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ABSTRACT

  • Waardenburg syndrome is a clinical label attached to a heterogeneous set of auditory-pigmentary syndromes, the primary cause of which is a patchy lack of melanocytes in the hair, eyes, skin, and stria vascularis. The syndrome is classified into four subtypes. Type 1, with dystopia canthorum, is caused by mutations in the PAX3 gene (MIM 193500). Type 2, without dystopia, is heterogeneous; a proportion is caused by changes in the MITF gene (MIM 193510). Type 3, resembling type 1 but with additional contractures or hypoplasia of the upper limb joints and muscles, is a rare variant presentation of type 1 (MIM 148820). Type 4, with Hirschsprung disease, is heterogeneous, being caused by mutations in the EDN3, EDNRB, SOX10, or other unidentified genes (MIM 277580). All forms are inherited as autosomal dominant characters, except for the type 4, caused by mutations in EDN3 or EDNRB, which are recessive. The hearing loss in all forms is congenital, sensorineural, and nonprogressive. There are no specific treatments, and management is symptomatic.

  • The classic description of the syndrome was given by Waardenburg in 1951; the name of David Klein is sometimes attached to the syndrome in recognition of his description of a severely affected patient at about the same time. The prevalence is about 1 in 40,000, or 1 to 2 percent of congenitally deaf people.

  • Waardenburg syndrome is an example of an auditory-pigmentary syndrome. Related syndromes are known in many mammals and particularly in mice. The mouse mutants fall into the cochleosaccular group of Steel, which has as immediate cause a physical absence of melanocytes from areas of the hair, eye, skin, and stria vascularis. Without melanocytes in the stria vascularis, no endocochlear potential is generated, and there is no hearing. All melanocytes except those of the retinal pigment epithelium derive from the embryonic neural crest. Waardenburg syndrome types 1, 3, and 4 are neurocristopathies, affecting more than one neural crest derivative. Type 2 appears to be melanocyte-specific.

  • Formal diagnostic criteria are shown in Table 294-2. Waardenburg syndrome is variable between and within families, and the penetrance of the major signs is tabulated in Table 294-3. Many complications have been described, but most are of uncertain status. Cleft lip or palate and neural tube defects are rare complications of type 1 WS.

  • Dystopia canthorum must be established by measuring the inner canthal, interpupillary, and outer canthal distances and calculating the W index according to the formula in Fig. 294-4. If the W value, averaged across all affected family members, is greater than 1.95, a diagnosis of type 1 WS may be made. Type 1 WS is a distinctive and fairly homogeneous entity; none of the other types forms a single distinct genetic entity.

  • Mouse models exist for each subtype of Waardenburg syndrome: Splotch for type 1 and type 3, microphthalmia for type 2, and piebald-lethal, lethal-spotted, and Dominant megacolon for type 4. These models were important aids to ...

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