osteosarcomas, the first (of the tibia) diagnosed and successfully treated at age nine years, and the second (of the humerus) diagnosed and successfully treated ten years later at age 20 years One child, diagnosed with osteosarcoma of the femur with pulmonary nodules at age four years, who succumbed 18 months later Heterozygous females rarely show clinical manifestations. Typically, carrier females have marked skewing of X-chromosome inactivation (>90:10) with preferential inactivation of the X chromosome with the A five-generation pedigree in which three females had signs of ATR-X syndrome [ Moderate ID without other phenotypic features of ATR-X syndrome in a female carrier with random X-chromosome inactivation [ A girl conceived by in vitro fertilization (IVF) who had craniofacial features, growth restriction, and developmental impairment typical of ATR-X syndrome [ • Hypertelorism/telecanthus • Small nose • Tented upper lip • Open mouth • Prominent lips • One individual with two metachronous osteosarcomas, the first (of the tibia) diagnosed and successfully treated at age nine years, and the second (of the humerus) diagnosed and successfully treated ten years later at age 20 years • One child, diagnosed with osteosarcoma of the femur with pulmonary nodules at age four years, who succumbed 18 months later • A five-generation pedigree in which three females had signs of ATR-X syndrome [ • Moderate ID without other phenotypic features of ATR-X syndrome in a female carrier with random X-chromosome inactivation [ • A girl conceived by in vitro fertilization (IVF) who had craniofacial features, growth restriction, and developmental impairment typical of ATR-X syndrome [ ## Developmental Impairment / Intellectual Disability Severe developmental impairment and intellectual disability are the most important clinical manifestations. From the outset, developmental milestones are globally and markedly delayed. Speech and ambulation occur late in childhood. Some affected individuals never walk independently or develop significant speech. ## Growth Impairment Growth impairment with microcephaly and short stature occurs in most individuals with ATR-X syndrome and is often present at birth. Stature is typically short (>2 SD below the mean in 67% of individuals using standard growth charts; syndrome-specific growth charts are not available). Growth above average is exceptional. ## Gastrointestinal Manifestations Gastrointestinal manifestations, present in the majority of individuals, contribute significantly to morbidity. Approximately three fourths have gastroesophageal reflux and one third have chronic constipation. Gastric pseudo-obstruction can result from abnormal suspension of the stomach and constipation can result from colon hypoganglionosis [ ## Genital Anomalies Genital anomalies are often minor, including first-degree hypospadias, undescended testes, and underdevelopment of the scrotum. Although all individuals with ATR-X syndrome have a normal 46,XY karyotype, gonadal dysgenesis resulting in inadequate testosterone production can cause more severe defects that can include second- and third-degree hypospadias, small penis, ambiguous genitalia, or even normal-appearing female external genitalia. Although all individuals with ATR-X syndrome have a normal 46,XY karyotype, occasionally gonadal dysgenesis results in inadequate testosterone production and ambiguous genitalia. Although the spectrum of possible genital anomalies in ATR-X syndrome is broad, the type of genital anomaly appears to be consistent within a family. ## Hypotonia Hypotonia, a hallmark of ATR-X syndrome, contributes to the facial manifestations, drooling, developmental delay, and possibly to the gastrointestinal manifestations. ## Seizures Seizures of various types occur in about one third of individuals with ATR-X syndrome but are not a defining manifestation of the syndrome [ ## Other The Although One individual with two metachronous osteosarcomas, the first (of the tibia) diagnosed and successfully treated at age nine years, and the second (of the humerus) diagnosed and successfully treated ten years later at age 20 years One child, diagnosed with osteosarcoma of the femur with pulmonary nodules at age four years, who succumbed 18 months later • One individual with two metachronous osteosarcomas, the first (of the tibia) diagnosed and successfully treated at age nine years, and the second (of the humerus) diagnosed and successfully treated ten years later at age 20 years • One child, diagnosed with osteosarcoma of the femur with pulmonary nodules at age four years, who succumbed 18 months later ## Heterozygous Females Heterozygous females rarely show clinical manifestations. Typically, carrier females have marked skewing of X-chromosome inactivation (>90:10) with preferential inactivation of the X chromosome with the A five-generation pedigree in which three females had signs of ATR-X syndrome [ Moderate ID without other phenotypic features of ATR-X syndrome in a female carrier with random X-chromosome inactivation [ A girl conceived by in vitro fertilization (IVF) who had craniofacial features, growth restriction, and developmental impairment typical of ATR-X syndrome [ • A five-generation pedigree in which three females had signs of ATR-X syndrome [ • Moderate ID without other phenotypic features of ATR-X syndrome in a female carrier with random X-chromosome inactivation [ • A girl conceived by in vitro fertilization (IVF) who had craniofacial features, growth restriction, and developmental impairment typical of ATR-X syndrome [ ## Genotype-Phenotype Correlations Pathogenic variants that affect the ATRX zinc finger domain produce severe psychomotor impairment and urogenital anomalies, whereas pathogenic variants in the helicase domains cause milder phenotypes [ More severe genital anomalies occur with variants in the plant homeodomain-like domain. A nonsense variant in exon 2 ( ## Nomenclature "Alpha-thalassemia X-linked intellectual disability syndrome" and "ATR-X syndrome" are the preferred designations for this disorder. Note: A family considered to have Juberg-Marsidi syndrome had an Although two families considered to have Smith-Fineman-Myers syndrome have ## Prevalence The prevalence is not known. More than 200 affected individuals are known to the laboratories conducting molecular genetic testing; substantial underascertainment, especially of those with milder phenotypes, is probable. No racial or ethnic concentration of individuals has been reported. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this See also ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Alpha-Thalassemia X-Linked Intellectual Disability Syndrome Persons w/ATR-X syndrome have normal α-globin genotype (αα/αα); those w/HbH disease have deletion or dysfunction of 3 of 4 α-globin alleles. ID is not a component of alpha-thalassemia involving α-globin production. Severe ID, spasticity, infantile hypotonia, absent or limited speech, seizures, & recurrent respiratory infections Autistic behaviors & GI dysfunction observed in several affected boys 50% of affected males die by early adulthood. Face is not characteristically hypotonic as in ATR-X syndrome. Microcephaly is less common. Downslanted palpebral fissures Severe-to-profound ID in males Large open mouth & prominent lips Short stature, microcephaly, & dental anomalies common Childhood-onset kyphoscoliosis (often progressive) Life span ↓ in some persons Short, soft, fleshy hands, often w/hyperextensible & tapering fingers Childhood-onset SIDAs in ~20% of persons Carrier females often have fullness of face & lips, fleshy & hyperextensible fingers, & learning difficulties. AR = autosomal recessive; DiffDx = differential diagnosis; GI = gastrointestinal; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Alpha-thalassemia is usually inherited in an autosomal recessive manner. Childhood-onset SIDAs ( • Persons w/ATR-X syndrome have normal α-globin genotype (αα/αα); those w/HbH disease have deletion or dysfunction of 3 of 4 α-globin alleles. • ID is not a component of alpha-thalassemia involving α-globin production. • Severe ID, spasticity, infantile hypotonia, absent or limited speech, seizures, & recurrent respiratory infections • Autistic behaviors & GI dysfunction observed in several affected boys • 50% of affected males die by early adulthood. • Face is not characteristically hypotonic as in ATR-X syndrome. • Microcephaly is less common. • Downslanted palpebral fissures • Severe-to-profound ID in males • Large open mouth & prominent lips • Short stature, microcephaly, & dental anomalies common • Childhood-onset kyphoscoliosis (often progressive) • Life span ↓ in some persons • Short, soft, fleshy hands, often w/hyperextensible & tapering fingers • Childhood-onset SIDAs in ~20% of persons • Carrier females often have fullness of face & lips, fleshy & hyperextensible fingers, & learning difficulties. ## Management To establish the extent of disease and needs in an individual diagnosed with alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ATR-X Syndrome To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / speech therapy / PT & OT / special education To assess muscle tone, evidence for spasticity (↑ reflexes, Babinski response) To incl EEG & MRI if seizures a concern Nutritional status Swallowing difficulties & aspiration risk GERD &/or recurrent vomiting Gastric pseudo-obstruction Constipation Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Use of Social work involvement for parental support. GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with ATR-X Syndrome Many ASMs may be effective; none demonstrated effective specifically for this disorder Education of parents/caregivers Usual treatment for GERD, constipation Treatment for gastric pseudo-obstruction per treating gastroenterologist/pediatric surgeon ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine if any changes are needed. As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with ATR-X Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor for excessive vomiting, GERD, abdominal distention & pain, constipation. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, movement disorders. See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / speech therapy / PT & OT / special education • To assess muscle tone, evidence for spasticity (↑ reflexes, Babinski response) • To incl EEG & MRI if seizures a concern • Nutritional status • Swallowing difficulties & aspiration risk • GERD &/or recurrent vomiting • Gastric pseudo-obstruction • Constipation • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Use of • Social work involvement for parental support. • Many ASMs may be effective; none demonstrated effective specifically for this disorder • Education of parents/caregivers • Usual treatment for GERD, constipation • Treatment for gastric pseudo-obstruction per treating gastroenterologist/pediatric surgeon • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor for excessive vomiting, GERD, abdominal distention & pain, constipation. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, movement disorders. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ATR-X Syndrome To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / speech therapy / PT & OT / special education To assess muscle tone, evidence for spasticity (↑ reflexes, Babinski response) To incl EEG & MRI if seizures a concern Nutritional status Swallowing difficulties & aspiration risk GERD &/or recurrent vomiting Gastric pseudo-obstruction Constipation Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Use of Social work involvement for parental support. GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / speech therapy / PT & OT / special education • To assess muscle tone, evidence for spasticity (↑ reflexes, Babinski response) • To incl EEG & MRI if seizures a concern • Nutritional status • Swallowing difficulties & aspiration risk • GERD &/or recurrent vomiting • Gastric pseudo-obstruction • Constipation • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Use of • Social work involvement for parental support. ## Treatment of Manifestations Treatment of Manifestations in Individuals with ATR-X Syndrome Many ASMs may be effective; none demonstrated effective specifically for this disorder Education of parents/caregivers Usual treatment for GERD, constipation Treatment for gastric pseudo-obstruction per treating gastroenterologist/pediatric surgeon ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine if any changes are needed. As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Many ASMs may be effective; none demonstrated effective specifically for this disorder • Education of parents/caregivers • Usual treatment for GERD, constipation • Treatment for gastric pseudo-obstruction per treating gastroenterologist/pediatric surgeon • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine if any changes are needed. As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Social/Behavioral Concerns Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with ATR-X Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor for excessive vomiting, GERD, abdominal distention & pain, constipation. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, movement disorders. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor for excessive vomiting, GERD, abdominal distention & pain, constipation. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, movement disorders. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is inherited in an X-linked manner. The father of an affected individual with a 46,XY karyotype will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected individual with a 46,XY karyotype is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If an affected individual with a 46,XY karyotype is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected individual may have a If the mother of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Molecular genetic testing may be able to identify the family member in whom a Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the Note: (1) Females who are heterozygous for this X-linked disorder rarely show clinical manifestations of ATR-X syndrome (see Clinical Description, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected individual with a 46,XY karyotype will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected individual with a 46,XY karyotype is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If an affected individual with a 46,XY karyotype is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected individual may have a • If the mother of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is inherited in an X-linked manner. ## Risk to Family Members The father of an affected individual with a 46,XY karyotype will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected individual with a 46,XY karyotype is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If an affected individual with a 46,XY karyotype is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected individual may have a If the mother of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected individual with a 46,XY karyotype will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected individual with a 46,XY karyotype is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If an affected individual with a 46,XY karyotype is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected individual may have a • If the mother of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the ## Carrier Detection Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the Note: (1) Females who are heterozygous for this X-linked disorder rarely show clinical manifestations of ATR-X syndrome (see Clinical Description, ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Alpha-Thalassemia X-Linked Intellectual Disability Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alpha-Thalassemia X-Linked Intellectual Disability Syndrome ( The abnormal ATRX protein downregulates the α-globin locus, resulting in thalassemia, and probably suppresses expression of other genes by disturbances in transcription and chromatin structure, leading to malformations and intellectual disability [ Notable Variants listed in the table have been provided by the author. Somatic ## Molecular Pathogenesis The abnormal ATRX protein downregulates the α-globin locus, resulting in thalassemia, and probably suppresses expression of other genes by disturbances in transcription and chromatin structure, leading to malformations and intellectual disability [ Notable Variants listed in the table have been provided by the author. ## Cancer and Benign Tumors Somatic ## Chapter Notes Web: Dr Stevenson's work focuses on the clinical and laboratory delineation of intellectual disability and birth defects. 28 May 2020 (bp) Comprehensive update posted live 6 November 2014 (me) Comprehensive update posted live 3 June 2010 (me) Comprehensive update posted live 15 October 2007 (me) Comprehensive update posted live 14 June 2005 (me) Comprehensive update posted live 15 April 2003 (me) Comprehensive update posted live 19 June 2000 (me) Review posted live 29 November 1999 (rs) Original submission • 28 May 2020 (bp) Comprehensive update posted live • 6 November 2014 (me) Comprehensive update posted live • 3 June 2010 (me) Comprehensive update posted live • 15 October 2007 (me) Comprehensive update posted live • 14 June 2005 (me) Comprehensive update posted live • 15 April 2003 (me) Comprehensive update posted live • 19 June 2000 (me) Review posted live • 29 November 1999 (rs) Original submission ## Author Notes Web: Dr Stevenson's work focuses on the clinical and laboratory delineation of intellectual disability and birth defects. ## Revision History 28 May 2020 (bp) Comprehensive update posted live 6 November 2014 (me) Comprehensive update posted live 3 June 2010 (me) Comprehensive update posted live 15 October 2007 (me) Comprehensive update posted live 14 June 2005 (me) Comprehensive update posted live 15 April 2003 (me) Comprehensive update posted live 19 June 2000 (me) Review posted live 29 November 1999 (rs) Original submission • 28 May 2020 (bp) Comprehensive update posted live • 6 November 2014 (me) Comprehensive update posted live • 3 June 2010 (me) Comprehensive update posted live • 15 October 2007 (me) Comprehensive update posted live • 14 June 2005 (me) Comprehensive update posted live • 15 April 2003 (me) Comprehensive update posted live • 19 June 2000 (me) Review posted live • 29 November 1999 (rs) Original submission ## References ## Literature Cited	[]	19/6/2000	28/5/2020	13/8/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
xp	xp	[ "DNA damage-binding protein 2", "DNA excision repair protein ERCC-1", "DNA excision repair protein ERCC-5", "DNA polymerase eta", "DNA repair endonuclease XPF", "DNA repair protein complementing XP-A cells", "DNA repair protein complementing XP-C cells", "General transcription and DNA repair factor IIH helicase subunit XPD", "General transcription and DNA repair factor IIH helicase/translocase subunit XPB", "DDB2", "ERCC1", "ERCC2", "ERCC3", "ERCC4", "ERCC5", "POLH", "XPA", "XPC", "Xeroderma Pigmentosum" ]	Xeroderma Pigmentosum	Kenneth H Kraemer, John J DiGiovanna, Deborah Tamura	Summary Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years). The diagnosis of XP is established in a proband on the basis of clinical findings and family history and/or by the identification of biallelic pathogenic variants in XP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an XP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the XP-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for XP are possible.	## Diagnosis XP Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) Marked freckle-like pigmentation (lentigos) on the face before age two years Skin cancer within the first decade of life Photophobia with prominent conjunctival injection Severe keratitis, sometimes resulting in corneal opacification and vascularization Increased pigmentation of the lids with loss of lashes Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids Ocular surface neoplasms Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. Progressive cognitive impairment Ataxia The diagnosis of XP Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click NOTE: Some regions of the world have increased prevalence of XP and the proportion of XP attributed to pathogenic variants in a specific gene may vary by country of origin of the proband associated with particular founder variants in that region. See Molecular Genetic Testing Used in Xeroderma Pigmentosum XP = xeroderma pigmentosum Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ No data on detection rate of gene-targeted deletion/duplication analysis are available. • • Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) • Marked freckle-like pigmentation (lentigos) on the face before age two years • Skin cancer within the first decade of life • Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) • Marked freckle-like pigmentation (lentigos) on the face before age two years • Skin cancer within the first decade of life • • Photophobia with prominent conjunctival injection • Severe keratitis, sometimes resulting in corneal opacification and vascularization • Increased pigmentation of the lids with loss of lashes • Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids • Ocular surface neoplasms • Photophobia with prominent conjunctival injection • Severe keratitis, sometimes resulting in corneal opacification and vascularization • Increased pigmentation of the lids with loss of lashes • Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids • Ocular surface neoplasms • • Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. • Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. • Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. • Progressive cognitive impairment • Ataxia • Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. • Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. • Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. • Progressive cognitive impairment • Ataxia • Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) • Marked freckle-like pigmentation (lentigos) on the face before age two years • Skin cancer within the first decade of life • Photophobia with prominent conjunctival injection • Severe keratitis, sometimes resulting in corneal opacification and vascularization • Increased pigmentation of the lids with loss of lashes • Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids • Ocular surface neoplasms • Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. • Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. • Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. • Progressive cognitive impairment • Ataxia ## Suggestive Findings XP Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) Marked freckle-like pigmentation (lentigos) on the face before age two years Skin cancer within the first decade of life Photophobia with prominent conjunctival injection Severe keratitis, sometimes resulting in corneal opacification and vascularization Increased pigmentation of the lids with loss of lashes Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids Ocular surface neoplasms Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. Progressive cognitive impairment Ataxia • • Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) • Marked freckle-like pigmentation (lentigos) on the face before age two years • Skin cancer within the first decade of life • Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) • Marked freckle-like pigmentation (lentigos) on the face before age two years • Skin cancer within the first decade of life • • Photophobia with prominent conjunctival injection • Severe keratitis, sometimes resulting in corneal opacification and vascularization • Increased pigmentation of the lids with loss of lashes • Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids • Ocular surface neoplasms • Photophobia with prominent conjunctival injection • Severe keratitis, sometimes resulting in corneal opacification and vascularization • Increased pigmentation of the lids with loss of lashes • Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids • Ocular surface neoplasms • • Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. • Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. • Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. • Progressive cognitive impairment • Ataxia • Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. • Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. • Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. • Progressive cognitive impairment • Ataxia • Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) • Marked freckle-like pigmentation (lentigos) on the face before age two years • Skin cancer within the first decade of life • Photophobia with prominent conjunctival injection • Severe keratitis, sometimes resulting in corneal opacification and vascularization • Increased pigmentation of the lids with loss of lashes • Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids • Ocular surface neoplasms • Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy. • Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss. • Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull. • Progressive cognitive impairment • Ataxia ## Establishing the Diagnosis The diagnosis of XP Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click NOTE: Some regions of the world have increased prevalence of XP and the proportion of XP attributed to pathogenic variants in a specific gene may vary by country of origin of the proband associated with particular founder variants in that region. See Molecular Genetic Testing Used in Xeroderma Pigmentosum XP = xeroderma pigmentosum Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click NOTE: Some regions of the world have increased prevalence of XP and the proportion of XP attributed to pathogenic variants in a specific gene may vary by country of origin of the proband associated with particular founder variants in that region. See Molecular Genetic Testing Used in Xeroderma Pigmentosum XP = xeroderma pigmentosum Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics The findings from 106 individuals with XP examined at the National Institutes of Health (US) in a long-term study from 1971 to 2009 by Xeroderma Pigmentosum: Frequency of Select Features CNS = central nervous system The median onset of the cutaneous symptoms is between ages one and two years. These abnormalities are limited to sun-exposed areas. Continued sun exposure causes the skin to become dry and parchment-like with increased pigmentation; hence the name xeroderma pigmentosum ("dry pigmented skin"). Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia). Premalignant actinic keratoses develop at an early age. XP is an example of accelerated photoaging. The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of extreme sun exposure [ Dry eyes are a common finding in XP and may be seen in patients in the first decade of life. Epithelioma, squamous cell carcinoma, and melanoma of UV-exposed portions of the eye are common. The ocular manifestations may be more severe in heavily pigmented individuals. Benign conjunctival inflammatory masses that develop can spread to obscure the cornea [ Corneal findings include photophobia, severe keratitis, corneal opacification, and neovascularization. Lid findings include atrophy of the skin of the lids resulting in ectropion, entropion, or (in severe cases) complete loss of the lids. Lentigines, freckling on the lids, and lash loss are also common findings. The onset may be early in infancy or, in some individuals, delayed until the second decade or later [ The neurologic abnormalities may be mild (e.g., isolated hyporeflexia) or severe, including acquired microcephaly, progressive intellectual impairment, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, and/or seizures. During an upper respiratory infection some individuals may develop difficulty swallowing or, rarely, vocal cord paralysis [ Reduced nerve conduction velocity may also be present on nerve conduction studies [ Surprisingly, those with XP who had the most severe sun sensitivity had a later onset of skin cancer – perhaps because they used greater sun protection. A substantial number of people with XP have oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location [ Gliomas of the brain and spinal cord, tumors of the lung, uterus, breast, pancreas, stomach, kidney, and testicles, and leukemia have been reported in a few individuals with XP [ Because some of the carcinogens in cigarette smoke bind to DNA, resulting in damage that is repaired by the nucleotide excision repair system, this unrepaired DNA damage may contribute to the development of lung cancer in individuals with XP who smoke. The risk for lung cancer due to exposure from secondhand smoke has not been determined. Overall, there is an estimated 34-fold increase in internal neoplasms in XP, and tumors arise 50 years earlier compared to the US general population [ Women with XP are at increased risk for premature menopause (menopause before age 40 years) and may require assisted reproductive technology to experience pregnancy [Authors, personal communication]. A study of reproductive health in women with XP identified premature menopause in 31% of the participants, the majority of whom had pathogenic variants in Individuals with XP are at risk for thyroid nodules and carcinoma. Xeroderma Pigmentosum: Phenotype Correlations by Gene When present in those with No genotype-phenotype correlations, besides those shown in Xeroderma pigmentosum was first described in Vienna by Moriz Kaposi in the textbook of dermatology he published in 1870 with his father-in-law, Ferdinand Hebra. The disorder was first called xeroderma or parchment skin. See discussion in Previously, an individual with XP with any neurologic abnormality was said to have DeSanctis-Cacchione syndrome. With clarification of the spectrum of XP disease, this term is now reserved for XP with severe neurologic disease, dwarfism, and immature sexual development. The complete DeSanctis-Cacchione syndrome has been recognized in very few individuals; however, many individuals with XP have one or more of its neurologic features. "Pigmented xerodermoid" is now known to be identical to the XP variant. Before the genes responsible for XP were identified, complementation groups were used to categorize functional defects in affected individuals. In an XP complementation analysis, cells from affected individuals were fused in the laboratory to determine whether their defects were different, in which case they would be able to supply all functions necessary to restore a normal cellular phenotype. Complementation is therefore a test of function and enabled the categorization of affected individuals as having the same or different defects. Subsequently, each complementation group was found to result from a defect in a distinct gene [ Prevalence is estimated at 1:1,000,000 in the United States and Europe [ Certain populations have a higher prevalence. This is usually related to the presence of founder variants (see In Japan prevalence is estimated at 1:22,000 [ In North Africa (Tunisia, Algeria, Morocco, Libya, and Egypt) [ • The median onset of the cutaneous symptoms is between ages one and two years. • These abnormalities are limited to sun-exposed areas. • Continued sun exposure causes the skin to become dry and parchment-like with increased pigmentation; hence the name xeroderma pigmentosum ("dry pigmented skin"). • Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia). • Premalignant actinic keratoses develop at an early age. • XP is an example of accelerated photoaging. The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of extreme sun exposure [ • Dry eyes are a common finding in XP and may be seen in patients in the first decade of life. • Epithelioma, squamous cell carcinoma, and melanoma of UV-exposed portions of the eye are common. • The ocular manifestations may be more severe in heavily pigmented individuals. • Benign conjunctival inflammatory masses that develop can spread to obscure the cornea [ • Corneal findings include photophobia, severe keratitis, corneal opacification, and neovascularization. • Lid findings include atrophy of the skin of the lids resulting in ectropion, entropion, or (in severe cases) complete loss of the lids. Lentigines, freckling on the lids, and lash loss are also common findings. • The onset may be early in infancy or, in some individuals, delayed until the second decade or later [ • The neurologic abnormalities may be mild (e.g., isolated hyporeflexia) or severe, including acquired microcephaly, progressive intellectual impairment, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, and/or seizures. • During an upper respiratory infection some individuals may develop difficulty swallowing or, rarely, vocal cord paralysis [ • Reduced nerve conduction velocity may also be present on nerve conduction studies [ • Surprisingly, those with XP who had the most severe sun sensitivity had a later onset of skin cancer – perhaps because they used greater sun protection. • A substantial number of people with XP have oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location [ • Gliomas of the brain and spinal cord, tumors of the lung, uterus, breast, pancreas, stomach, kidney, and testicles, and leukemia have been reported in a few individuals with XP [ • Because some of the carcinogens in cigarette smoke bind to DNA, resulting in damage that is repaired by the nucleotide excision repair system, this unrepaired DNA damage may contribute to the development of lung cancer in individuals with XP who smoke. The risk for lung cancer due to exposure from secondhand smoke has not been determined. • Women with XP are at increased risk for premature menopause (menopause before age 40 years) and may require assisted reproductive technology to experience pregnancy [Authors, personal communication]. A study of reproductive health in women with XP identified premature menopause in 31% of the participants, the majority of whom had pathogenic variants in • Individuals with XP are at risk for thyroid nodules and carcinoma. • In Japan prevalence is estimated at 1:22,000 [ • In North Africa (Tunisia, Algeria, Morocco, Libya, and Egypt) [ ## Clinical Description The findings from 106 individuals with XP examined at the National Institutes of Health (US) in a long-term study from 1971 to 2009 by Xeroderma Pigmentosum: Frequency of Select Features CNS = central nervous system The median onset of the cutaneous symptoms is between ages one and two years. These abnormalities are limited to sun-exposed areas. Continued sun exposure causes the skin to become dry and parchment-like with increased pigmentation; hence the name xeroderma pigmentosum ("dry pigmented skin"). Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia). Premalignant actinic keratoses develop at an early age. XP is an example of accelerated photoaging. The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of extreme sun exposure [ Dry eyes are a common finding in XP and may be seen in patients in the first decade of life. Epithelioma, squamous cell carcinoma, and melanoma of UV-exposed portions of the eye are common. The ocular manifestations may be more severe in heavily pigmented individuals. Benign conjunctival inflammatory masses that develop can spread to obscure the cornea [ Corneal findings include photophobia, severe keratitis, corneal opacification, and neovascularization. Lid findings include atrophy of the skin of the lids resulting in ectropion, entropion, or (in severe cases) complete loss of the lids. Lentigines, freckling on the lids, and lash loss are also common findings. The onset may be early in infancy or, in some individuals, delayed until the second decade or later [ The neurologic abnormalities may be mild (e.g., isolated hyporeflexia) or severe, including acquired microcephaly, progressive intellectual impairment, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, and/or seizures. During an upper respiratory infection some individuals may develop difficulty swallowing or, rarely, vocal cord paralysis [ Reduced nerve conduction velocity may also be present on nerve conduction studies [ Surprisingly, those with XP who had the most severe sun sensitivity had a later onset of skin cancer – perhaps because they used greater sun protection. A substantial number of people with XP have oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location [ Gliomas of the brain and spinal cord, tumors of the lung, uterus, breast, pancreas, stomach, kidney, and testicles, and leukemia have been reported in a few individuals with XP [ Because some of the carcinogens in cigarette smoke bind to DNA, resulting in damage that is repaired by the nucleotide excision repair system, this unrepaired DNA damage may contribute to the development of lung cancer in individuals with XP who smoke. The risk for lung cancer due to exposure from secondhand smoke has not been determined. Overall, there is an estimated 34-fold increase in internal neoplasms in XP, and tumors arise 50 years earlier compared to the US general population [ Women with XP are at increased risk for premature menopause (menopause before age 40 years) and may require assisted reproductive technology to experience pregnancy [Authors, personal communication]. A study of reproductive health in women with XP identified premature menopause in 31% of the participants, the majority of whom had pathogenic variants in Individuals with XP are at risk for thyroid nodules and carcinoma. • The median onset of the cutaneous symptoms is between ages one and two years. • These abnormalities are limited to sun-exposed areas. • Continued sun exposure causes the skin to become dry and parchment-like with increased pigmentation; hence the name xeroderma pigmentosum ("dry pigmented skin"). • Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia). • Premalignant actinic keratoses develop at an early age. • XP is an example of accelerated photoaging. The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of extreme sun exposure [ • Dry eyes are a common finding in XP and may be seen in patients in the first decade of life. • Epithelioma, squamous cell carcinoma, and melanoma of UV-exposed portions of the eye are common. • The ocular manifestations may be more severe in heavily pigmented individuals. • Benign conjunctival inflammatory masses that develop can spread to obscure the cornea [ • Corneal findings include photophobia, severe keratitis, corneal opacification, and neovascularization. • Lid findings include atrophy of the skin of the lids resulting in ectropion, entropion, or (in severe cases) complete loss of the lids. Lentigines, freckling on the lids, and lash loss are also common findings. • The onset may be early in infancy or, in some individuals, delayed until the second decade or later [ • The neurologic abnormalities may be mild (e.g., isolated hyporeflexia) or severe, including acquired microcephaly, progressive intellectual impairment, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, and/or seizures. • During an upper respiratory infection some individuals may develop difficulty swallowing or, rarely, vocal cord paralysis [ • Reduced nerve conduction velocity may also be present on nerve conduction studies [ • Surprisingly, those with XP who had the most severe sun sensitivity had a later onset of skin cancer – perhaps because they used greater sun protection. • A substantial number of people with XP have oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location [ • Gliomas of the brain and spinal cord, tumors of the lung, uterus, breast, pancreas, stomach, kidney, and testicles, and leukemia have been reported in a few individuals with XP [ • Because some of the carcinogens in cigarette smoke bind to DNA, resulting in damage that is repaired by the nucleotide excision repair system, this unrepaired DNA damage may contribute to the development of lung cancer in individuals with XP who smoke. The risk for lung cancer due to exposure from secondhand smoke has not been determined. • Women with XP are at increased risk for premature menopause (menopause before age 40 years) and may require assisted reproductive technology to experience pregnancy [Authors, personal communication]. A study of reproductive health in women with XP identified premature menopause in 31% of the participants, the majority of whom had pathogenic variants in • Individuals with XP are at risk for thyroid nodules and carcinoma. ## Phenotype Correlations by Gene Xeroderma Pigmentosum: Phenotype Correlations by Gene When present in those with ## Genotype-Phenotype Correlations No genotype-phenotype correlations, besides those shown in ## Nomenclature Xeroderma pigmentosum was first described in Vienna by Moriz Kaposi in the textbook of dermatology he published in 1870 with his father-in-law, Ferdinand Hebra. The disorder was first called xeroderma or parchment skin. See discussion in Previously, an individual with XP with any neurologic abnormality was said to have DeSanctis-Cacchione syndrome. With clarification of the spectrum of XP disease, this term is now reserved for XP with severe neurologic disease, dwarfism, and immature sexual development. The complete DeSanctis-Cacchione syndrome has been recognized in very few individuals; however, many individuals with XP have one or more of its neurologic features. "Pigmented xerodermoid" is now known to be identical to the XP variant. Before the genes responsible for XP were identified, complementation groups were used to categorize functional defects in affected individuals. In an XP complementation analysis, cells from affected individuals were fused in the laboratory to determine whether their defects were different, in which case they would be able to supply all functions necessary to restore a normal cellular phenotype. Complementation is therefore a test of function and enabled the categorization of affected individuals as having the same or different defects. Subsequently, each complementation group was found to result from a defect in a distinct gene [ ## Prevalence Prevalence is estimated at 1:1,000,000 in the United States and Europe [ Certain populations have a higher prevalence. This is usually related to the presence of founder variants (see In Japan prevalence is estimated at 1:22,000 [ In North Africa (Tunisia, Algeria, Morocco, Libya, and Egypt) [ • In Japan prevalence is estimated at 1:22,000 [ • In North Africa (Tunisia, Algeria, Morocco, Libya, and Egypt) [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this In addition to the xeroderma pigmentosum (XP) phenotypes discussed in this Allelic Disorders See Allelic complex phenotypes in the differential diagnosis of XP are summarized in One individual with phenotypic features of Cockayne syndrome, XP, and • Allelic complex phenotypes in the differential diagnosis of XP are summarized in • One individual with phenotypic features of Cockayne syndrome, XP, and ## Differential Diagnosis Other nucleotide excision repair disorders associated with cutaneous photosensitivity to consider in the differential diagnosis of xeroderma pigmentosum (XP) are summarized in Autosomal Recessive Nucleotide Excision Repair Disorders Exhibiting Cutaneous Photosensitivity COFS = cerebrooculofacioskeletal syndrome; CNS = central nervous system; CS = Cockayne syndrome; ID = intellectual disability; NER = nucleotide excision repair; PNS = peripheral nervous system; TTD = trichothiodystrophy; UDS = unscheduled DNA synthesis; XP = xeroderma pigmentosum Allelic with XP See See Hartnup disorder (OMIM The cutaneous findings of • Hartnup disorder (OMIM • The cutaneous findings of ## Management General clinical care guidelines for individuals with xeroderma pigmentosum (XP) have been proposed by the Japanese Dermatological Association [ To establish the extent of disease and needs in an individual diagnosed with XP, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Xeroderma Pigmentosum Look for evidence of sun-induced damage incl ectropion, entropion, inflammatory masses (pterygia, pinguecula), clouding of cornea, cataracts, & cancer of lids, conjunctiva, or cornea. Eversion of lids may be necessary to detect cancers of mucosal surface. Dilated eye exam looking for retinal changes Baseline developmental assessment in children & assess for need for educational support. Neurologic eval w/baseline neurocognitive testing if neurologic problems are detected Measurement of head circumference to determine if microcephaly is present. Deep tendon reflex testing MRI of brain & NCVs, if other neurologic problems are detected Baseline audiometry eval to screen for sensorineural hearing loss Thyroid ultrasound is more sensitive in identifying presence of thyroid nodules. TI-RADS score provides descriptors for suspicion levels of nodules. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; NCV = nerve conduction velocity; XP = xeroderma pigmentosum Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Xeroderma Pigmentosum Because multiple surgical procedures are often needed, removal of non-cancerous skin should be minimized. Severe cases have been treated by excision of large portions of facial surface & grafting w/sun-protected skin. Some persons may respond to lower doses of isotretinoin or acitretin w/less toxicity. Toxicity incl hepatic, hyperlipidemic, & teratogenic effects; calcification of ligaments & tendons; premature closure of epiphyses. Standard therapy When x-radiation therapy is indicated, an initial small dose is advisable to test for clinical hypersensitivity. Most persons w/XP are not abnormally sensitive to therapeutic x-rays & have responded normally to full-dose therapeutic x-radiation for treatment of inoperable neoplasms. However, cultured cells from a few persons w/XP were found to be hypersensitive to x-radiation. Surgical treatment Topical 5-fluorouracil 1% Topical interferon beta 1b Use of hearing aids Cochlear implants Treatment of XP depends on early diagnosis and immediate, aggressive avoidance of sun and other UV exposure. This involves avoiding or minimizing outdoor exposure at times when UV radiation is present (when the sun is out or during daytime through clouds). Clinical suspicion of XP should prompt immediate sun-protective measures until the diagnosis is confirmed or an alternative explanation is determined. Individuals should be educated to protect all body surfaces from UV radiation by wearing protective clothing including hats, long sleeves, long pants and gloves, broad-spectrum, high-SPF sunscreens, UV-absorbing glasses, and long hair styles. Multiple layers of clothing are preferred. The eyes should be protected by wearing UV-absorbing glasses with side shields. Some individuals have custom-made hats with UV-absorbing face shields to permit visibility outdoors while protecting the face from UV. Because the cells of individuals with XP are hypersensitive to UVA and UVB (found in sunlight) and UVC (found in some artificial light sources), it is useful to measure UV light in an individual's home, school, or work environment with a light meter so that high levels of environmental UV (e.g., halogen lamps) can be identified and eliminated if possible. While no standards exist for perfectly safe UV exposure in individuals with XP, the use of UV meters can alert individuals to unexpected sources of high levels of environmental UV. Unlike UVB, UVA is not blocked by window glass. Windows in areas where individuals with XP will be spending large amounts of time should have UV blocking film applied. Low vitamin D levels can result from aggressive avoidance of sun exposure. Vitamin D is produced in the skin by a reaction involving exposure to UV radiation. Active adults with XP and skin cancers received sufficient vitamin D in their diet in the past to result in normal serum concentrations of the active form (1,25 dihydroxy vitamin D) [ Recommended Surveillance for Individuals with Xeroderma Pigmentosum UV exposure from sunlight and artificial sources of UV radiation should be avoided (see It is appropriate to evaluate the apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Treatment of XP depends on early diagnosis and immediate, aggressive avoidance of sun and other UV exposure (see See The systemic retinoids isotretinoin and acitretin are used as skin cancer chemopreventive agents in individuals who are actively developing large numbers of skin cancers, and thus may be used by some women with XP [ To access isotretinoin in the US, women and their prescribing providers must be enrolled in the See Search • Look for evidence of sun-induced damage incl ectropion, entropion, inflammatory masses (pterygia, pinguecula), clouding of cornea, cataracts, & cancer of lids, conjunctiva, or cornea. • Eversion of lids may be necessary to detect cancers of mucosal surface. • Dilated eye exam looking for retinal changes • Baseline developmental assessment in children & assess for need for educational support. • Neurologic eval w/baseline neurocognitive testing if neurologic problems are detected • Measurement of head circumference to determine if microcephaly is present. • Deep tendon reflex testing • MRI of brain & NCVs, if other neurologic problems are detected • Baseline audiometry eval to screen for sensorineural hearing loss • Thyroid ultrasound is more sensitive in identifying presence of thyroid nodules. • TI-RADS score provides descriptors for suspicion levels of nodules. • Community or • Social work involvement for parental support; • Home nursing referral. • Because multiple surgical procedures are often needed, removal of non-cancerous skin should be minimized. • Severe cases have been treated by excision of large portions of facial surface & grafting w/sun-protected skin. • Some persons may respond to lower doses of isotretinoin or acitretin w/less toxicity. • Toxicity incl hepatic, hyperlipidemic, & teratogenic effects; calcification of ligaments & tendons; premature closure of epiphyses. • Standard therapy • When x-radiation therapy is indicated, an initial small dose is advisable to test for clinical hypersensitivity. • Most persons w/XP are not abnormally sensitive to therapeutic x-rays & have responded normally to full-dose therapeutic x-radiation for treatment of inoperable neoplasms. • However, cultured cells from a few persons w/XP were found to be hypersensitive to x-radiation. • Surgical treatment • Topical 5-fluorouracil 1% • Topical interferon beta 1b • Use of hearing aids • Cochlear implants • Clinical suspicion of XP should prompt immediate sun-protective measures until the diagnosis is confirmed or an alternative explanation is determined. • Individuals should be educated to protect all body surfaces from UV radiation by wearing protective clothing including hats, long sleeves, long pants and gloves, broad-spectrum, high-SPF sunscreens, UV-absorbing glasses, and long hair styles. Multiple layers of clothing are preferred. The eyes should be protected by wearing UV-absorbing glasses with side shields. Some individuals have custom-made hats with UV-absorbing face shields to permit visibility outdoors while protecting the face from UV. ## Evaluations Following Initial Diagnosis General clinical care guidelines for individuals with xeroderma pigmentosum (XP) have been proposed by the Japanese Dermatological Association [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with XP, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Xeroderma Pigmentosum Look for evidence of sun-induced damage incl ectropion, entropion, inflammatory masses (pterygia, pinguecula), clouding of cornea, cataracts, & cancer of lids, conjunctiva, or cornea. Eversion of lids may be necessary to detect cancers of mucosal surface. Dilated eye exam looking for retinal changes Baseline developmental assessment in children & assess for need for educational support. Neurologic eval w/baseline neurocognitive testing if neurologic problems are detected Measurement of head circumference to determine if microcephaly is present. Deep tendon reflex testing MRI of brain & NCVs, if other neurologic problems are detected Baseline audiometry eval to screen for sensorineural hearing loss Thyroid ultrasound is more sensitive in identifying presence of thyroid nodules. TI-RADS score provides descriptors for suspicion levels of nodules. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; NCV = nerve conduction velocity; XP = xeroderma pigmentosum Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Look for evidence of sun-induced damage incl ectropion, entropion, inflammatory masses (pterygia, pinguecula), clouding of cornea, cataracts, & cancer of lids, conjunctiva, or cornea. • Eversion of lids may be necessary to detect cancers of mucosal surface. • Dilated eye exam looking for retinal changes • Baseline developmental assessment in children & assess for need for educational support. • Neurologic eval w/baseline neurocognitive testing if neurologic problems are detected • Measurement of head circumference to determine if microcephaly is present. • Deep tendon reflex testing • MRI of brain & NCVs, if other neurologic problems are detected • Baseline audiometry eval to screen for sensorineural hearing loss • Thyroid ultrasound is more sensitive in identifying presence of thyroid nodules. • TI-RADS score provides descriptors for suspicion levels of nodules. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Xeroderma Pigmentosum Because multiple surgical procedures are often needed, removal of non-cancerous skin should be minimized. Severe cases have been treated by excision of large portions of facial surface & grafting w/sun-protected skin. Some persons may respond to lower doses of isotretinoin or acitretin w/less toxicity. Toxicity incl hepatic, hyperlipidemic, & teratogenic effects; calcification of ligaments & tendons; premature closure of epiphyses. Standard therapy When x-radiation therapy is indicated, an initial small dose is advisable to test for clinical hypersensitivity. Most persons w/XP are not abnormally sensitive to therapeutic x-rays & have responded normally to full-dose therapeutic x-radiation for treatment of inoperable neoplasms. However, cultured cells from a few persons w/XP were found to be hypersensitive to x-radiation. Surgical treatment Topical 5-fluorouracil 1% Topical interferon beta 1b Use of hearing aids Cochlear implants • Because multiple surgical procedures are often needed, removal of non-cancerous skin should be minimized. • Severe cases have been treated by excision of large portions of facial surface & grafting w/sun-protected skin. • Some persons may respond to lower doses of isotretinoin or acitretin w/less toxicity. • Toxicity incl hepatic, hyperlipidemic, & teratogenic effects; calcification of ligaments & tendons; premature closure of epiphyses. • Standard therapy • When x-radiation therapy is indicated, an initial small dose is advisable to test for clinical hypersensitivity. • Most persons w/XP are not abnormally sensitive to therapeutic x-rays & have responded normally to full-dose therapeutic x-radiation for treatment of inoperable neoplasms. • However, cultured cells from a few persons w/XP were found to be hypersensitive to x-radiation. • Surgical treatment • Topical 5-fluorouracil 1% • Topical interferon beta 1b • Use of hearing aids • Cochlear implants ## Prevention of Primary Manifestations Treatment of XP depends on early diagnosis and immediate, aggressive avoidance of sun and other UV exposure. This involves avoiding or minimizing outdoor exposure at times when UV radiation is present (when the sun is out or during daytime through clouds). Clinical suspicion of XP should prompt immediate sun-protective measures until the diagnosis is confirmed or an alternative explanation is determined. Individuals should be educated to protect all body surfaces from UV radiation by wearing protective clothing including hats, long sleeves, long pants and gloves, broad-spectrum, high-SPF sunscreens, UV-absorbing glasses, and long hair styles. Multiple layers of clothing are preferred. The eyes should be protected by wearing UV-absorbing glasses with side shields. Some individuals have custom-made hats with UV-absorbing face shields to permit visibility outdoors while protecting the face from UV. Because the cells of individuals with XP are hypersensitive to UVA and UVB (found in sunlight) and UVC (found in some artificial light sources), it is useful to measure UV light in an individual's home, school, or work environment with a light meter so that high levels of environmental UV (e.g., halogen lamps) can be identified and eliminated if possible. While no standards exist for perfectly safe UV exposure in individuals with XP, the use of UV meters can alert individuals to unexpected sources of high levels of environmental UV. Unlike UVB, UVA is not blocked by window glass. Windows in areas where individuals with XP will be spending large amounts of time should have UV blocking film applied. Low vitamin D levels can result from aggressive avoidance of sun exposure. Vitamin D is produced in the skin by a reaction involving exposure to UV radiation. Active adults with XP and skin cancers received sufficient vitamin D in their diet in the past to result in normal serum concentrations of the active form (1,25 dihydroxy vitamin D) [ • Clinical suspicion of XP should prompt immediate sun-protective measures until the diagnosis is confirmed or an alternative explanation is determined. • Individuals should be educated to protect all body surfaces from UV radiation by wearing protective clothing including hats, long sleeves, long pants and gloves, broad-spectrum, high-SPF sunscreens, UV-absorbing glasses, and long hair styles. Multiple layers of clothing are preferred. The eyes should be protected by wearing UV-absorbing glasses with side shields. Some individuals have custom-made hats with UV-absorbing face shields to permit visibility outdoors while protecting the face from UV. ## Surveillance Recommended Surveillance for Individuals with Xeroderma Pigmentosum ## Agents/Circumstances to Avoid UV exposure from sunlight and artificial sources of UV radiation should be avoided (see ## Evaluation of Relatives at Risk It is appropriate to evaluate the apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Treatment of XP depends on early diagnosis and immediate, aggressive avoidance of sun and other UV exposure (see See ## Pregnancy Management The systemic retinoids isotretinoin and acitretin are used as skin cancer chemopreventive agents in individuals who are actively developing large numbers of skin cancers, and thus may be used by some women with XP [ To access isotretinoin in the US, women and their prescribing providers must be enrolled in the See ## Therapies Under Investigation Search ## Genetic Counseling Xeroderma pigmentosum (XP) is inherited in an autosomal recessive manner. The parents of an individual with XP are presumed to be heterozygous for an XP-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an XP-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an XP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an individual with XP has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an XP-related pathogenic variant. The offspring of an individual with XP and an individual who is heterozygous for an XP-related pathogenic variant in the same gene as the proband have a 50% chance of having XP. This is a consideration in populations with a founder variant or with a high rate of consanguinity (see Carrier testing for at-risk relatives requires prior identification of the XP-related pathogenic variants in the family (see See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the XP-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for XP are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an individual with XP are presumed to be heterozygous for an XP-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an XP-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an XP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an individual with XP has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an XP-related pathogenic variant. • The offspring of an individual with XP and an individual who is heterozygous for an XP-related pathogenic variant in the same gene as the proband have a 50% chance of having XP. This is a consideration in populations with a founder variant or with a high rate of consanguinity (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Xeroderma pigmentosum (XP) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an individual with XP are presumed to be heterozygous for an XP-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an XP-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an XP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an individual with XP has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an XP-related pathogenic variant. The offspring of an individual with XP and an individual who is heterozygous for an XP-related pathogenic variant in the same gene as the proband have a 50% chance of having XP. This is a consideration in populations with a founder variant or with a high rate of consanguinity (see • The parents of an individual with XP are presumed to be heterozygous for an XP-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an XP-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an XP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an individual with XP has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an XP-related pathogenic variant. • The offspring of an individual with XP and an individual who is heterozygous for an XP-related pathogenic variant in the same gene as the proband have a 50% chance of having XP. This is a consideration in populations with a founder variant or with a high rate of consanguinity (see ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the XP-related pathogenic variants in the family (see ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the XP-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for XP are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Westfield, Cushnie, Nr Alford, Aberdeenshire, AB33 8LP United Kingdom Siège de l’association 3 Rue Corneille 01200 Bellegarde sur Valserine France 437 Syndertown Road Craryville NY 12521 10259 Atlantis Drive Elk Grove CA 95624 Postfach 2124 48550 Steinfurt Germany • • Westfield, Cushnie, Nr Alford, Aberdeenshire, AB33 8LP • United Kingdom • • • Siège de l’association • 3 Rue Corneille 01200 Bellegarde sur Valserine • France • • • 437 Syndertown Road • Craryville NY 12521 • • • 10259 Atlantis Drive • Elk Grove CA 95624 • • • Postfach 2124 • 48550 Steinfurt • Germany • ## Molecular Genetics Xeroderma Pigmentosum: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Xeroderma Pigmentosum ( An intact DNA repair system that senses, excises, and repairs UV-induced dipyrimidine photoproducts and other forms of DNA damage is necessary to prevent replication errors and subsequent tumorigenesis ( Exposure to UV radiation from sunlight forms cyclobutane dimers or other photoproducts at adjacent pyrimidines, thereby distorting the DNA. Initial lesion recognition in non-transcribed DNA (global genome repair-GGR) is performed by DNA damage in transcribed genes (transcription coupled repair) is marked by stalled RNA polymerase. The CS (Cockayne syndrome)-encoded proteins (along with others) bind to the damage in the transcribed DNA strand. ERCC2 is part of basal transcription factor TFIIH that is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in nucleotide excision repair (NER). In both global genome repair and transcription-coupled repair, the XPA protein probably functions in conjunction with replication protein A and TFIIH – the basal transcription factor that is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in NER. The XPB/ERCC3 and XPD/ERCC2 proteins (helicases that are part of the TFIIH complex) partially unwind the DNA in the region of the damage, thereby exposing the lesion for further processing. The XPF/ERCC4 product, in a complex with ERCC1, makes a single-strand nick at the 5' side of the lesion, while the XPG/ERCC5 product makes a similar nick on the 3' side, resulting in the release of a region of approximately 30 nucleotides containing the damage. The resulting gap is filled by DNA polymerase using the other (undamaged) strand as a template in a process involving proliferating cell nuclear antigen. DNA ligase I seals the region, restoring the original undamaged sequence [ Individuals with the XP variant have a normal nucleotide excision pathway and a defect in Xeroderma Pigmentosum: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Results in abnormal splicing [ Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis An intact DNA repair system that senses, excises, and repairs UV-induced dipyrimidine photoproducts and other forms of DNA damage is necessary to prevent replication errors and subsequent tumorigenesis ( Exposure to UV radiation from sunlight forms cyclobutane dimers or other photoproducts at adjacent pyrimidines, thereby distorting the DNA. Initial lesion recognition in non-transcribed DNA (global genome repair-GGR) is performed by DNA damage in transcribed genes (transcription coupled repair) is marked by stalled RNA polymerase. The CS (Cockayne syndrome)-encoded proteins (along with others) bind to the damage in the transcribed DNA strand. ERCC2 is part of basal transcription factor TFIIH that is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in nucleotide excision repair (NER). In both global genome repair and transcription-coupled repair, the XPA protein probably functions in conjunction with replication protein A and TFIIH – the basal transcription factor that is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in NER. The XPB/ERCC3 and XPD/ERCC2 proteins (helicases that are part of the TFIIH complex) partially unwind the DNA in the region of the damage, thereby exposing the lesion for further processing. The XPF/ERCC4 product, in a complex with ERCC1, makes a single-strand nick at the 5' side of the lesion, while the XPG/ERCC5 product makes a similar nick on the 3' side, resulting in the release of a region of approximately 30 nucleotides containing the damage. The resulting gap is filled by DNA polymerase using the other (undamaged) strand as a template in a process involving proliferating cell nuclear antigen. DNA ligase I seals the region, restoring the original undamaged sequence [ Individuals with the XP variant have a normal nucleotide excision pathway and a defect in Xeroderma Pigmentosum: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Results in abnormal splicing [ Variant designation that does not conform to current naming conventions ## Chapter Notes This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and National Human Genome Research Institute. We wish to thank the many patients and families throughout the world who have participated in the XP protocols at the National Institutes of Health, National Cancer Institute. John J DiGiovanna, MD (2011-present)Kenneth H Kraemer, MD (2003-present)Deborah Tamura, RN (2022-present)Daniel J Wattendorf, MD; National Institutes of Health (2003-2008) 24 March 2022 (ha) Comprehensive update posted live 29 September 2016 (ma) Comprehensive update posted live 13 February 2014 (me) Comprehensive update posted live 14 February 2013 (cd) Revision: changes in testing available for 1 November 2012 (cd) Revision: testing for 15 March 2012 (cd) Revision: sequence analysis available clinically for 4 August 2011 (me) Comprehensive update posted live 22 April 2008 (me) Comprehensive update posted live 14 May 2007 (cd) Revision: sequence analysis clinically available for 1 June 2006 (cd) Revision: confirmation of 15 September 2005 (me) Comprehensive update posted live 24 February 2004 (kk) Revision: Molecular Genetics 1 October 2003 (kk) Revision: clinical testing no longer available 20 June 2003 (me) Review posted live 28 April 2003 (kk) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 24 March 2022 (ha) Comprehensive update posted live • 29 September 2016 (ma) Comprehensive update posted live • 13 February 2014 (me) Comprehensive update posted live • 14 February 2013 (cd) Revision: changes in testing available for • 1 November 2012 (cd) Revision: testing for • 15 March 2012 (cd) Revision: sequence analysis available clinically for • 4 August 2011 (me) Comprehensive update posted live • 22 April 2008 (me) Comprehensive update posted live • 14 May 2007 (cd) Revision: sequence analysis clinically available for • 1 June 2006 (cd) Revision: confirmation of • 15 September 2005 (me) Comprehensive update posted live • 24 February 2004 (kk) Revision: Molecular Genetics • 1 October 2003 (kk) Revision: clinical testing no longer available • 20 June 2003 (me) Review posted live • 28 April 2003 (kk) Original submission ## Author Notes ## Acknowledgements This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and National Human Genome Research Institute. We wish to thank the many patients and families throughout the world who have participated in the XP protocols at the National Institutes of Health, National Cancer Institute. ## Author History John J DiGiovanna, MD (2011-present)Kenneth H Kraemer, MD (2003-present)Deborah Tamura, RN (2022-present)Daniel J Wattendorf, MD; National Institutes of Health (2003-2008) ## Revision History 24 March 2022 (ha) Comprehensive update posted live 29 September 2016 (ma) Comprehensive update posted live 13 February 2014 (me) Comprehensive update posted live 14 February 2013 (cd) Revision: changes in testing available for 1 November 2012 (cd) Revision: testing for 15 March 2012 (cd) Revision: sequence analysis available clinically for 4 August 2011 (me) Comprehensive update posted live 22 April 2008 (me) Comprehensive update posted live 14 May 2007 (cd) Revision: sequence analysis clinically available for 1 June 2006 (cd) Revision: confirmation of 15 September 2005 (me) Comprehensive update posted live 24 February 2004 (kk) Revision: Molecular Genetics 1 October 2003 (kk) Revision: clinical testing no longer available 20 June 2003 (me) Review posted live 28 April 2003 (kk) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 24 March 2022 (ha) Comprehensive update posted live • 29 September 2016 (ma) Comprehensive update posted live • 13 February 2014 (me) Comprehensive update posted live • 14 February 2013 (cd) Revision: changes in testing available for • 1 November 2012 (cd) Revision: testing for • 15 March 2012 (cd) Revision: sequence analysis available clinically for • 4 August 2011 (me) Comprehensive update posted live • 22 April 2008 (me) Comprehensive update posted live • 14 May 2007 (cd) Revision: sequence analysis clinically available for • 1 June 2006 (cd) Revision: confirmation of • 15 September 2005 (me) Comprehensive update posted live • 24 February 2004 (kk) Revision: Molecular Genetics • 1 October 2003 (kk) Revision: clinical testing no longer available • 20 June 2003 (me) Review posted live • 28 April 2003 (kk) Original submission ## References ## Published Guidelines / Consensus Statements ## Literature Cited Relationship between genotype and phenotype in the xeroderma pigmentosum-Cockayne syndrome-trichothiodystrophy spectrum Modified from Italicized letters in purple shapes indicate the genes. Blue rectangles are phenotypes. Because of the complexity of the relationship, it is difficult to predict an individual's phenotype based on the associated gene, in part because specific pathogenic variants have different effects on the overall DNA repair/transcription pathways. Nucleotide excision repair (NER) pathway Modified from	[ "S Moriwaki, F Kanda, M Hayashi, D Yamashita, Y Sakai, C Nishigori. Xeroderma pigmentosum clinical practice guidelines.. J Dermatol. 2017;44:1087-96" ]	20/6/2003	24/3/2022	14/2/2013	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
xq28-dup	xq28-dup	[ "Chloride intracellular channel protein 2", "Ras-related protein Rab-39B", "CLIC2", "RAB39B", "Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated" ]	Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated	Rami A Ballout, Ayman W El-Hattab, Christian P Schaaf, Sau Wai Cheung	Summary The int22h1/int22h2-mediated Xq28 duplication syndrome is an X-linked intellectual disability syndrome characterized by variable degrees of cognitive impairment (typically more severe in males), a wide spectrum of neurobehavioral abnormalities, and variable facial dysmorphic features. Affected males also exhibit a peculiar combination of recurrent sinopulmonary infections and atopy, findings that have not been observed in affected females. All males reported to date with the syndrome have moderate-to-severe intellectual disability; in contrast, a minority of heterozygous females have been reported to have mild intellectual disability, while the majority have no discernible health or learning issues and are considered clinically unaffected. The diagnosis of int22h1/int22h2-mediated Xq28 duplication in a hemizygous male or a heterozygous female is established by detection of a 0.5-Mb duplication within the q28 region of the X chromosome extending between 154.1 Mb and 154.6 Mb in the reference genome (NCBI Build GRCh37/hg19). The int22h1/int22h2-mediated Xq28 duplication syndrome is inherited in an X-linked manner. Most affected individuals inherited the duplication from their heterozygous and often asymptomatic mother. However, individuals with	## Diagnosis The int22h1/int22h2-mediated Xq28 duplication syndrome Mild-to-moderate intellectual disability, with or without mild-to-moderate neurodevelopmental delays Any of the following features presenting in infancy or childhood: Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) Obesity with or without tall stature Nonspecific but consistent facial features (See The int22h1/int22h2-mediated Xq28 duplication syndrome Mild learning disabilities Neurobehavioral manifestations resembling those of the inattentive-type childhood ADHD (impulsivity, inattention, and emotional lability) Mild-to-moderate socialization deficits Nonspecific but consistent facial features (See The diagnosis of int22h1/int22h2-mediated Xq28 duplication syndrome More specifically, the duplicated segment extends from a low copy repeat (LCR) region within intron 22 of However, it is worth noting that several reported individuals have duplications nested within or partially overlapping with the typical int22h1/int22h2-mediated 0.5-Mb Xq28 duplication (see Note: (1) Most individuals with an int22h1/int22h2-mediated Xq28 duplication can be identified with the current CMA performed routinely for a clinical indication of neurodevelopmental delay and/or intellectual disability. (2) Routine CMA platforms before 2011 did not include coverage for this region and thus, could not detect this duplication. Likewise, the earlier BAC (bacterial artificial chromosome)-based arrays were also incapable of detecting this duplication. (3) Metaphase FISH is not reliable for detecting a duplication of this size (i.e., ~0.5 Mb). However, interphase FISH (iFISH) may be used if appropriate control studies are performed. (4) FISH analysis can also be sought to determine whether the duplicated segment may have been inserted elsewhere in the genome (i.e., insertion translocation). Genomic Testing Used in Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated See Standardized clinical annotation and interpretation for genomic variants from the Genomic coordinates represent the minimum duplication size associated with the int22h1/int22h2-mediated Xq28 duplication as designated by ClinGen. Duplication coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the duplication as calculated from these genomic positions may differ from the expected duplication size due to the presence of segmental duplications near breakpoints. See Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including int22h1/int22h2). CMA designs in current clinical use target the Xq28 region. The ability to determine the size of the duplication depends on the type of microarray used and the density of probes in the Xq28 region. Note: The int22h1/int22h2-mediated Xq28 duplication may not have been detectable by older oligonucleotide or BAC platforms. Not applicable. Targeted duplication analysis methods can include quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), and iFISH as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for an individual in whom the int22h1/int22h2-mediated Xq28 duplication was not detected by CMA designed to target this region. • Mild-to-moderate intellectual disability, with or without mild-to-moderate neurodevelopmental delays • Any of the following features presenting in infancy or childhood: • Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia • Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) • Obesity with or without tall stature • Nonspecific but consistent facial features (See • Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia • Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) • Obesity with or without tall stature • Nonspecific but consistent facial features (See • Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia • Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) • Obesity with or without tall stature • Nonspecific but consistent facial features (See • Mild learning disabilities • Neurobehavioral manifestations resembling those of the inattentive-type childhood ADHD (impulsivity, inattention, and emotional lability) • Mild-to-moderate socialization deficits • Nonspecific but consistent facial features (See ## Suggestive Findings The int22h1/int22h2-mediated Xq28 duplication syndrome Mild-to-moderate intellectual disability, with or without mild-to-moderate neurodevelopmental delays Any of the following features presenting in infancy or childhood: Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) Obesity with or without tall stature Nonspecific but consistent facial features (See The int22h1/int22h2-mediated Xq28 duplication syndrome Mild learning disabilities Neurobehavioral manifestations resembling those of the inattentive-type childhood ADHD (impulsivity, inattention, and emotional lability) Mild-to-moderate socialization deficits Nonspecific but consistent facial features (See • Mild-to-moderate intellectual disability, with or without mild-to-moderate neurodevelopmental delays • Any of the following features presenting in infancy or childhood: • Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia • Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) • Obesity with or without tall stature • Nonspecific but consistent facial features (See • Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia • Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) • Obesity with or without tall stature • Nonspecific but consistent facial features (See • Characteristic neurobehavioral profile consisting of aggression and irritability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, socialization deficits, and sleep disturbances – typically insomnia • Recurrent sinopulmonary infections (including otitis media) with existent atopic conditions (e.g., asthma, allergic rhinitis, eczema) • Obesity with or without tall stature • Nonspecific but consistent facial features (See • Mild learning disabilities • Neurobehavioral manifestations resembling those of the inattentive-type childhood ADHD (impulsivity, inattention, and emotional lability) • Mild-to-moderate socialization deficits • Nonspecific but consistent facial features (See ## Establishing the Diagnosis The diagnosis of int22h1/int22h2-mediated Xq28 duplication syndrome More specifically, the duplicated segment extends from a low copy repeat (LCR) region within intron 22 of However, it is worth noting that several reported individuals have duplications nested within or partially overlapping with the typical int22h1/int22h2-mediated 0.5-Mb Xq28 duplication (see Note: (1) Most individuals with an int22h1/int22h2-mediated Xq28 duplication can be identified with the current CMA performed routinely for a clinical indication of neurodevelopmental delay and/or intellectual disability. (2) Routine CMA platforms before 2011 did not include coverage for this region and thus, could not detect this duplication. Likewise, the earlier BAC (bacterial artificial chromosome)-based arrays were also incapable of detecting this duplication. (3) Metaphase FISH is not reliable for detecting a duplication of this size (i.e., ~0.5 Mb). However, interphase FISH (iFISH) may be used if appropriate control studies are performed. (4) FISH analysis can also be sought to determine whether the duplicated segment may have been inserted elsewhere in the genome (i.e., insertion translocation). Genomic Testing Used in Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated See Standardized clinical annotation and interpretation for genomic variants from the Genomic coordinates represent the minimum duplication size associated with the int22h1/int22h2-mediated Xq28 duplication as designated by ClinGen. Duplication coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the duplication as calculated from these genomic positions may differ from the expected duplication size due to the presence of segmental duplications near breakpoints. See Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including int22h1/int22h2). CMA designs in current clinical use target the Xq28 region. The ability to determine the size of the duplication depends on the type of microarray used and the density of probes in the Xq28 region. Note: The int22h1/int22h2-mediated Xq28 duplication may not have been detectable by older oligonucleotide or BAC platforms. Not applicable. Targeted duplication analysis methods can include quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), and iFISH as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for an individual in whom the int22h1/int22h2-mediated Xq28 duplication was not detected by CMA designed to target this region. ## Clinical Characteristics The int22h1/int22h2-mediated Xq28 duplication syndrome is a relatively newly identified X-linked intellectual disability syndrome characterized by cognitive impairment, neurobehavioral abnormalities, and a peculiar combination of recurrent sinopulmonary infections (e.g., otitis media, sinusitis, recurrent upper respiratory tract infections) and atopic conditions (i.e., asthma, allergic rhinitis, and eczema) in affected males, who also often have obesity and exhibit nonspecific facial dysmorphic features ( To date, approximately 35 individuals (19 males and 16 females) with int22h1/int22h2-mediated Xq28 duplication syndrome have been identified and reported within the literature. The clinical features discussed below are based on the phenotypic manifestations of all 35 affected individuals identified to date (see Clinical Manifestations in Individuals with Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ID = intellectual disability Two males were diagnosed while fetuses (i.e., in utero), one of which was terminated, while the other was born with multiple malformations and subsequently lost to follow up. Therefore, several of the features listed in Intellectual disability could not be assessed in three affected males because one of them was still an infant (age <1 year) at the time of writing this report, another was an aborted fetus, and the third was never formally evaluated for cognitive impairment because he was lost to follow up. ADHD, the predominant associated neurobehavioral manifestation in either sex Aggression and irritability, seen in nearly one third of males but only one female Autism spectrum disorder Anxiety, which affects both sexes equally Various socialization deficits In contrast, none of the heterozygous affected females have been reported to have either recurrent sinopulmonary infections or atopic diseases (see Tall stature was identified in three affected males and no heterozygous females. However, males and females showed similar prevalence of acquired microcephaly (~5%). Two additional features involving the morphology of the nose appear to discriminate by sex among affected individuals. While three reported males have a bulbous nose, no heterozygous female has been reported with this feature. In contrast, heterozygous females appeared to be nearly twice as likely as affected males (19% vs 11%, respectively) to have a high nasal root and depressed nasal bridge, long eyelashes, large ears, and depressed nasal bridge. Limb and digital anomalies A single palmar crease Fetal finger pads Rocker bottom feet Pes valgus Pes planus Metatarsus adductus Sandal gap 2-3 toe syndactyly Short second toe Short heel cords Arthrogryposis of the lower limbs with bilateral clubfoot [ Skeletal anomalies Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) Sacral agenesis Hip dysplasia Sensorineural hearing loss Genitourinary malformations [ Micropenis with hypospadias Bilateral grade I hydronephrosis Cryptorchisim with phimosis Imperforate anus [ Motor mannerisms and stereotypy (1 male, 1 heterozygous female) [ Recurrent seizures (1 heterozygous female) [ Eye anomalies/refractive error Strabismus (2 males) Myopia Astigmatism Micrognathia (3 males and 1 heterozygous female) A café au lait macule with multiple facial freckles (1 heterozygous female) [ Esophageal atresia with tracheoesophageal fistula, associated with cleft lip and cleft palate (2 males) Atrial septal defects (2 males, 1 of whom had a concomitant patent ductus arteriosus, while the other had a ventricular septal defect) Hemihyperplasia (1 heterozygous female) Hypothyroidism (1 heterozygous female) Generalized hypotonia that is worse on one side of the body [ Multiple malignancies with no underlying hereditary cancer syndromes identified on genetic testing [ The region located between int22h1 and int22h2 on Xq28, which is the segment typically duplicated in int22h1/int22h2-mediated Xq28 duplication syndrome, includes several genes: An atypical shortened version (~0.26 Mb) of the classic 0.5-Mb duplication reported in int22h1/int22h2-mediated Xq28 duplication syndrome has been reported in a newborn male, with his duplicated segment spanning only the centromeric half of the classically involved segment; that is, his duplication extended from 154.1 Mb to ~154.3 Mb of the q28 region of the X chromosome in the reference genome (NCBI Build GRCh37/hg19) [ For information about other Xq28 duplications with partially overlapping breakpoints compared to the int22h1/int22h2-mediated Xq28 duplication syndrome, see Int22h1/int22h2-mediated Xq28 duplication has been reported in only 35 individuals (19 males and 16 females) to date [ • ADHD, the predominant associated neurobehavioral manifestation in either sex • Aggression and irritability, seen in nearly one third of males but only one female • Autism spectrum disorder • Anxiety, which affects both sexes equally • Various socialization deficits • Limb and digital anomalies • A single palmar crease • Fetal finger pads • Rocker bottom feet • Pes valgus • Pes planus • Metatarsus adductus • Sandal gap • 2-3 toe syndactyly • Short second toe • Short heel cords • Arthrogryposis of the lower limbs with bilateral clubfoot [ • A single palmar crease • Fetal finger pads • Rocker bottom feet • Pes valgus • Pes planus • Metatarsus adductus • Sandal gap • 2-3 toe syndactyly • Short second toe • Short heel cords • Arthrogryposis of the lower limbs with bilateral clubfoot [ • Skeletal anomalies • Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) • Sacral agenesis • Hip dysplasia • Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) • Sacral agenesis • Hip dysplasia • Sensorineural hearing loss • Genitourinary malformations [ • Micropenis with hypospadias • Bilateral grade I hydronephrosis • Cryptorchisim with phimosis • Micropenis with hypospadias • Bilateral grade I hydronephrosis • Cryptorchisim with phimosis • Imperforate anus [ • Motor mannerisms and stereotypy (1 male, 1 heterozygous female) [ • Recurrent seizures (1 heterozygous female) [ • Eye anomalies/refractive error • Strabismus (2 males) • Myopia • Astigmatism • Strabismus (2 males) • Myopia • Astigmatism • Micrognathia (3 males and 1 heterozygous female) • A café au lait macule with multiple facial freckles (1 heterozygous female) [ • Esophageal atresia with tracheoesophageal fistula, associated with cleft lip and cleft palate (2 males) • Atrial septal defects (2 males, 1 of whom had a concomitant patent ductus arteriosus, while the other had a ventricular septal defect) • Hemihyperplasia (1 heterozygous female) • Hypothyroidism (1 heterozygous female) • Generalized hypotonia that is worse on one side of the body [ • Multiple malignancies with no underlying hereditary cancer syndromes identified on genetic testing [ • A single palmar crease • Fetal finger pads • Rocker bottom feet • Pes valgus • Pes planus • Metatarsus adductus • Sandal gap • 2-3 toe syndactyly • Short second toe • Short heel cords • Arthrogryposis of the lower limbs with bilateral clubfoot [ • Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) • Sacral agenesis • Hip dysplasia • Micropenis with hypospadias • Bilateral grade I hydronephrosis • Cryptorchisim with phimosis • Strabismus (2 males) • Myopia • Astigmatism ## Clinical Description The int22h1/int22h2-mediated Xq28 duplication syndrome is a relatively newly identified X-linked intellectual disability syndrome characterized by cognitive impairment, neurobehavioral abnormalities, and a peculiar combination of recurrent sinopulmonary infections (e.g., otitis media, sinusitis, recurrent upper respiratory tract infections) and atopic conditions (i.e., asthma, allergic rhinitis, and eczema) in affected males, who also often have obesity and exhibit nonspecific facial dysmorphic features ( To date, approximately 35 individuals (19 males and 16 females) with int22h1/int22h2-mediated Xq28 duplication syndrome have been identified and reported within the literature. The clinical features discussed below are based on the phenotypic manifestations of all 35 affected individuals identified to date (see Clinical Manifestations in Individuals with Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ID = intellectual disability Two males were diagnosed while fetuses (i.e., in utero), one of which was terminated, while the other was born with multiple malformations and subsequently lost to follow up. Therefore, several of the features listed in Intellectual disability could not be assessed in three affected males because one of them was still an infant (age <1 year) at the time of writing this report, another was an aborted fetus, and the third was never formally evaluated for cognitive impairment because he was lost to follow up. ADHD, the predominant associated neurobehavioral manifestation in either sex Aggression and irritability, seen in nearly one third of males but only one female Autism spectrum disorder Anxiety, which affects both sexes equally Various socialization deficits In contrast, none of the heterozygous affected females have been reported to have either recurrent sinopulmonary infections or atopic diseases (see Tall stature was identified in three affected males and no heterozygous females. However, males and females showed similar prevalence of acquired microcephaly (~5%). Two additional features involving the morphology of the nose appear to discriminate by sex among affected individuals. While three reported males have a bulbous nose, no heterozygous female has been reported with this feature. In contrast, heterozygous females appeared to be nearly twice as likely as affected males (19% vs 11%, respectively) to have a high nasal root and depressed nasal bridge, long eyelashes, large ears, and depressed nasal bridge. Limb and digital anomalies A single palmar crease Fetal finger pads Rocker bottom feet Pes valgus Pes planus Metatarsus adductus Sandal gap 2-3 toe syndactyly Short second toe Short heel cords Arthrogryposis of the lower limbs with bilateral clubfoot [ Skeletal anomalies Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) Sacral agenesis Hip dysplasia Sensorineural hearing loss Genitourinary malformations [ Micropenis with hypospadias Bilateral grade I hydronephrosis Cryptorchisim with phimosis Imperforate anus [ Motor mannerisms and stereotypy (1 male, 1 heterozygous female) [ Recurrent seizures (1 heterozygous female) [ Eye anomalies/refractive error Strabismus (2 males) Myopia Astigmatism Micrognathia (3 males and 1 heterozygous female) A café au lait macule with multiple facial freckles (1 heterozygous female) [ Esophageal atresia with tracheoesophageal fistula, associated with cleft lip and cleft palate (2 males) Atrial septal defects (2 males, 1 of whom had a concomitant patent ductus arteriosus, while the other had a ventricular septal defect) Hemihyperplasia (1 heterozygous female) Hypothyroidism (1 heterozygous female) Generalized hypotonia that is worse on one side of the body [ Multiple malignancies with no underlying hereditary cancer syndromes identified on genetic testing [ • ADHD, the predominant associated neurobehavioral manifestation in either sex • Aggression and irritability, seen in nearly one third of males but only one female • Autism spectrum disorder • Anxiety, which affects both sexes equally • Various socialization deficits • Limb and digital anomalies • A single palmar crease • Fetal finger pads • Rocker bottom feet • Pes valgus • Pes planus • Metatarsus adductus • Sandal gap • 2-3 toe syndactyly • Short second toe • Short heel cords • Arthrogryposis of the lower limbs with bilateral clubfoot [ • A single palmar crease • Fetal finger pads • Rocker bottom feet • Pes valgus • Pes planus • Metatarsus adductus • Sandal gap • 2-3 toe syndactyly • Short second toe • Short heel cords • Arthrogryposis of the lower limbs with bilateral clubfoot [ • Skeletal anomalies • Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) • Sacral agenesis • Hip dysplasia • Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) • Sacral agenesis • Hip dysplasia • Sensorineural hearing loss • Genitourinary malformations [ • Micropenis with hypospadias • Bilateral grade I hydronephrosis • Cryptorchisim with phimosis • Micropenis with hypospadias • Bilateral grade I hydronephrosis • Cryptorchisim with phimosis • Imperforate anus [ • Motor mannerisms and stereotypy (1 male, 1 heterozygous female) [ • Recurrent seizures (1 heterozygous female) [ • Eye anomalies/refractive error • Strabismus (2 males) • Myopia • Astigmatism • Strabismus (2 males) • Myopia • Astigmatism • Micrognathia (3 males and 1 heterozygous female) • A café au lait macule with multiple facial freckles (1 heterozygous female) [ • Esophageal atresia with tracheoesophageal fistula, associated with cleft lip and cleft palate (2 males) • Atrial septal defects (2 males, 1 of whom had a concomitant patent ductus arteriosus, while the other had a ventricular septal defect) • Hemihyperplasia (1 heterozygous female) • Hypothyroidism (1 heterozygous female) • Generalized hypotonia that is worse on one side of the body [ • Multiple malignancies with no underlying hereditary cancer syndromes identified on genetic testing [ • A single palmar crease • Fetal finger pads • Rocker bottom feet • Pes valgus • Pes planus • Metatarsus adductus • Sandal gap • 2-3 toe syndactyly • Short second toe • Short heel cords • Arthrogryposis of the lower limbs with bilateral clubfoot [ • Kyphoscoliosis (1 male / 2 male fetuses and 1 heterozygous female. In 1 male fetus, kyphoscoliosis was associated with thoracic vertebral malformations and unilateral missing ribs.) • Sacral agenesis • Hip dysplasia • Micropenis with hypospadias • Bilateral grade I hydronephrosis • Cryptorchisim with phimosis • Strabismus (2 males) • Myopia • Astigmatism ## Genotype-Phenotype Correlations The region located between int22h1 and int22h2 on Xq28, which is the segment typically duplicated in int22h1/int22h2-mediated Xq28 duplication syndrome, includes several genes: An atypical shortened version (~0.26 Mb) of the classic 0.5-Mb duplication reported in int22h1/int22h2-mediated Xq28 duplication syndrome has been reported in a newborn male, with his duplicated segment spanning only the centromeric half of the classically involved segment; that is, his duplication extended from 154.1 Mb to ~154.3 Mb of the q28 region of the X chromosome in the reference genome (NCBI Build GRCh37/hg19) [ For information about other Xq28 duplications with partially overlapping breakpoints compared to the int22h1/int22h2-mediated Xq28 duplication syndrome, see ## Prevalence Int22h1/int22h2-mediated Xq28 duplication has been reported in only 35 individuals (19 males and 16 females) to date [ ## Genetically Related (Allelic) Disorders Three sibs were reported to have a 0.8-Mb Xq28 duplication that extends from 154.4 to 155.2 Mb, overlapping the duplicated segment of int22h1/int22h2-mediated Xq28 duplication syndrome, and including the genes A 0.8-Mb Xq28 duplication overlapping with the 0.5-Mb duplicated region in int22h1/int22h2-mediated Xq28 duplication syndrome has also been reported in individuals sharing some of the clinical features of int22h1/int22h2-mediated Xq28 duplication syndrome. A 0.2-Mb telomerically shifted and slightly shortened version (~0.4 Mb) of the classic 0.5-Mb duplication reported in int22h1/int22h2-mediated Xq28 duplication syndrome has been reported in two sibs with typical manifestations of the syndrome. Their duplications were identical and extended between 154.3 Mb and 154.7 Mb of the q28 region of the X chromosome, according to the reference genome (NCBI Build GRCh37/hg19) [ • Three sibs were reported to have a 0.8-Mb Xq28 duplication that extends from 154.4 to 155.2 Mb, overlapping the duplicated segment of int22h1/int22h2-mediated Xq28 duplication syndrome, and including the genes • A 0.8-Mb Xq28 duplication overlapping with the 0.5-Mb duplicated region in int22h1/int22h2-mediated Xq28 duplication syndrome has also been reported in individuals sharing some of the clinical features of int22h1/int22h2-mediated Xq28 duplication syndrome. • A 0.2-Mb telomerically shifted and slightly shortened version (~0.4 Mb) of the classic 0.5-Mb duplication reported in int22h1/int22h2-mediated Xq28 duplication syndrome has been reported in two sibs with typical manifestations of the syndrome. Their duplications were identical and extended between 154.3 Mb and 154.7 Mb of the q28 region of the X chromosome, according to the reference genome (NCBI Build GRCh37/hg19) [ ## Differential Diagnosis Because the phenotypic features associated with int22h1/int22h2-mediated Xq28 duplication syndrome are not sufficient on their own to make a diagnosis of the condition, all other X-linked intellectual disability syndromes (XLIDS) without specific distinctive features should be considered in the differential diagnosis. See The syndrome is caused by duplications in the q28 region of the X chromosome spanning the Intellectual disability and recurrent infections are common findings in both syndromes, with males being more severely affected than females. However, spasticity has not been reported to date in int22h1/int22h2-mediated Xq28 duplication syndrome, and seizures and hypotonia have only recently been reported – each in a single affected individual [ ## Management No evidence-based or consensus guidelines have been established to date for the management of individuals with int22h1/int22h2-mediated Xq28 duplication syndrome. Thus, the clinical management of affected individuals remains primarily supportive at this time. Although the features of int22h1/int22h2-mediated Xq28 duplication syndrome are typically more pronounced in affected males compared with heterozygous females, affected males and heterozygous females are managed with a similar clinical approach. In order to establish the extent and severity of manifestations in individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome, Recommended Evaluations Following Initial Diagnosis in Individuals with the Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome Neurodevelopmental milestone assessment should incl motor, cognitive, & speech-language eval. Early identification of neurodevelopmental delays would allow for early intervention. Community or Social work involvement for parental/caregiver support; Home nursing referral. ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy For psychiatric conditions (e.g., attention-deficit/hyperactivity disorder, anxiety, mood or psychotic disorders), follow the DSM-V criteria for screening and diagnosing the respective condition(s) based on age group. Evaluations for (e.g.,) hypotonia, spasticity, atrophy, and hemihypertrophy are suggested. Through obtaining a thorough history of prior infections and vaccinations, any reactions to the latter, and history of allergic reactions (e.g., seasonal allergies) Medical geneticist, certified genetic counselor, and/or certified advanced genetic nurse Treatment of Manifestations in Individuals with the Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome Referral to pulmonologist, immunologist, &/or infectious disease specialist in those w/recurrent infections; Chest PT & mucolytics for those w/recurrent pneumonia; Referral to otolaryngologist for consideration of PE tube placement in those w/recurrent otitis media. Ensure appropriate involvement of social workers to connect affected persons &/or their families w/local resources, respite, or support. Help coordinate care to manage multiple subspecialty appointments, mobility assistance or other needed medical equipment, & medications & supplies. Ongoing assessment for need for palliative care involvement &/or home nursing for cases w/severe congenital malformations & severe ID Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ID = intellectual disability; OT = occupational therapy; PE = pressure equalizing; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor The following information summarizes the typical management recommendations for individuals with developmental delay or intellectual disability in the United States. It is worth noting that standard recommendations may vary from country to country for the management of individuals with developmental delay and/or intellectual disability. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually and amended or updated as needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for individuals requiring special accommodations or educational modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Enrollment at the Developmental Disabilities Administration (DDA) is also recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is generally determined by diagnosis and/or associated intellectual and adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Affected children may qualify for and benefit from interventions used in autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive profile and typically performed one on one with a trained and board-certified behavioral analyst. Consultation with a developmental pediatrician may be helpful in guiding parents or caregivers through appropriate behavior management strategies and/or providing prescription medications such as those used to treat attention-deficit/hyperactivity disorder, when needed. Concerns about serious aggressive, destructive, or self-mutilating behaviors can be discussed with and addressed by a child and adolescent psychiatrist. Recommended Surveillance and Follow Up for Individuals with Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome OT = occupational therapy; PT = physical therapy It is relevant from clinical and family planning standpoints to evaluate the genetic status of asymptomatic relatives of an affected individual in order to identify as early as possible those who would benefit from early intervention services. Targeted duplication analysis can be performed by quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or interphase FISH (iFISH) to test the relatives of a proband who is known to have the int22h1/int22h2-mediated Xq28 duplication. Note: Clinically asymptomatic children identified as having the familial duplication should be assessed and monitored regularly for neurodevelopmental delays and neurobehavioral abnormalities. See Search Note: There are no registered, recruiting, or ongoing clinical trials for int22h1/int22h2-mediated Xq28 duplication syndrome as of the chapter posting date. • Neurodevelopmental milestone assessment should incl motor, cognitive, & speech-language eval. • Early identification of neurodevelopmental delays would allow for early intervention. • Community or • Social work involvement for parental/caregiver support; • Home nursing referral. • Referral to pulmonologist, immunologist, &/or infectious disease specialist in those w/recurrent infections; • Chest PT & mucolytics for those w/recurrent pneumonia; • Referral to otolaryngologist for consideration of PE tube placement in those w/recurrent otitis media. • Ensure appropriate involvement of social workers to connect affected persons &/or their families w/local resources, respite, or support. • Help coordinate care to manage multiple subspecialty appointments, mobility assistance or other needed medical equipment, & medications & supplies. • Ongoing assessment for need for palliative care involvement &/or home nursing for cases w/severe congenital malformations & severe ID • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for individuals requiring special accommodations or educational modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Enrollment at the Developmental Disabilities Administration (DDA) is also recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is generally determined by diagnosis and/or associated intellectual and adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. ## Evaluations Following Initial Diagnosis In order to establish the extent and severity of manifestations in individuals with the int22h1/int22h2-mediated Xq28 duplication syndrome, Recommended Evaluations Following Initial Diagnosis in Individuals with the Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome Neurodevelopmental milestone assessment should incl motor, cognitive, & speech-language eval. Early identification of neurodevelopmental delays would allow for early intervention. Community or Social work involvement for parental/caregiver support; Home nursing referral. ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy For psychiatric conditions (e.g., attention-deficit/hyperactivity disorder, anxiety, mood or psychotic disorders), follow the DSM-V criteria for screening and diagnosing the respective condition(s) based on age group. Evaluations for (e.g.,) hypotonia, spasticity, atrophy, and hemihypertrophy are suggested. Through obtaining a thorough history of prior infections and vaccinations, any reactions to the latter, and history of allergic reactions (e.g., seasonal allergies) Medical geneticist, certified genetic counselor, and/or certified advanced genetic nurse • Neurodevelopmental milestone assessment should incl motor, cognitive, & speech-language eval. • Early identification of neurodevelopmental delays would allow for early intervention. • Community or • Social work involvement for parental/caregiver support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with the Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome Referral to pulmonologist, immunologist, &/or infectious disease specialist in those w/recurrent infections; Chest PT & mucolytics for those w/recurrent pneumonia; Referral to otolaryngologist for consideration of PE tube placement in those w/recurrent otitis media. Ensure appropriate involvement of social workers to connect affected persons &/or their families w/local resources, respite, or support. Help coordinate care to manage multiple subspecialty appointments, mobility assistance or other needed medical equipment, & medications & supplies. Ongoing assessment for need for palliative care involvement &/or home nursing for cases w/severe congenital malformations & severe ID Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ID = intellectual disability; OT = occupational therapy; PE = pressure equalizing; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor The following information summarizes the typical management recommendations for individuals with developmental delay or intellectual disability in the United States. It is worth noting that standard recommendations may vary from country to country for the management of individuals with developmental delay and/or intellectual disability. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually and amended or updated as needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for individuals requiring special accommodations or educational modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Enrollment at the Developmental Disabilities Administration (DDA) is also recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is generally determined by diagnosis and/or associated intellectual and adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Affected children may qualify for and benefit from interventions used in autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive profile and typically performed one on one with a trained and board-certified behavioral analyst. Consultation with a developmental pediatrician may be helpful in guiding parents or caregivers through appropriate behavior management strategies and/or providing prescription medications such as those used to treat attention-deficit/hyperactivity disorder, when needed. Concerns about serious aggressive, destructive, or self-mutilating behaviors can be discussed with and addressed by a child and adolescent psychiatrist. • Referral to pulmonologist, immunologist, &/or infectious disease specialist in those w/recurrent infections; • Chest PT & mucolytics for those w/recurrent pneumonia; • Referral to otolaryngologist for consideration of PE tube placement in those w/recurrent otitis media. • Ensure appropriate involvement of social workers to connect affected persons &/or their families w/local resources, respite, or support. • Help coordinate care to manage multiple subspecialty appointments, mobility assistance or other needed medical equipment, & medications & supplies. • Ongoing assessment for need for palliative care involvement &/or home nursing for cases w/severe congenital malformations & severe ID • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for individuals requiring special accommodations or educational modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Enrollment at the Developmental Disabilities Administration (DDA) is also recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is generally determined by diagnosis and/or associated intellectual and adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. ## Neurodevelopmental Delay / Intellectual Disability Management Issues The following information summarizes the typical management recommendations for individuals with developmental delay or intellectual disability in the United States. It is worth noting that standard recommendations may vary from country to country for the management of individuals with developmental delay and/or intellectual disability. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually and amended or updated as needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for individuals requiring special accommodations or educational modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Enrollment at the Developmental Disabilities Administration (DDA) is also recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is generally determined by diagnosis and/or associated intellectual and adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for individuals requiring special accommodations or educational modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Enrollment at the Developmental Disabilities Administration (DDA) is also recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is generally determined by diagnosis and/or associated intellectual and adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually and amended or updated as needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school, with inclusion in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be part of the child's IEP team to help support access to appropriate academic material. • PT, OT, and speech therapy services will be provided within the IEP to the extent needed to support the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by the developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated into the existing IEP. For those receiving IEP services, the public school district is required to provide services up until age 21. ## Motor Dysfunction ## Social and Behavioral Concerns Affected children may qualify for and benefit from interventions used in autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive profile and typically performed one on one with a trained and board-certified behavioral analyst. Consultation with a developmental pediatrician may be helpful in guiding parents or caregivers through appropriate behavior management strategies and/or providing prescription medications such as those used to treat attention-deficit/hyperactivity disorder, when needed. Concerns about serious aggressive, destructive, or self-mutilating behaviors can be discussed with and addressed by a child and adolescent psychiatrist. ## Surveillance Recommended Surveillance and Follow Up for Individuals with Int22h1/Int22h2-Mediated Xq28 Duplication Syndrome OT = occupational therapy; PT = physical therapy ## Evaluation of Relatives at Risk It is relevant from clinical and family planning standpoints to evaluate the genetic status of asymptomatic relatives of an affected individual in order to identify as early as possible those who would benefit from early intervention services. Targeted duplication analysis can be performed by quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or interphase FISH (iFISH) to test the relatives of a proband who is known to have the int22h1/int22h2-mediated Xq28 duplication. Note: Clinically asymptomatic children identified as having the familial duplication should be assessed and monitored regularly for neurodevelopmental delays and neurobehavioral abnormalities. See ## Therapies Under Investigation Search Note: There are no registered, recruiting, or ongoing clinical trials for int22h1/int22h2-mediated Xq28 duplication syndrome as of the chapter posting date. ## Genetic Counseling The int22h1/int22h2-mediated Xq28 duplication syndrome is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the int22h1/int22h2-mediated Xq28 duplication; therefore, he does not require further testing. In contrast, in a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (i.e., a carrier). Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If the proband is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the duplication; or the duplication may have occurred Most of the mothers of the individuals reported to date with the int22h1/int22h2-mediated Xq28 duplication syndrome have been found to be heterozygous (i.e., carriers) for the duplication. Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. Note: Testing of maternal leukocyte DNA may not always detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. A female proband may have inherited an int22h1/int22h2-mediated Xq28 duplication from her mother or, theoretically, her father if he has germline mosaicism. Alternatively, the duplication may have occurred Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. The risk to sibs of a male proband of inheriting the duplication depends on the genetic status of the mother. (However, if the proband is female, the risk to sibs of inheriting the duplication depends on the genetic status of the mother and, theoretically, the father because of the possibility of paternal germline mosaicism.) If the mother is heterozygous for the int22h1/int22h2-mediated Xq28 duplication, the chance of transmission of the duplication is 50% in each pregnancy. Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see If the proband represents a simplex case (i.e., a single occurrence within the family), and the int22h1/int22h2-mediated Xq28 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs of inheriting the duplication is low, albeit greater than that of the general population due to the possibility of maternal germline mosaicism. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.) Males who inherit the int22h1/int22h2-mediated Xq28 duplication will be affected. Females who inherit the int22h1/int22h2-mediated Xq28 duplication will be heterozygous, often exhibiting a milder phenotype than affected males or, alternatively, being clinically unaffected (see Note: Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication in the proband can help identify the family member in whom a See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the int22h1/int22h2-mediated Xq28 duplication syndrome. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the int22h1/int22h2-mediated Xq28 duplication; therefore, he does not require further testing. • In contrast, in a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (i.e., a carrier). Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If the proband is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the duplication; or the duplication may have occurred • Most of the mothers of the individuals reported to date with the int22h1/int22h2-mediated Xq28 duplication syndrome have been found to be heterozygous (i.e., carriers) for the duplication. • Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. Note: Testing of maternal leukocyte DNA may not always detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • A female proband may have inherited an int22h1/int22h2-mediated Xq28 duplication from her mother or, theoretically, her father if he has germline mosaicism. Alternatively, the duplication may have occurred • Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. • The risk to sibs of a male proband of inheriting the duplication depends on the genetic status of the mother. (However, if the proband is female, the risk to sibs of inheriting the duplication depends on the genetic status of the mother and, theoretically, the father because of the possibility of paternal germline mosaicism.) • If the mother is heterozygous for the int22h1/int22h2-mediated Xq28 duplication, the chance of transmission of the duplication is 50% in each pregnancy. • Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see • Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see • If the proband represents a simplex case (i.e., a single occurrence within the family), and the int22h1/int22h2-mediated Xq28 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs of inheriting the duplication is low, albeit greater than that of the general population due to the possibility of maternal germline mosaicism. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.) • Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see • Males who inherit the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the int22h1/int22h2-mediated Xq28 duplication will be heterozygous, often exhibiting a milder phenotype than affected males or, alternatively, being clinically unaffected (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the int22h1/int22h2-mediated Xq28 duplication syndrome. ## Mode of Inheritance The int22h1/int22h2-mediated Xq28 duplication syndrome is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the int22h1/int22h2-mediated Xq28 duplication; therefore, he does not require further testing. In contrast, in a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (i.e., a carrier). Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If the proband is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the duplication; or the duplication may have occurred Most of the mothers of the individuals reported to date with the int22h1/int22h2-mediated Xq28 duplication syndrome have been found to be heterozygous (i.e., carriers) for the duplication. Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. Note: Testing of maternal leukocyte DNA may not always detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. A female proband may have inherited an int22h1/int22h2-mediated Xq28 duplication from her mother or, theoretically, her father if he has germline mosaicism. Alternatively, the duplication may have occurred Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. The risk to sibs of a male proband of inheriting the duplication depends on the genetic status of the mother. (However, if the proband is female, the risk to sibs of inheriting the duplication depends on the genetic status of the mother and, theoretically, the father because of the possibility of paternal germline mosaicism.) If the mother is heterozygous for the int22h1/int22h2-mediated Xq28 duplication, the chance of transmission of the duplication is 50% in each pregnancy. Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see If the proband represents a simplex case (i.e., a single occurrence within the family), and the int22h1/int22h2-mediated Xq28 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs of inheriting the duplication is low, albeit greater than that of the general population due to the possibility of maternal germline mosaicism. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.) Males who inherit the int22h1/int22h2-mediated Xq28 duplication will be affected. Females who inherit the int22h1/int22h2-mediated Xq28 duplication will be heterozygous, often exhibiting a milder phenotype than affected males or, alternatively, being clinically unaffected (see Note: Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication in the proband can help identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the int22h1/int22h2-mediated Xq28 duplication; therefore, he does not require further testing. • In contrast, in a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (i.e., a carrier). Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If the proband is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the duplication; or the duplication may have occurred • Most of the mothers of the individuals reported to date with the int22h1/int22h2-mediated Xq28 duplication syndrome have been found to be heterozygous (i.e., carriers) for the duplication. • Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. Note: Testing of maternal leukocyte DNA may not always detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • A female proband may have inherited an int22h1/int22h2-mediated Xq28 duplication from her mother or, theoretically, her father if he has germline mosaicism. Alternatively, the duplication may have occurred • Genomic testing capable of detecting the int22h1/int22h2-mediated Xq28 duplication is recommended for the mother of a proband. • The risk to sibs of a male proband of inheriting the duplication depends on the genetic status of the mother. (However, if the proband is female, the risk to sibs of inheriting the duplication depends on the genetic status of the mother and, theoretically, the father because of the possibility of paternal germline mosaicism.) • If the mother is heterozygous for the int22h1/int22h2-mediated Xq28 duplication, the chance of transmission of the duplication is 50% in each pregnancy. • Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see • Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see • If the proband represents a simplex case (i.e., a single occurrence within the family), and the int22h1/int22h2-mediated Xq28 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs of inheriting the duplication is low, albeit greater than that of the general population due to the possibility of maternal germline mosaicism. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.) • Males who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the maternal X chromosome containing the int22h1/int22h2-mediated Xq28 duplication will be heterozygous and will therefore be likely have a milder phenotype than affected males or be clinically unaffected (see • Males who inherit the int22h1/int22h2-mediated Xq28 duplication will be affected. • Females who inherit the int22h1/int22h2-mediated Xq28 duplication will be heterozygous, often exhibiting a milder phenotype than affected males or, alternatively, being clinically unaffected (see ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the int22h1/int22h2-mediated Xq28 duplication syndrome. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the int22h1/int22h2-mediated Xq28 duplication syndrome. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • United Kingdom • ## Molecular Genetics Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated ( The int22h1/int22h2-mediated Xq28 duplication breakpoints are located at the directly oriented LCRs: int22h1 (located within intron 22 of It is worth noting that a third homologous region, int22h3, is located 0.6 Mb telomeric to int22h1, or about 0.1 Mb telomeric to int22h2. Until recently, no duplications involving the int22h3 locus (which is in opposite orientation to int22h1) had been identified. However, in the recent case series by Genomic inversions between int22h1 and either int22h2 or int22h3 are known to disrupt Loss-of-function pathogenic variants in In contrast, increased dosages of • Loss-of-function pathogenic variants in • In contrast, increased dosages of • Loss-of-function pathogenic variants in • In contrast, increased dosages of • Loss-of-function pathogenic variants in • In contrast, increased dosages of ## Molecular Pathogenesis The int22h1/int22h2-mediated Xq28 duplication breakpoints are located at the directly oriented LCRs: int22h1 (located within intron 22 of It is worth noting that a third homologous region, int22h3, is located 0.6 Mb telomeric to int22h1, or about 0.1 Mb telomeric to int22h2. Until recently, no duplications involving the int22h3 locus (which is in opposite orientation to int22h1) had been identified. However, in the recent case series by Genomic inversions between int22h1 and either int22h2 or int22h3 are known to disrupt Loss-of-function pathogenic variants in In contrast, increased dosages of • Loss-of-function pathogenic variants in • In contrast, increased dosages of • Loss-of-function pathogenic variants in • In contrast, increased dosages of • Loss-of-function pathogenic variants in • In contrast, increased dosages of ## Chapter Notes We wish to thank all the patients and their families/caregivers and overseeing physicians, without whom none of the original studies cited in this chapter would have been conducted. 25 February 2021 (ma) Comprehensive update posted live 10 March 2016 (bp) Review posted live 31 July 2015 (aweh) Original submission • 25 February 2021 (ma) Comprehensive update posted live • 10 March 2016 (bp) Review posted live • 31 July 2015 (aweh) Original submission ## Author Notes ## Acknowledgments We wish to thank all the patients and their families/caregivers and overseeing physicians, without whom none of the original studies cited in this chapter would have been conducted. ## Revision History 25 February 2021 (ma) Comprehensive update posted live 10 March 2016 (bp) Review posted live 31 July 2015 (aweh) Original submission • 25 February 2021 (ma) Comprehensive update posted live • 10 March 2016 (bp) Review posted live • 31 July 2015 (aweh) Original submission ## References ## Literature Cited Facial features of affected males (A-E) and heterozygous females (F-K) with int22h1/int22h2-mediated Xq28 duplication syndrome A and B are brothers, ages 11 and 3 years, respectively. C, D, and E are ages 3 years, 15 years, and 9 months, respectively. F, G, and H are sisters, ages 4, 6, and 8 years, respectively. I, J, and K are ages 32, 25, and 47 years, respectively. Note the tall forehead, large ears, wide and depressed nasal bridge, high nasal root, and thick vermilion of the lower lip in most of these individuals [	[]	10/3/2016	25/2/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
xxms	xxms	[ "46,XX Testicular DSD", "46,XX Testicular DSD", "SRY-Negative 46,XX Testicular Disorders/Differences of Sex Development", "SRY-Positive 46,XX Testicular Disorders/Differences of Sex Development", "Sex-determining region Y protein", "Steroidogenic factor 1", "Transcription factor SOX-3", "Transcription factor SOX-9", "Wilms tumor protein", "NR5A1", "SOX3", "SOX9", "SRY", "WT1", "Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development" ]	Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development	Emmanuèle C Délot, Eric J Vilain	Summary Nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are characterized by: the presence of a 46,XX karyotype; external genitalia ranging from typical male to ambiguous; two testicles; azoospermia; absence of müllerian structures; and absence of other syndromic features, such as congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues. Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia. Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia. Gender role and gender identity are reported as male. If untreated, males with 46,XX testicular DSD experience the consequences of testosterone deficiency. Diagnosis of nonsyndromic 46,XX testicular DSD is based on the combination of clinical findings, endocrine testing, and cytogenetic testing. Endocrine studies usually show hypergonadotropic hypogonadism secondary to testicular failure. Cytogenetic studies at the 550-band level demonstrate a 46,XX karyotype. The mode of inheritance and recurrence risk to sibs of a proband with a nonsyndromic 46,XX testicular DSD depend on the molecular diagnosis in the proband and the genetic status of the parents. Pathogenic variants in To date, all known individuals with CNVs in or around Autosomal dominant inheritance has been documented for familial cases thought to be caused by CNVs in or around To date, all known individuals with a pathogenic	For synonyms and outdated names see ## Diagnosis No consensus clinical diagnostic criteria for nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have been published. However, algorithms have been developed for the evaluation and diagnosis of DSD, including nonsyndromic 46,XX testicular DSD [ Nonsyndromic 46,XX testicular DSD Male external genitalia that ranges from typical to ambiguous (penoscrotal hypospadias with or without chordee) Two testicles, typically smaller than average for age Absence of dysmorphic features and congenital anomalies outside of the genitourinary system Normal cognitive development A 46,XX karyotype using conventional staining methods Azoospermia Endocrine studies that demonstrate hypergonadotropic hypogonadism secondary to testicular failure: Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. Preservation of the hypothalamic-pituitary axis. Gonadotropin-releasing hormone (GnRH) stimulation testing shows a normal LH and FSH response. Note: Such testing is not required for diagnosis. Testicular biopsy shows a decrease in size and number of seminiferous tubules, peritubular fibrosis, absence of germ cells, and hyperplasia of Leydig cells. Note: Such testing is not required for diagnosis. The diagnosis of nonsyndromic 46,XX testicular DSD Presence of Note: Some individuals will be diagnosed solely by CMA when there is evidence for two X chromosomes, no Y chromosome, and presence of Small copy number variants in or around Note: (1) Depending on the microarray platform used and the probe coverage in and around Specific heterozygous pathogenic variants in If Note: Only a specific pathogenic variant in For an introduction to multigene panels click Note: A balanced chromosomal translocation involving the 17q24.3 region has also been reported [ For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development by Phenotype CMA = chromosomal microarray; DSD = disorders/differences of sex development; FISH = fluorescent in situ hybridization; GS = genome sequencing; NA = not applicable Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the regions surrounding Genome sequencing is typically performed by next-generation sequencing of sheared genomic DNA. Genome sequencing techniques have nonstandardized, highly variable coverage. Unlike exome sequencing, genome sequencing has the ability to identify structural variants and chromosome breakpoints in noncoding regions. The coverage of the genome is less than 100% and varies by laboratory. To date, the only pathogenic variants in Due to the mechanism of disease causation, copy number variants in this gene are unlikely to lead to nonsyndromic 46,XX testicular DSD. Depending on the microarray platform used and the probe coverage in and around It is important to verify with the testing laboratory that they will report variants in the gene desert around As implied by the title of this table, sequence analysis that detects the present of The only pathogenic variants described in individuals with this phenotype specifically affect the ZF4 domain (see • Male external genitalia that ranges from typical to ambiguous (penoscrotal hypospadias with or without chordee) • Two testicles, typically smaller than average for age • Absence of dysmorphic features and congenital anomalies outside of the genitourinary system • Normal cognitive development • A 46,XX karyotype using conventional staining methods • Azoospermia • Endocrine studies that demonstrate hypergonadotropic hypogonadism secondary to testicular failure: • Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). • Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). • Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. • Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). • Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). • Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. • Preservation of the hypothalamic-pituitary axis. Gonadotropin-releasing hormone (GnRH) stimulation testing shows a normal LH and FSH response. • Note: Such testing is not required for diagnosis. • Testicular biopsy shows a decrease in size and number of seminiferous tubules, peritubular fibrosis, absence of germ cells, and hyperplasia of Leydig cells. • Note: Such testing is not required for diagnosis. • Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). • Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). • Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. • Presence of • Note: Some individuals will be diagnosed solely by CMA when there is evidence for two X chromosomes, no Y chromosome, and presence of • Small copy number variants in or around • Note: (1) Depending on the microarray platform used and the probe coverage in and around • Specific heterozygous pathogenic variants in • Note: Only a specific pathogenic variant in • For an introduction to multigene panels click ## Suggestive Findings Nonsyndromic 46,XX testicular DSD Male external genitalia that ranges from typical to ambiguous (penoscrotal hypospadias with or without chordee) Two testicles, typically smaller than average for age Absence of dysmorphic features and congenital anomalies outside of the genitourinary system Normal cognitive development A 46,XX karyotype using conventional staining methods Azoospermia Endocrine studies that demonstrate hypergonadotropic hypogonadism secondary to testicular failure: Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. Preservation of the hypothalamic-pituitary axis. Gonadotropin-releasing hormone (GnRH) stimulation testing shows a normal LH and FSH response. Note: Such testing is not required for diagnosis. Testicular biopsy shows a decrease in size and number of seminiferous tubules, peritubular fibrosis, absence of germ cells, and hyperplasia of Leydig cells. Note: Such testing is not required for diagnosis. • Male external genitalia that ranges from typical to ambiguous (penoscrotal hypospadias with or without chordee) • Two testicles, typically smaller than average for age • Absence of dysmorphic features and congenital anomalies outside of the genitourinary system • Normal cognitive development • A 46,XX karyotype using conventional staining methods • Azoospermia • Endocrine studies that demonstrate hypergonadotropic hypogonadism secondary to testicular failure: • Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). • Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). • Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. • Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). • Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). • Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. • Preservation of the hypothalamic-pituitary axis. Gonadotropin-releasing hormone (GnRH) stimulation testing shows a normal LH and FSH response. • Note: Such testing is not required for diagnosis. • Testicular biopsy shows a decrease in size and number of seminiferous tubules, peritubular fibrosis, absence of germ cells, and hyperplasia of Leydig cells. • Note: Such testing is not required for diagnosis. • Basal serum concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are moderately elevated (normal range for LH: 1.5-9 mIU/mL in adult males; for FSH: 2.0-9.2 mIU/mL). • Serum testosterone concentration is usually decreased, typically with serum testosterone concentration below 300 ng/dL in adults (normal range: 350-1,030 ng/dL in adult males). • Human chorionic gonadotropin (hCG) stimulation test typically shows a low-to-subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular injection of hCG. ## Establishing the Diagnosis The diagnosis of nonsyndromic 46,XX testicular DSD Presence of Note: Some individuals will be diagnosed solely by CMA when there is evidence for two X chromosomes, no Y chromosome, and presence of Small copy number variants in or around Note: (1) Depending on the microarray platform used and the probe coverage in and around Specific heterozygous pathogenic variants in If Note: Only a specific pathogenic variant in For an introduction to multigene panels click Note: A balanced chromosomal translocation involving the 17q24.3 region has also been reported [ For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development by Phenotype CMA = chromosomal microarray; DSD = disorders/differences of sex development; FISH = fluorescent in situ hybridization; GS = genome sequencing; NA = not applicable Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the regions surrounding Genome sequencing is typically performed by next-generation sequencing of sheared genomic DNA. Genome sequencing techniques have nonstandardized, highly variable coverage. Unlike exome sequencing, genome sequencing has the ability to identify structural variants and chromosome breakpoints in noncoding regions. The coverage of the genome is less than 100% and varies by laboratory. To date, the only pathogenic variants in Due to the mechanism of disease causation, copy number variants in this gene are unlikely to lead to nonsyndromic 46,XX testicular DSD. Depending on the microarray platform used and the probe coverage in and around It is important to verify with the testing laboratory that they will report variants in the gene desert around As implied by the title of this table, sequence analysis that detects the present of The only pathogenic variants described in individuals with this phenotype specifically affect the ZF4 domain (see • Presence of • Note: Some individuals will be diagnosed solely by CMA when there is evidence for two X chromosomes, no Y chromosome, and presence of • Small copy number variants in or around • Note: (1) Depending on the microarray platform used and the probe coverage in and around • Specific heterozygous pathogenic variants in • Note: Only a specific pathogenic variant in • For an introduction to multigene panels click ## Gene-Targeted Testing If Note: Only a specific pathogenic variant in For an introduction to multigene panels click • Note: Only a specific pathogenic variant in • For an introduction to multigene panels click ## Comprehensive Genomic Testing Note: A balanced chromosomal translocation involving the 17q24.3 region has also been reported [ For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development by Phenotype CMA = chromosomal microarray; DSD = disorders/differences of sex development; FISH = fluorescent in situ hybridization; GS = genome sequencing; NA = not applicable Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the regions surrounding Genome sequencing is typically performed by next-generation sequencing of sheared genomic DNA. Genome sequencing techniques have nonstandardized, highly variable coverage. Unlike exome sequencing, genome sequencing has the ability to identify structural variants and chromosome breakpoints in noncoding regions. The coverage of the genome is less than 100% and varies by laboratory. To date, the only pathogenic variants in Due to the mechanism of disease causation, copy number variants in this gene are unlikely to lead to nonsyndromic 46,XX testicular DSD. Depending on the microarray platform used and the probe coverage in and around It is important to verify with the testing laboratory that they will report variants in the gene desert around As implied by the title of this table, sequence analysis that detects the present of The only pathogenic variants described in individuals with this phenotype specifically affect the ZF4 domain (see ## Clinical Characteristics By definition, nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are not associated with dysmorphic features, congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues. Approximately 85% of males with a 46,XX sex chromosome complement present after puberty with typical male pubic hair and penile size but small testes, gynecomastia, and sterility resulting from azoospermia [ Approximately 15% of individuals have ambiguous genitalia, typically penoscrotal hypospadias with or without chordee, noted at birth [ Anterior/distal hypospadias (atypical urethral opening) is also uncommon. There has only been one case report of a germ cell tumor in an individual with nonsyndromic 46,XX testicular DSD who presented with ambiguous genitalia [ Low libido and possible erectile dysfunction Decrease in secondary sexual characteristics, such as sparse body hair, infrequent need to shave, and reduced muscle mass Increase in fat mass with lower muscle strength Increased risk of osteopenia Increased risk of depression Typically, these individuals do not have hypospadias. The finding of ambiguous genitalia is uncommon. Gynecomastia is much less common compared to those who have Affected individuals tend to present with ambiguous genitalia at birth, such as penoscrotal hypospadias and cryptorchidism, and, if untreated, almost always develop gynecomastia around the time of puberty. Affected individuals may have shorter-than-average height. Shorter-than-average stature has been described. Three individuals without genital ambiguity were incidentally diagnosed while being evaluated for developmental delay or gender dysphoria [ Heterozygous pathogenic variants in At an international consensus conference on the management of intersexuality held in October 2005 under the auspices of the Lawson Wilkins Pediatric Endocrine Society (USA) and the European Society for Pediatric Endocrinology, a multidisciplinary panel of experts proposed that the names "XX male syndrome" and "true hermaphrodite" be replaced by the names "46,XX testicular DSD" and "46,XX ovotesticular DSD," respectively [ The prevalence of nonsyndromic 46,XX testicular DSD is estimated at 1:20,000 males. • Approximately 15% of individuals have ambiguous genitalia, typically penoscrotal hypospadias with or without chordee, noted at birth [ • Anterior/distal hypospadias (atypical urethral opening) is also uncommon. • Low libido and possible erectile dysfunction • Decrease in secondary sexual characteristics, such as sparse body hair, infrequent need to shave, and reduced muscle mass • Increase in fat mass with lower muscle strength • Increased risk of osteopenia • Increased risk of depression • Typically, these individuals do not have hypospadias. • The finding of ambiguous genitalia is uncommon. • Gynecomastia is much less common compared to those who have • Affected individuals tend to present with ambiguous genitalia at birth, such as penoscrotal hypospadias and cryptorchidism, and, if untreated, almost always develop gynecomastia around the time of puberty. • Affected individuals may have shorter-than-average height. • Shorter-than-average stature has been described. • Three individuals without genital ambiguity were incidentally diagnosed while being evaluated for developmental delay or gender dysphoria [ ## Clinical Description By definition, nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are not associated with dysmorphic features, congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues. Approximately 85% of males with a 46,XX sex chromosome complement present after puberty with typical male pubic hair and penile size but small testes, gynecomastia, and sterility resulting from azoospermia [ Approximately 15% of individuals have ambiguous genitalia, typically penoscrotal hypospadias with or without chordee, noted at birth [ Anterior/distal hypospadias (atypical urethral opening) is also uncommon. There has only been one case report of a germ cell tumor in an individual with nonsyndromic 46,XX testicular DSD who presented with ambiguous genitalia [ Low libido and possible erectile dysfunction Decrease in secondary sexual characteristics, such as sparse body hair, infrequent need to shave, and reduced muscle mass Increase in fat mass with lower muscle strength Increased risk of osteopenia Increased risk of depression • Approximately 15% of individuals have ambiguous genitalia, typically penoscrotal hypospadias with or without chordee, noted at birth [ • Anterior/distal hypospadias (atypical urethral opening) is also uncommon. • Low libido and possible erectile dysfunction • Decrease in secondary sexual characteristics, such as sparse body hair, infrequent need to shave, and reduced muscle mass • Increase in fat mass with lower muscle strength • Increased risk of osteopenia • Increased risk of depression ## Phenotype Correlations by Gene Typically, these individuals do not have hypospadias. The finding of ambiguous genitalia is uncommon. Gynecomastia is much less common compared to those who have Affected individuals tend to present with ambiguous genitalia at birth, such as penoscrotal hypospadias and cryptorchidism, and, if untreated, almost always develop gynecomastia around the time of puberty. Affected individuals may have shorter-than-average height. Shorter-than-average stature has been described. Three individuals without genital ambiguity were incidentally diagnosed while being evaluated for developmental delay or gender dysphoria [ • Typically, these individuals do not have hypospadias. • The finding of ambiguous genitalia is uncommon. • Gynecomastia is much less common compared to those who have • Affected individuals tend to present with ambiguous genitalia at birth, such as penoscrotal hypospadias and cryptorchidism, and, if untreated, almost always develop gynecomastia around the time of puberty. • Affected individuals may have shorter-than-average height. • Shorter-than-average stature has been described. • Three individuals without genital ambiguity were incidentally diagnosed while being evaluated for developmental delay or gender dysphoria [ ## Penetrance Heterozygous pathogenic variants in ## Nomenclature At an international consensus conference on the management of intersexuality held in October 2005 under the auspices of the Lawson Wilkins Pediatric Endocrine Society (USA) and the European Society for Pediatric Endocrinology, a multidisciplinary panel of experts proposed that the names "XX male syndrome" and "true hermaphrodite" be replaced by the names "46,XX testicular DSD" and "46,XX ovotesticular DSD," respectively [ ## Prevalence The prevalence of nonsyndromic 46,XX testicular DSD is estimated at 1:20,000 males. ## Genetically Related (Allelic) Disorders Nonsyndromic 46,XX testicular and 46,XX ovotesticular (defined as the presence of both testicular and ovarian tissue in an individual) disorders/differences of sex development (DSD) may represent the same genetic entity, as both phenotypes are represented in families with 46,XX males. However, it is critical to differentiate them, as their potential outcomes differ, requiring different management. The presence of ovarian tissue, however minimal, in a self-identified boy may lead to feminization of physical characteristics (reduced hair, gynecomastia, menstrual flow), a possible indication for surgical excision of the ovarian portion of the gonad. Conversely, the presence of testicular tissue in a self-identified girl could eventually lead to unwanted hirsutism and may increase tumor risk. Individuals with ovotesticular DSD (formerly known as "true hermaphrodites") have both testicular and ovarian tissue either as an ovotestis or as an ovary and a contralateral testis, whereas the gonads of individuals with 46,XX testicular DSD consist only of testicular tissue. The type of gonadal tissue can be established by gonadal biopsy. The possibility of bias of sampling of a gonadal biopsy that may miss the ovarian portion of the gonads needs to be considered. Ovotesticular DSD may be associated with the presence of a uterus or a hemi-uterus; individuals with nonsyndromic 46,XX testicular DSD have no müllerian structures. Endocrine investigations may reveal estrogen production in individuals with ovotesticular DSD. All known genetic causes of nonsyndromic 46,XX testicular DSD can also lead to 46,XX ovotesticular DSD: Allelic Nonsyndromic Disorders/Differences of Sex Development Conditions See Atypical genitalia; nonpalpable gonads; gonadoblastoma & dysgerminoma in 1 person. chr = chromosome; DSD = disorders/differences of sex development Genes are listed in alphabetic order. Heterozygous pathogenic variants in 46,XX ovotesticular DSD can also be caused by small duplications of regions upstream of Most commonly as the result of abnormal interchange between an X and Y chromosome resulting in translocation of Other Allelic Syndromic Disorders Skeletal dysplasia; distinctive facies; Pierre Robin sequence w/cleft palate; shortening & bowing of long bones; clubfeet Many affected infants die in neonatal period due to laryngotracheomalacia & respiratory compromise Ambiguous genitalia or typical female external genitalia are seen in most XY persons. DSD is not a feature of 46,XX persons w/CD. DD = developmental delay See also OMIM See also • Individuals with ovotesticular DSD (formerly known as "true hermaphrodites") have both testicular and ovarian tissue either as an ovotestis or as an ovary and a contralateral testis, whereas the gonads of individuals with 46,XX testicular DSD consist only of testicular tissue. The type of gonadal tissue can be established by gonadal biopsy. The possibility of bias of sampling of a gonadal biopsy that may miss the ovarian portion of the gonads needs to be considered. • Ovotesticular DSD may be associated with the presence of a uterus or a hemi-uterus; individuals with nonsyndromic 46,XX testicular DSD have no müllerian structures. • Endocrine investigations may reveal estrogen production in individuals with ovotesticular DSD. • See • Atypical genitalia; nonpalpable gonads; gonadoblastoma & dysgerminoma in 1 person. • Skeletal dysplasia; distinctive facies; Pierre Robin sequence w/cleft palate; shortening & bowing of long bones; clubfeet • Many affected infants die in neonatal period due to laryngotracheomalacia & respiratory compromise • Ambiguous genitalia or typical female external genitalia are seen in most XY persons. DSD is not a feature of 46,XX persons w/CD. ## Allelic Nonsyndromic Disorders Nonsyndromic 46,XX testicular and 46,XX ovotesticular (defined as the presence of both testicular and ovarian tissue in an individual) disorders/differences of sex development (DSD) may represent the same genetic entity, as both phenotypes are represented in families with 46,XX males. However, it is critical to differentiate them, as their potential outcomes differ, requiring different management. The presence of ovarian tissue, however minimal, in a self-identified boy may lead to feminization of physical characteristics (reduced hair, gynecomastia, menstrual flow), a possible indication for surgical excision of the ovarian portion of the gonad. Conversely, the presence of testicular tissue in a self-identified girl could eventually lead to unwanted hirsutism and may increase tumor risk. Individuals with ovotesticular DSD (formerly known as "true hermaphrodites") have both testicular and ovarian tissue either as an ovotestis or as an ovary and a contralateral testis, whereas the gonads of individuals with 46,XX testicular DSD consist only of testicular tissue. The type of gonadal tissue can be established by gonadal biopsy. The possibility of bias of sampling of a gonadal biopsy that may miss the ovarian portion of the gonads needs to be considered. Ovotesticular DSD may be associated with the presence of a uterus or a hemi-uterus; individuals with nonsyndromic 46,XX testicular DSD have no müllerian structures. Endocrine investigations may reveal estrogen production in individuals with ovotesticular DSD. All known genetic causes of nonsyndromic 46,XX testicular DSD can also lead to 46,XX ovotesticular DSD: Allelic Nonsyndromic Disorders/Differences of Sex Development Conditions See Atypical genitalia; nonpalpable gonads; gonadoblastoma & dysgerminoma in 1 person. chr = chromosome; DSD = disorders/differences of sex development Genes are listed in alphabetic order. Heterozygous pathogenic variants in 46,XX ovotesticular DSD can also be caused by small duplications of regions upstream of Most commonly as the result of abnormal interchange between an X and Y chromosome resulting in translocation of • Individuals with ovotesticular DSD (formerly known as "true hermaphrodites") have both testicular and ovarian tissue either as an ovotestis or as an ovary and a contralateral testis, whereas the gonads of individuals with 46,XX testicular DSD consist only of testicular tissue. The type of gonadal tissue can be established by gonadal biopsy. The possibility of bias of sampling of a gonadal biopsy that may miss the ovarian portion of the gonads needs to be considered. • Ovotesticular DSD may be associated with the presence of a uterus or a hemi-uterus; individuals with nonsyndromic 46,XX testicular DSD have no müllerian structures. • Endocrine investigations may reveal estrogen production in individuals with ovotesticular DSD. • See • Atypical genitalia; nonpalpable gonads; gonadoblastoma & dysgerminoma in 1 person. ## Allelic Syndromic Disorders Other Allelic Syndromic Disorders Skeletal dysplasia; distinctive facies; Pierre Robin sequence w/cleft palate; shortening & bowing of long bones; clubfeet Many affected infants die in neonatal period due to laryngotracheomalacia & respiratory compromise Ambiguous genitalia or typical female external genitalia are seen in most XY persons. DSD is not a feature of 46,XX persons w/CD. DD = developmental delay See also OMIM See also • Skeletal dysplasia; distinctive facies; Pierre Robin sequence w/cleft palate; shortening & bowing of long bones; clubfeet • Many affected infants die in neonatal period due to laryngotracheomalacia & respiratory compromise • Ambiguous genitalia or typical female external genitalia are seen in most XY persons. DSD is not a feature of 46,XX persons w/CD. ## Differential Diagnosis Nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) must be differentiated from ovotesticular DSD as their potential outcomes differ, thus affecting management; see Other disorders to consider in the differential diagnosis of nonsyndromic 46,XX testicular DSD are summarized in Disorders to Consider in the Differential Diagnosis of Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Klinefelter syndrome (males w/hypogonadism, small testes, gynecomastia) Unlike 46,XX testicular DSD, Klinefelter syndrome is often characterized by normal or tall stature, speech delay, learning disorders, & behavioral issues. Biallelic pathogenic variants are assoc w/ Virilized females may have an enlarged clitorophallic structure & urogenital sinus; uterus & ovaries are normal. DD = developmental delay; Mb = megabase See OMIM 46,XX,t(12;17)(q14.3;q24.3) [ See OMIM • Klinefelter syndrome (males w/hypogonadism, small testes, gynecomastia) • Unlike 46,XX testicular DSD, Klinefelter syndrome is often characterized by normal or tall stature, speech delay, learning disorders, & behavioral issues. • Biallelic pathogenic variants are assoc w/ • Virilized females may have an enlarged clitorophallic structure & urogenital sinus; uterus & ovaries are normal. ## Management No clinical practice guidelines for nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have been published. To establish the extent of the condition and needs in an individual diagnosed with nonsyndromic 46,XX testicular DSD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Community or Social work involvement for parental support. DSD = disorders/differences of sex development; DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; PSA = prostate-specific antigen Abnormalities in either of these may indicate the presence of prostate cancer; in this scenario, supplemental testosterone therapy may be contraindicated. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment of Manifestations in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Low-dose testosterone replacement therapy can be initiated after age 14 yrs. Testosterone enanthate In adulthood, treatment should plateau at best possible dosage, typically 50-400 mg every 2-4 wks. If person has short stature & is eligible for growth hormone therapy, testosterone therapy should be either delayed or given at lower doses initially to maximize growth potential. Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings. IM = intramuscularly Prior to initiating treatment with supplemental testosterone in adults, perform a digital rectal examination and measurement of prostate-specific antigen (PSA), abnormalities of which would be a contraindication to the treatment. Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy. Initial high doses of testosterone should be avoided to prevent priapism. Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage. Alternative delivery systems that result in more stable dosing include transdermal patches (scrotal and nonscrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of newer hydroalcoholic gels. Recommended Surveillance for Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Every 3 mos (prior to next injection) to evaluate nadir testosterone concentrations Once optimal dose is established, annual measurements are sufficient. DXA = dual-energy x-ray absorptiometry; PSA = prostate-specific antigen Concentrations lower than 200 ng/dL or higher than 500 ng/dL may require adjustment of total dose or frequency. To evaluate for the presence of an overt prostate cancer, which would be a contraindication to supplemental testosterone treatment. Increased hematocrit may lead to risk of hypoxia and sleep apnea. Contraindications to testosterone replacement therapy include prostate cancer (known or suspected) and breast cancer. Oral androgens such as methyltestosterone and fluoxymesterone should not be given (especially for long-term therapy) because of liver toxicity. See Search • Community or • Social work involvement for parental support. • Low-dose testosterone replacement therapy can be initiated after age 14 yrs. • Testosterone enanthate • In adulthood, treatment should plateau at best possible dosage, typically 50-400 mg every 2-4 wks. • If person has short stature & is eligible for growth hormone therapy, testosterone therapy should be either delayed or given at lower doses initially to maximize growth potential. • Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings. • Every 3 mos (prior to next injection) to evaluate nadir testosterone concentrations • Once optimal dose is established, annual measurements are sufficient. ## Evaluations Following Initial Diagnosis To establish the extent of the condition and needs in an individual diagnosed with nonsyndromic 46,XX testicular DSD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Community or Social work involvement for parental support. DSD = disorders/differences of sex development; DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; PSA = prostate-specific antigen Abnormalities in either of these may indicate the presence of prostate cancer; in this scenario, supplemental testosterone therapy may be contraindicated. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Community or • Social work involvement for parental support. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Low-dose testosterone replacement therapy can be initiated after age 14 yrs. Testosterone enanthate In adulthood, treatment should plateau at best possible dosage, typically 50-400 mg every 2-4 wks. If person has short stature & is eligible for growth hormone therapy, testosterone therapy should be either delayed or given at lower doses initially to maximize growth potential. Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings. IM = intramuscularly Prior to initiating treatment with supplemental testosterone in adults, perform a digital rectal examination and measurement of prostate-specific antigen (PSA), abnormalities of which would be a contraindication to the treatment. Physicians should check for the most current preparations and dosage recommendations before initiating testosterone replacement therapy. Initial high doses of testosterone should be avoided to prevent priapism. Injection of testosterone enanthate is the preferred method of replacement therapy because of low cost and easy, at-home regulation of dosage. Alternative delivery systems that result in more stable dosing include transdermal patches (scrotal and nonscrotal) and transdermal gels. Testosterone-containing gels, however, are associated with the risk of interpersonal transfer, which can be reduced by the use of newer hydroalcoholic gels. • Low-dose testosterone replacement therapy can be initiated after age 14 yrs. • Testosterone enanthate • In adulthood, treatment should plateau at best possible dosage, typically 50-400 mg every 2-4 wks. • If person has short stature & is eligible for growth hormone therapy, testosterone therapy should be either delayed or given at lower doses initially to maximize growth potential. • Side effects incl pain assoc w/injection & large variations of serum testosterone concentration between injections, resulting in ↑ risk of mood swings. ## Surveillance Recommended Surveillance for Individuals with Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development Every 3 mos (prior to next injection) to evaluate nadir testosterone concentrations Once optimal dose is established, annual measurements are sufficient. DXA = dual-energy x-ray absorptiometry; PSA = prostate-specific antigen Concentrations lower than 200 ng/dL or higher than 500 ng/dL may require adjustment of total dose or frequency. To evaluate for the presence of an overt prostate cancer, which would be a contraindication to supplemental testosterone treatment. Increased hematocrit may lead to risk of hypoxia and sleep apnea. • Every 3 mos (prior to next injection) to evaluate nadir testosterone concentrations • Once optimal dose is established, annual measurements are sufficient. ## Agents/Circumstances to Avoid Contraindications to testosterone replacement therapy include prostate cancer (known or suspected) and breast cancer. Oral androgens such as methyltestosterone and fluoxymesterone should not be given (especially for long-term therapy) because of liver toxicity. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The mode of inheritance and recurrence risk to sibs of a proband with a nonsyndromic 46,XX testicular disorder/difference of sex development (DSD) depend on the molecular diagnosis in the proband and the genetic status of the parents (see Mode of Inheritance and Recurrence Risk for Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development AD = autosomal dominant; AR = autosomal recessive; CNV = copy number variant; DSD = disorders/differences of sex development; MOI = mode of inheritance This risk could be theoretically increased in case of paternal germline mosaicism. Small duplication or triplication of the promoter region of Although recurrence in sibs has suggested autosomal recessive inheritance (e.g., Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. An The unknown reliability of the determination of the anatomic sex by ultrasound examination; The phenotypic variability associated with most known etiologies; The difficulty in prenatally diagnosing or ruling out all the conditions that could be associated with discordant phenotypic and chromosomal sex. • The unknown reliability of the determination of the anatomic sex by ultrasound examination; • The phenotypic variability associated with most known etiologies; • The difficulty in prenatally diagnosing or ruling out all the conditions that could be associated with discordant phenotypic and chromosomal sex. ## Mode of Inheritance and Risk to Sibs of a Proband The mode of inheritance and recurrence risk to sibs of a proband with a nonsyndromic 46,XX testicular disorder/difference of sex development (DSD) depend on the molecular diagnosis in the proband and the genetic status of the parents (see Mode of Inheritance and Recurrence Risk for Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development AD = autosomal dominant; AR = autosomal recessive; CNV = copy number variant; DSD = disorders/differences of sex development; MOI = mode of inheritance This risk could be theoretically increased in case of paternal germline mosaicism. Small duplication or triplication of the promoter region of Although recurrence in sibs has suggested autosomal recessive inheritance (e.g., ## Related Genetic Counseling Issues ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. An The unknown reliability of the determination of the anatomic sex by ultrasound examination; The phenotypic variability associated with most known etiologies; The difficulty in prenatally diagnosing or ruling out all the conditions that could be associated with discordant phenotypic and chromosomal sex. • The unknown reliability of the determination of the anatomic sex by ultrasound examination; • The phenotypic variability associated with most known etiologies; • The difficulty in prenatally diagnosing or ruling out all the conditions that could be associated with discordant phenotypic and chromosomal sex. ## Resources InterNational Council on Infertility Information Dissemination • • • • • • • • InterNational Council on Infertility Information Dissemination • • • ## Molecular Genetics Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development ( Approximately 80% of individuals with nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have the condition due to the presence of a small Y chromosome fragment (including Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Gene-Specific Laboratory Considerations Only the p.Arg92Trp pathogenic variant is clearly diagnostic. Variable expressivity / reduced penetrance in families make genetic counseling difficult. Only the presence of a copy of CNV = copy number variant; DSD = disorders/differences of sex development Genes are listed in alphabetic order. At least one case of a 46,XX individual who was mosaic for Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes are listed in alphabetic order. Variant designation that does not conform to current naming conventions • Only the p.Arg92Trp pathogenic variant is clearly diagnostic. • Variable expressivity / reduced penetrance in families make genetic counseling difficult. • Only the presence of a copy of ## Molecular Pathogenesis Approximately 80% of individuals with nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) have the condition due to the presence of a small Y chromosome fragment (including Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Gene-Specific Laboratory Considerations Only the p.Arg92Trp pathogenic variant is clearly diagnostic. Variable expressivity / reduced penetrance in families make genetic counseling difficult. Only the presence of a copy of CNV = copy number variant; DSD = disorders/differences of sex development Genes are listed in alphabetic order. At least one case of a 46,XX individual who was mosaic for Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes are listed in alphabetic order. Variant designation that does not conform to current naming conventions • Only the p.Arg92Trp pathogenic variant is clearly diagnostic. • Variable expressivity / reduced penetrance in families make genetic counseling difficult. • Only the presence of a copy of ## Chapter Notes Eric Vilain is a founder of the NIH-funded DSD-TRN (Disorders/Differences of Sex Development Translational Research Network). Emmanuèle Délot serves as the national coordinator and chair of the Publications & Research committee for the network. Both have investigated the genetics and mechanisms of DSD, including 46,XX testicular DSD, for more than 20 years. 26 May 2022 (ma) Comprehensive update posted live 7 May 2015 (me) Comprehensive update posted live 26 May 2009 (me) Comprehensive update posted live 5 April 2006 (me) Comprehensive update posted live 30 October 2003 (me) Review posted live 29 May 2003 (ejv) Original submission • 26 May 2022 (ma) Comprehensive update posted live • 7 May 2015 (me) Comprehensive update posted live • 26 May 2009 (me) Comprehensive update posted live • 5 April 2006 (me) Comprehensive update posted live • 30 October 2003 (me) Review posted live • 29 May 2003 (ejv) Original submission ## Author Notes Eric Vilain is a founder of the NIH-funded DSD-TRN (Disorders/Differences of Sex Development Translational Research Network). Emmanuèle Délot serves as the national coordinator and chair of the Publications & Research committee for the network. Both have investigated the genetics and mechanisms of DSD, including 46,XX testicular DSD, for more than 20 years. ## Revision History 26 May 2022 (ma) Comprehensive update posted live 7 May 2015 (me) Comprehensive update posted live 26 May 2009 (me) Comprehensive update posted live 5 April 2006 (me) Comprehensive update posted live 30 October 2003 (me) Review posted live 29 May 2003 (ejv) Original submission • 26 May 2022 (ma) Comprehensive update posted live • 7 May 2015 (me) Comprehensive update posted live • 26 May 2009 (me) Comprehensive update posted live • 5 April 2006 (me) Comprehensive update posted live • 30 October 2003 (me) Review posted live • 29 May 2003 (ejv) Original submission ## References ## Literature Cited	[]	30/10/2003	26/5/2022		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
yars1-def	yars1-def	[ "Autosomal Recessive YARS1-Related Disorder", "Tyrosyl-tRNA Synthetase 1 Deficiency (TyrRS 1 Deficiency)", "Autosomal Recessive YARS1-Related Disorder", "Tyrosyl-tRNA Synthetase Deficiency (TyrRS Deficiency)", "Tyrosine--tRNA ligase, cytoplasmic", "YARS1", "YARS1 Deficiency" ]	YARS1 Deficiency	Luisa Averdunk, Hua Wang, Eva MM Hoytema van Konijnenburg, Sabine A Fuchs, Nadra Nasser Samra, Hanna Mandel, Anne Mei-Kwun Kwok	Summary YARS1 deficiency is characterized by developmental delay / intellectual disability, poor prenatal and postnatal growth, gastrointestinal (GI) involvement (feeding difficulties, recurrent vomiting, GI bleeding, chronic diarrhea, pancreatic insufficiency), liver involvement (increased transaminases, cholestasis, steatosis, fibrosis, episodes of hepatic failure), chronic anemia, endocrine involvement (hypothyroidism, hypoglycemia), lung disease (cystic disease, interstitial fibrosis), retinitis pigmentosa, and sensorineural hearing loss. Other less frequent findings include kidney disease and primary amenorrhea. The multisystem clinical manifestations of YARS1 deficiency typically vary from individual to individual. The diagnosis of YARS1 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in YARS1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis No consensus diagnostic criteria for YARS1 deficiency have been published. YARS1 deficiency Intrauterine growth restriction (z score = −2.95 to −1.95) Poor postnatal linear growth and weight gain Developmental delay or intellectual disability of variable degree Hypotonia with impaired gross motor function Impaired fine motor development Impaired speech development Acquired microcephaly Feeding difficulties Gastroesophageal reflux disease Recurrent vomiting Exocrine pancreatic insufficiency in severely affected individuals Hepatomegaly with hyperechogenicity on ultrasound examination Cholestasis, increased liver transaminases Steatosis Fibrosis Episodes of hepatic failure Pneumonia Tracheobronchitis Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism Primary hypothyroidism Cystic disease Interstitial fibrosis The diagnosis of YARS1 deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in YARS1 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ • • Intrauterine growth restriction (z score = −2.95 to −1.95) • Poor postnatal linear growth and weight gain • Intrauterine growth restriction (z score = −2.95 to −1.95) • Poor postnatal linear growth and weight gain • • Developmental delay or intellectual disability of variable degree • Hypotonia with impaired gross motor function • Impaired fine motor development • Impaired speech development • Acquired microcephaly • Developmental delay or intellectual disability of variable degree • Hypotonia with impaired gross motor function • Impaired fine motor development • Impaired speech development • Acquired microcephaly • • Feeding difficulties • Gastroesophageal reflux disease • Recurrent vomiting • Exocrine pancreatic insufficiency in severely affected individuals • Feeding difficulties • Gastroesophageal reflux disease • Recurrent vomiting • Exocrine pancreatic insufficiency in severely affected individuals • • Hepatomegaly with hyperechogenicity on ultrasound examination • Cholestasis, increased liver transaminases • Steatosis • Fibrosis • Episodes of hepatic failure • Hepatomegaly with hyperechogenicity on ultrasound examination • Cholestasis, increased liver transaminases • Steatosis • Fibrosis • Episodes of hepatic failure • • Pneumonia • Tracheobronchitis • Pneumonia • Tracheobronchitis • • Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism • Primary hypothyroidism • Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism • Primary hypothyroidism • • Cystic disease • Interstitial fibrosis • Cystic disease • Interstitial fibrosis • Intrauterine growth restriction (z score = −2.95 to −1.95) • Poor postnatal linear growth and weight gain • Developmental delay or intellectual disability of variable degree • Hypotonia with impaired gross motor function • Impaired fine motor development • Impaired speech development • Acquired microcephaly • Feeding difficulties • Gastroesophageal reflux disease • Recurrent vomiting • Exocrine pancreatic insufficiency in severely affected individuals • Hepatomegaly with hyperechogenicity on ultrasound examination • Cholestasis, increased liver transaminases • Steatosis • Fibrosis • Episodes of hepatic failure • Pneumonia • Tracheobronchitis • Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism • Primary hypothyroidism • Cystic disease • Interstitial fibrosis • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings YARS1 deficiency Intrauterine growth restriction (z score = −2.95 to −1.95) Poor postnatal linear growth and weight gain Developmental delay or intellectual disability of variable degree Hypotonia with impaired gross motor function Impaired fine motor development Impaired speech development Acquired microcephaly Feeding difficulties Gastroesophageal reflux disease Recurrent vomiting Exocrine pancreatic insufficiency in severely affected individuals Hepatomegaly with hyperechogenicity on ultrasound examination Cholestasis, increased liver transaminases Steatosis Fibrosis Episodes of hepatic failure Pneumonia Tracheobronchitis Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism Primary hypothyroidism Cystic disease Interstitial fibrosis • • Intrauterine growth restriction (z score = −2.95 to −1.95) • Poor postnatal linear growth and weight gain • Intrauterine growth restriction (z score = −2.95 to −1.95) • Poor postnatal linear growth and weight gain • • Developmental delay or intellectual disability of variable degree • Hypotonia with impaired gross motor function • Impaired fine motor development • Impaired speech development • Acquired microcephaly • Developmental delay or intellectual disability of variable degree • Hypotonia with impaired gross motor function • Impaired fine motor development • Impaired speech development • Acquired microcephaly • • Feeding difficulties • Gastroesophageal reflux disease • Recurrent vomiting • Exocrine pancreatic insufficiency in severely affected individuals • Feeding difficulties • Gastroesophageal reflux disease • Recurrent vomiting • Exocrine pancreatic insufficiency in severely affected individuals • • Hepatomegaly with hyperechogenicity on ultrasound examination • Cholestasis, increased liver transaminases • Steatosis • Fibrosis • Episodes of hepatic failure • Hepatomegaly with hyperechogenicity on ultrasound examination • Cholestasis, increased liver transaminases • Steatosis • Fibrosis • Episodes of hepatic failure • • Pneumonia • Tracheobronchitis • Pneumonia • Tracheobronchitis • • Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism • Primary hypothyroidism • Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism • Primary hypothyroidism • • Cystic disease • Interstitial fibrosis • Cystic disease • Interstitial fibrosis • Intrauterine growth restriction (z score = −2.95 to −1.95) • Poor postnatal linear growth and weight gain • Developmental delay or intellectual disability of variable degree • Hypotonia with impaired gross motor function • Impaired fine motor development • Impaired speech development • Acquired microcephaly • Feeding difficulties • Gastroesophageal reflux disease • Recurrent vomiting • Exocrine pancreatic insufficiency in severely affected individuals • Hepatomegaly with hyperechogenicity on ultrasound examination • Cholestasis, increased liver transaminases • Steatosis • Fibrosis • Episodes of hepatic failure • Pneumonia • Tracheobronchitis • Hypoglycemia ranging from transient to recurrent; sometimes associated with liver failure; rarely associated with hyperinsulinism • Primary hypothyroidism • Cystic disease • Interstitial fibrosis ## Establishing the Diagnosis The diagnosis of YARS1 deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in YARS1 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics YARS1 deficiency is characterized by developmental delay / intellectual disability, poor prenatal and postnatal growth, gastrointestinal (GI) involvement (feeding difficulties, recurrent vomiting, GI bleeding, chronic diarrhea, pancreatic insufficiency), liver involvement (increased transaminases, cholestasis, steatosis, fibrosis, episodes of hepatic failure), chronic anemia, endocrine involvement (hypothyroidism, hypoglycemia), lung disease (cystic disease, interstitial fibrosis), retinitis pigmentosa, and sensorineural hearing loss. Other less frequent findings include kidney disease and primary amenorrhea. To date, more than 30 individuals with YARS1 deficiency have been reported: 17 individuals (from seven families) with a range of biallelic Intrauterine growth restriction was reported in some infants [ None of the individuals homozygous for the p.Arg367Trp pathogenic variant were born prematurely or had intrauterine growth restriction [ All individuals homozygous for the p.Arg367Trp pathogenic variant had linear growth failure (weight proportional to height) ranging to 5.6 standard deviations below the mean and postnatal onset of microcephaly (ranging to a z score of −7) [ Individuals homozygous for the p.Arg367Trp pathogenic variant required assistance in feeding and dressing but were able to follow simple commands (e.g., help setting the table). Most learned to use single words by age three to six years or to speak in simple two- to three-word sentences. Deceased velocity of motor and sensory nerve conduction was reported in one individual [ In surviving infants, liver function usually stabilized after age two to three years [ Less common endocrinologic findings in a few individuals included: Central adrenal insufficiency [A Kwok, personal observation] Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ Neonatal nystagmus [ Retinal dystrophy / retinitis pigmentosa with reduced central vision, constricted visual fields, and loss of night vision. Retinal findings included macular pigmentation, degeneration, and atrophy [ One individual homozygous for the p.Arg367Trp pathogenic variant died at age 15 years; the cause of death is unknown [ Given that the oldest reported individuals were born around 2002, to date no data on the life expectancy of these individuals are available. Micro- and macrovesicular hepatic steatosis with or without steatohepatitis Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease Regenerative nodules indicative of cirrhosis in one individual Homozygosity for the pathogenic variant p.Arg367Trp is associated with a relatively consistent phenotype [ No clinically relevant genotype-phenotype correlations are available to date in individuals with other To date, more than 30 individuals with YARS1 deficiency have been reported [ The The frequency of the pathogenic variant • Less common endocrinologic findings in a few individuals included: • Central adrenal insufficiency [A Kwok, personal observation] • Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ • Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ • Central adrenal insufficiency [A Kwok, personal observation] • Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ • Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ • Central adrenal insufficiency [A Kwok, personal observation] • Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ • Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ • Neonatal nystagmus [ • Retinal dystrophy / retinitis pigmentosa with reduced central vision, constricted visual fields, and loss of night vision. Retinal findings included macular pigmentation, degeneration, and atrophy [ • Micro- and macrovesicular hepatic steatosis with or without steatohepatitis • Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease • Regenerative nodules indicative of cirrhosis in one individual • Micro- and macrovesicular hepatic steatosis with or without steatohepatitis • Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease • Regenerative nodules indicative of cirrhosis in one individual • Micro- and macrovesicular hepatic steatosis with or without steatohepatitis • Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease • Regenerative nodules indicative of cirrhosis in one individual ## Clinical Description YARS1 deficiency is characterized by developmental delay / intellectual disability, poor prenatal and postnatal growth, gastrointestinal (GI) involvement (feeding difficulties, recurrent vomiting, GI bleeding, chronic diarrhea, pancreatic insufficiency), liver involvement (increased transaminases, cholestasis, steatosis, fibrosis, episodes of hepatic failure), chronic anemia, endocrine involvement (hypothyroidism, hypoglycemia), lung disease (cystic disease, interstitial fibrosis), retinitis pigmentosa, and sensorineural hearing loss. Other less frequent findings include kidney disease and primary amenorrhea. To date, more than 30 individuals with YARS1 deficiency have been reported: 17 individuals (from seven families) with a range of biallelic Intrauterine growth restriction was reported in some infants [ None of the individuals homozygous for the p.Arg367Trp pathogenic variant were born prematurely or had intrauterine growth restriction [ All individuals homozygous for the p.Arg367Trp pathogenic variant had linear growth failure (weight proportional to height) ranging to 5.6 standard deviations below the mean and postnatal onset of microcephaly (ranging to a z score of −7) [ Individuals homozygous for the p.Arg367Trp pathogenic variant required assistance in feeding and dressing but were able to follow simple commands (e.g., help setting the table). Most learned to use single words by age three to six years or to speak in simple two- to three-word sentences. Deceased velocity of motor and sensory nerve conduction was reported in one individual [ In surviving infants, liver function usually stabilized after age two to three years [ Less common endocrinologic findings in a few individuals included: Central adrenal insufficiency [A Kwok, personal observation] Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ Neonatal nystagmus [ Retinal dystrophy / retinitis pigmentosa with reduced central vision, constricted visual fields, and loss of night vision. Retinal findings included macular pigmentation, degeneration, and atrophy [ One individual homozygous for the p.Arg367Trp pathogenic variant died at age 15 years; the cause of death is unknown [ Given that the oldest reported individuals were born around 2002, to date no data on the life expectancy of these individuals are available. Micro- and macrovesicular hepatic steatosis with or without steatohepatitis Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease Regenerative nodules indicative of cirrhosis in one individual • Less common endocrinologic findings in a few individuals included: • Central adrenal insufficiency [A Kwok, personal observation] • Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ • Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ • Central adrenal insufficiency [A Kwok, personal observation] • Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ • Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ • Central adrenal insufficiency [A Kwok, personal observation] • Hypogonadotropic hypogonadism (manifesting in females as primary amenorrhea) [ • Low growth hormone levels in one individual who did not experience linear growth acceleration following treatment with recombinant growth hormone [ • Neonatal nystagmus [ • Retinal dystrophy / retinitis pigmentosa with reduced central vision, constricted visual fields, and loss of night vision. Retinal findings included macular pigmentation, degeneration, and atrophy [ • Micro- and macrovesicular hepatic steatosis with or without steatohepatitis • Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease • Regenerative nodules indicative of cirrhosis in one individual • Micro- and macrovesicular hepatic steatosis with or without steatohepatitis • Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease • Regenerative nodules indicative of cirrhosis in one individual • Micro- and macrovesicular hepatic steatosis with or without steatohepatitis • Minor to severe portal and periportal fibrosis with or without either cholestasis or bile duct proliferation in more progressive stages of liver disease • Regenerative nodules indicative of cirrhosis in one individual ## Genotype-Phenotype Correlations Homozygosity for the pathogenic variant p.Arg367Trp is associated with a relatively consistent phenotype [ No clinically relevant genotype-phenotype correlations are available to date in individuals with other ## Prevalence To date, more than 30 individuals with YARS1 deficiency have been reported [ The The frequency of the pathogenic variant ## Genetically Related (Allelic) Disorders Heterozygous pathogenic variants in Features consistent with DI-CMT (painful feet, weakness in lower legs and feet, and adult-onset hearing loss) were reported in a heterozygous parent of a child with YARS1 deficiency. Of note, nerve conduction studies were not performed on the parent [ ## Differential Diagnosis Given the protean manifestations in affected individuals, the genetic differential diagnosis of YARS1 deficiency is unavoidably broad and includes other early-onset multisystem disorders including the following: Mitochondrial disorders (See Metabolic disorders with liver involvement Disorders involving members of the aminoacyl-tRNA synthase family of enzymes, almost all of which are associated with developmental delay, hypotonia, and poor growth. Note that liver disease is a prominent feature in MARS1, LARS1, and IARS1 deficiencies [ Note: Congenital cytomegalovirus infection, which is associated with hepatosplenomegaly, microcephaly, poor growth, hearing impairment, vision impairment, and developmental delay, can mimic YARS1 deficiency. • Mitochondrial disorders (See • Metabolic disorders with liver involvement • Disorders involving members of the aminoacyl-tRNA synthase family of enzymes, almost all of which are associated with developmental delay, hypotonia, and poor growth. Note that liver disease is a prominent feature in MARS1, LARS1, and IARS1 deficiencies [ ## Management No clinical practice guidelines for YARS1 deficiency have been published. The following recommendations are based on the authors' personal experience managing individuals with YARS1 deficiency. To establish the extent of disease and needs in an individual diagnosed with YARS1 deficiency, the evaluations summarized in YARS1 Deficiency: Recommended Evaluations Following Initial Diagnosis To incl brain MRI if not performed at time of initial eval Consider EEG if seizures are a concern. Evaluate total caloric & protein intake to assure sufficient protein intake (≥2 g/kg/day and up to 3 g/kg/day); Consider eval for gastrostomy tube placement in children w/dysphagia &/or aspiration risk. Liver size & echogenicity Transaminases Liver function To incl motor, adaptive, cognitive, & speech-language eval Evaluate preschool-age children to determine eligibility for an early intervention program & school-age children for an IEP. Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Evaluate iron reserves. Consider referral to hematologist esp if blood transfusion is needed. Measure blood concentration of insulin & lactate; Determine if ketones & free fatty acids are suppressed. Measure FSH/LH & sex hormones (discuss w/gynecologist familiar w/endocrine disorders). Consider possible primary amenorrhea if menarche is delayed. Urine for proteinuria; Blood sodium & potassium concentrations; Kidney function. Inquire about history of reduced visual acuity &/or impaired vision in the dark. Assess visual acuity & fundus for evidence of retinal dystrophy (retinitis pigmentosa). Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; FSH = follicle-stimulating hormone; IEP = individual education plan; LH = luteinizing hormone; MOI = mode of inheritance; OFC = occipitofrontal circumference; OT = occupational therapist; PT = physical therapist Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for YARS1 deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see YARS1 Deficiency: Outpatient Routine Treatment of Manifestations Assess need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills). Determine eligibility for an early intervention program & an IEP (for school-age children). Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Hearing aids Assess potential for cochlear implantation. Carbohydrates w/low glycemic index Continuous feeding, continuous maltodextrin, or glucose intake via gastrostomy tube or intravenously (if needed) Consider trial of diazoxide/thiazide in case of hyperinsulinemic hypoglycemia. Consider addition of glucagon if needed. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. IEP = individual education plan Many parents of affected individuals have emergency treatment plans on file with their local providers and/or emergency department regarding the following recommendations. Individuals with YARS1 deficiency generally have less physiologic reserve due to insufficient protein intake and tyrosine availability during rapid growth during the first years of life and during catabolism associated with infection, fever, poor feeding, vomiting, and/or diarrhea, often also becoming more symptomatic. During these metabolic exacerbations the general recommendations are the following [ Increase protein intake (up to 2-2.5 g/kg/day). Note: This recommendation differs from the usual recommendation to stop feeding and to give glucose infusions. Consider tyrosine supplementation (see Avoid prolonged fasting because of the increased risk of hypoglycemia. During intercurrent illness it is important for care providers to have a low threshold for in-hospital feeding. Treat fever aggressively with antipyretics because aminoacylation activity can be further decreased during fevers. Provide appropriate steroid coverage for individuals with known adrenal insufficiency. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in YARS1 Deficiency: Recommended Surveillance Assess developmental progress & educational needs. Monitor for development of new neurologic findings &/or progression of known neurologic findings. Assess for dyspnea during exercise. Consider need for chest radiograph or MRI to assess for pulmonary cystic disease &/or pulmonary consultation. Urine for proteinuria; Blood sodium & potassium; Cystatin C if feasible. Blood count incl MCV & MCH Determine iron reserve. Discuss w/hematologist as needed. Ask for signs of puberty, menarche FSH, LH, & sex hormones per gynecologist familiar w/endocrine disorders AFP = alpha-fetoprotein; ALT = alanine transaminase; AST = aspartate transaminase; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; TSH = thyroid-stimulating hormone Avoid the following: Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day) Prolonged fasting given the increased risk of hypoglycemia Fever See YARS1 deficiency belongs to the group of aminoacyl-tRNA synthetase (ARS) deficiencies. Other ARS deficiencies include MARS1, LARS1, IARS1, SARS1, and FARBSB deficiencies. In three additional studies, treatment with the respective amino acid was associated with an improvement of liver function and/or improved growth and/or reduced frequency of infections in individuals with MARS1 and IARS1 deficiencies [ Whether tyrosine supplementation improves the course of YARS1 deficiency is unclear at the current stage. As high-dose supplementation of the respective amino acid has shown beneficial effects for other ARS deficiencies, it is worth considering treatment with tyrosine (in addition to high-protein diet) for YARS1 deficiency. Compassionate use treatment of tyrosine supplementation is currently under way in a few individuals with YARS1 deficiency. For further information contact Dr Luisa Averdunk ( Search • To incl brain MRI if not performed at time of initial eval • Consider EEG if seizures are a concern. • Evaluate total caloric & protein intake to assure sufficient protein intake (≥2 g/kg/day and up to 3 g/kg/day); • Consider eval for gastrostomy tube placement in children w/dysphagia &/or aspiration risk. • Liver size & echogenicity • Transaminases • Liver function • To incl motor, adaptive, cognitive, & speech-language eval • Evaluate preschool-age children to determine eligibility for an early intervention program & school-age children for an IEP. • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Evaluate iron reserves. • Consider referral to hematologist esp if blood transfusion is needed. • Measure blood concentration of insulin & lactate; • Determine if ketones & free fatty acids are suppressed. • Measure FSH/LH & sex hormones (discuss w/gynecologist familiar w/endocrine disorders). • Consider possible primary amenorrhea if menarche is delayed. • Urine for proteinuria; • Blood sodium & potassium concentrations; • Kidney function. • Inquire about history of reduced visual acuity &/or impaired vision in the dark. • Assess visual acuity & fundus for evidence of retinal dystrophy (retinitis pigmentosa). • Community or • Social work involvement for parental support; • Home nursing referral. • Assess need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills). • Determine eligibility for an early intervention program & an IEP (for school-age children). • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Hearing aids • Assess potential for cochlear implantation. • Carbohydrates w/low glycemic index • Continuous feeding, continuous maltodextrin, or glucose intake via gastrostomy tube or intravenously (if needed) • Consider trial of diazoxide/thiazide in case of hyperinsulinemic hypoglycemia. • Consider addition of glucagon if needed. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Increase protein intake (up to 2-2.5 g/kg/day). Note: This recommendation differs from the usual recommendation to stop feeding and to give glucose infusions. • Consider tyrosine supplementation (see • Avoid prolonged fasting because of the increased risk of hypoglycemia. During intercurrent illness it is important for care providers to have a low threshold for in-hospital feeding. • Treat fever aggressively with antipyretics because aminoacylation activity can be further decreased during fevers. • Provide appropriate steroid coverage for individuals with known adrenal insufficiency. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Assess developmental progress & educational needs. • Monitor for development of new neurologic findings &/or progression of known neurologic findings. • Assess for dyspnea during exercise. • Consider need for chest radiograph or MRI to assess for pulmonary cystic disease &/or pulmonary consultation. • Urine for proteinuria; • Blood sodium & potassium; • Cystatin C if feasible. • Blood count incl MCV & MCH • Determine iron reserve. • Discuss w/hematologist as needed. • Ask for signs of puberty, menarche • FSH, LH, & sex hormones per gynecologist familiar w/endocrine disorders • Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day) • Prolonged fasting given the increased risk of hypoglycemia • Fever ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with YARS1 deficiency, the evaluations summarized in YARS1 Deficiency: Recommended Evaluations Following Initial Diagnosis To incl brain MRI if not performed at time of initial eval Consider EEG if seizures are a concern. Evaluate total caloric & protein intake to assure sufficient protein intake (≥2 g/kg/day and up to 3 g/kg/day); Consider eval for gastrostomy tube placement in children w/dysphagia &/or aspiration risk. Liver size & echogenicity Transaminases Liver function To incl motor, adaptive, cognitive, & speech-language eval Evaluate preschool-age children to determine eligibility for an early intervention program & school-age children for an IEP. Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Evaluate iron reserves. Consider referral to hematologist esp if blood transfusion is needed. Measure blood concentration of insulin & lactate; Determine if ketones & free fatty acids are suppressed. Measure FSH/LH & sex hormones (discuss w/gynecologist familiar w/endocrine disorders). Consider possible primary amenorrhea if menarche is delayed. Urine for proteinuria; Blood sodium & potassium concentrations; Kidney function. Inquire about history of reduced visual acuity &/or impaired vision in the dark. Assess visual acuity & fundus for evidence of retinal dystrophy (retinitis pigmentosa). Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; FSH = follicle-stimulating hormone; IEP = individual education plan; LH = luteinizing hormone; MOI = mode of inheritance; OFC = occipitofrontal circumference; OT = occupational therapist; PT = physical therapist Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • To incl brain MRI if not performed at time of initial eval • Consider EEG if seizures are a concern. • Evaluate total caloric & protein intake to assure sufficient protein intake (≥2 g/kg/day and up to 3 g/kg/day); • Consider eval for gastrostomy tube placement in children w/dysphagia &/or aspiration risk. • Liver size & echogenicity • Transaminases • Liver function • To incl motor, adaptive, cognitive, & speech-language eval • Evaluate preschool-age children to determine eligibility for an early intervention program & school-age children for an IEP. • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Evaluate iron reserves. • Consider referral to hematologist esp if blood transfusion is needed. • Measure blood concentration of insulin & lactate; • Determine if ketones & free fatty acids are suppressed. • Measure FSH/LH & sex hormones (discuss w/gynecologist familiar w/endocrine disorders). • Consider possible primary amenorrhea if menarche is delayed. • Urine for proteinuria; • Blood sodium & potassium concentrations; • Kidney function. • Inquire about history of reduced visual acuity &/or impaired vision in the dark. • Assess visual acuity & fundus for evidence of retinal dystrophy (retinitis pigmentosa). • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for YARS1 deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see YARS1 Deficiency: Outpatient Routine Treatment of Manifestations Assess need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills). Determine eligibility for an early intervention program & an IEP (for school-age children). Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Hearing aids Assess potential for cochlear implantation. Carbohydrates w/low glycemic index Continuous feeding, continuous maltodextrin, or glucose intake via gastrostomy tube or intravenously (if needed) Consider trial of diazoxide/thiazide in case of hyperinsulinemic hypoglycemia. Consider addition of glucagon if needed. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. IEP = individual education plan Many parents of affected individuals have emergency treatment plans on file with their local providers and/or emergency department regarding the following recommendations. Individuals with YARS1 deficiency generally have less physiologic reserve due to insufficient protein intake and tyrosine availability during rapid growth during the first years of life and during catabolism associated with infection, fever, poor feeding, vomiting, and/or diarrhea, often also becoming more symptomatic. During these metabolic exacerbations the general recommendations are the following [ Increase protein intake (up to 2-2.5 g/kg/day). Note: This recommendation differs from the usual recommendation to stop feeding and to give glucose infusions. Consider tyrosine supplementation (see Avoid prolonged fasting because of the increased risk of hypoglycemia. During intercurrent illness it is important for care providers to have a low threshold for in-hospital feeding. Treat fever aggressively with antipyretics because aminoacylation activity can be further decreased during fevers. Provide appropriate steroid coverage for individuals with known adrenal insufficiency. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Assess need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills). • Determine eligibility for an early intervention program & an IEP (for school-age children). • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Hearing aids • Assess potential for cochlear implantation. • Carbohydrates w/low glycemic index • Continuous feeding, continuous maltodextrin, or glucose intake via gastrostomy tube or intravenously (if needed) • Consider trial of diazoxide/thiazide in case of hyperinsulinemic hypoglycemia. • Consider addition of glucagon if needed. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Increase protein intake (up to 2-2.5 g/kg/day). Note: This recommendation differs from the usual recommendation to stop feeding and to give glucose infusions. • Consider tyrosine supplementation (see • Avoid prolonged fasting because of the increased risk of hypoglycemia. During intercurrent illness it is important for care providers to have a low threshold for in-hospital feeding. • Treat fever aggressively with antipyretics because aminoacylation activity can be further decreased during fevers. • Provide appropriate steroid coverage for individuals with known adrenal insufficiency. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Urgent Treatment of Acute Episodic Illnesses Many parents of affected individuals have emergency treatment plans on file with their local providers and/or emergency department regarding the following recommendations. Individuals with YARS1 deficiency generally have less physiologic reserve due to insufficient protein intake and tyrosine availability during rapid growth during the first years of life and during catabolism associated with infection, fever, poor feeding, vomiting, and/or diarrhea, often also becoming more symptomatic. During these metabolic exacerbations the general recommendations are the following [ Increase protein intake (up to 2-2.5 g/kg/day). Note: This recommendation differs from the usual recommendation to stop feeding and to give glucose infusions. Consider tyrosine supplementation (see Avoid prolonged fasting because of the increased risk of hypoglycemia. During intercurrent illness it is important for care providers to have a low threshold for in-hospital feeding. Treat fever aggressively with antipyretics because aminoacylation activity can be further decreased during fevers. Provide appropriate steroid coverage for individuals with known adrenal insufficiency. • Increase protein intake (up to 2-2.5 g/kg/day). Note: This recommendation differs from the usual recommendation to stop feeding and to give glucose infusions. • Consider tyrosine supplementation (see • Avoid prolonged fasting because of the increased risk of hypoglycemia. During intercurrent illness it is important for care providers to have a low threshold for in-hospital feeding. • Treat fever aggressively with antipyretics because aminoacylation activity can be further decreased during fevers. • Provide appropriate steroid coverage for individuals with known adrenal insufficiency. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in YARS1 Deficiency: Recommended Surveillance Assess developmental progress & educational needs. Monitor for development of new neurologic findings &/or progression of known neurologic findings. Assess for dyspnea during exercise. Consider need for chest radiograph or MRI to assess for pulmonary cystic disease &/or pulmonary consultation. Urine for proteinuria; Blood sodium & potassium; Cystatin C if feasible. Blood count incl MCV & MCH Determine iron reserve. Discuss w/hematologist as needed. Ask for signs of puberty, menarche FSH, LH, & sex hormones per gynecologist familiar w/endocrine disorders AFP = alpha-fetoprotein; ALT = alanine transaminase; AST = aspartate transaminase; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; TSH = thyroid-stimulating hormone • Assess developmental progress & educational needs. • Monitor for development of new neurologic findings &/or progression of known neurologic findings. • Assess for dyspnea during exercise. • Consider need for chest radiograph or MRI to assess for pulmonary cystic disease &/or pulmonary consultation. • Urine for proteinuria; • Blood sodium & potassium; • Cystatin C if feasible. • Blood count incl MCV & MCH • Determine iron reserve. • Discuss w/hematologist as needed. • Ask for signs of puberty, menarche • FSH, LH, & sex hormones per gynecologist familiar w/endocrine disorders ## Agents/Circumstances to Avoid Avoid the following: Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day) Prolonged fasting given the increased risk of hypoglycemia Fever • Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day) • Prolonged fasting given the increased risk of hypoglycemia • Fever ## Evaluation of Relatives at Risk See ## Therapies Under Investigation YARS1 deficiency belongs to the group of aminoacyl-tRNA synthetase (ARS) deficiencies. Other ARS deficiencies include MARS1, LARS1, IARS1, SARS1, and FARBSB deficiencies. In three additional studies, treatment with the respective amino acid was associated with an improvement of liver function and/or improved growth and/or reduced frequency of infections in individuals with MARS1 and IARS1 deficiencies [ Whether tyrosine supplementation improves the course of YARS1 deficiency is unclear at the current stage. As high-dose supplementation of the respective amino acid has shown beneficial effects for other ARS deficiencies, it is worth considering treatment with tyrosine (in addition to high-protein diet) for YARS1 deficiency. Compassionate use treatment of tyrosine supplementation is currently under way in a few individuals with YARS1 deficiency. For further information contact Dr Luisa Averdunk ( Search ## Genetic Counseling YARS1 deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are not at risk of developing YARS1 deficiency. Specific signs consistent with the allelic disorder If both parents are known to be heterozygous for a Heterozygotes (carriers) are not at risk of developing YARS1 deficiency (see also Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals known to be carriers of a Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are not at risk of developing YARS1 deficiency. Specific signs consistent with the allelic disorder • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are not at risk of developing YARS1 deficiency (see also • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals known to be carriers of a ## Mode of Inheritance YARS1 deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are not at risk of developing YARS1 deficiency. Specific signs consistent with the allelic disorder If both parents are known to be heterozygous for a Heterozygotes (carriers) are not at risk of developing YARS1 deficiency (see also • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are not at risk of developing YARS1 deficiency. Specific signs consistent with the allelic disorder • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are not at risk of developing YARS1 deficiency (see also ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals known to be carriers of a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals known to be carriers of a ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Speaking out for People with Intellectual and Developmental Disabilities • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics YARS1 Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for YARS1 Deficiency ( Biallelic pathogenic variants in It is likely that Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Biallelic pathogenic variants in It is likely that Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Luisa Averdunk ( Contact Dr Averdunk to inquire about review of We thank Dr Karin Konzett (Department of General Pediatrics, Feldkirch, Austria) and Dr Tobias Linden (Department of General Pediatrics, Oldenburg, Germany) for sharing clinical data of their unpublished cases and discussing the clinical presentation. We also acknowledge the Elterninitiative Kinderkrebsklinik e.V. (Düsseldorf, Germany) and the Junior Clinician Scientist Programmes by the Heinrich-Heine University (#9772792) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (#493659010), which granted Dr Luisa Averdunk protected working time for scientific work and this review. 3 July 2025 (bp) Review posted live 22 December 2023 (la) Original submission • 3 July 2025 (bp) Review posted live • 22 December 2023 (la) Original submission ## Author Notes Dr Luisa Averdunk ( Contact Dr Averdunk to inquire about review of ## Acknowledgments We thank Dr Karin Konzett (Department of General Pediatrics, Feldkirch, Austria) and Dr Tobias Linden (Department of General Pediatrics, Oldenburg, Germany) for sharing clinical data of their unpublished cases and discussing the clinical presentation. We also acknowledge the Elterninitiative Kinderkrebsklinik e.V. (Düsseldorf, Germany) and the Junior Clinician Scientist Programmes by the Heinrich-Heine University (#9772792) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (#493659010), which granted Dr Luisa Averdunk protected working time for scientific work and this review. ## Revision History 3 July 2025 (bp) Review posted live 22 December 2023 (la) Original submission • 3 July 2025 (bp) Review posted live • 22 December 2023 (la) Original submission ## References ## Literature Cited Coronal MRI of the head of an individual with YARS1 deficiency at age seven years showing cystic changes in periventricular white matter (green arrows) Reproduced with permission from (A) Axial sequences (head MRI) of three different individuals with YARS1 deficiency showing wide lateral ventricles as a sign of diffuse cerebral volume loss due to periventricular white matter loss. (B) Sagittal sequences (head MRI) of the same three individuals showing thinning of the corpus callosum. Reproduced with permission from Computerized tomography of the chest of an individual with YARS1 deficiency age ten years showing cystic lesions in the lower lobes bilaterally Reproduced with permission from	[]	3/7/2025			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
yci	yci	[ "Y Chromosome-Related Azoospermia", "Y Chromosome-Related Azoospermia", "ATP-dependent RNA helicase DDX3Y", "Not applicable", "Ubiquitin carboxyl-terminal hydrolase 9Y", "DDX3Y", "Not applicable", "USP9Y", "Y Chromosome Infertility" ]	Y Chromosome Infertility	Yuting Fan, Sherman J Silber	Summary Y chromosome infertility is characterized by azoospermia (absence of sperm), severe oligozoospermia (<1 x 10 The diagnosis of Y chromosome infertility is established in a male with characteristic clinical and laboratory features and by identification of a hemizygous deletion of Yq involving the AZF regions or identification of a heterozygous pathogenic variant involving Y chromosome infertility is inherited in a Y-linked manner. Because males with Y chromosome deletions are infertile, the deletions are usually	## Diagnosis Y chromosome infertility A history of infertility Normal physical examination in ~30% Small testes in ~70% (males with Sertoli cell-only syndrome) Classification of Sperm Count In each category, the morphology and/or motility of the sperm can be normal or abnormal (asthenoteratozoospermia). These estimates have a poor correlation to pregnancy rate, when the count is >5 million/mL. Other than males with gr/gr interstitial AZFc deletions, individuals with deletion of Yq involving the AZF regions never have a sperm count >2 million/mL. Sertoli cell-only (SCO) syndrome, in which azoospermia is associated with the absence of or only occasional germ cells in tubules that for the most part have only Sertoli cells lining them with no or rare spermatogenesis Maturation arrest with spermatocytes but no spermatids or mature sperm The diagnosis of Y chromosome infertility A hemizygous deletion of Yq involving the AZF regions (see A heterozygous Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Interstitial AZFa deletion (HERV15yq1-HERV15yq2; region includes Interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) Interstitial AZFc deletion (b2/b4, gr/gr) Terminal AZF deletion (often representing a pseudodicentric Y chromosome with duplication and deletion) Note: (1) Note: (1) A pseudodicentric Y chromosome results in both deletion of part of Yq and duplication of Yp and proximal Yq. (2) Complex Y chromosome rearrangements (e.g., pseudodicentric Y chromosomes and ring Y chromosomes) are often associated with a 45,X cell line [ Note: Complete deletion of Genomic Testing Used in Y Chromosome Infertility See AZF regions include interstitial AZFa deletion (HERV15yq1-HERV15yq2); interstitial AZFc deletion (b2/b4); interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1); and terminal AZF deletion (often representing a pseudodicentric Y chromosome w/duplication & deletion). Targeted deletion analysis methods can include a range of techniques such as FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods. Two individuals with intragenic Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including The detection rate by CMA may be higher than that of targeted deletion/duplication analysis depending on the targeted method used. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click • A history of infertility • Normal physical examination in ~30% • Small testes in ~70% (males with Sertoli cell-only syndrome) • Sertoli cell-only (SCO) syndrome, in which azoospermia is associated with the absence of or only occasional germ cells in tubules that for the most part have only Sertoli cells lining them with no or rare spermatogenesis • Maturation arrest with spermatocytes but no spermatids or mature sperm • A hemizygous deletion of Yq involving the AZF regions (see • A heterozygous • Interstitial AZFa deletion (HERV15yq1-HERV15yq2; region includes • Interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) • Interstitial AZFc deletion (b2/b4, gr/gr) • Terminal AZF deletion (often representing a pseudodicentric Y chromosome with duplication and deletion) ## Suggestive Findings Y chromosome infertility A history of infertility Normal physical examination in ~30% Small testes in ~70% (males with Sertoli cell-only syndrome) Classification of Sperm Count In each category, the morphology and/or motility of the sperm can be normal or abnormal (asthenoteratozoospermia). These estimates have a poor correlation to pregnancy rate, when the count is >5 million/mL. Other than males with gr/gr interstitial AZFc deletions, individuals with deletion of Yq involving the AZF regions never have a sperm count >2 million/mL. Sertoli cell-only (SCO) syndrome, in which azoospermia is associated with the absence of or only occasional germ cells in tubules that for the most part have only Sertoli cells lining them with no or rare spermatogenesis Maturation arrest with spermatocytes but no spermatids or mature sperm • A history of infertility • Normal physical examination in ~30% • Small testes in ~70% (males with Sertoli cell-only syndrome) • Sertoli cell-only (SCO) syndrome, in which azoospermia is associated with the absence of or only occasional germ cells in tubules that for the most part have only Sertoli cells lining them with no or rare spermatogenesis • Maturation arrest with spermatocytes but no spermatids or mature sperm ## Establishing the Diagnosis The diagnosis of Y chromosome infertility A hemizygous deletion of Yq involving the AZF regions (see A heterozygous Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Interstitial AZFa deletion (HERV15yq1-HERV15yq2; region includes Interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) Interstitial AZFc deletion (b2/b4, gr/gr) Terminal AZF deletion (often representing a pseudodicentric Y chromosome with duplication and deletion) Note: (1) Note: (1) A pseudodicentric Y chromosome results in both deletion of part of Yq and duplication of Yp and proximal Yq. (2) Complex Y chromosome rearrangements (e.g., pseudodicentric Y chromosomes and ring Y chromosomes) are often associated with a 45,X cell line [ Note: Complete deletion of Genomic Testing Used in Y Chromosome Infertility See AZF regions include interstitial AZFa deletion (HERV15yq1-HERV15yq2); interstitial AZFc deletion (b2/b4); interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1); and terminal AZF deletion (often representing a pseudodicentric Y chromosome w/duplication & deletion). Targeted deletion analysis methods can include a range of techniques such as FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods. Two individuals with intragenic Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including The detection rate by CMA may be higher than that of targeted deletion/duplication analysis depending on the targeted method used. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click • A hemizygous deletion of Yq involving the AZF regions (see • A heterozygous • Interstitial AZFa deletion (HERV15yq1-HERV15yq2; region includes • Interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) • Interstitial AZFc deletion (b2/b4, gr/gr) • Terminal AZF deletion (often representing a pseudodicentric Y chromosome with duplication and deletion) ## Tier 1 Testing Interstitial AZFa deletion (HERV15yq1-HERV15yq2; region includes Interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) Interstitial AZFc deletion (b2/b4, gr/gr) Terminal AZF deletion (often representing a pseudodicentric Y chromosome with duplication and deletion) Note: (1) • Interstitial AZFa deletion (HERV15yq1-HERV15yq2; region includes • Interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) • Interstitial AZFc deletion (b2/b4, gr/gr) • Terminal AZF deletion (often representing a pseudodicentric Y chromosome with duplication and deletion) ## Tier 2 Testing Note: (1) A pseudodicentric Y chromosome results in both deletion of part of Yq and duplication of Yp and proximal Yq. (2) Complex Y chromosome rearrangements (e.g., pseudodicentric Y chromosomes and ring Y chromosomes) are often associated with a 45,X cell line [ Note: Complete deletion of Genomic Testing Used in Y Chromosome Infertility See AZF regions include interstitial AZFa deletion (HERV15yq1-HERV15yq2); interstitial AZFc deletion (b2/b4); interstitial AZFb & AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1); and terminal AZF deletion (often representing a pseudodicentric Y chromosome w/duplication & deletion). Targeted deletion analysis methods can include a range of techniques such as FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods. Two individuals with intragenic Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including The detection rate by CMA may be higher than that of targeted deletion/duplication analysis depending on the targeted method used. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click ## Clinical Characteristics Males with Y chromosome infertility usually have no symptoms other than infertility. A physical examination may reveal small testes in those with Sertoli cell-only (SCO) syndrome. Physical examination is normal in approximately 30% of males with Y chromosome infertility. Males with Y chromosome infertility have azoospermia or severe, moderate, or mild oligozoospermia depending on the location and size of the Y chromosome deletion (see Oligozoospermia may be compatible with fertility when the female partner is very fertile. Each AZF region contains several genes that play a role in different stages of spermatogenesis. It is likely that future analysis of these individual genes in infertile males will result in more precise genotype-phenotype correlations. However, the multicopy and polymorphic nature of most fertility genes located on the Y chromosome makes it difficult to define their role precisely. The regions initially defined as AZFb and AZFc have been found to partially overlap ( Interstitial or terminal deletions that include all of AZFa are rare and usually result in the severe phenotype of Sertoli cell-only (SCO) syndrome [ Interstitial or terminal deletions that include AZFb and/or AZFb+c (hereafter designated AZFb/c) are mediated by recombination between palindromic repeats, either P5/proxP1, P5/distP1, or P4/distP1. These deletions are uncommon and usually result in severe azoospermia due to mature arrest [ Interstitial or terminal deletions that include AZFc only are mediated by recombination between the b2/b4 palindromic repeats and result in a variable infertility phenotype, ranging from azoospermia and SCO syndrome to severe oligozoospermia [ Two partial deletions of AZFc, called b1/b3, b2/b3, are considered benign copy number variants (polymorphisms) [ Another partial deletion of AZFc, gr/gr, may have some impact on fertility depending on ethnicity and geographic region [ Duplication of the AZFa or AZFc regions has been reported and does not appear to be associated with an abnormal phenotype [ Rarely within a family, the same deletion of the Y chromosome has been reported to occasionally cause infertility in some males but not in others [ The prevalence of Y chromosome deletions and microdeletions is estimated at 1:2,000 to 1:3,000 males [ The frequency of Yq microdeletions in males with azoospermia or severe oligozoospermia is about 5% [ Differences in prevalence based on ethnicity have not been observed. However, the gr/gr deletion may have a different impact on fertility depending on ethnicity and geographic region [ • Interstitial or terminal deletions that include all of AZFa are rare and usually result in the severe phenotype of Sertoli cell-only (SCO) syndrome [ • Interstitial or terminal deletions that include AZFb and/or AZFb+c (hereafter designated AZFb/c) are mediated by recombination between palindromic repeats, either P5/proxP1, P5/distP1, or P4/distP1. These deletions are uncommon and usually result in severe azoospermia due to mature arrest [ • Interstitial or terminal deletions that include AZFc only are mediated by recombination between the b2/b4 palindromic repeats and result in a variable infertility phenotype, ranging from azoospermia and SCO syndrome to severe oligozoospermia [ • Two partial deletions of AZFc, called b1/b3, b2/b3, are considered benign copy number variants (polymorphisms) [ • Another partial deletion of AZFc, gr/gr, may have some impact on fertility depending on ethnicity and geographic region [ • Duplication of the AZFa or AZFc regions has been reported and does not appear to be associated with an abnormal phenotype [ ## Clinical Description Males with Y chromosome infertility usually have no symptoms other than infertility. A physical examination may reveal small testes in those with Sertoli cell-only (SCO) syndrome. Physical examination is normal in approximately 30% of males with Y chromosome infertility. Males with Y chromosome infertility have azoospermia or severe, moderate, or mild oligozoospermia depending on the location and size of the Y chromosome deletion (see Oligozoospermia may be compatible with fertility when the female partner is very fertile. ## Genotype-Phenotype Correlations Each AZF region contains several genes that play a role in different stages of spermatogenesis. It is likely that future analysis of these individual genes in infertile males will result in more precise genotype-phenotype correlations. However, the multicopy and polymorphic nature of most fertility genes located on the Y chromosome makes it difficult to define their role precisely. The regions initially defined as AZFb and AZFc have been found to partially overlap ( Interstitial or terminal deletions that include all of AZFa are rare and usually result in the severe phenotype of Sertoli cell-only (SCO) syndrome [ Interstitial or terminal deletions that include AZFb and/or AZFb+c (hereafter designated AZFb/c) are mediated by recombination between palindromic repeats, either P5/proxP1, P5/distP1, or P4/distP1. These deletions are uncommon and usually result in severe azoospermia due to mature arrest [ Interstitial or terminal deletions that include AZFc only are mediated by recombination between the b2/b4 palindromic repeats and result in a variable infertility phenotype, ranging from azoospermia and SCO syndrome to severe oligozoospermia [ Two partial deletions of AZFc, called b1/b3, b2/b3, are considered benign copy number variants (polymorphisms) [ Another partial deletion of AZFc, gr/gr, may have some impact on fertility depending on ethnicity and geographic region [ Duplication of the AZFa or AZFc regions has been reported and does not appear to be associated with an abnormal phenotype [ • Interstitial or terminal deletions that include all of AZFa are rare and usually result in the severe phenotype of Sertoli cell-only (SCO) syndrome [ • Interstitial or terminal deletions that include AZFb and/or AZFb+c (hereafter designated AZFb/c) are mediated by recombination between palindromic repeats, either P5/proxP1, P5/distP1, or P4/distP1. These deletions are uncommon and usually result in severe azoospermia due to mature arrest [ • Interstitial or terminal deletions that include AZFc only are mediated by recombination between the b2/b4 palindromic repeats and result in a variable infertility phenotype, ranging from azoospermia and SCO syndrome to severe oligozoospermia [ • Two partial deletions of AZFc, called b1/b3, b2/b3, are considered benign copy number variants (polymorphisms) [ • Another partial deletion of AZFc, gr/gr, may have some impact on fertility depending on ethnicity and geographic region [ • Duplication of the AZFa or AZFc regions has been reported and does not appear to be associated with an abnormal phenotype [ ## Penetrance Rarely within a family, the same deletion of the Y chromosome has been reported to occasionally cause infertility in some males but not in others [ ## Prevalence The prevalence of Y chromosome deletions and microdeletions is estimated at 1:2,000 to 1:3,000 males [ The frequency of Yq microdeletions in males with azoospermia or severe oligozoospermia is about 5% [ Differences in prevalence based on ethnicity have not been observed. However, the gr/gr deletion may have a different impact on fertility depending on ethnicity and geographic region [ ## Genetically Related Disorders No disorders other than infertility are known to be caused by deletions of the long arm of the Y chromosome in the AZF regions. Men with Y chromosome deletions and infertility are otherwise healthy. However, complex Y chromosome rearrangements can lead to disruption of genes within the pseudoautosomal region (e.g., Short stature may occur in individuals with Yq deletions that extend close to the centromere in a region containing a putative growth-controlling gene, Terminal deletions often associated with severely impaired spermatogenesis remove either all or part of the AZF regions along with the terminal q12 band of the Y chromosome. These so-called "terminal deletions" are usually not terminal, but rather are more complex rearrangements such as isodicentric Y chromosomes, which are often unstable and associated with a mosaic 45,X cell line. In fact, Turner syndrome (45,X) can be caused by the loss of an isodicentric Y chromosome [ ## Differential Diagnosis Infertility affects 15%-20% of couples of reproductive age. Infertility, dependent to a great extent on the age of the female partner, has been estimated to be male related in about half of those couples, but this often-quoted figure is poorly documented. Most likely, oligospermia sufficiently severe to cause infertility would only be present in 10% of infertile couples. Causes of male infertility other than deletion of the Y chromosome are numerous and often controversial. In most cases, male infertility is of unknown etiology. Possible causes of male infertility other than Y chromosome deletion include the following conditions: In males with In males with • In males with • In males with • In males with • In males with • In males with • In males with ## Management To establish the extent of disease and needs in an individual diagnosed with Y chromosome infertility, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Semen analysis to determine the number, motility, and morphology of sperm Consultation with a clinical geneticist and/or genetic counselor A couple in which the male has Y chromosome infertility can be offered the option of in vitro fertilization using ICSI (intracytoplasmic sperm injection) [ Retrieval of sperm has been successful for most males with deletions of AZFc, but rarely for males with deletions of AZFb or AZFa. The reason for this is that an autosomal copy of The definition of Sertoli cell-only (SCO) syndrome has been the subject of confusion in the literature. There are two main causes of non-obstructive azoospermia (NOA): maturation arrest and Sertoli cell-only. With maturation arrest, there is a failure of spermatocytes to progress beyond meiosis I. But in 60% of individuals, a few spermatocytes do progress to sperm and can be retrieved from the testis. Similarly, in about 60% of males with SCO syndrome a tiny number of tubules actually contain a few spermatozoa resulting from small foci of spermatogenesis. It is important to discuss the possibility of transmission of Y chromosome infertility to male offspring (see In males with retrievable spermatozoa, the presence or absence of deletion of the long arm of the Y chromosome has no apparent effect on fertilization or pregnancy rates [ Hormones or nutritional supplements could reduce severe oligospermia to complete azoospermia [ See Ongoing studies are evaluating the use of skin biopsy in azoospermic men to make induced pluripotent stem cells (iPSC) differentiate into primordial germ cells and ultimately sperm [Author, personal communication]. Search Testicular sperm retrieval for in vitro fertilization is ineffective for males with AZFb and AZFa deletions, but has been achieved for the majority of males with AZFc deletions [ • Semen analysis to determine the number, motility, and morphology of sperm • Consultation with a clinical geneticist and/or genetic counselor ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Y chromosome infertility, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Semen analysis to determine the number, motility, and morphology of sperm Consultation with a clinical geneticist and/or genetic counselor • Semen analysis to determine the number, motility, and morphology of sperm • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations A couple in which the male has Y chromosome infertility can be offered the option of in vitro fertilization using ICSI (intracytoplasmic sperm injection) [ Retrieval of sperm has been successful for most males with deletions of AZFc, but rarely for males with deletions of AZFb or AZFa. The reason for this is that an autosomal copy of The definition of Sertoli cell-only (SCO) syndrome has been the subject of confusion in the literature. There are two main causes of non-obstructive azoospermia (NOA): maturation arrest and Sertoli cell-only. With maturation arrest, there is a failure of spermatocytes to progress beyond meiosis I. But in 60% of individuals, a few spermatocytes do progress to sperm and can be retrieved from the testis. Similarly, in about 60% of males with SCO syndrome a tiny number of tubules actually contain a few spermatozoa resulting from small foci of spermatogenesis. It is important to discuss the possibility of transmission of Y chromosome infertility to male offspring (see In males with retrievable spermatozoa, the presence or absence of deletion of the long arm of the Y chromosome has no apparent effect on fertilization or pregnancy rates [ ## Agents/Circumstances to Avoid Hormones or nutritional supplements could reduce severe oligospermia to complete azoospermia [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Ongoing studies are evaluating the use of skin biopsy in azoospermic men to make induced pluripotent stem cells (iPSC) differentiate into primordial germ cells and ultimately sperm [Author, personal communication]. Search ## Other Testicular sperm retrieval for in vitro fertilization is ineffective for males with AZFb and AZFa deletions, but has been achieved for the majority of males with AZFc deletions [ ## Genetic Counseling Y chromosome infertility is inherited in a Y-linked manner. Because males with deletion of the AZF regions of the long arm of the Y chromosome are typically infertile, the deletions are usually Rarely, a male with an AZFc deletion of the Y chromosome has fathered a son, who is infertile [ Men with gr/gr deletions have variable fertility, and can readily transmit the deletion to future generations [ The gr/gr deletion is a "partial AZFc deletion" of only two of the four copies of Deletions of b1/b3 and b2/b3 are inconsequential, and have no effect on male fertility. Note: Using ICSI-IVF (see Because most Y chromosome deletions found in an infertile male are On very rare occasions, the brothers of a proband may be at risk because within a family the same deletion of the AZFc region may appear to result in infertility in some individuals but not in others [ Pregnancies have been achieved from males with infertility caused by Y chromosome deletion using ICSI. Male fetuses have the same Y chromosome deletion as their father, with a high risk for male infertility. The deletion is not amplified or corrected in subsequent generations [ Female fetuses from a father with a Y chromosome deletion are not at increased risk for congenital abnormalities or infertility [ Once the causative genetic alteration has been identified in a male with Y chromosome infertility, prenatal testing for pregnancies conceived through assisted reproductive technology (ART) and at risk of resulting in a male with Y chromosome deletion is possible. Testing includes determining the sex of the fetus and/or the presence of a Y chromosome deletion. Prenatal testing is also possible for pregnancies at risk for chromosome abnormalities (e.g., 45,X mosaicism) resulting from a paternal Y chromosome rearrangement (e.g., pseudodicentric Y or ring Y), although such Y chromosome alterations would rarely be associated with residual spermatogenesis. • Because males with deletion of the AZF regions of the long arm of the Y chromosome are typically infertile, the deletions are usually • Rarely, a male with an AZFc deletion of the Y chromosome has fathered a son, who is infertile [ • Men with gr/gr deletions have variable fertility, and can readily transmit the deletion to future generations [ • The gr/gr deletion is a "partial AZFc deletion" of only two of the four copies of • Deletions of b1/b3 and b2/b3 are inconsequential, and have no effect on male fertility. • Note: Using ICSI-IVF (see • Because most Y chromosome deletions found in an infertile male are • On very rare occasions, the brothers of a proband may be at risk because within a family the same deletion of the AZFc region may appear to result in infertility in some individuals but not in others [ • Pregnancies have been achieved from males with infertility caused by Y chromosome deletion using ICSI. • Male fetuses have the same Y chromosome deletion as their father, with a high risk for male infertility. The deletion is not amplified or corrected in subsequent generations [ • Female fetuses from a father with a Y chromosome deletion are not at increased risk for congenital abnormalities or infertility [ ## Mode of Inheritance Y chromosome infertility is inherited in a Y-linked manner. ## Risk to Family Members Because males with deletion of the AZF regions of the long arm of the Y chromosome are typically infertile, the deletions are usually Rarely, a male with an AZFc deletion of the Y chromosome has fathered a son, who is infertile [ Men with gr/gr deletions have variable fertility, and can readily transmit the deletion to future generations [ The gr/gr deletion is a "partial AZFc deletion" of only two of the four copies of Deletions of b1/b3 and b2/b3 are inconsequential, and have no effect on male fertility. Note: Using ICSI-IVF (see Because most Y chromosome deletions found in an infertile male are On very rare occasions, the brothers of a proband may be at risk because within a family the same deletion of the AZFc region may appear to result in infertility in some individuals but not in others [ Pregnancies have been achieved from males with infertility caused by Y chromosome deletion using ICSI. Male fetuses have the same Y chromosome deletion as their father, with a high risk for male infertility. The deletion is not amplified or corrected in subsequent generations [ Female fetuses from a father with a Y chromosome deletion are not at increased risk for congenital abnormalities or infertility [ • Because males with deletion of the AZF regions of the long arm of the Y chromosome are typically infertile, the deletions are usually • Rarely, a male with an AZFc deletion of the Y chromosome has fathered a son, who is infertile [ • Men with gr/gr deletions have variable fertility, and can readily transmit the deletion to future generations [ • The gr/gr deletion is a "partial AZFc deletion" of only two of the four copies of • Deletions of b1/b3 and b2/b3 are inconsequential, and have no effect on male fertility. • Note: Using ICSI-IVF (see • Because most Y chromosome deletions found in an infertile male are • On very rare occasions, the brothers of a proband may be at risk because within a family the same deletion of the AZFc region may appear to result in infertility in some individuals but not in others [ • Pregnancies have been achieved from males with infertility caused by Y chromosome deletion using ICSI. • Male fetuses have the same Y chromosome deletion as their father, with a high risk for male infertility. The deletion is not amplified or corrected in subsequent generations [ • Female fetuses from a father with a Y chromosome deletion are not at increased risk for congenital abnormalities or infertility [ ## Related Genetic Counseling Issues ## Prenatal Testing and Preimplantation Genetic Testing Once the causative genetic alteration has been identified in a male with Y chromosome infertility, prenatal testing for pregnancies conceived through assisted reproductive technology (ART) and at risk of resulting in a male with Y chromosome deletion is possible. Testing includes determining the sex of the fetus and/or the presence of a Y chromosome deletion. Prenatal testing is also possible for pregnancies at risk for chromosome abnormalities (e.g., 45,X mosaicism) resulting from a paternal Y chromosome rearrangement (e.g., pseudodicentric Y or ring Y), although such Y chromosome alterations would rarely be associated with residual spermatogenesis. ## Resources InterNational Council on Infertility Information Dissemination • • • • InterNational Council on Infertility Information Dissemination • ## Molecular Genetics Y Chromosome Infertility: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Y Chromosome Infertility ( Other Y chromosome genes, such as AZFa: 792 kb long and just distal to the centromere Recombination between two HERV15 (HERV15yq1-HERV15yq2) proviral sequences [ AZFb and AZFc: Just proximal to the Yq12 heterochromatic band The most common Y chromosome deletion removes 3.5 Mb between palindromes b2 and b4 [ Recurrent deletions: 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 7.7 Mb between palindromes P5 and distal P1 7 Mb between palindromes P4 and distal P1 Smaller deletions (AZFb) between palindromes gr/gr, b1/b3, or b2/b3 are generally considered benign but may be associated with infertility in certain ethnic groups [ Partial deletion in AZFb that removes the entire P4 palindrome apparently decreases spermatocyte maturation but can be transmitted [ Y chromosome infertility due to pathogenic variants in Laboratory Considerations for Genes Causing Y-Chromosome Infertility Genes are in alphabetic order. • 792 kb long and just distal to the centromere • Recombination between two HERV15 (HERV15yq1-HERV15yq2) proviral sequences [ • Just proximal to the Yq12 heterochromatic band • The most common Y chromosome deletion removes 3.5 Mb between palindromes b2 and b4 [ • Recurrent deletions: • 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 • 7.7 Mb between palindromes P5 and distal P1 • 7 Mb between palindromes P4 and distal P1 • 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 • 7.7 Mb between palindromes P5 and distal P1 • 7 Mb between palindromes P4 and distal P1 • Smaller deletions (AZFb) between palindromes gr/gr, b1/b3, or b2/b3 are generally considered benign but may be associated with infertility in certain ethnic groups [ • Partial deletion in AZFb that removes the entire P4 palindrome apparently decreases spermatocyte maturation but can be transmitted [ • 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 • 7.7 Mb between palindromes P5 and distal P1 • 7 Mb between palindromes P4 and distal P1 ## Molecular Pathogenesis Other Y chromosome genes, such as AZFa: 792 kb long and just distal to the centromere Recombination between two HERV15 (HERV15yq1-HERV15yq2) proviral sequences [ AZFb and AZFc: Just proximal to the Yq12 heterochromatic band The most common Y chromosome deletion removes 3.5 Mb between palindromes b2 and b4 [ Recurrent deletions: 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 7.7 Mb between palindromes P5 and distal P1 7 Mb between palindromes P4 and distal P1 Smaller deletions (AZFb) between palindromes gr/gr, b1/b3, or b2/b3 are generally considered benign but may be associated with infertility in certain ethnic groups [ Partial deletion in AZFb that removes the entire P4 palindrome apparently decreases spermatocyte maturation but can be transmitted [ Y chromosome infertility due to pathogenic variants in Laboratory Considerations for Genes Causing Y-Chromosome Infertility Genes are in alphabetic order. • 792 kb long and just distal to the centromere • Recombination between two HERV15 (HERV15yq1-HERV15yq2) proviral sequences [ • Just proximal to the Yq12 heterochromatic band • The most common Y chromosome deletion removes 3.5 Mb between palindromes b2 and b4 [ • Recurrent deletions: • 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 • 7.7 Mb between palindromes P5 and distal P1 • 7 Mb between palindromes P4 and distal P1 • 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 • 7.7 Mb between palindromes P5 and distal P1 • 7 Mb between palindromes P4 and distal P1 • Smaller deletions (AZFb) between palindromes gr/gr, b1/b3, or b2/b3 are generally considered benign but may be associated with infertility in certain ethnic groups [ • Partial deletion in AZFb that removes the entire P4 palindrome apparently decreases spermatocyte maturation but can be transmitted [ • 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1 • 7.7 Mb between palindromes P5 and distal P1 • 7 Mb between palindromes P4 and distal P1 ## Chapter Notes Infertility Center of St. LouisSt Luke's HospitalSt Louis Missouri Whitehead InstituteMassachusetts Institute of Technology Cambridge, Massachusetts American Society for Reproductive MedicineBirmingham, AlabamaTelephone: (205) 978-5000Fax: (205) 978-5005 [email protected] Christine M Disteche, PhD; University of Washington (2002-2019)Yuting Fan, MD (2019-present)Sherman J Silber, MD (2012-present) 1 August 2019 (sw) Comprehensive update posted live 18 October 2012 (me) Comprehensive update posted live 19 March 2007 (me) Comprehensive update posted live 28 February 2006 (cmd) Revision: Diagnosis: Cytogenetic analysis 16 September 2004 (me) Comprehensive update posted live 6 February 2004 (cd) Revision: change in gene name 31 October 2002 (me) Review posted live January 2001 (cmd) Original submission • 1 August 2019 (sw) Comprehensive update posted live • 18 October 2012 (me) Comprehensive update posted live • 19 March 2007 (me) Comprehensive update posted live • 28 February 2006 (cmd) Revision: Diagnosis: Cytogenetic analysis • 16 September 2004 (me) Comprehensive update posted live • 6 February 2004 (cd) Revision: change in gene name • 31 October 2002 (me) Review posted live • January 2001 (cmd) Original submission ## Author Notes Infertility Center of St. LouisSt Luke's HospitalSt Louis Missouri Whitehead InstituteMassachusetts Institute of Technology Cambridge, Massachusetts American Society for Reproductive MedicineBirmingham, AlabamaTelephone: (205) 978-5000Fax: (205) 978-5005 [email protected] ## Author History Christine M Disteche, PhD; University of Washington (2002-2019)Yuting Fan, MD (2019-present)Sherman J Silber, MD (2012-present) ## Revision History 1 August 2019 (sw) Comprehensive update posted live 18 October 2012 (me) Comprehensive update posted live 19 March 2007 (me) Comprehensive update posted live 28 February 2006 (cmd) Revision: Diagnosis: Cytogenetic analysis 16 September 2004 (me) Comprehensive update posted live 6 February 2004 (cd) Revision: change in gene name 31 October 2002 (me) Review posted live January 2001 (cmd) Original submission • 1 August 2019 (sw) Comprehensive update posted live • 18 October 2012 (me) Comprehensive update posted live • 19 March 2007 (me) Comprehensive update posted live • 28 February 2006 (cmd) Revision: Diagnosis: Cytogenetic analysis • 16 September 2004 (me) Comprehensive update posted live • 6 February 2004 (cd) Revision: change in gene name • 31 October 2002 (me) Review posted live • January 2001 (cmd) Original submission ## References CUA Guideline: The workup and management of azoospermic males. Canadian Urological Association. Available Evaluation of the azoospermic male: a committee opinion. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology. Available • CUA Guideline: The workup and management of azoospermic males. Canadian Urological Association. Available • Evaluation of the azoospermic male: a committee opinion. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology. Available ## Published Guidelines / Policy Statements CUA Guideline: The workup and management of azoospermic males. Canadian Urological Association. Available Evaluation of the azoospermic male: a committee opinion. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology. Available • CUA Guideline: The workup and management of azoospermic males. Canadian Urological Association. Available • Evaluation of the azoospermic male: a committee opinion. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology. Available ## Literature Cited Schematic of the Y chromosome indicating the approximate position of the previously defined regions AZFa, AZFb, and AZFc and the position of recurrent deletions currently defined on the basis of the flanking palindromic repeats (see The schematic is modified with permission from	[ "E Bosch, MA Jobling. Duplications of the AZFa region of the human Y chromosome are mediated by homologous recombination between HERVs and are compatible with male fertility.. Hum Mol Genet. 2003;12:341-7", "PL Chang, MV Sauer, S Brown. Y chromosome microdeletion in a father and his four infertile sons.. Hum Reprod. 1999;14:2689-94", "M Chillón, T Casals, B Mercier, L Bassas, W Lissens, S Silber, MC Romey, J Ruiz-Romero, C Verlingue, M Claustres, V Nunes, C Férec, X Estivill. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens.. N Engl J Med. 1995;332:1475-80", "S Colaco, D Modi. Genetics of the human Y chromosome and its association with male infertility.. Reprod Biol Endocrinol. 2018;16:14", "MJ Davies, VM Moore, KJ Willson, P Van Essen, K Priest, H Scott, EA Haan, A Chan. Reproductive technologies and the risk of birth defects.. N Engl J Med. 2012;366:1803-13", "JW de Vries, S Repping, SK van Daalen, CM Korver, NJ Leschot, F van der Veen. Clinical relevance of partial AZFc deletions.. Fertil Steril. 2002;78:1209-14", "HJ Ditton, J Zimmer, C Kamp, E Rajpert-De Meyts, PH Vogt. The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control.. Hum Mol Genet. 2004;13:2333-41", "MJ Faddy, SJ Silber, RG Gosden. Intra-cytoplasmic sperm injection and infertility.. Nat Genet. 2001;29:131", "A Ferlin, B Arredi, E Speltra, C Cazzadore, R Selice, A Garolla, A Lenzi, C Foresta. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy.. J Clin Endocrinol Metab 2007;92:762-70", "S Fernandes, S Paracchini, LH Meyer, G Floridia, C Tyler-Smith, PH Vogt. A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N.. Am J Hum Genet 2004;74:180-7", "C Giachini, I Laface, E Guarducci, G Balercia, G Forti, C Krausz. Partial AZFc deletions and duplications: clinical correlates in the Italian population.. Hum Genet. 2008;124:399-410", "JF Hughes, DC Page. The biology and evolution of mammalian Y chromosomes.. Annu Rev Genet. 2015;49:507-27", "CJ Jorgez, JW Weedin, A Sahin, M Tannour-Louet, S Han, JC Bournat, A Mielnik, SW Cheung, AK Nangia, PN Schlegel, LI Lipshultz, DJ Lamb. Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y-chromosome microdeletions.. J Clin Endocrinol Metab 2011;96:E674-9", "C Kamp, P Hirschmann, H Voss, K Huellen, PH Vogt. Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events.. Hum Mol Genet. 2000;9:2563-72", "C Kamp, K Huellen, S Fernandes, M Sousa, PN Schlegel, A Mielnik, S Kleiman, H Yavetz, W Krause, W Küpker, R Johannisson, W Schulze, W Weidner, A Barros, PH Vogt. High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome.. Mol Hum Reprod. 2001;7:987-94", "M Katsumi, H Ishikawa, Y Tanaka, K Saito, Y Kobori, H Okada, H Saito, K Nakabayashi, Y Matsubara, T Ogata, M Fukami, M Miyado. Microhomology-mediated microduplication in the y chromosomal azoospermia factor a region in a male with mild asthenozoospermia.. Cytogenet Genome Res. 2014;144:285-9", "E Kichine, V Rozé, J Di Cristofaro, D Taulier, A Navarro, E Streichemberger, F Decarpentrie, C Metzler-Guillemain, N Lévy, J Chiaroni, V Paquis-Flucklinger, F Fellmann, MJ Mitchell. HSFY genes and the P4 palindrome in the AZFb interval of the human Y chromosome are not required for spermatocyte maturation.. Hum Reprod. 2012;27:615-24", "SY Kim, HJ Kim, BY Lee, SY Park, HS Lee, JT Seo. Y chromosome microdeletions in infertile men with non-obstructive azoospermia and severe oligozoospermia.. J Reprod Infertil. 2017;18:307-15", "S Kirsch, B Weiss, K Schön, GA Rappold. The definition of the Y chromosome growth-control gene (GCY) critical region: relevance of terminal and interstitial deletions.. J Pediatr Endocrinol Metab. 2002;15:1295-300", "S Kirsch, B Weiss, K Zumbach, G Rappold. Molecular and evolutionary analysis of the growth-controlling region on the human Y chromosome.. Hum Genet. 2004;114:173-81", "T Kuroda-Kawaguchi, H Skaletsky, LG Brown, PJ Minx, HS Cordum, RH Waterston, RK Wilson, S Silber, R Oates, S Rozen, DC Page. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men.. Nat Genet. 2001;29:279-86", "BT Lahn, DC Page. Functional coherence of the human Y chromosome.. Science. 1997;278:675-80", "J Lange, H Skaletsky, SK van Daalen, SL Embry, CM Korver, LG Brown, RD Oates, S Silber, S Repping, DC Page. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes.. Cell. 2009;138:855-69", "A Luddi, M Margollicci, L Gambera, F Serafini, M Cioni, V De Leo, P Balestri, P Piomboni. Spermatogenesis in a man with complete deletion of USP9Y.. N Engl J Med. 2009;360:881-5", "N Machev, N Saut, G Longepied, P Terriou, A Navarro, N Levy, M Guichaoua, C Metzler-Guillemain, P Collignon, AM Frances, J Belougne, E Clemente, J Chiaroni, C Chevillard, C Durand, A Ducourneau, N Pech, K McElreavey, MG Mattei, MJ Mitchell. Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility.. J Med Genet. 2004;41:814-25", "MJ Noordam, GH Westerveld, SE Hovingh, SK van Daalen, CM Korver, F van der Veen, AM van Pelt, S Repping. Gene copy number reduction in the azoospermia factor c (AZFc) region and its effect on total motile sperm count.. Hum Mol Genet. 2011;20:2457-63", "RD Oates, S Silber, LG Brown, DC Page. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI.. Hum Reprod. 2002;17:2813-24", "Report on evaluation of the azoospermic male.. Fertil Steril. 2004;82:S131-6", "S Repping, H Skaletsky, L Brown, SK van Daalen, CM Korver, T Pyntikova, T Kuroda-Kawaguchi, JW de Vries, RD Oates, S Silber, F van der Veen, DC Page, S Rozen. Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection.. Nat Genet. 2003;35:247-51", "S Repping, H Skaletsky, J Lange, S Silber, F Van Der Veen, RD Oates, DC Page, S Rozen. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure.. Am J Hum Genet 2002;71:906-22", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "N Saut, P Terriou, A Navarro, N Levy, MJ Mitchell. The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility.. Mol Hum Reprod 2000;6:789-93", "SJ Silber. The varicocele dilemma.. Hum Reprod Update. 2001;7:70-7", "SJ Silber, R Alagappan, LG Brown, DC Page. Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction.. Hum Reprod. 1998;13:3332-7", "SJ Silber, S Repping. Transmission of male infertility to future generations: Lessons from the Y chromosome.. Hum Reprod Update. 2002;8:217-29", "K Stouffs, W Lissens, H Tournaye, P Haentjens. What about gr/gr deletions and male infertility? Systematic review and meta-analysis.. Hum Reprod Update. 2011;17:197-209", "K Stouffs, W Lissens, H Tournaye, A Van Steirteghem, I Liebaers. The choice and outcome of the fertility treatment of 38 couples in whom the male partner has a Yq microdeletion.. Hum Reprod. 2005;20:1887-96", "C Sun, H Skaletsky, B Birren, K Devon, Z Tang, S Silber, R Oates, DC Page. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y.. Nat Genet. 1999;23:429-32", "C Sun, H Skaletsky, S Rozen, J Gromoll, E Nieschlag, R Oates, DC Page. Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses.. Hum Mol Genet. 2000;9:2291-6", "PH Vogt. Azoospermia factor (AZF) in Yq11: towards a molecular understanding of its function for human male fertility and spermatogenesis.. Reprod Biomed Online. 2005;10:81-93" ]	31/10/2002	1/8/2019		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
yif1b-ndd	yif1b-ndd	[ "Kaya-Barakat-Masson Syndrome (KABAMAS)", "Kaya-Barakat-Masson Syndrome (KABAMAS)", "Protein YIF1B", "YIF1B", "YIF1B-Related Neurodevelopmental Disorder" ]		Eva Medico-Salsench, Namik Kaya, Tahsin Stefan Barakat	Summary The diagnosis of	## Diagnosis Severe-to-profound developmental delay; most individuals do not obtain any developmental milestones. Severe-to-profound intellectual disability, with no speech development or limited speech with subsequent regression Generalized axial hypotonia of infancy and concurrent peripheral hypertonia Infant feeding difficulties Movement disorders, including dystonia and dyskinesia or tremors Epilepsy, varying from myoclonic seizures to generalized tonic-clonic seizures and infantile spasms Neurobehavioral/psychiatric manifestations including autism spectrum disorder and anxiety Postnatal microcephaly Ophthalmologic involvement, including strabismus, nystagmus, optic atrophy, and cortical blindness Hypoventilation and ventilation dependency in the presence of brain stem atrophy The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click To date, 24/25 reported individuals had biallelic pathogenic variants identified using exome sequencing [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Severe-to-profound developmental delay; most individuals do not obtain any developmental milestones. • Severe-to-profound intellectual disability, with no speech development or limited speech with subsequent regression • Generalized axial hypotonia of infancy and concurrent peripheral hypertonia • Infant feeding difficulties • Movement disorders, including dystonia and dyskinesia or tremors • Epilepsy, varying from myoclonic seizures to generalized tonic-clonic seizures and infantile spasms • Neurobehavioral/psychiatric manifestations including autism spectrum disorder and anxiety • Postnatal microcephaly • Ophthalmologic involvement, including strabismus, nystagmus, optic atrophy, and cortical blindness • Hypoventilation and ventilation dependency in the presence of brain stem atrophy ## Suggestive Findings Severe-to-profound developmental delay; most individuals do not obtain any developmental milestones. Severe-to-profound intellectual disability, with no speech development or limited speech with subsequent regression Generalized axial hypotonia of infancy and concurrent peripheral hypertonia Infant feeding difficulties Movement disorders, including dystonia and dyskinesia or tremors Epilepsy, varying from myoclonic seizures to generalized tonic-clonic seizures and infantile spasms Neurobehavioral/psychiatric manifestations including autism spectrum disorder and anxiety Postnatal microcephaly Ophthalmologic involvement, including strabismus, nystagmus, optic atrophy, and cortical blindness Hypoventilation and ventilation dependency in the presence of brain stem atrophy • Severe-to-profound developmental delay; most individuals do not obtain any developmental milestones. • Severe-to-profound intellectual disability, with no speech development or limited speech with subsequent regression • Generalized axial hypotonia of infancy and concurrent peripheral hypertonia • Infant feeding difficulties • Movement disorders, including dystonia and dyskinesia or tremors • Epilepsy, varying from myoclonic seizures to generalized tonic-clonic seizures and infantile spasms • Neurobehavioral/psychiatric manifestations including autism spectrum disorder and anxiety • Postnatal microcephaly • Ophthalmologic involvement, including strabismus, nystagmus, optic atrophy, and cortical blindness • Hypoventilation and ventilation dependency in the presence of brain stem atrophy ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click To date, 24/25 reported individuals had biallelic pathogenic variants identified using exome sequencing [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click To date, 24/25 reported individuals had biallelic pathogenic variants identified using exome sequencing [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics Based on Not all features have been reported for all currently known 25 affected individuals. Three individuals were older than age 25 years (the oldest reported individual was age 37 years) at the time of publication, demonstrating that survival into adulthood is possible [ Although the number of reported individuals with To date, 25 individuals with ## Clinical Description Based on Not all features have been reported for all currently known 25 affected individuals. Three individuals were older than age 25 years (the oldest reported individual was age 37 years) at the time of publication, demonstrating that survival into adulthood is possible [ ## Genotype-Phenotype Correlations Although the number of reported individuals with ## Prevalence To date, 25 individuals with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The phenotypic features associated with • • • • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gastroenterology / nutrition / feeding team eval Growth assessment To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Assess for movement disorder & signs of hypoventilation. Assess muscle tone. Consider EEG if seizures are a concern. Consider brain MRI if not performed previously. Community or Social work involvement for parental support Home nursing referral ASD = autism spectrum disorder; MOI = mode of inheritance; Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; OT = occupational therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, movement disorders, or manifestations of central hypoventilation. ASD = autism spectrum disorder See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gastroenterology / nutrition / feeding team eval • Growth assessment • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Assess for movement disorder & signs of hypoventilation. • Assess muscle tone. • Consider EEG if seizures are a concern. • Consider brain MRI if not performed previously. • Community or • Social work involvement for parental support • Home nursing referral • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, movement disorders, or manifestations of central hypoventilation. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gastroenterology / nutrition / feeding team eval Growth assessment To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Assess for movement disorder & signs of hypoventilation. Assess muscle tone. Consider EEG if seizures are a concern. Consider brain MRI if not performed previously. Community or Social work involvement for parental support Home nursing referral ASD = autism spectrum disorder; MOI = mode of inheritance; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gastroenterology / nutrition / feeding team eval • Growth assessment • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Assess for movement disorder & signs of hypoventilation. • Assess muscle tone. • Consider EEG if seizures are a concern. • Consider brain MRI if not performed previously. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; OT = occupational therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, movement disorders, or manifestations of central hypoventilation. ASD = autism spectrum disorder • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, movement disorders, or manifestations of central hypoventilation. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children. It is appropriate to offer Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children. • It is appropriate to offer ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children. It is appropriate to offer • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children. • It is appropriate to offer ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada Speaking out for People with Intellectual and Developmental Disabilities • • • • • • Canada • • • • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics YIF1B-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for YIF1B-Related Neurodevelopmental Disorder ( Although the precise molecular mechanisms underlying Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Although the precise molecular mechanisms underlying Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Tahsin Stefan Barakat is a clinical geneticist and experimental biologist with broad clinical and research interests in neurodevelopmental disorders. The Barakat laboratory aims to decipher novel mechanisms of neurodevelopmental disorders and develop novel therapies based on this knowledge. Department of Clinical GeneticsErasmus MC University Medical CenterRotterdam, the NetherlandsEmail: Dr TS Barakat ( Contact Dr TS Barakat to inquire about review of The Barakat lab was supported by the Netherlands Organisation for Scientific Research (ZonMw Veni, grant 91617021; ZonMw Vidi, grant 09150172110002), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018, and acknowledges other ongoing support for rare disease research from Stichting 12q, EpilepsieNL, CURE Epilepsy, Spastic Paraplegia Foundation, Inc, and the Sophia Research Foundation (Stichting Sophia Kinderziekenhuis Fonds). Funding bodies did not have any influence on study design, results, and data interpretation or final manuscript. 12 September 2024 (sw) Review posted live 21 May 2024 (tsb) Original submission • • • 12 September 2024 (sw) Review posted live • 21 May 2024 (tsb) Original submission ## Author Notes Dr Tahsin Stefan Barakat is a clinical geneticist and experimental biologist with broad clinical and research interests in neurodevelopmental disorders. The Barakat laboratory aims to decipher novel mechanisms of neurodevelopmental disorders and develop novel therapies based on this knowledge. Department of Clinical GeneticsErasmus MC University Medical CenterRotterdam, the NetherlandsEmail: Dr TS Barakat ( Contact Dr TS Barakat to inquire about review of • • ## Acknowledgments The Barakat lab was supported by the Netherlands Organisation for Scientific Research (ZonMw Veni, grant 91617021; ZonMw Vidi, grant 09150172110002), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018, and acknowledges other ongoing support for rare disease research from Stichting 12q, EpilepsieNL, CURE Epilepsy, Spastic Paraplegia Foundation, Inc, and the Sophia Research Foundation (Stichting Sophia Kinderziekenhuis Fonds). Funding bodies did not have any influence on study design, results, and data interpretation or final manuscript. ## Revision History 12 September 2024 (sw) Review posted live 21 May 2024 (tsb) Original submission • 12 September 2024 (sw) Review posted live • 21 May 2024 (tsb) Original submission ## References ## Literature Cited T Reproduced with permission from Images of Individuals 4–7 and 8 at ages 1 year, 27 years, 7.5 years, 11 months, and 4.5 years, respectively. No consistent dysmorphic features were observed. Note the neurologic posture in Individuals 4, 5, and 7. Reproduced with permission from	[]	12/9/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
zap70-scid	zap70-scid	[ "Tyrosine-protein kinase ZAP-70", "ZAP70", "ZAP70-Related Combined Immunodeficiency" ]		Kelly Walkovich, Mark Vander Lugt	Summary The diagnosis of	## Diagnosis Recurrent viral, bacterial, and opportunistic infections Chronic diarrhea and failure to thrive Characteristic results of lymphocyte subset analysis of CD3, CD4, and CD8 T cells, lymphocyte functional testing, and ZAP-70 protein expression (See Note: Individuals with non-classic Thymic architecture is largely preserved in individuals with T-cell counts: CD3 CD4 CD8 Numbers of regulatory T cells may be normal or decreased [ B cell counts and NK cell counts are normal. Absent or decreased proliferation to CD3 antibody [ Absent or decreased proliferation of CD4 Intact proliferative response to mitogenic stimuli that bypass the TCR (e.g., PMA/Ionomycin) [ Normal TCR Vβ repertoire in both CD4+ and CD8+ T cells [ In CD4 cells: limited differentiation into Th2 cells and resistance to Fas-induced cell death [ In regulatory T cells: potentially decreased expression of Immunoglobulin levels vary by individual. Many affected individuals have severe hypogammaglobulinemia, but normal immunoglobulins or elevated IgA, IgM, and/or IgE can also be seen [ Although functional antibody responses to immunization are present in a few persons [ The diagnosis of Molecular genetic testing approaches can include Note: (1) No deletions or duplications of Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Recurrent viral, bacterial, and opportunistic infections • Chronic diarrhea and failure to thrive • Characteristic results of lymphocyte subset analysis of CD3, CD4, and CD8 T cells, lymphocyte functional testing, and ZAP-70 protein expression (See • Thymic architecture is largely preserved in individuals with • T-cell counts: • CD3 • CD4 • CD8 • Numbers of regulatory T cells may be normal or decreased [ • CD3 • CD4 • CD8 • Numbers of regulatory T cells may be normal or decreased [ • B cell counts and NK cell counts are normal. • CD3 • CD4 • CD8 • Numbers of regulatory T cells may be normal or decreased [ • Absent or decreased proliferation to CD3 antibody [ • Absent or decreased proliferation of CD4 • Intact proliferative response to mitogenic stimuli that bypass the TCR (e.g., PMA/Ionomycin) [ • Normal TCR Vβ repertoire in both CD4+ and CD8+ T cells [ • In CD4 cells: limited differentiation into Th2 cells and resistance to Fas-induced cell death [ • In regulatory T cells: potentially decreased expression of • Immunoglobulin levels vary by individual. Many affected individuals have severe hypogammaglobulinemia, but normal immunoglobulins or elevated IgA, IgM, and/or IgE can also be seen [ • Although functional antibody responses to immunization are present in a few persons [ • Note: (1) No deletions or duplications of • Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this • For an introduction to multigene panels click ## Suggestive Findings Recurrent viral, bacterial, and opportunistic infections Chronic diarrhea and failure to thrive Characteristic results of lymphocyte subset analysis of CD3, CD4, and CD8 T cells, lymphocyte functional testing, and ZAP-70 protein expression (See Note: Individuals with non-classic Thymic architecture is largely preserved in individuals with T-cell counts: CD3 CD4 CD8 Numbers of regulatory T cells may be normal or decreased [ B cell counts and NK cell counts are normal. Absent or decreased proliferation to CD3 antibody [ Absent or decreased proliferation of CD4 Intact proliferative response to mitogenic stimuli that bypass the TCR (e.g., PMA/Ionomycin) [ Normal TCR Vβ repertoire in both CD4+ and CD8+ T cells [ In CD4 cells: limited differentiation into Th2 cells and resistance to Fas-induced cell death [ In regulatory T cells: potentially decreased expression of Immunoglobulin levels vary by individual. Many affected individuals have severe hypogammaglobulinemia, but normal immunoglobulins or elevated IgA, IgM, and/or IgE can also be seen [ Although functional antibody responses to immunization are present in a few persons [ • Recurrent viral, bacterial, and opportunistic infections • Chronic diarrhea and failure to thrive • Characteristic results of lymphocyte subset analysis of CD3, CD4, and CD8 T cells, lymphocyte functional testing, and ZAP-70 protein expression (See • Thymic architecture is largely preserved in individuals with • T-cell counts: • CD3 • CD4 • CD8 • Numbers of regulatory T cells may be normal or decreased [ • CD3 • CD4 • CD8 • Numbers of regulatory T cells may be normal or decreased [ • B cell counts and NK cell counts are normal. • CD3 • CD4 • CD8 • Numbers of regulatory T cells may be normal or decreased [ • Absent or decreased proliferation to CD3 antibody [ • Absent or decreased proliferation of CD4 • Intact proliferative response to mitogenic stimuli that bypass the TCR (e.g., PMA/Ionomycin) [ • Normal TCR Vβ repertoire in both CD4+ and CD8+ T cells [ • In CD4 cells: limited differentiation into Th2 cells and resistance to Fas-induced cell death [ • In regulatory T cells: potentially decreased expression of • Immunoglobulin levels vary by individual. Many affected individuals have severe hypogammaglobulinemia, but normal immunoglobulins or elevated IgA, IgM, and/or IgE can also be seen [ • Although functional antibody responses to immunization are present in a few persons [ ## Establishing the Diagnosis The diagnosis of Molecular genetic testing approaches can include Note: (1) No deletions or duplications of Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Note: (1) No deletions or duplications of • Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this • For an introduction to multigene panels click ## Clinical Characteristics Individuals with Other presentations have also been reported: Reports of milder phenotypes in sibs of children who had died from A child age nine years with a A child age 11 months with BCG-related complications including axillary lymphadenitis or disseminated mycobacterial disease following BCG vaccination may be presenting features [ Two individuals presented with recurrent infections and silent brain infarcts; one also had congenital nephrotic syndrome and autoimmune hemolytic anemia [ An individual with isolated treatment-refractory immune thrombocytopenia (ITP) has been described [ Two sibs had refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis; one also developed autoantibodies to factor VIII caused by a hypomorphic and weakly activating An adult with a history of infantile-onset colitis, recurrent respiratory-tract infections, mucocutaneous candidiasis, HSV stomatitis, VZV infection, EBV lymphoproliferative disorder, recurrent CMV viremia, polyomaviremia, and epidermodysplasia verruciformis-like lesions due to HHV-23 was recently reported. A novel pathogenic variant ( The long-term prognosis of untreated There is very little genotype-phenotype correlation reported in A child with a hypomorphic intronic pathogenic variant ( Two sibs with refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis. One sib also developed autoantibodies to factor VIII. These sibs had compound heterozygous The prevalence of • Reports of milder phenotypes in sibs of children who had died from • A child age nine years with a • A child age 11 months with • BCG-related complications including axillary lymphadenitis or disseminated mycobacterial disease following BCG vaccination may be presenting features [ • Two individuals presented with recurrent infections and silent brain infarcts; one also had congenital nephrotic syndrome and autoimmune hemolytic anemia [ • An individual with isolated treatment-refractory immune thrombocytopenia (ITP) has been described [ • Two sibs had refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis; one also developed autoantibodies to factor VIII caused by a hypomorphic and weakly activating • An adult with a history of infantile-onset colitis, recurrent respiratory-tract infections, mucocutaneous candidiasis, HSV stomatitis, VZV infection, EBV lymphoproliferative disorder, recurrent CMV viremia, polyomaviremia, and epidermodysplasia verruciformis-like lesions due to HHV-23 was recently reported. A novel pathogenic variant ( • A child with a hypomorphic intronic pathogenic variant ( • Two sibs with refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis. One sib also developed autoantibodies to factor VIII. These sibs had compound heterozygous ## Clinical Description Individuals with Other presentations have also been reported: Reports of milder phenotypes in sibs of children who had died from A child age nine years with a A child age 11 months with BCG-related complications including axillary lymphadenitis or disseminated mycobacterial disease following BCG vaccination may be presenting features [ Two individuals presented with recurrent infections and silent brain infarcts; one also had congenital nephrotic syndrome and autoimmune hemolytic anemia [ An individual with isolated treatment-refractory immune thrombocytopenia (ITP) has been described [ Two sibs had refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis; one also developed autoantibodies to factor VIII caused by a hypomorphic and weakly activating An adult with a history of infantile-onset colitis, recurrent respiratory-tract infections, mucocutaneous candidiasis, HSV stomatitis, VZV infection, EBV lymphoproliferative disorder, recurrent CMV viremia, polyomaviremia, and epidermodysplasia verruciformis-like lesions due to HHV-23 was recently reported. A novel pathogenic variant ( The long-term prognosis of untreated • Reports of milder phenotypes in sibs of children who had died from • A child age nine years with a • A child age 11 months with • BCG-related complications including axillary lymphadenitis or disseminated mycobacterial disease following BCG vaccination may be presenting features [ • Two individuals presented with recurrent infections and silent brain infarcts; one also had congenital nephrotic syndrome and autoimmune hemolytic anemia [ • An individual with isolated treatment-refractory immune thrombocytopenia (ITP) has been described [ • Two sibs had refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis; one also developed autoantibodies to factor VIII caused by a hypomorphic and weakly activating • An adult with a history of infantile-onset colitis, recurrent respiratory-tract infections, mucocutaneous candidiasis, HSV stomatitis, VZV infection, EBV lymphoproliferative disorder, recurrent CMV viremia, polyomaviremia, and epidermodysplasia verruciformis-like lesions due to HHV-23 was recently reported. A novel pathogenic variant ( ## Genotype-Phenotype Correlations There is very little genotype-phenotype correlation reported in A child with a hypomorphic intronic pathogenic variant ( Two sibs with refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis. One sib also developed autoantibodies to factor VIII. These sibs had compound heterozygous • A child with a hypomorphic intronic pathogenic variant ( • Two sibs with refractory autoimmune features including nephrotic syndrome/proteinuria, bullous pemphigoid, and colitis. One sib also developed autoantibodies to factor VIII. These sibs had compound heterozygous ## Nomenclature ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Combined Immunodeficiencies in the Differential Diagnosis of BLS = bare lymphocyte syndrome; MHC II = major histocompatibility complex class II T-Cell-Negative Forms of CID in the Differential Diagnosis of ## Management The care of individuals diagnosed with Assessment of growth Evaluation for common and opportunistic viral, bacterial, and fungal disease-causing agents Complete metabolic panel (liver and renal function), complete blood count (CBC) with differential and platelet count, lymphocyte subsets and mitogen proliferation, and quantitative immunoglobulins Consultation with a clinical geneticist and/or genetic counselor Consultation with a clinical immunologist Consultation for hematopoietic stem cell transplantation Treatment relies on prompt reconstitution of the individual's immune system (see Supportive treatment includes IVIG and antibacterial, antifungal, antiviral, and The only curative therapy for Outcomes are the best with HLA-matched, related donors. If an HLA-matched, related donor is not available, alternatives include: Matched unrelated donor; Umbilical cord blood donor; Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. In contrast to individuals with SCID, individuals with The largest series of eight individuals with All individuals were alive at a median of 13.5 years of follow up. Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. Two individuals receiving myeloablative conditioning have developed premature ovarian failure. Cellular reconstitution following HSCT takes up to one year, while restoration of humoral immunity can take significantly longer, and may not occur in some individuals. Complications from HSCT include graft-versus-host disease, failure to reconstitute the humoral immune compartment, graft failure over time, and post-transplant lymphoproliferative disease [ Affected individuals with poor humoral reconstitution are maintained on long-term immunoglobulin replacement. Individuals who do not undergo HSCT require close monitoring for worsening of immune function manifested by increased susceptibility to severe or opportunistic infections (see also The following are appropriate: Use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products Delay of immunizations until immune reconstitution Consideration for formula feeds in place of breast feeding until CMV status of mother is known. Caution should be taken to assess the quality of the water source for the infant formula. Following a successful HSCT, the following should be routinely monitored: Growth Psychomotor development Complete blood counts Liver and renal function Immune status Donor and recipient chimerism Development of post-transplant complications, particularly chronic graft-versus-host disease, decreased bone density, pulmonary and cardiac function, and gonadal function Individuals with milder findings or those who have not undergone HSCT also need to be monitored for worsening of immune function with periodic assessment of clinical status and functional lymphocyte responsiveness. Individuals with Non-irradiated blood products Live virus vaccinations Contaminated water sources Exposure to fungus-enriched environments (e.g., construction sites, agricultural areas with active soil disruption, mulch, hay) Because the outcome of HSCT in children with If the If the pathogenic variants in the family are not known, CBC, quantitative immunoglobulins, and lymphocyte subsets and proliferation can be used to clarify the genetic status (immunologic status) of at-risk sibs. See Appropriately screened blood products should be available, if needed, during the course of the pregnancy and delivery. Search • Assessment of growth • Evaluation for common and opportunistic viral, bacterial, and fungal disease-causing agents • Complete metabolic panel (liver and renal function), complete blood count (CBC) with differential and platelet count, lymphocyte subsets and mitogen proliferation, and quantitative immunoglobulins • Consultation with a clinical geneticist and/or genetic counselor • Consultation with a clinical immunologist • Consultation for hematopoietic stem cell transplantation • Outcomes are the best with HLA-matched, related donors. • If an HLA-matched, related donor is not available, alternatives include: • Matched unrelated donor; • Umbilical cord blood donor; • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. • Matched unrelated donor; • Umbilical cord blood donor; • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. • In contrast to individuals with SCID, individuals with • The largest series of eight individuals with • All individuals were alive at a median of 13.5 years of follow up. • Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. • 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. • Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. • Two individuals receiving myeloablative conditioning have developed premature ovarian failure. • All individuals were alive at a median of 13.5 years of follow up. • Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. • 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. • Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. • Two individuals receiving myeloablative conditioning have developed premature ovarian failure. • Cellular reconstitution following HSCT takes up to one year, while restoration of humoral immunity can take significantly longer, and may not occur in some individuals. • Complications from HSCT include graft-versus-host disease, failure to reconstitute the humoral immune compartment, graft failure over time, and post-transplant lymphoproliferative disease [ • Affected individuals with poor humoral reconstitution are maintained on long-term immunoglobulin replacement. • Matched unrelated donor; • Umbilical cord blood donor; • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. • All individuals were alive at a median of 13.5 years of follow up. • Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. • 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. • Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. • Two individuals receiving myeloablative conditioning have developed premature ovarian failure. • Use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products • Delay of immunizations until immune reconstitution • Consideration for formula feeds in place of breast feeding until CMV status of mother is known. Caution should be taken to assess the quality of the water source for the infant formula. • Growth • Psychomotor development • Complete blood counts • Liver and renal function • Immune status • Donor and recipient chimerism • Development of post-transplant complications, particularly chronic graft-versus-host disease, decreased bone density, pulmonary and cardiac function, and gonadal function • Non-irradiated blood products • Live virus vaccinations • Contaminated water sources • Exposure to fungus-enriched environments (e.g., construction sites, agricultural areas with active soil disruption, mulch, hay) • If the • If the pathogenic variants in the family are not known, CBC, quantitative immunoglobulins, and lymphocyte subsets and proliferation can be used to clarify the genetic status (immunologic status) of at-risk sibs. ## Evaluations Following Initial Diagnosis The care of individuals diagnosed with Assessment of growth Evaluation for common and opportunistic viral, bacterial, and fungal disease-causing agents Complete metabolic panel (liver and renal function), complete blood count (CBC) with differential and platelet count, lymphocyte subsets and mitogen proliferation, and quantitative immunoglobulins Consultation with a clinical geneticist and/or genetic counselor Consultation with a clinical immunologist Consultation for hematopoietic stem cell transplantation • Assessment of growth • Evaluation for common and opportunistic viral, bacterial, and fungal disease-causing agents • Complete metabolic panel (liver and renal function), complete blood count (CBC) with differential and platelet count, lymphocyte subsets and mitogen proliferation, and quantitative immunoglobulins • Consultation with a clinical geneticist and/or genetic counselor • Consultation with a clinical immunologist • Consultation for hematopoietic stem cell transplantation ## Treatment of Manifestations Treatment relies on prompt reconstitution of the individual's immune system (see Supportive treatment includes IVIG and antibacterial, antifungal, antiviral, and ## Prevention of Primary Manifestations The only curative therapy for Outcomes are the best with HLA-matched, related donors. If an HLA-matched, related donor is not available, alternatives include: Matched unrelated donor; Umbilical cord blood donor; Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. In contrast to individuals with SCID, individuals with The largest series of eight individuals with All individuals were alive at a median of 13.5 years of follow up. Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. Two individuals receiving myeloablative conditioning have developed premature ovarian failure. Cellular reconstitution following HSCT takes up to one year, while restoration of humoral immunity can take significantly longer, and may not occur in some individuals. Complications from HSCT include graft-versus-host disease, failure to reconstitute the humoral immune compartment, graft failure over time, and post-transplant lymphoproliferative disease [ Affected individuals with poor humoral reconstitution are maintained on long-term immunoglobulin replacement. Individuals who do not undergo HSCT require close monitoring for worsening of immune function manifested by increased susceptibility to severe or opportunistic infections (see also • Outcomes are the best with HLA-matched, related donors. • If an HLA-matched, related donor is not available, alternatives include: • Matched unrelated donor; • Umbilical cord blood donor; • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. • Matched unrelated donor; • Umbilical cord blood donor; • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. • In contrast to individuals with SCID, individuals with • The largest series of eight individuals with • All individuals were alive at a median of 13.5 years of follow up. • Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. • 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. • Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. • Two individuals receiving myeloablative conditioning have developed premature ovarian failure. • All individuals were alive at a median of 13.5 years of follow up. • Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. • 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. • Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. • Two individuals receiving myeloablative conditioning have developed premature ovarian failure. • Cellular reconstitution following HSCT takes up to one year, while restoration of humoral immunity can take significantly longer, and may not occur in some individuals. • Complications from HSCT include graft-versus-host disease, failure to reconstitute the humoral immune compartment, graft failure over time, and post-transplant lymphoproliferative disease [ • Affected individuals with poor humoral reconstitution are maintained on long-term immunoglobulin replacement. • Matched unrelated donor; • Umbilical cord blood donor; • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T-cell depleted. • All individuals were alive at a median of 13.5 years of follow up. • Two-thirds of the individuals who did not receive conditioning failed to have myeloid engraftment but have maintained stable mixed chimerism. In addition, three individuals who received stem cells from a matched sib did not receive conditioning prior to transplant and achieved engraftment. • 75% of individuals developed acute graft-versus-host disease (GVHD) and 50% developed chronic GVHD. • Seven of eight individuals achieved freedom from IVIG and show evidence of class switching with resolution of dysregulated immunoglobulin production and six of the eight show evidence of antibody production to both protein and polysaccharide vaccines. • Two individuals receiving myeloablative conditioning have developed premature ovarian failure. ## Prevention of Secondary Complications The following are appropriate: Use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products Delay of immunizations until immune reconstitution Consideration for formula feeds in place of breast feeding until CMV status of mother is known. Caution should be taken to assess the quality of the water source for the infant formula. • Use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products • Delay of immunizations until immune reconstitution • Consideration for formula feeds in place of breast feeding until CMV status of mother is known. Caution should be taken to assess the quality of the water source for the infant formula. ## Surveillance Following a successful HSCT, the following should be routinely monitored: Growth Psychomotor development Complete blood counts Liver and renal function Immune status Donor and recipient chimerism Development of post-transplant complications, particularly chronic graft-versus-host disease, decreased bone density, pulmonary and cardiac function, and gonadal function Individuals with milder findings or those who have not undergone HSCT also need to be monitored for worsening of immune function with periodic assessment of clinical status and functional lymphocyte responsiveness. • Growth • Psychomotor development • Complete blood counts • Liver and renal function • Immune status • Donor and recipient chimerism • Development of post-transplant complications, particularly chronic graft-versus-host disease, decreased bone density, pulmonary and cardiac function, and gonadal function ## Agents/Circumstances to Avoid Individuals with Non-irradiated blood products Live virus vaccinations Contaminated water sources Exposure to fungus-enriched environments (e.g., construction sites, agricultural areas with active soil disruption, mulch, hay) • Non-irradiated blood products • Live virus vaccinations • Contaminated water sources • Exposure to fungus-enriched environments (e.g., construction sites, agricultural areas with active soil disruption, mulch, hay) ## Evaluation of Relatives at Risk Because the outcome of HSCT in children with If the If the pathogenic variants in the family are not known, CBC, quantitative immunoglobulins, and lymphocyte subsets and proliferation can be used to clarify the genetic status (immunologic status) of at-risk sibs. See • If the • If the pathogenic variants in the family are not known, CBC, quantitative immunoglobulins, and lymphocyte subsets and proliferation can be used to clarify the genetic status (immunologic status) of at-risk sibs. ## Pregnancy Management Appropriately screened blood products should be available, if needed, during the course of the pregnancy and delivery. ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes usually do not have CID-like symptoms. Parents of probands who did not appear to have clinical symptoms had intermediate expression levels compared to healthy controls [ At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see The offspring of an individual with The genetic status of the offspring will depend on the genetic status of the reproductive partner of the proband. If the reproductive partner is not affected and not a carrier, all offspring will be carriers. If the reproductive partner is a carrier of a If the reproductive partner is also affected, all offspring will be affected. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the An affected fetus does not require any specific management prior to delivery. Following delivery, early evaluation for potential HSCT should be performed because of the known benefit of early HSCT (see • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes usually do not have CID-like symptoms. Parents of probands who did not appear to have clinical symptoms had intermediate expression levels compared to healthy controls [ • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see • The offspring of an individual with • The genetic status of the offspring will depend on the genetic status of the reproductive partner of the proband. • If the reproductive partner is not affected and not a carrier, all offspring will be carriers. • If the reproductive partner is a carrier of a • If the reproductive partner is also affected, all offspring will be affected. • If the reproductive partner is not affected and not a carrier, all offspring will be carriers. • If the reproductive partner is a carrier of a • If the reproductive partner is also affected, all offspring will be affected. • If the reproductive partner is not affected and not a carrier, all offspring will be carriers. • If the reproductive partner is a carrier of a • If the reproductive partner is also affected, all offspring will be affected. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes usually do not have CID-like symptoms. Parents of probands who did not appear to have clinical symptoms had intermediate expression levels compared to healthy controls [ At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see The offspring of an individual with The genetic status of the offspring will depend on the genetic status of the reproductive partner of the proband. If the reproductive partner is not affected and not a carrier, all offspring will be carriers. If the reproductive partner is a carrier of a If the reproductive partner is also affected, all offspring will be affected. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes usually do not have CID-like symptoms. Parents of probands who did not appear to have clinical symptoms had intermediate expression levels compared to healthy controls [ • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see • The offspring of an individual with • The genetic status of the offspring will depend on the genetic status of the reproductive partner of the proband. • If the reproductive partner is not affected and not a carrier, all offspring will be carriers. • If the reproductive partner is a carrier of a • If the reproductive partner is also affected, all offspring will be affected. • If the reproductive partner is not affected and not a carrier, all offspring will be carriers. • If the reproductive partner is a carrier of a • If the reproductive partner is also affected, all offspring will be affected. • If the reproductive partner is not affected and not a carrier, all offspring will be carriers. • If the reproductive partner is a carrier of a • If the reproductive partner is also affected, all offspring will be affected. ## Carrier (Heterozygote) Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the An affected fetus does not require any specific management prior to delivery. Following delivery, early evaluation for potential HSCT should be performed because of the known benefit of early HSCT (see ## Resources United Kingdom Canada • • United Kingdom • • • • • Canada • • • • • • • • • • • ## Molecular Genetics ZAP70-Related Combined Immunodeficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ZAP70-Related Combined Immunodeficiency ( Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( Variant designation that does not conform to current naming conventions The variant is predicted to be silent (p.Gly355=) but has been demonstrated to result in a splicing defect [ The residual function seen in CD4 and CD8 cells in individuals lacking ZAP-70 may be related to increased expression of Syk in affected cells [ ## Chapter Notes Tara Capece, MPH; University of Pittsburgh (2009-2012)Marc Ikeda, MD; Children's Hospital of Pittsburgh (2012-2014)Allyson Larkin, MD; Children's Hospital of Pittsburgh (2012-2017)David Nash, MD; Children's Hospital of Pittsburgh (2009-2012)Stacy Lyn Rosenberg, MD; Children's Hospital of Pittsburgh (2014-2017)Mark Vander Lugt, MD (2017-present)Kelly Walkovich, MD (2017-present) 23 September 2021 (sw) Revision: nucleotide variant correction: c.1065C>T 8 June 2017 (sw) Comprehensive update posted live 25 September 2014 (me) Comprehensive update posted live 6 September 2012 (cd) Revision: prenatal diagnosis available clinically 1 March 2012 (me) Comprehensive update posted live 20 October 2009 (me) Review posted live 1 June 2009 (tc) Original submission • 23 September 2021 (sw) Revision: nucleotide variant correction: c.1065C>T • 8 June 2017 (sw) Comprehensive update posted live • 25 September 2014 (me) Comprehensive update posted live • 6 September 2012 (cd) Revision: prenatal diagnosis available clinically • 1 March 2012 (me) Comprehensive update posted live • 20 October 2009 (me) Review posted live • 1 June 2009 (tc) Original submission ## Author History Tara Capece, MPH; University of Pittsburgh (2009-2012)Marc Ikeda, MD; Children's Hospital of Pittsburgh (2012-2014)Allyson Larkin, MD; Children's Hospital of Pittsburgh (2012-2017)David Nash, MD; Children's Hospital of Pittsburgh (2009-2012)Stacy Lyn Rosenberg, MD; Children's Hospital of Pittsburgh (2014-2017)Mark Vander Lugt, MD (2017-present)Kelly Walkovich, MD (2017-present) ## Revision History 23 September 2021 (sw) Revision: nucleotide variant correction: c.1065C>T 8 June 2017 (sw) Comprehensive update posted live 25 September 2014 (me) Comprehensive update posted live 6 September 2012 (cd) Revision: prenatal diagnosis available clinically 1 March 2012 (me) Comprehensive update posted live 20 October 2009 (me) Review posted live 1 June 2009 (tc) Original submission • 23 September 2021 (sw) Revision: nucleotide variant correction: c.1065C>T • 8 June 2017 (sw) Comprehensive update posted live • 25 September 2014 (me) Comprehensive update posted live • 6 September 2012 (cd) Revision: prenatal diagnosis available clinically • 1 March 2012 (me) Comprehensive update posted live • 20 October 2009 (me) Review posted live • 1 June 2009 (tc) Original submission ## References ## Literature Cited	[ "O Adjali, G Marodon, M Steinberg, C Mongellaz, V Thomas-Vaslin, C Jacquet, N Taylor, D Klatzmann. 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Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency.. Eur J Pediatr 2009;168:87-93" ]	20/10/2009	8/6/2017	23/9/2021	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]

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