The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by a triad of diagnostic clinical elements: immunodeficiency, eczema and hemorrhage due to thrombocytopenia with small-sized platelets. Manifestations of immunodeficiency in patients with WAS include recurrent and severe infections, autoimmunity, and malignancies. WAS was originally described in 1936 , but the X-linked pattern of inheritance was defined only 18 years later . The gene responsible for disease, WAS, was cloned in 1994  and encodes a 502-amino acid protein (WAS protein, WASp) selectively expressed in hematopoietic cells, where it acts as a key regulator of the actin cytoskeleton (reviewed in ]. WAS mutations that abrogate or significantly impair expression and/or function of WASp are responsible for not only for WAS but also for its milder form, X-linked thrombocytopenia (XLT) . The latter, characterized by hemorrhages due to thrombocytopenia associated with no or minor infections and eczema, is allelic to WAS . The platelet count may significantly fluctuate, and hemorrhagic manifestations may be particularly mild, in patients with intermittent X-linked thrombocytopenia . In contrast, some missense mutations in the Cdc42-binding domain of WAS result in constitutive activation of the protein, causing X-linked neutropenia (XLN) [7–9], with neither thrombocytopenia nor signs of T-cell immunodeficiency. The phenotype of XLN is very different from that observed in WAS/XLT, and is characterized by increased apoptosis and defects of mitosis and cytokinesis  that may lead to myelodysplasia. The variability of clinical manifestations associated with null and hypomorphic WAS mutations has led to the development of a scoring system to grade the severity of the disease (Table 1).
Thrombocytopenia with small-sized platelets is the most consistent feature of the disease. Hemorrhages occur in >80% of the patients [11, 12] and commonly include petechiae, epistaxis and bloody diarrhea. Severe bleeding episodes (intestinal or intracranial hemorrhages) are also common (20–30%) and cause death in 4–10% of the patients [11, 12].
Bacterial (otitis media, skin abscesses, pneumonia, sepsis, meningitis) and viral (especially due to herpes simplex and cytomegalovirus) infections are common, and are particularly severe in patients with WAS . Several immunological abnormalities contribute to the increased susceptibility to infections. Patients with WAS are unable to mount antibody responses to carbohydrate antigens , and their response to protein antigens is also often impaired; in contrast, response to T-dependent antigens is typically normal in patients with XLT . The inability to mount antibody responses to carbohydrate antigens and the increased susceptibility to invasive infections caused by blood-borne pathogens correlate with severe abnormalities of the marginal zone of the spleen , and similar findings have been reported in Was−/− mice [16, 17]. Immunoglobulin abnormalities (low IgM, high IgA and high IgE serum levels) are observed with similar frequency in patients with WAS and with XLT (, Notarangelo unpublished observation). However, defects of cell-mediated immunity are more common and severe among WAS patients. In particular, T lymphocytes from patients with WAS fail to respond immobilized anti-CD3 monoclonal antibody, show reduced proliferation to mitogens and antigens and are impaired in their ability to secrete interleukin-2 and other Th1 cytokines upon in vitro activation [18–20]. In addition, patients with WAS show progressive T and B cell lymphopenia, but reduction of naive circulating T lymphocytes is apparent already early in life . Defective cytolytic activity of natural killer cells may also contribute to increased frequency of viral infections , and is more severe in patients with WAS than with XLT . Finally, monocytes and dendritic cells (DCs) from patients with WAS show severe abnormalities of the actin cytoskeleton and impaired directional migration . Defective interaction between DCs and T lymphocytes may cause impaired T-cell priming, as also shown in the murine model of the disease [25, 26]. Eczema is common (80%) in patients with WAS , but less so (41%) in patients with XLT . In addition to increased IgE serum levels  and skewed Th2 cytokine profile , defective migration of Langerhans cells has also been implicated in the pathophysiology [27, 28].
The incidence of autoimmune manifestations is markedly increased among patients with WAS, and ranges from 22% to 72% in various series [11, 12, 29, 30]. Autoimmune hemolytic anemia (AIHA), vasculitis, arthritis, nephropathy and inflammatory bowel disease are particularly common. In addition, idiopathic thrombocytopenic purpura (ITP) has been frequently observed in patients who develop a relapse of thrombocytopenia following splenectomy, and may even contribute to the pathophysiology of thrombocytopenia in unsplenectomized WAS patients . Although the scoring system (Table 1) dictates that patients with XLT do not have autoimmune manifestations at diagnosis, these may develop over time, and IgA nephropathy is particularly common (19%) . Occurrence of autoimmunity in WAS has prognostic implications and has been associated with reduced survival and higher risk of developing malignancies [12, 29]. Multiple mechanisms may account for autoimmunity in WAS [30, 32]. WASP-deficient natural regulatory T (nTreg) cells are severely impaired in their suppressive function [33–35]. Furthermore, patients with WAS and Was−/− mice have a reduced number and impaired function of invariant natural killer T (NKT) cells [36, 37], another population of cells with important immunoregulatory properties. Finally, impairment in the ability of DCs to migrate in response to chemoattractants and to interact with T lymphocytes, and chronic immune activation resulting from inefficient pathogen clearance may also play a role in the autoimmunity of WAS .
Tumors have been reported in 13%  and 22%  of the patients in two series. They may occur in childhood, but are more frequent during adolescence or early adulthood, and are mainly represented by leukemias, myelodysplasia and lymphomas. WAS patients are particularly susceptible to lymphoproliferative disease due to Epstein-Barr virus (EBV) . It has been speculated that the increased occurrence of tumors in patients with WAS reflects the immunodeficiency of the disease, however the observation that tumors are almost uniquely restricted to hematopoietic cells (i.e., the same cell types to which expression of WASp is restricted) indicates that WASp-dependent, hematopoietic cell-intrinsic abnormalities may play an important role in tumorigenesis.
Initial reports had indicated that median survival in patients with WAS is 20 years of age . Death is mostly caused by hemorrhage, malignancy and severe infection. Conservative management includes prompt and aggressive treatment of infections, immunoglobulin replacement therapy in patients with antibody deficiency, immunosuppressive drugs for autoimmune manifestations, surveillance for tumors, and anti-CD20 monoclonal antibody in patients with EBV lymphoproliferative disease. In the past, elective splenectomy has been used to reverse the thrombocytopenia, resulting in significant increase of the platelet count in up to 85% of the patients. However, a significant fraction of patients (15%) develop chronic ITP after splenectomy. Furthermore, splenectomy in WAS leads to increased risk of invasive pyogenic infections even in patients who receive antimicrobial prophylaxis. For this reason, many no longer considered splenectomy to be part of the routine therapeutic plan .
In spite of advances in diagnosis and clinical care, patients with severe disease (in particular, those who fail to express WASp) continue to have poor survival. In one recent study, the 20-year probability of overall survival was 0% for patients who fail to express WASp vs. 92.3% among those who express reduced levels of normal-sized protein . These data emphasize the importance of considering hematopoietic cell transplantation (HCT) in the treatment of WAS, especially for patients with more severe forms of the disease.