Waardenburg Syndrome

Definition and epidemiology

Waardenburg syndrome is an inherited condition in which sensorineural hearing loss occurs together with pigmentary differences of the hair, skin and eyes. The features arise from disturbed number, migration or function of melanocytes derived from the neural crest during development (Read and Newton, 1997). The reported incidence is 1 in 212,000, but because the clinical picture varies so widely and many cases go unrecognised, the true population frequency is estimated at about 1 in 42,000; the syndrome accounts for 2-5% of people with congenital hearing loss (Song et al., 2016).

Four clinical types are described. Type 1 has lateral displacement of the inner corners of the eyes (dystopia canthorum); type 2 does not. Type 3 (Klein-Waardenburg) adds upper limb muscle and joint anomalies to type 1 features, and type 4 (Shah-Waardenburg) is defined by associated Hirschsprung disease (Read and Newton, 1997; Milunsky, 2022).

Diagnosis of type 1 is based on the Waardenburg Consortium criteria. The major criteria are congenital sensorineural hearing loss, a white forelock or hair hypopigmentation, iris pigment anomalies (complete or segmental heterochromia, brilliant blue irides), dystopia canthorum (W index > 1.95) and an affected first-degree relative. Minor criteria are congenital leukoderma, synophrys or medial eyebrow flare, a broad or high nasal root, underdeveloped alae nasi and greying before the age of 30. Two major criteria, or one major and two minor criteria, establish the diagnosis (Milunsky, 2022).

Symptoms and signs

Pigmentary signs vary greatly between individuals and within families. In type 1 a white forelock has been reported in about 43-48%, greying before 30 in 23-38%, heterochromia in 15-31%, hypoplastic blue irides in 15-18% and depigmented skin patches (leukoderma) in 22-36%; medial eyebrow flare, at 63-73%, is the commonest minor sign (Milunsky, 2022). A white forelock can be present at birth and fade, or be hidden with hair dye, so parents’ childhood photographs help with diagnosis.

Dystopia canthorum from an increased inner canthal distance is prominent in types 1 and 3. Type 3 brings upper limb muscle and joint hypoplasia, joint contractures, carpal bone fusion or syndactyly. In type 4, Hirschsprung disease can cause delayed passage of the first stool, abdominal distension and vomiting in the newborn. Neurological features involving the peripheral and central nervous system have also been reported in SOX10-related cases (Pingault et al., 2010).

The hearing loss is sensorineural and mostly congenital: onset is at or before four years in 90.3% of cases. It is bilateral in 89.4%, most often profound and stable in 91.9%. There is no typical audiogram shape, and about 10% of cases have unilateral loss (Song et al., 2016).

Causes and risk factors

Types 1 and 3 are associated with variants in PAX3. MITF, SOX10, SNAI2 and KITLG are responsible in type 2, and EDNRB, EDN3 and SOX10 in type 4 (Pingault et al., 2010; Milunsky, 2022). These genes belong to a shared network that controls the development and migration of melanocytes from neural crest cells. Melanocytes are found not only in the hair, skin and iris but also in the stria vascularis of the cochlea, where they are needed to generate the endocochlear potential; their absence causes sensorineural loss (Read and Newton, 1997).

PAX3-, MITF- and SOX10-related forms are inherited in an autosomal dominant way, and SOX10 variants often arise de novo. In type 4, EDNRB and EDN3 variants are mostly autosomal recessive, and heterozygous carriers may show isolated features (Pingault et al., 2010). Type 3 due to a homozygous PAX3 variant has been described in a consanguineous family (Milunsky, 2022). Expressivity is highly variable: within one family a person may have only a white forelock while a relative has profound hearing loss.

The frequency of hearing loss also varies by gene: it has been reported in 52.5% of PAX3-related, about 90% of MITF-related and 96% of SOX10-related cases (Song et al., 2016). The differential diagnosis includes non-syndromic hearing loss and other genetic causes without pigmentary signs.

Audiological and clinical assessment

The congenital and often profound loss is picked up early through newborn hearing screening followed by diagnostic ABR. Audiological findings are consistent with a cochlear sensorineural loss, and the middle ear is normal. In a child with pigmentary signs and normal hearing, it is worth remembering that the loss may be unilateral or may progress.

• Pure-tone and behavioural audiometry: sensorineural loss, usually bilateral and profound; there is no typical audiogram shape, and unilateral or asymmetrical cases occur (Song et al., 2016).
• Tympanometry and acoustic reflexes: the tympanogram is normal; reflexes are elevated or absent according to the degree of loss.
• OAEs and ABR: with severe to profound loss OAEs are absent and the ABR shows no response or a clearly raised threshold.
• Imaging: temporal bone CT and MRI are needed before a CI. In SOX10-related cases, semicircular canal agenesis or hypoplasia, an enlarged or malformed vestibule and, in some cases, cochlear nerve aplasia have been reported (Song et al., 2016); see inner ear malformations for details.
• Vestibular assessment: in a child with semicircular canal anomalies or delayed motor milestones, vestibular function can be assessed with the video head impulse test (vHIT), caloric testing and vestibular evoked myogenic potentials (VEMP).
• Genetic testing: a panel including PAX3, MITF, SOX10, EDNRB, EDN3 and SNAI2 clarifies the type and mode of inheritance.

The W index is used to document dystopia canthorum objectively. The inner canthal distance (a), interpupillary distance (b) and outer canthal distance (c) are measured in millimetres; X = (2a − (0.2119c + 3.909))/c, Y = (2a − (0.2479b + 3.909))/b and W = X + Y + a/b. A value above 1.95 supports dystopia canthorum. In a Japanese cohort, 61% of people with type 1 who exceeded this cut-off had MITF, SOX10 or EDNRB variants rather than PAX3, showing that the cut-off may not apply equally to every ethnic group (Milunsky, 2022).

Treatment and audiological rehabilitation

Management is planned according to the degree of hearing loss. Mild to moderate loss calls for early hearing aid fitting verified with real-ear measurement; a CI is considered for severe to profound loss. In a meta-analysis of nine studies including 132 people with Waardenburg syndrome and 815 controls, categories of auditory performance (CAP), speech intelligibility rating (SIR) and PEACH scores after implantation did not differ from those of CI users without the syndrome (Qin et al., 2024). The fact that most studies came from a single country and that type and genotype data were missing limits this conclusion.

Inner ear and cochlear nerve anomalies are common in SOX10-related cases, so detailed imaging is needed before implantation; cochlear nerve aplasia can limit the benefit of an implant. For unilateral loss the options include a hearing aid, a CROS system and a CI; in Türkiye a cochlear implant for unilateral profound loss is not reimbursed by the national health insurer (SGK), and the options are discussed with the physician and audiologist. For the general approach, see unilateral hearing loss.

In type 4, Hirschsprung disease is treated by paediatric surgeons. Depigmented skin should be protected from the sun, and eye findings followed by an ophthalmologist. Folic acid is recommended for pregnant women at risk of having a child with type 1, because of a possible link with neural tube defects; the right dose has not been established in human studies and the decision rests with the physician (Milunsky, 2022).

Impact on quality of life and advice

With early diagnosis and appropriate amplification or a CI, most children develop spoken communication. Although the loss is usually stable, progression has been reported in SOX10-related cases (Song et al., 2016), so regular audiological follow-up should continue. For children with unilateral loss, a remote microphone system and suitable seating are advised for noisy classrooms.

A white forelock, early greying and heterochromia are usually not a health problem, but they can be a source of concern about appearance for some people. Hair dye and cosmetic options are a personal choice. Depigmented skin burns more easily, so sunscreen is important.

In the autosomal dominant types each child of an affected person has a 50% chance of inheriting the variant, but the pigmentary signs do not predict whether a child will have hearing loss. Every baby in a family with Waardenburg syndrome should therefore have hearing confirmed with diagnostic tests beyond the newborn screen, and the family should be offered genetic counselling.