A kindred with a non-WASP-associated Wiskott-Aldrich syndrome variant characterized by mental impairment and dominant inheritance

Abstract

Rationale Classic Wiskott-Aldrich Syndrome (WAS) is an X-linked disorder characterized by a triad of thrombocytopenia with small platelets, eczema and recurrent infections. We report a family with dominant inheritance of a WAS variant. Methods We studied a three generation kindred in which four individuals have features of WAS. We evaluated quantitative immunoglobulins, peripheral blood lymphocyte subpopulations by flow cytometry, response to polysaccharide antigens, gene analysis and psychological testing. Results In this family, four of nine individuals available for study displayed the classic WAS triad of thrombocytopenia, eczema and frequent infections with varying expressivity. They had decreased IgM levels, low T and B lymphocyte subpopulations and decreased antibody responses to polysaccharide antigens. Anti-platelet antibodies were not observed. However, in contrast to typical WAS, these individuals displayed a wide spectrum of platelet size including megakaryocytosis. The male proband is 30 years old and doing well. Interestingly, the kindred displayed a Mendelian dominant pattern of transmission, and three of the four affected individuals were female. Gene analysis did not reveal a mutation in the gene that encodes the protein WASP (Wiskott-Aldrich Syndrome Protein). All four individuals exhibit similar morphological features including a piquant face with a small pursed mouth. All four subjects also have a history of mental impairment ranging from moderate retardation to behavioral disturbances. Conclusions This is the second report of a WAS variant kindred with probable autosomal dominant transmission. This kindred differs from the previous family in that evidence of neurologic dysfunction is associated with the trait.