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.

Molecular Genetic Testing

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

Clinical testing

• Sequence analysis. More than 90% of individuals who meet the clinical diagnostic criteria for Waardenburg syndrome type I have identifiable mutations in PAX3 [Pingault et al 2010; Milunsky 2011, unpublished data].
• Deletion/duplication analysis*. Partial and whole PAX3 deletions may account for approximately 6% of cases [Milunsky et al 2007]. No duplications have been reported.
  
  *Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Diseases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establishthe diagnosis in a proband

• PAX3 sequencing is performed first.
• Deletion testing is recommended for those individuals who meet the clinical diagnostic criteria for WS1 and have no detectable mutation by PAX3 sequencing.

Predictive testing for at-risk asymptomatic family members for clarification of genetic status requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Germline PAX3 mutations also cause the following:

• Waardenburg syndrome type 3 (WS3) (Klein-Waardenburg syndrome), is characterized by a combination of typical WS1 features and hypoplasia or contractures of the limb muscles or joints, carpal bone fusion, or syndactyly [Hoth et al 1993]. In a consanguineous Turkish family, both parents who are heterozygous for the PAX3 Tyr90His mutation have WS1; their child who is homozygous for the Tyr90His mutation has WS3 [Wollnik et al 2003].
• Craniofacial-deafness-hand syndrome (CDHS) [OMIM 122880] is characterized by a flat facial profile, ocular hypertelorism, hypoplastic nose with slit-like nares, and sensorineural hearing loss. X-ray findings include a small maxilla, absent or small nasal bones, and ulnar deviation of the hands [Sommer & Bartholomew 2003]. Asher et al [1996] identified a missense mutation in PAX3 in individuals with this disorder. This disorder is apparently distinct from both WS1 and WS3. Gad et al [2008] reported a woman who shares some, but not all features of WS3 and CDHS, and who also has abnormal cranial bones (hypoplastic sinuses and small cochlea). Whereas no sequence alteration or whole-gene deletion of PAX3 was found, partial-gene deletions were not ruled out. The authors suggest genetic heterogeneity even within the CDHS subtype.

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

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. Similar percentages were documented compared to the Liu et al [1995] study. However, ascertainment bias was evident, as all 95 affected individuals had hearing loss and were among the institutionalized deaf population in Colombia.

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 is variable among and within families.

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.

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):

• Cleft lip and palate
• Spina bifida [da-Silva 1991], a finding that is not surprising given that WS is considered a neurocristopathy with PAX3 being expressed in the neural crest:
  • Kujat et al [2007] described the prenatal diagnosis of spina bifida in a WS1 family.
  • Studies by Lu et al [2007] indicated that PAX3 SNPs were not strong risk factors for spina bifida [Kujat et al 2007].
• Vestibular symptoms including vertigo, dizziness, and balance difficulties, even without hearing loss [Black et al 2001]

Otopathology. The otopathology of an individual with WS1 and a PAX3 mutation 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 Asn47His mutation in WS3 [Hoth et al 1993] and the Asn47Lys mutation 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 mutations that delete the homeodomain than with missense mutations or deletions 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 severity between whole-gene/partial-gene deletions and the clinical spectrum reported for PAX3 mutations [Milunsky et al 2007].

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 mutation 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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).

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 mutation 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].

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.

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 a 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 mutations for WS1.
• Recommendations for the evaluation of parents of a proband with an 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 mutation, 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 disease-causing mutation.
• 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 an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Although this testing can determine whether the fetus has inherited the PAX3 mutation, it cannot determine the clinical manifestations or their severity.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 disease-causing mutation has been identified.

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].

Normal allelic variants. PAX3 has ten exons [Read 2001], with the paired box in exons 2-4 and the homeobox in exons 5 and 6.

Pathologic allelic variants. Mutations within the gene or deletion of the entire gene result in haploinsufficiency of PAX3. Mutations within PAX3 causing WS1 were first described in 1992 [Baldwin et al 1992, Tassabehji et al 1992]. Multiple abnormal allelic variants in different populations [Yang et al 2007, Chen et al 2010, Pingault et al 2010, Wang et al 2010] — including multiple mutations within PAX3 causing WS1, WS1 with spina bifida, WS3, and craniofacial-deafness-hand syndrome (CDHS) [OMIM 122880] — have been described.

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 mutation, 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 mutations 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 disease-causing mutations. Corry et al [2008] showed that the subnuclear localization and altered mobility of the PAX3 protein when the gene is mutated is a key determinant in its dysfunction. Birrane et al [2009] further demonstrated that certain PAX3 missense mutations could destabilize the folding of the PAX3 homeodomain, whereas others affect its interaction with DNA.

Published Guidelines/Consensus Statements

1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel (pdf). Available online. 2002. Accessed 12-10-12. [PMC free article: PMC3110944] [PubMed: 12180152]
2. American College of Medical Genetics (2000) Statement on universal newborn hearing screening. Available online. 2000. Accessed 12-10-12.

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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 12-10-12.

Author Notes

Dr. Milunsky is a Professor in the Department of Pediatrics, Genetics and Genomics at Boston University School of Medicine. He has directed a deafness clinic in conjunction with Otolaryngology at Boston University for several years. His interest in Waardenburg syndrome predates the identification of PAX3, when he was involved in gene mapping of several families with WS1. He is Senior Director of Molecular Genetics, Medical Director of Boston University's Genetic Counseling Training Program and Co-Director of the Center for Human Genetics.

Revision History

• 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