Waardenburg syndrome type 3 (Klein-Waardenburg syndrome) segregating with a heterozygous deletion in box domain of PAX3: a simple variant or a true syndrome

Klein - Waardenburg syndrome or Waardenburg syndrome type 3 (WS-III; MIM 14 8820) is characterized by the presence of masculoskeletal abnormalities in association with clinical features of Waardenburg syndrome type I (WS-I). S ince the description of the first patient in 1947 (D. Klein, Arch Klaus Sti ft Vererb Forsch 1947: 22: 336-342), a few cases have been reported. Only o ccasional families have demonstrated autosomal-dominant inheritance of WS-I II. In a previous report, a missense mutation in the paired domain of the P AX3 gene has been described in a family with dominant segregation of WS-III . In this report, we present a second family (mother and son) with typical clinical findings of WS-III segregating with a heterozygous 13-bp deletion in the , paired domain of the PAX3 gene. Although homozygosity or compound heterozygosity has also been documented in patients with severe limb involv ement, a consistent genotype-phenotype correlation for limb abnormalities a ssociated with heterozygous PAX3 mutations has not previously been apparent . Heterozygous mutations could either reflect a unique dominant-negative ef fect or possibly the contribution of other unlinked genetic modifiers in de termining the phenotype.