WISKOTT-ALDRICH SYNDROME - REPORT OF AN AUTOSOMAL-DOMINANT VARIANT

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder o riginally described as a clinical triad of thrombocytopenia with small platelets, eczema, and immunodeficiency. Impaired CD43 glycoprotein e xpression on lymphocytes is a typical hallmark of this disorder. The C D43 gene is located on chromosome 16, and the WAS gene, WASP, was rece ntly isolated from the chromosome X p11.22-p11.23. This gene, mutated in WAS patients, encodes a protein that is likely to play a role in co ntrolling the expression of CD43. However, the molecular mechanism(s) causing WAS are not yet known. Herein, we describe a three-generation family in which clinical and laboratory WAS features were expressed in six of nine subjects available for study. At variance with classic X- linked WAS, this disorder was characterized by the presence of thrombo cytopenia with a broad spectrum of platelet size, including giant plat elets, and was inherited as an autosomal dominant trait. This last fin ding led us to hypothesize a mutation of the CD43 gene. However, South ern blot analysis failed to detect structural abnormalities of this ge ne, and genotype analysis ruled out the possibility that a CD43 allele might be shared by the affected individuals. These findings indicate that an alteration(s) of an autosomal gene distinct from the CD43 gene is responsible for the disease. Thus, results from this family, provi ding the first observation of an autosomally transmitted WAS variant, indicate that genetic mechanism(s) leading to WAS are more complex tha n previously recognized. (C) 1996 by The American Society of Hematolog y.