Clinical Guidance

PAX3. Genotype-phenotype correlations in PAX3 are not well established, except for the pathogenic variant, which causes Waardenburg syndrome type III , and the pathogenic variant, which is described in craniofacial-deafness-hand syndrome . 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 .

Source: GeneReviews — "Waardenburg Syndrome Type I"

Penetrance

Penetrance is likely almost complete.

Source: GeneReviews — "Waardenburg Syndrome Type I"

Diagnostic Criteria

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)

Source: GeneReviews — "Waardenburg Syndrome Type I"

Differential Diagnosis

Waardenburg syndrome type I (WS1) needs to be differentiated from other causes of congenital, non-progressive sensorineural hearing loss (see Hereditary Hearing Loss and Deafness 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 4. Comparison of Clinical Features in Waardenburg Syndrome Type I and Waardenburg Syndrome Type II Clinical Finding | % of Affected Persons WS1 | WS2

Management Guidelines

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 [, , , ].

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

Pregnancy Management

Folic acid supplementation in pregnancy has been recommended for w...

Source: GeneReviews — "Waardenburg Syndrome Type I"

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.

Source: GeneReviews — "Waardenburg Syndrome Type I"

Surveillance Guidelines

The hearing loss in WS1 is typically non-progressive. Hence, repeat audiogram would usually not be necessary.

Source: GeneReviews — "Waardenburg Syndrome Type I"