Waardenburg Syndrome Type I

Clinical 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 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 PAX3 pathogenic variant by molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Management of the hearing loss depends on its severity; cochlear implantation has been successfully used in individuals with WS1.

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 the possibly increased risk for neural tube defects associated 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 a de novo pathogenic variant. 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 a pregnancy 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.

Suggestive Findings

Waardenburg syndrome type I (WS1) should be suspected in individuals with several of the following major and minor criteria.

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 (See Note – W index.)
• Affected first-degree relative

Minor criteria

• 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)

Note – 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

Click here to download a tool (xlsx) for calculating the W index.

Minami et al [2019] reported that 61% of individuals with WS1 (based on W index >1.95) from a Japanese cohort had pathogenic variants identified in MITF, SOX10, or EDNRB rather than PAX3, suggesting that use of a W index >1.95 is not valid for all ethnicities.

Establishing the Diagnosis

The clinical diagnosis of WS1 is established in a proband with two major criteria or one major plus two minor criteria (see Suggestive Findings) as proposed by the Waardenburg Consortium [Farrer et al 1992].

Identification of a heterozygous pathogenic (or likely pathogenic) variant in PAX3 by molecular genetic testing (see Table 1) confirms the diagnosis if clinical features are inconclusive.

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 [Richards et al 2015]. Reference to "pathogenic variant" in this section is understood to include any likely pathogenic variant. (2) Identification of a heterozygous PAX3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

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 Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with hearing loss are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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 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.

Hearing loss. The hearing loss in WS1 is congenital, typically non-progressive, either unilateral or bilateral, and sensorineural. The most common type of hearing loss 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 WS1; it 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 WS1 may 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) have 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):

• Cleft lip and palate
• Spina bifida. This finding is not surprising given that WS1 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 family with WS1. Lemay et al [2015] reported a de novo PAX3 pathogenic nonsense variant in an individual with myelomeningocele and WS1.
• 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 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, which causes Waardenburg syndrome type III [Hoth et al 1993], and the p.Asn47Lys pathogenic variant, which is 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- or 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 (WS1 and Waardenburg syndrome type II [WS2] combined phenotype). Yang et al [2013] reported a family in which one parent had WS1 as the result of a heterozygous pathogenic variant in PAX3 and the other parent had WS2 (see Differential Diagnosis) as the result of 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

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 [Tamayo et al 2008].

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

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 successful in individuals with Waardenburg syndrome [Amirsalari et al 2012, de Sousa Andrade et al 2012, Koyama et al 2016, Fan et al 2022].

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 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 in the US and EU Clinical Trials Register in Europe 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 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 de novo pathogenic variant.
• 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 de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Kapur & Karam 1991, Chen et al 2018]. 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 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).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents.

• If a parent of the proband is affected and/or is known to have the PAX3 pathogenic variant identified in the proband, the risk to the sibs is 50%.
  Intrafamilial clinical variability is observed in WS1. The clinical manifestations in a sib who inherits a PAX3 pathogenic variant cannot be predicted by the phenotype in other affected family members and can range from mild or subclinical features through the classic phenotype of WS1, including deafness.
• If the proband has a known PAX3 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Kapur & Karam 1991, Chen et al 2018].
• 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 [Kapur & Karam 1991, Chen et al 2018].

Offspring of a proband

• Each child of an individual with WS1 has a 50% chance of inheriting the PAX3 pathogenic variant.
• The clinical manifestations in the offspring who inherit a PAX3 pathogenic variant cannot be predicted and can range from mild or subclinical features through the classic phenotype of WS1, including deafness.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have the PAX3 pathogenic variant, the parent's family members may be 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.

Family planning

• 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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PAX3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for WS1 are possible. Although such testing can determine whether the PAX3 pathogenic variant has been inherited, the results of such testing cannot be used to predict clinical manifestations or their severity.

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.

Molecular 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 paired box protein Pax-3 is an essential regulator of muscle and neural crest-derived cell types, including melanocytes. Analysis of PAX3 pathogenic variants observed in WS1 revealed varying ability of Pax-3 to bind to and regulate reporter genes fused to either the MITF or TYRP1 (encoding tyrosinase-related protein 1) promoters [Corry & Underhill 2005]. Hence, Pax-3 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 mutated Pax-3 protein is a key determinant in its dysfunction. Birrane et al [2009] further demonstrated that certain PAX3 pathogenic missense variants could destabilize the folding of the Pax-3 homeodomain, whereas others affect its interaction with DNA. Wu et al [2015] have examined the loading of PAX3 on mitotic chromosomes in zebra fish and suggest that mutated Pax-3 proteins have dominant-negative effects.

Mechanism of disease causation. Loss of function (haploinsufficiency)

Cancer and Benign Tumors

Somatic PAX3 variants have been observed in alveolar rhabdomyosarcoma. PAX3 can fuse with FKHR, 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 WS1.

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

• 20 October 2022 (sw) Comprehensive update posted live
• 4 May 2017 (sw) Revision: W index calculator tool added
• 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

Published Guidelines / Consensus Statements

• American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 10-11-22.
• 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 10-24-22.

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