Chapter 6 - Well-Known Combined Immune Deficiency Syndromes

Abstract

The Wiskott-Aldrich syndrome (WAS) and WAS interacting protein (WIP) deficiency are phenotypically similar genetic disorders. WAS is an X-linked disorder with an estimated frequency of approximately 4 per million live male births, while WIP deficiency is a very rare autosomal recessive disorder reported in only one family to date. WAS is characterized by microplatelet thrombocytopenia, eczema, recurrent infections, and an increased risk of autoimmunity and malignancy. Both innate and acquired (cellular and humoral) immunity are compromised in WAS. Mutations of the WAS protein (WASP) gene, mapped to the short arm of the X-chromosome within the region of Xpll.23, can cause three allelic disorders: WAS, chronic or intermittent X-linked thrombocytopenia (XLT), or X-linked neutropenia (XLN). WASP is an important regulator of actin polymerization, and the WASP gene is exclusively expressed in all hematopoietic cells. XLT is a milder form of WAS characterized by thrombocytopenia and small platelets. XLN is a recently identified rare WAS-associated disorder which is characterized by congenital neutropenia and an increased risk of myelodysplasia. WIP deficiency should be considered in any patient manifesting with the WAS phenotype and undetectable WASP but normal WAS gene sequence and mRNA. Hematopoietic stem cell transplantation (HSCT), using bone marrow or cord blood and conditioning, is the only curative therapy for WAS. In WAS patients with early-onset life-threatening manifestations, HSCT should be performed as early as possible, even in the absence of a fully matched donor. Gene therapy for WAS is currently under investigation, and shows some promise as an alternative treatment for the WAS patients who do not have HLA-compatible donors. Splenectomy is recommended only in emergency situations and for patients who are unlikely to be candidates for transplantation.