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Waardenburg syndrome

MIM.277580

Thursday 9 February 2006

Definition: The features of Waardenburg syndrome are wide bridge of the nose owing to lateral displacement of the inner canthus of each eye, pigmentary disturbance (frontal white blaze of hair, heterochromia iridis, white eye lashes, leukoderma), and cochlear deafness. The severity varies widely and some affected persons escape deafness.

Waardenburg syndrome is an autosomal dominant condition. It is by far the most frequent condition combining pigmentary anomalies and sensorineural deafness (1/50 000 live births and 2–5% of all congenital deafness), resulting from the absence of melanocytes of the skin and the stria vascularis of the cochlea. The Waardenburg syndromes (WS) account for approximately 2% of congenital sensorineural deafness.

WS is clinically and genetically heterogeneous (WS1, WS2A, WS2B, WS2C, WS2D, WS3, WS4).

Multiple genes have been implicated in WS, and mutations in some genes can cause more than one WS subtype. In addition to eye, hair, and skin pigmentary abnormalities, dystopia canthorum and broad nasal bridge are seen in WS type 1 (WS1).

Mutations in the PAX3 gene are responsible for the condition in the majority of these patients. In addition, mutations in PAX3 have been found in WS type 3 (WS3) that is distinguished by musculoskeletal abnormalities, and in a family with a rare subtype of WS, craniofacial-deafness-hand syndrome (CDHS), characterized by dysmorphic facial features, hand abnormalities, and absent or hypoplastic nasal and wrist bones.

Hirschsprung disease association

The combination of Hirschsprung disease with WS defines the WS4 type (Shah-Waardenburg syndrome (MIM.277580), a genetically heterogeneous condition.

Indeed, homozygous mutations of the endothelin pathway and heterozygous SOX10 mutations have been identified in WS4 patients.

Patients carrying a SOX10 mutation may also present with CNS involvement including seizures, ataxia, and demyelinating peripheral and central neuropathies and WS2.

Related syndromes associating pigmentary anomalies and Hirschsprung disease include:

- Yemenite deaf-blind hypopigmentation syndrome (MIM.601706), a SOX10 mutation having been reported in one of these families;
- Black Locks-Albinism-Deafness syndrome (BADS) (MIM.227010) with total colonic aganglionosis-Hirschsprung disease in one case;
- aganglionic megacolon associated with familial piebaldism (MIM.172800)
- Hirschsprung disease and profound congenital deafness but with no other WS features has also been reported.

Type

- Waardenburg syndrome type 1 (WS1) (PAX3 at 2q35) (MIM.193500)
- Waardenburg syndrome type 2A (WS2A) (3p14.1-p12.3) (MIM.193510)
- Waardenburg syndrome type 2B (WS2B) (1p21-p13.3) (MIM.600193)
- Waardenburg syndrome type 2C (WS2C) (8p23) (MIM.606662)
- Waardenburg syndrome type 2D (WS2D) (8q11) (MIM.608890)
- Waardenburg syndrome type 3 (WS3) (PAX3 at 2q35) (MIM.148820)

Associations

- neural tube defects (NTDs) (PAX3 mutations at 2q35)