Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome.

Type I Waardenburg syndrome (WS-I) is an auditory-pigmentary syndrome caused by heterozygous loss of function mutations in the PAX3 gene. Klein-Waardenburg syndrome (WS-III) is a very rare condition and represents an extreme presentation of WS-I, additionally associated with musculoskeletal abnormalities. We present an 18-months old Turkish child with typical Klein-Waardenburg syndrome (WS) including dystopia canthorum, partial albinism, and upper-limb defects. The child was born to a consanguineous couple and both parents had WS-I. We screened the entire coding region of the PAX3 gene for mutations and identified a novel missense mutation, Y90H, within the paired box domain of PAX3. Both parents were heterozygous for the mutation and the proposita was homozygous. This is the third report of a homozygous PAX3 mutation causing the WS-III phenotype. Molecular analysis of four additional Turkish families with variable clinical expression of WS-I identified two missense mutations, one splice-site mutation, and one small insertion in the PAX3 gene.