Diagnosis of Wiskott-Aldrich syndrome by analysis of the X chromosome inactivation patterns in maternal leucocyte populations using the hypervariable DXS255 locus.

The Wiskott-Aldrich syndrome (WAS) is characterized by severe recurrent infections, petachiae and chronic eczema. The syndrome involves differentiation disorders in several haematopoietic cell lineages usually manifested as T lymphocyte deficiency, dysgammaglobulinaemia and thrombocytopenia. The defect is inherited in an X-linked recessive mode. A 1-year-old boy presented with otitis, upper respiratory infections, eczema, a persistent granulocytopenia and a dysgammaglobulinaemia. In his family five males in two generations had been shown to have WAS, which entailed a significant risk for the patient to have WAS. As the WAS gene or gene product is not delineated, the symptoms of the patient presented a diagnostic dilemma. If the boy had inherited the disease, his mother should be a WAS carrier. Segregation analysis in the family using the closely linked restriction fragment length polymorphisms (RFLP) DXS7, DXS255 and DXS14 did not exclude her carriership, although the probability was low. As a result of the differentiation arrest, obligate female WAS carriers manifest a unilateral X chromosome inactivation pattern in several haematopoietic cell lineages. Methylation analysis of the X chromosomal DXS255 loci exposed random X chromosome inactivation patterns in the peripheral blood granulocytes, T lymphocytes and B lymphocytes of the patient's mother. These findings excluded her WAS carriership and therefore excluded the diagnosis of WAS in the patient. This was further substantiated in a 1-year follow up with recovery from the haematological and immunological symptoms. These results demonstrated that X inactivation analysis in maternal leucocytes is decisive in the exclusion of the diagnosis of WAS.