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Waardenburg Syndrome Type I

, MD
Co-Director, Center for Human Genetics, Inc
Director, Clinical Genetics
Senior Director, Molecular Genetics
Center for Human Genetics, Inc
Cambridge, Massachusetts

Initial Posting: ; Last Update: August 7, 2014.

Summary

Disease characteristics. 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.

Diagnosis/testing. The diagnosis of WS1 is established by clinical findings in most individuals: sensorineural hearing loss, pigmentary changes in the hair and eyes, and dystopia canthorum identified by calculation of the W index. PAX3 is the only gene in which pathogenic variants are known to cause WS1; molecular genetic testing by sequencing and deletion/duplication analysis of PAX3 detects more than 90% of pathogenic variants.

Management. Treatment of manifestations: Management of the hearing loss depends on its severity; choclear implantation has been successfully used in individuals with WS.

Evaluation of relatives at risk: If the family-specific PAX3 pathogenic variant is known, molecular genetic testing of relatives at risk allows for early screening of those at risk for hearing loss.

Pregnancy management: Folic acid supplementation in pregnancy is recommended for women at increased risk of having a child with WS1 because of possibly increased risk for neural tube defects in association with WS1.

Genetic counseling. 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 de novo mutation. Offspring of an individual with WS1 have a 50% chance of inheriting the pathogenic variant. If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing. Although this testing can determine whether the fetus has inherited the PAX3 pathogenic variant, it cannot determine the clinical manifestations or their severity.

Diagnosis

Clinical Diagnosis

Diagnostic criteria for Waardenburg syndrome type I (WS1) have been proposed by the Waardenburg Consortium [Farrer et al 1992]. An individual must have two major criteria or one major plus two minor criteria to be considered affected.

Major criteria

  • 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 *

Minor criteria

  • Skin hypopigmentation (congenital leukoderma)
  • Synophrys/medial eyebrow flare
  • Broad/high nasal root, prominent columella
  • Hypoplastic alae nasi
  • Premature gray hair (age <30 years)

* W index: The measurements necessary to calculate the W index (in mm) are as follows: inner canthal distance (a), interpupillary distance (b), and outer canthal distance (c).

Calculate X = (2a – (0.2119c + 3.909))/c
Calculate Y = (2a – (0.2479b + 3.909))/b
Calculate W = X + Y + a/b

A W index result >1.95 is abnormal. Previously, a W index of >2.07 was necessary to diagnose WS1 in an individual meeting all of the other diagnostic criteria. With molecular analysis, a family previously classified clinically as having WS2 based on the W index was found to have a PAX3 pathogenic variant and was reclassified as having WS1 [Tassabehji et al 1993]. Hence, the W index threshold was reduced to its current value of greater than 1.95.

Molecular Genetic Testing

Gene. PAX3 is the only gene in which pathogenic variants are known to cause Waardenburg syndrome type I (WS1).

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Waardenburg Syndrome Type I

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
PAX3Sequence analysis 2>90% 3
Deletion/duplication analysis 4~6% 5

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Pingault et al [2010], Milunsky [2011, unpublished data], Wildhardt et al [2013]

4. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Milunsky et al [2007]. Note: No duplications have been reported.

Testing Strategy

To confirm/establish the diagnosis in a proband. An algorithm for the diagnostic evaluation of an individual suspected of having Waardenburg syndrome has been proposed [Jamal & Milunsky 2014].

  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having Waardenburg syndrome type I is analysis of PAX3.
    • PAX3 sequence analysis is performed first.
    • Deletion/duplication analysis is recommended for those individuals who meet the clinical diagnostic criteria for WS1 and have no detectable pathogenic variant by PAX3 sequencing.
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having WS1 is use of a multi-gene panel (see Differential Diagnosis). These panels vary be methods used and genes included; thus, the ability of a panel to detect a causative mutation in any given individual with features of WS1 also varies.

Clinical Description

Natural History

The phenotype of Waardenburg syndrome type I (WS1) is variable even within a family. Liu et al [1995] summarized the penetrance (percentage) of clinical features of WS1 (see Table 2) in 60 individuals with WS1 and 210 affected individuals reported elsewhere in the literature. Newton [2002] reviewed the clinical features of the Waardenburg syndromes and more recently, Tamayo et al [2008] discussed their screening program for Waardenburg syndrome in Colombia, detailing the percentage of each clinical manifestation; percentages similar to those found in the Liu et al [1995] study were documented. However, ascertainment bias was evident, as all 95 affected individuals had hearing loss and were among the institutionalized deaf population in Colombia.

Table 2. Penetrance of Clinical Features of Waardenberg Syndrome Type I

Clinical Finding% of Affected Individuals
Sensorineural hearing loss47%-58%
Heterochromic irides15%-31%
Hypoplastic blue irides15%-18%
White forelock43%-48%
Early graying23%-38%
Leukoderma22%-36%
High nasal root52%-100%
Medial eyebrow flare63%-73%

Hearing loss. The hearing loss in WS1 is congenital, typically non-progressive, either unilateral or bilateral, and of the sensorineural type. The most common type in WS1 is profound bilateral hearing loss (>100 dB). The laterality of the hearing loss shows both inter- and intrafamilial variation.

Various temporal bone abnormalities have been identified in persons with WS1 and hearing loss [Madden et al 2003]. The temporal bone abnormalities include enlargement of the vestibular aqueduct and upper vestibule, narrowing of the internal auditory canal porus, and hypoplasia of the modiolus.

Hair color. The classic white forelock is the most common hair pigmentation anomaly seen in WS. The white forelock may be present at birth, or appear later, typically in the teen years. The white forelock may become normally pigmented over time. The white forelock is typically in the midline but the patch of white hair may also be elsewhere. In evaluating an individual with suspected WS1 without a white forelock, the individual should be asked whether the hair has been dyed. Red and black forelocks have also been described. The majority of individuals with WS1 have either a white forelock or early graying of scalp hair before age 30 years [Farrer et al 1992].

The hypopigmentation can also involve the eyebrows and eyelashes.

Ocular findings. Individuals with WS1may have a variety of ocular pigmentary manifestations. The most commonly observed are complete or segmental heterochromia or hypoplastic or brilliant blue irides. Iris and choroidal hypopigmentation (sector pattern more than diffuse pattern) has been described [Shields et al 2013]. Visual acuity does not differ from the general population.

Skin pigmentation. Congenital leukoderma (white skin patches) is frequently seen in WS1 on the face, trunk, or limbs. These areas of hypopigmentation frequently have hyperpigmented borders and may be associated with an adjacent white forelock.

Occasional findings identified in multiple families (although too few to determine the percentage occurrence in this disorder):

Otopathology. The otopathology of an individual with WS1 and a PAX3 pathogenic variant has been described [Merchant et al 2001]. The findings are consistent with defective melanocyte migration or function resulting in defective development of the stria vascularis leading to sensorineural hearing loss.

Genotype-Phenotype Correlations

PAX3. Genotype/phenotype correlations in PAX3 are not well established except for the p.Asn47His pathogenic variant in WS3 [Hoth et al 1993] and the p.Asn47Lys pathogenic variant described in craniofacial-deafness-hand syndrome [Asher et al 1996]. DeStefano et al [1998] found that the presence of pigmentary disturbances in individuals with WS1 correlated more with PAX3 pathogenic variants that delete the homeodomain than with missense or deletion pathogenic variants that include the paired domain. No genotype-phenotype correlation for the hearing loss in WS1 has been found.

PAX3 partial- / whole-gene deletions. There appears to be no discernable difference in the severity associated with whole- or partial-gene deletions and the clinical spectrum reported for small intragenic PAX3 pathogenic variants [Milunsky et al 2007].

PAX3 and MITF double heterozygotes (Waardenburg syndrome type I and Waardenburg syndrome type II [WS2] combined phenotype). Yang et al [2013] reported a family in which one parent had WS1 due to a heterozygous pathogenic variant in PAX3 and the other parent had WS2 (see Differential Diagnosis) due to a heterozygous pathogenic variant in MITF. Their child was heterozygous for both pathogenic variants and had significantly more pigmentary findings (i.e., white forelock, white eyebrows/eyelashes, and leukoderma) than either parent.

Penetrance

WS1 showed penetrance of at least 85% [Preus et al 1983] before the advent of molecular testing. Careful examination of individuals identified on the basis of pedigree analysis as having a PAX3 pathogenic variant usually reveals subtle findings (minor criteria). Hence, those individuals with an affected first-degree relative should be examined closely as the penetrance is likely almost complete.

Anticipation

WS1 does not exhibit anticipation.

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, comprising approximately 3% of congenitally deaf children [Tamayo et al 2008].

Differential Diagnosis

Waardenburg syndrome type I (WS1) needs to be differentiated from other causes of congenital, non-progressive sensorineural hearing loss (see Deafness and Hereditary Hearing Loss Overview) and from other forms of Waardenburg syndrome.

Waardenburg syndrome type II (WS2). WS1 is distinguished from WS2 by the presence in WS1 of lateral displacement of the inner canthi (dystopia canthorum). If the average W index across a family is less than 1.95, the diagnosis is WS2. Sensorineural hearing loss and heterochromia iridum are the two most characteristic features of WS2. Both are more common in WS2 than WS1. White forelock and leukoderma are both more common in WS1 than in WS2 (Table 3).

MITF pathogenic variants [Tassabehji et al 1994, Yang et al 2013] have been described in approximately 10%-20% of individuals with WS2. MITF pathogenic variants have also been identified in individuals with Tietz syndrome (deafness with uniform hypopigmentation) [Tassabehji et al 1995, Leger et al 2012].

SOX10 single nucleotide [Iso et al 2008] and deletion variants [Bondurand et al 2007, Brezo et al 2014] have been described in about 15% of individuals with WS2. Chen et al [2010] indicated that SOX10 pathogenic variants occurred with a frequency similar to MITF pathogenic variants in individuals with WS2 of Chinese ancestry. Temporal bone abnormalities (specifically bilateral agenesis or hypoplasia of the semicircular canals with a cochlear deformity and enlarged vestibule) are also found in individuals with SOX10 pathogenic variants [Elmaleh-Berges et al 2013]. Zhang et al [2012] and Chaoui et al [2011] performed functional analysis of SOX10 pathogenic variants. A frameshift mutation showed a dominant-negative effect on wild type SOX10, leading to faster protein decay, possibly resulting in a milder WS2 phenotype [Zhang et al 2012].

Table 3. Comparison of Clinical Features in WS1 and WS2

Clinical Finding% of Affected Individuals
WS1WS2
Sensorineural hearing loss47%-58%77%-80%
Heterochromic irides15%-31%42%-54%
Hypoplastic blue irides15%-18%3%-23%
White forelock43%-48%16%-23%
Early graying23%-38%14%-30%
Leukoderma22%-36%5%-12%
High nasal root52%-100%0%-14%
Medial eyebrow flare63%-73%7%-12%

Waardenburg syndrome type IV (WS4). Individuals having a rare combination of pigmentary abnormalities, hearing loss, and Hirschsprung disease have WS4 [Jan et al 2008] caused by pathogenic variants in one of the following genes: EDNRB, EDN3 [Ohtani et al 2006], or SOX10 [Bondurand et al 2007, Sznajer et al 2008].

Piebaldism. Piebaldism has some pigmentary features in common with Waardenburg syndrome. A white forelock is commonly seen along with absent pigmentation of the medial forehead and eyebrows. Absent pigmentation of the chest, abdomen, and limbs is also common. A characteristic feature is hyperpigmented borders surrounding the unpigmented areas. Heterochromia irides and sensorineural deafness are rarely described. This disorder has shown genetic heterogeneity with dominant loss of function mutations/whole-gene deletions described involving the KIT proto-oncogene. SNAI2 has also been implicated in the etiology of some cases of piebaldism [Sánchez-Martín et al 2003].

See Waardenburg syndrome: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Waardenburg syndrome type I (WS1), no evaluations other than audiology assessment are necessary.

Treatment of Manifestations

Management of the hearing loss associated with WS1 depends on its severity (see Deafness and Hereditary Hearing Loss Overview). Cochlear implantation has been successfully utilized in individuals with WS [Amirsalari et al 2011, de Sousa Andrade et al 2012]

Surveillance

The hearing loss in WS1 is typically non-progressive. Hence, repeating the audiogram would typically be unnecessary.

Evaluation of Relatives at Risk

If the family-specific PAX3 pathogenic variant is known, molecular genetic testing of relatives at risk allows for early screening of those at risk for hearing loss.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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 [Fleming & Copp 1998]; however, no human studies have addressed the ideal dose of folic acid to be used during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Waardenburg syndrome type I (WS1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority of probands have an affected parent.
  • A minority of probands do not have an affected parent and are presumed to have de novo mutation. The mutation rate has been estimated at 0.4 per 100,000 [Waardenburg 1951]. Jones et al [1975] found evidence of advanced paternal age effect in de novo mutation of WS1.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include examination for clinical manifestations of WS1 by assessing the facial features, calculating the W index, examining the skin and hair for hypopigmentation, and obtaining an audiogram. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a PAX3 pathogenic variant, the risk to the sibs is 50%.
  • If neither parent has clinical findings of WS1, the risk to sibs of a proband is low.
  • Germline mosaicism has been reported [Kapur & Karam 1991].

Offspring of a proband

  • Each child of an individual with WS1 has a 50% chance of inheriting the pathogenic variant.
  • The clinical manifestations in the offspring cannot be predicted and range from mild or subclinical features through the classic phenotype of WS1, including deafness.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has the disorder as a result of de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk 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 affected or at risk of being affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing. Although such testing can determine whether the fetus has inherited the PAX3 pathogenic variant, it cannot determine the clinical manifestations or their severity.

Prenatal testing is rarely requested, given the clinical variability even within families. In addition, prenatal testing for conditions associated with a good prognosis and not affecting intellect or life span is not common. Although most centers would consider prenatal testing to be the choice of the parents, discussion and examination of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Hereditary Hearing Loss Homepage
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Organization of Albinism and Hypopigmentation (NOAH)
    PO Box 959
    East Hampstead NH 03826-0959
    Phone: 800-473-2310 (toll-free); 603-887-2310
    Fax: 800-648-2310 (toll-free)
    Email: info@albinism.org
  • National Vitiligo Foundation, Inc.
    PO Box 23226
    Cincinnati OH 45223
    Phone: 513-541-3903
    Email: info@nvfi.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Waardenburg Syndrome Type I: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PAX32q36​.1Paired box protein Pax-3Deafness Gene Mutation Database (PAX3)PAX3

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Waardenburg Syndrome Type I (View All in OMIM)

193500WAARDENBURG SYNDROME, TYPE 1; WS1
606597PAIRED BOX GENE 3; PAX3

Molecular Genetic Pathogenesis

PAX3 is one of a family of nine human PAX genes coding for DNA-binding transcription factors that are expressed in the early embryo. The PAX genes are defined by the presence of a paired box (128-amino acid DNA-binding domain). In addition, PAX3 contains a homeobox [Birrane et al 2009].

Gene structure. PAX3 has a number of transcript variants that encode different isoforms (see Table A, Gene Symbol). PAX3 has ten exons, with the paired box in exons 2-4 and the homeobox in exons 5 and 6 [Birrane et al 2009].

Pathogenic allelic variants. Pathogenic variants within PAX3 or deletion of the entire gene result in haploinsufficiency of the encoded protein, paired box protein Pax-3. Pathogenic variants within PAX3 causing Waardenburg syndrome type I (WS1) were first described in 1992 [Baldwin et al 1992, Tassabehji et al 1992]. Multiple abnormal allelic variants in different populations [Chen et al 2010, Pingault et al 2010, Wang et al 2010, Matsunaga et al 2013] — including multiple pathogenic variants within PAX3 causing WS1, WS1 with spina bifida, WS3, and craniofacial-deafness-hand syndrome (CDHS) (OMIM 122880) — have been described (see Natural History, Differential Diagnosis, and Genotype-Phenotype Correlations).

Normal gene product. Bondurand et al [2000] have shown that an interaction among PAX3, SOX10, and MITF in the regulation of melanocyte development affects a molecular pathway leading to the auditory-pigmentary abnormalities seen in WS. Given the marked variability in expression of phenotypic features among family members having the same pathogenic variant, the potential role of modifier genes may be significant. Sato-Jin et al [2008] further added to this research by demonstrating that EDNRB expression was dependent on MITF. In addition, they found that EDN directly stimulates the expression of melanocytic pigmentation in an MITF-dependent fashion.

Abnormal gene product. The paired box protein Pax3 is an essential regulator of muscle and neural crest-derived cell types, including melanocytes. Analysis of PAX3 pathogenic variants observed in WS1 reveals distinct effects on the ability of PAX3 to regulate reporter genes fused to either the MITF or TRP-1 (tyrosinase-related protein 1) promoters [Corry & Underhill 2005]. Hence, Pax3 appears to be able to regulate target genes through alternate modes of DNA recognition that are dependent on the specific pathogenic variants. Corry et al [2008] showed that the subnuclear localization and altered mobility of the mutant Pax3 protein is a key determinant in its dysfunction. Birrane et al [2009] further demonstrated that certain PAX3 missense pathogenic variants could destabilize the folding of the Pax3 homeodomain, whereas others affect its interaction with DNA.

Cancer and Benign Tumors

Somatic PAX3 mutations have been observed in alveolar rhabdomyosarcoma. PAX3 can fuse with FKHR, this fusion creating a gain of function that results in alveolar rhabdomyosarcoma [Wang et al 2008]. Individuals with alveolar rhabdomyosarcoma resulting from this mechanism do not have WS.

References

Published Guidelines/Consensus Statements

  1. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 8-4-14.
  2. 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 online. 2002. Accessed 8-4-14.

Literature Cited

  1. Amirasalari S, Ajallouyean M, Saburi A, Haddadi Fard A, Abed M, Ghazavi Y. Cochlear implantation outcomes in children with Waardenburg syndrome. Eur Arch Otorhinolaryngol. 2012;269:2179–83. [PubMed: 22159916]
  2. Asher JH, Sommer A, Morell R, Friedman TB. Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome. Hum Mutat. 1996;7:30–5. [PubMed: 8664898]
  3. Baldwin CT, Hoth CF, Amos JA, da-Silva EO, Milunsky A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature. 1992;355:637–8. [PubMed: 1347149]
  4. Birrane G, Soni A, Ladias JA. Structural basis for DNA recognition by the human PAX3 homeodomain. Biochemistry. 2009;48:1148–55. [PubMed: 19199574]
  5. Black FO, Pesznecker SC, Allen K, Gianna C. A vestibular phenotype for Waardenburg syndrome? Otol Neurotol. 2001;22:188–94. [PubMed: 11300267]
  6. Bondurand N, Dastot-Le Moal F, Stanchina L, Collot N, Baral V, Marlin S, Attie-Bitach T. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4. Am J Hum Genet. 2007;81:1169–85. [PMC free article: PMC2276340] [PubMed: 17999358]
  7. Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Caignec CL, Wegner M, Goossens M. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet. 2000;9:1907–17. [PubMed: 10942418]
  8. Brezo J, Lam C, Vilain E, Quintero-Rivera F. Phenotypic variability in Waardenburg syndrome resulting from a 22q12.3-q13.1 microdeletion involving SOX10. Am J Med Genet Part A. 2013;164A:1512–1519. [PubMed: 24715709]
  9. Chaoui A, Watanabe Y, Touraine R, Baral V, Goossens M, Pingault V, Bondurand N. Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome. Hum Mut. 2011;32:1436–49. [PubMed: 21898658]
  10. Chen H, Jiang L, Xie Z, Mei L, He C, Hu Z, Xia K, Feng Y. Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome. Biochem Biophys Res Commun. 2010;397:70–4. [PubMed: 20478267]
  11. Corry GN, Hendzel MJ, Underhill DA. Subnuclear localization and mobility are key indicators of PAX3 dysfunction in Waardenburg syndrome. Hum Mol Genet. 2008;17:1825–37. [PubMed: 18325909]
  12. Corry GN, Underhill DA. Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations. Pigment Cell Res. 2005;18:427–38. [PubMed: 16280008]
  13. da-Silva EO. Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review. Am J Med Genet. 1991;40:65–74. [PubMed: 1887852]
  14. de Sousa Andrade SM, Monteiro AR, Martins JH, Alves MC, Santos Silva LF, Quadros JM, Ribeiro CA. Cochlear implant rehabilitation outcomes in Waardenburg syndrome children. Int J Pediatr Otorhinolaryngol. 2012;76:1375–8. [PubMed: 22784507]
  15. DeStefano AL, Cupples LA, Arnos KS, Asher JH, Baldwin CT, Blanton S, Carey ML, da Silva EO, Friedman TB, Greenberg J, Lalwani AK, Milunsky A, Nance WE, Pandya A, Ramesar RS, Read AP, Tassabejhi M, Wilcox ER, Farrer LA. Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations. Hum Genet. 1998;102:499–506. [PubMed: 9654197]
  16. Elmaleh-Berges M, Baumann C, Noel-Petroff N, Sekkal A, Couloigner V, Devriendt K, Wilson M, Marlin S, Sebag G, Pingault V. Spectrum of temporal bone abnormalities in patients with Waardenburg syndrome and SOX10 mutations. AJNR Am J Neuroradiol. 2013;34(6):1257–63. [PubMed: 23237859]
  17. Farrer LA, Grundfast KM, Amos J, Arnos KS, Asher JH, Beighton P, Diehl SR, Fex J, Foy C, Friedman TB. et al. 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. [PMC free article: PMC1682585] [PubMed: 1349198]
  18. Fleming A, Copp AJ. Embryonic folate metabolism and mouse neural tube defects. Science. 1998;280:2107–9. [PubMed: 9641914]
  19. Gad A, Laurino M, Maravilla KR, Matsushita M, Raskind WH. Sensorineural deafness, distinctive facial features, and abnormal cranial bones: a new variant of Waardenburg syndrome? Am J Med Genet A. 2008;146A:1880–5. [PMC free article: PMC2533638] [PubMed: 18553554]
  20. Hoth CF, Milunsky A, Lipsky N, Sheffer R, Clarren SK, Baldwin CT. 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. [PMC free article: PMC1682157] [PubMed: 8447316]
  21. Iso M, Fukami M, Horikawa R, Azuma N, Kawashiro N, Ogata T. SOX10 mutation in Waardenburg syndrome type II. Am J Med Genet A. 2008;146A:2162–3. [PubMed: 18627047]
  22. Jamal S, Milunsky JM. Waardenburg syndrome. In: Murray MF, Babyatsky MW, Giovanni MA, eds. Clinical Genomics: Practical Applications in Adult Patient Care. New York: McGraw Hill Education. 2014:752-7.
  23. Jan IA, Stroedter L, Haq AU, Din ZU. Association of Shah-Waardenburgh syndrome: a review of 6 cases. J Pediatr Surg. 2008;43:744–7. [PubMed: 18405726]
  24. Jones KL, Smith DW, Harvey MA, Hall BD, Quan L. Older paternal age and fresh gene mutation: data on additional disorders. J Pediatr. 1975;86:84–8. [PubMed: 1110452]
  25. Kapur S, Karam S. Germ-line mosaicism in Waardenburg syndrome. Clin Genet. 1991;39:194–8. [PubMed: 2036740]
  26. Kujat A, Veith VP, Faber R, Froster UG. 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. [PubMed: 17139175]
  27. Leger S, Balguerie X, Goldenberg A, Drouin-Garraud V, Cabot A, Amstutz-Montadert I, Young P, Joly P, Bodereau V, Holder-Espinasse M, Jamieson RV, Krause A, Chen H, Baumann C, Nunes L, Dollfus H, Goossens M, Pingault V. Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes. Eur J Hum Genet. 2012;20:584–7. [PMC free article: PMC3330215] [PubMed: 22258527]
  28. Liu XZ, Newton VE, Read AP. Waardenburg syndrome type II: phenotypic findings and diagnostic criteria. Am J Med Genet. 1995;55:95–100. [PubMed: 7702105]
  29. Lu W, Zhu H, Wen S, Laurent C, Shaw GM, Lammer EJ, Finnell RH. Screening for novel PAX3 polymorphisms and risks of spina bifida. Birth Defects Res A Clin Mol Teratol. 2007;79:45–9. [PubMed: 17149730]
  30. Madden C, Halsted MJ, Hopkin RJ, Choo DI, Benton C, Greinwald JH. Temporal bone abnormalities associated with hearing loss in Waardenburg syndrome. Laryngoscope. 2003;113:2035–41. [PubMed: 14603070]
  31. Matsunaga T, Mutai H, Namba K, Morita N, Masuda S. Genetic analysis of PAX3 for diagnosis of Waardenburg syndrome type I. Acta Otolaryngol. 2013;133:345–51. [PubMed: 23163891]
  32. Merchant SN, McKenna MJ, Baldwin CT, Milunsky A, Nadol JB. Otopathology in a case of type I Waardenburg's syndrome. Ann Otol Rhinol Laryngol. 2001;110:875–82. [PubMed: 11558766]
  33. Milunsky JM, Maher TA, Ito M, Milunsky A. The value of MLPA in Waardenburg syndrome. Genet Test. 2007;11:179–82. [PubMed: 17627390]
  34. Newton VE. Clinical features of the Waardenburg syndromes. Adv Otorhinolaryngol. 2002;61:201–8. [PubMed: 12408085]
  35. Ohtani S, Skinkai Y, Horibe A, Katayama K, Tsuji T, Matsushima Y, Tachibana M, Kunieda T. A deletion in the endothelin-B receptor gene is responsible for the Waardenburg syndrome-like phenotypes of WS4 mice. Exp Anim. 2006;55:491–5. [PubMed: 17090968]
  36. Pardono E, van Bever Y, van den Ende J, Havrenne PC, Iughetti P, Maestrelli SR, Costa F O, Richieri-Costa A, Frota-Pessoa O, Otto PA. Waardenburg syndrome: clinical differentiation between types I and II. Am J Med Genet A. 2003;117A:223–35. [PubMed: 12599185]
  37. Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010;31:391–406. [PubMed: 20127975]
  38. Preus M, Linstrom C, Polomeno RC, Milot J. Waardenburg syndrome--penetrance of major signs. Am J Med Genet. 1983;15:383–8. [PubMed: 6881207]
  39. Sánchez-Martín M, Pérez-Losada J, Rodríguez-García A, González-Sánchez B, Korf BR, Kuster W, Moss C, Spritz RA, Sánchez-García I. Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am J Med Genet A. 2003;122A:125–32. [PubMed: 12955764]
  40. Sato-Jin K, Nishimura EK, Akasaka E, Huber W, Nakano H, Miller A, Du J, Wu M, Hanada K, Sawamura D, Fisher DE, Imokawa G. Epistatic connections between micropthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders. FASEB J. 2008;22:1155–68. [PubMed: 18039926]
  41. Shields CL, Nickerson SJ, Al-Dahmash S, Shields JA. Waardenburg syndrome: iris and choroidal hypopigmentation: findings on anterior and posterior segment imaging. JAMA Ophthalmol. 2013;131:1167–73. [PubMed: 23868078]
  42. Sommer A, Bartholomew DW. Craniofacial-deafness-hand syndrome revisited. Am J Med Genet A. 2003;123A:91–4. [PubMed: 14556253]
  43. Sznajer Y, Coldea C, Meire F, Delpierre I, Sekhara T, Touraine RL. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease. Am J Med Genet A. 2008;146A:1038–41. [PubMed: 18348267]
  44. Tamayo ML, Gelvez N, Rodriguez M, Florez S, Varon C, Medina D, Bernal JE. Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability. Am J Med Genet A. 2008;146A:1026–31. [PubMed: 18241065]
  45. Tassabehji M, Newton VE, Liu XZ, Brady A, Donnai D, Krajewska-Walasek M, Murday V, Norman A, Obersztyn E, Reardon W. et al. The mutational spectrum in Waardenburg syndrome. Hum Mol Genet. 1995;4:2131–7. [PubMed: 8589691]
  46. Tassabehji M, Read AP, Newton VE, Patton M, Gruss P, Harris R, Strachan T. Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2. Nat Genet. 1993;3:26–30. [PubMed: 8490648]
  47. Tassabehji M, Newton VE, Read AP. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet. 1994;8:251–5. [PubMed: 7874167]
  48. Tassabehji M, Read AP, Newton VE, Harris R, Balling R, Gruss P, Strachan T. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature. 1992;355:635–6. [PubMed: 1347148]
  49. Waardenburg PJ. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet. 1951;3:195–253. [PMC free article: PMC1716407] [PubMed: 14902764]
  50. Wang J, Li S, Xiao X, Wang P, Guo X, Zhang Q. PAX3 mutations and clinical characteristics in Chinese patients with Waardenburg syndrome type 1. Mol Vis. 2010;16:1146–53. [PMC free article: PMC2901192] [PubMed: 20664692]
  51. Wang W, Fang WH, Krupinski J, Kumar S, Slevin M, Kumar P. Pax genes in embryogenesis and oncogenesis. J Cell Mol Med. 2008;12:2281–94. [PubMed: 18627422]
  52. Wildhardt G, Zirn B, Graul-Neumann LM, Wechtenbruch J, Suckfull M, Buske A, Bohring A, Kubisch C, Vogt, S, Strobl-Wildemann G, Greally M, Bartsch O, Steinberger D (2013) Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. BMJ Open 3(3). pii:e001917. [PMC free article: PMC3612789] [PubMed: 23512835]
  53. Wollnik B, Tukel T, Uyguner O, Ghanbari A, Kayserili H, Emiroglu M, Yuksel-Apak M. Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. Am J Med Genet A. 2003;122A:42–5. [PubMed: 12949970]
  54. Yang S, Dai P, Liu X, Kang D, Zhang X, Yang W, Zhou C, Yang S, Yuan H. Genetic and phenotypic heterogeneity in Chinese patients with Waardenburg syndrome type II. PLoS One. 2013;8:e77149. [PMC free article: PMC3806753] [PubMed: 24194866]
  55. Yang T, Li X, Huang Q, Li L, Chai Y, Sun L, Wang X, Zhu Y, Wang Z, Huang Z, Li Y, Wu H. Double heterozygous mutations of MITF and PAX3 result in Waardenburg syndrome with increased penetrance in pigmentary defects. Clin Genet. 2013;83:78–82. [PubMed: 22320238]
  56. Zhang H, Chen H, Luo H, An J, Sun L, Mei L, He C, Jiang L, Jiang W, Xia K, Li JD, Feng Y. Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II. Hum Genet. 2012;131:491–503. [PubMed: 21965087]

Suggested Reading

  1. Vicente-Duenas C, Bermejo-Rodriguez C, Perez-Caro M, Gonzalez-Herrero I, Sanchez-Martin M, Sanchez-Garcia I. Waardenburg syndrome (WS). Atlas of Genetics and Cytogenetics Oncology and Haematology. Available at atlasgeneticsoncology.org. 2005. Accessed 8-1-14.

Chapter Notes

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 PAX3, when he was involved in gene mapping of several families with WS1.

Revision History

  • 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 to live Web site
  • 22 October 2003 (me) Comprehensive update posted to live Web site
  • 30 July 2001 (me) Review posted to live Web site
  • 12 February 2001 (jm) Original submission
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