Chapter 244

## Abstract

Abstract

1. 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.

2. 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.

3. 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.

4. Formal diagnostic criteria are shown in Table 244-2. Waardenburg syndrome is variable between and within families, and the penetrance of the major signs is tabulated in Table 244-3. 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.

5. 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. 244-4. 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.

6. 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 identifying the human genes.

7. Type 1 WS was mapped to 2q35 and type 2 to 3p12-p14.3 by family linkage studies, and positional candidate genes were identified. Type 3 WS patients are either heterozygous or homozygous for mutations in the type 1 gene. The three genes identified in type 4 were identified from mouse candidate genes with only limited human mapping work.

8. Type 1 WS is caused by haploinsufficiency due to loss-of-function mutations in the PAX3 gene. This gene encodes a transcription factor that is active in the early embryo, and the human mutations affect the two DNA-binding domains of the protein, the paired domain and homeodomain. Most mutations are private to particular families. Identifying a mutation does not allow the nature or severity of the syndrome in an individual to be predicted. Two homozygotes have been described. One was a fetus with lethal neural tube defects; the other was a child without a neural tube defect and with generally normal development apart from very severe type 3 WS.

9. MITF mutations are seen in about 10 percent of patients with type 2 WS. The MITF gene encodes a transcription factor that is believed to be a master gene for melanocyte differentiation. Most mutations cause loss of function, and the symptoms are caused by haploinsufficiency. In two families with MITF mutations, a more severe and consistent dominant albinism-deafness phenotype (Tietz-Smith syndrome) is probably the result of a dominant-negative effect.

10. Type 4 WS is very rare and heterogeneous. A few patients have been shown to be homozygous for loss-of-function mutations in the EDN3 or EDNRB genes, encoding endothelin-3 and its receptor. In heterozygotes, these mutations appear as low-penetrance Hirschsprung disease genes. A few patients have been found who are heterozygous for mutations in the SOX10 transcription-factor gene. In the mouse, homozygosity for SOX10 deficiency is lethal.

11. Identifying the genes and pathways involved in the different types of Waardenburg syndrome casts light on the normal processes of neural crest differentiation. Different downstream targets of PAX3 action show differential sensitivity to reduced dosage levels of PAX3 protein. PAX3 controls development of limb muscles through MyoD and Met; when this fails, the result is type 3 WS. PAX3 also controls the expression of MITF. MITF is probably the master gene for melanocyte development, which explains the very similar melanocyte defects in type 1 and type 2 WS.

12. The symptoms of Waardenburg syndrome are nonprogressive, and treatment is symptomatic. When a mutation has been defined, it is possible to predict prenatally whether a fetus will carry the mutation but not how severely it will be affected. Supplements of folate in pregnancy probably are advisable where the fetus is at risk for type 1 WS (to prevent neural tube defects).

*GENBANK accession numbers: human: PAX3-U12263, X15043, X15252, X15253, U12262, U12260, U12258, U12259 (exons 1-8, respectively); MITF-Z29678; EDN3-J05081; EDNRB-L06623; SOX10-AJ001183; mouse: Pax-3-X59358; Mi-U16322; Edn3-U32330; Ednrb-U32329; Sox10-AF047043. Mutation database: There is no specific Waardenburg mutation database at present. The Human Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php) finds PAX3, MITF, and EDN3 mutations queried with “Waardenburg.”

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