All the above conditions are caused by mutations in the gene WASP; which condition develops depends on the type and/or position of the mutations found in WASP. The classic X-linked recessive disorder, Wiskott–Aldrich syndrome (WAS), is rare – its incidence is between 1 and 10 per million persons. It is characterized by immunodeficiency, eczema, and microthrombocytopenia. The typical presentations (often at birth) include mucocutaneous petechiae, bruising, and bloody diarrhea. Severe eczema often develops in infancy or childhood. Hepatosplenomegaly can occur.
Complications include susceptibility to pyogenic infection (especially otitis media and pneumonia), arthritis, autoimmune disease, and lymphoma. Death in childhood may occur from overwhelming bacterial or viral infections.
Eczema can be complicated by molluscum contagiosum, herpes simplex, and bacterial infections (Thrasher 2009). Patients have small platelets, and the immunodeficiency involves both T cell and B cell function. There is low antigen-induced lymphocyte proliferation, with low IgM and defective antibody production. There is progressive loss of lymphoid elements normally found in the thymus, spleen, lymph nodes, etc. Malignancy of the reticuloendothelial system, lymphomas, and lymphomatoid granulomatosis are common, being the cause of death in about 10 % of cases (ten Bensel et al. 1964). However, by the age of 30 years, the risk of non-Hodgkin lymphoma approaches 100 %. The basic defect underlying all four disorders is dysregulated actin polymerization in hematopoietic cells on account of loss or inappropriate activity of the WAS protein, WASP.
The WASP gene was identified in 1994 (Derry et al. 1994a, b). Since then, numerous WASP mutations have been characterized, including a small number of hot spot mutations (~25 % of all identified mutations) and genotype–phenotype correlations have also been characterized. WASP mutations may result in four distinct phenotypes: the classic WAS triad of thrombocytopenia/small platelets, recurrent infections as a result of immunodeficiency, and eczema; the milder X-linked thrombocytopenia (XLT) variant, where eczema, immune deficiency, infection, and cancer may or may not occur; intermittent XLT, where microthrombocytopenia may be the sole manifestation; and X-linked neutropenia (XLN) where congenital neutropenia and associated infections are the only manifestations. Persons with a normal-sized but mutated protein (usually reduced in quantity), associated with a missense mutation in exons 1–3 (or in-frame deletions elsewhere in WASP), nearly always have XLT. Missense mutations that disrupt autoinhibition cause XLN, whereas other missense mutations can cause IXLT (Thrasher 2009). Those with mutations leading to complete loss of protein expression or expression of a truncated protein have a more severe classical WAS phenotype and a higher risk of malignancy (Imai et al. 2004; Jin et al. 2004). Treatment of severely affected children is with intravenous immunoglobulins (even if total IgG levels are normal) and prompts hematopoietic stem cell transplantation.