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

Types I and III are caused by mutations in the PAX3 gene. Among other things, the gene codes for a protein that is involved in the regulation of the transcription factor MITF (microphthalmia-associated transcription factor). MITF is involved in the regulation of melanocyte development, which is disturbed 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 (WSIIB: 1p21-p13.3, WSIIC) in which mutations occur is known to date. WSIIE is caused by a 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 the SOX10 gene, both genes responsible for neural crest differentiation, have been detected. In addition, there is an aganglionosis of the colon (similar to Hirschsprung's disease).

A rare variant of type IV is ABCD syndrome, which is caused by a homozygous mutation in the EDNRB gene (endothelin receptor gene B).

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

The sensorineural hearing loss in Waardenburg syndrome is due to defects in tissue synthesis in the neural crest. The disorder of the melanocytes, which also arise from neuronal tissue, mainly affects the iris, the eyebrows, sometimes also the skin and scalp hair (poliosis). Heterochromia of the iris (e.g. one blue and one brown eye) is clinically conspicuous. Furthermore: eye malpositions, malformations of the bony skull (displacement of the eyelid crease or the inner eye angle of both eyes (dystopia canthorum)). In WS type IV, there is also aganglionosis of the colon (similar to Hirschsprung's disease)

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

Tietz syndrome (autosomal dominant inherited special form of total albinism with deafness (or deaf-mutism), 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 Mutat 31:391-406.

2. Verheij JB et al. (2002) ABCD syndrome is caused by a homozygous mutation in the EDNRB gene. Am J Med Genet 108:223-225.