The Wiskott-Aldrich syndrome

In 1937, Wiskott described three brothers with congenital thrombocytopenia, bloody diarrhea, eczema, and recurrent ear infections. Seventeen years later, Aldrich showed X-linked (a gene carried on the X chromosome) inheritance. Subsequently, the characteristic immune defects of Wiskott-Aldrich syndrome (WAS) were reported, including lymphopenia, lymphocyte depletion in the thymus, T-dependent pericortical areas of lymph nodes, defective delayed type hypersensitivity, and failure to produce antibodies to polysaccharides and to a variety of bacterial, protein, and viral antigens. The consistent platelet abnormalities were explained by ineffective thrombocytopoiesis. The increased risk of autoimmune diseases and malignancies was recognized. In addition to the classic WAS phenotype, a milder form designated as hereditary X-linked thrombocytopenia (XLT) has been described. The genes for both WAS and XLT have been mapped to Xp11.22 and sequence analysis has identified mutations of the same gene in both phenotypes. The gene coding for the WAS protein (WASP) is composed of 12 exons containing 1,823 base pairs and encodes a 502-amino acid protein. WASP is expressed in the cytoplasm of all hematopoietic stem cell-derived lineages. Although the precise function of WASP is unknown, several unique binding domains have been identified, and WASP appears to play a critical role in signal transduction by interacting with SH3-containing molecules and in the regulation of the cytoskeletal reorganization. The identification of the WASP gene allows the diagnosis of WAS on a molecular basis, carrier detection, and prenatal diagnosis. Treatment is largely symptomatic and includes antibiotics, prophylactic intravenous immunoglobulin (i.v.IG) and splenectomy in selected cases to reduce hemorrhages. Stem cell transplantation corrects the defect and should be considered in younger patients.