Waardenburg syndrome (overview) E70.32

First described in 1948 by the Dutch ophthalmologist and geneticist Petrus Johannes Waardenburg (1886-1979); Klein 1947;

Group of very rare, congenital, autosomal dominant (exception: WS Type-IV: autosomal recessive inheritance) inherited malformation syndromes with variable penetrance and expressivity of malformations in the eye area, sensorineural hearing loss to deafness, dyschromia.
Type III (most common type) is called Klein-Waardenburg syndrome (MIM 148820).

According to genetic and clinical criteria, 4 main types of Waardenburg syndrome (WS) are distinguished (WS1-WS4):

• Type I: mutation on gene locus 2q35.
• Type II: (with subtypes: WS2A, WS2B, WS2C, WS2D) mutations on gene loci 3p14.1-p12.3, 1p21-p13.3, 8p23, 8q11(SNAI2 gene).
• Type III(Klein-Waardenburg syndrome): Mutation at gene locus 2q35.
• Type IV (Waardenburg-Shah and Waardenburg-Hirschsprung syndromes): mutations detected on gene loci 13q22, 22q13, 20q13.2-q13.3.

Type I and III are caused by mutations in the PAX3 gene. The gene encodes, among others, a protein involved in the regulation of the transcription factor MITF (microphthalmia-associated transcription factor). MITF is involved in the regulation of melanocyte development, which is disrupted in all known Waardenburg syndromes.

In type II (WS II A), a mutation is found directly in the MITF gene. In WSIIB, only the DNA locus is known so far (WSIIB: 1p21-p13.3, WSIIC), where mutations occur. WSIIE is caused by a gene mutation in the SOX10 gene.

WS IV is inherited in an autosomal recessive manner. Mutations of the endothelin-3 and endothelin-B receptor genes as well as of the SOX10 gene, both genes responsible for neural crest differentiation, have been detected. In addition, there is aganglionosis of the colon (similar to Hirschsprung's disease).

Prevalence is 1:42,000; about 1-3% of all congenital deafness cases are due to Waardenburg Syndrome.

Inner ear hearing loss in Waardenburg Syndrome is caused by defects in tissue synthesis in the neural crest. The disorder of melanocytes, which also originate from neuronal tissue, mainly affects the iris, the eyebrows, and sometimes also skin and scalp hairs (poliosis). Clinically conspicuous is a heterochromia of the iris (e.g. one blue and one brown eye). Furthermore: malposition of the eyes, malformations of the bony skull (shifting of the eyelid crease or the inner eye angle of both eyes (dystopia canthorum). In case of WS type IV an additional aganglionosis of the colon occurs (similar to Hirschsprung's disease).

Clinically, 4 main types (besides genetically different secondary types) are distinguished (WSI-IV).

Tietz syndrome (Autosomal-dominantly inherited special form of total albinism with deafness (or deaf-muteness), light blue irides, muteness, and eyebrow hypoplasia. OMIM 103500)

Ziprkowski-Margolis syndrome (Albnism-deafness syndrome - OMIM 300700)

BADS syndrome (Black locks, albinism and deafness-syndrome)

1. Pingault V et al (2010) Review and update of mutations causing Waardenburg syndrome. Hum mutation 31:391-406.