Wiskott-Aldrich syndrome (WAS) is an X-linked disorder, characterized by thrombocytopenia with small-sized platelets, eczema, and immunodeficiency. Autoimmune manifestations are common, and there is an increased risk of developing hematologic malignancies (primarily non-Hodgkin lymphoma, often EBV-driven). The estimated incidence is 1 in 100,000 births. The defect is due to mutations in the WAS gene, which encodes an intracytoplasmic protein (WAS protein [WASp]) expressed in hematopoietic cells and involved in cytoskeleton reorganization and immune synapse formation. Deficiency of WASp results in impaired T-cell activation, poor production of antibodies, particularly to carbohydrate antigens, defective NK cell function, impaired phagocytic cell migration, and defective antigen presentation, thus explaining the immunodeficiency associated with the disease.
The clinical phenotype may range from typical and severe WAS to isolated thrombocytopenia; milder phenotypes are often associated with residual expression of WASp. Rarely, mutations occurring in the GTPase binding domain of the protein results in a hyperactive form of WASp, resulting in X-linked neutropenia and myelodysplasia without thrombocytopenia, eczema, or immunodeficiency.
Boys with WAS typically present in infancy with bleeding manifestations that can range from petechiae and bruising, to severe gastrointestinal and intracranial hemorrhages. Eczema can be mild to severe. Common infections in WAS patients include otitis, sinusitis, pneumonia, and cellulitis. Viral infections (especially from herpesviruses, including CMV, EBV, and HSV-1) and opportunistic infections, such as P. jiroveci pneumonia, are also frequent. Approximately 40% of patients with WAS develop autoimmunity, including autoimmune hemolytic anemia, autoimmune thrombocytopenia, thyroiditis, colitis, vasculitis, nephropathy, and arthritis. In addition to thrombocytopenia, typical laboratory findings include inability to mount responses to polysaccharide antigens, low or absent isohemagglutinin titers, high IgE, and poor proliferation of T cells when stimulated with anti-CD3 antibody. Other immune findings are more variable, including progressive T cell lymphopenia with age, low IgM, and high IgA. Analysis of WASp expression and demonstration of WAS gene mutations confirm the diagnosis.
Supportive treatment for WAS consists of monitoring and treatment for bleeding, antimicrobial prophylaxis, immunoglobulin replacement therapy, and treatment of eczema and autoimmune manifestations with immunosuppressive drugs. Splenectomy can be effective in many to correct thrombocytopenia, but leads to an increased risk of sepsis.
Allogeneic SCT (typically with myeloablative regimens) for WAS has become standard at many institutions, and may be indicated early in life, especially in patients with severe mutations that abrogate protein expression.
SCT is usually associated with robust T-cell engraftment, whereas some patients develop mixed chimerism in the B and myeloid lineages, indicating differential requirement for normal WAS protein to promote lineage-specific development or survival.
Survival after SCT for WAS is influenced by donor type and age at transplantation, but continuous improvement of outcome has been reported during the last decades. However, mixed chimerism may be associated with increased risk of autoimmunity, and low myeloid chi merism with persistence of thrombocytopenia.
Gene therapy represents another treatment option for patients with WAS. In a first trial, 10 boys with WAS were treated with gene therapy by transduction of CD34+-selected peripheral blood stem cells using a murine leukemia virus-based gammaretroviral vector after low-dose busulfan conditioning. Immune reconstitution was attained in nine patients; however, seven of these developed leukemia due to insertional mutagenesis. More recently, gene therapy for WAS has been performed using a self-inactivating lentiviral vector. Results show good immune reconstitution and improved safety (with no leukemic events reported); however, the platelet count, although increased, remains low in most patients.
