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Wiskott–Aldrich syndrome (WAS) is a rare X linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema thrombocytopenia immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS related disorders of X linked thrombocytopenia (XLT) and X linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of the same gene.

WAS occurs most often in males due to its X linked recessive pattern of inheritance, affecting between 1 and 10 males per million. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to thrombocytopenia, WAS patients have abnormally small platelets (i. e. microthrombocytes) and ~30% also have elevated eosinophil counts (i. e. eosinophilia).

The microthrombocytes seen in WAS patients have only been observed in one other condition, ARPC1B deficiency. In both conditions the defective platelets are thought to be removed from circulation by the spleen and/or liver, leading to low platelet counts. WAS patients have increased susceptibility to infections, particularly of the ears and sinuses, and this immune deficiency has been linked to decreased antibody production and the inability of immune T cells to effectively combat infection.

WAS is associated with mutations in a gene on the short arm of the X chromosome (Xp11.23) that was originally termed the Wiskott–Aldrich syndrome protein gene and is officially known as WAS (Gene ID: 7454). X linked thrombocytopenia (XLT) is also linked to pathogenic variants in the WAS gene, although some variants tend to be more strongly associated with XLT versus others that are more associated with WAS. The rare disorder X linked neutropenia has also been linked to a specific subset of WAS mutations. The protein product of WAS is known as WASp. It contains 502 amino acids and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by serving as a nucleation promoting factor (NPF) for the Arp2/3 complex, which generates branched actin filaments. Several proteins can serve as NPFs, and it has been observed that in WAS platelets the Arp2/3 complex functions normally, indicating that WASp is not required for its activation in platelets. In T cells, WASp is important because it is known to be activated via T cell receptor signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse. The severity of the symptoms produced by pathogenic variants in the WAS gene generally correlates with their effects on WASp. Missense variants generally are associated with less severe disease than truncating variants that produce no protein due to nonsense mediated decay. CD43, a transmembrane sialoglycoprotein also known as a leukosialin, is part of a greater complex involved in T cell activation and acts as a sensitive indicator of abnormal, malignant B cell populations. Defects in this molecule may be detrimental to WAS patients, who are at a much higher risk of autoimmune diseases that may be exacerbated in later detected B cell lymphomas.

Jin et al. (2004) employ a numerical grading of severity: This score, which ranges from 0 to 5, may have clinical utility for predicting disease severity. Those with higher WAS scores (e. g., 5) at younger ages (e. g., age less than 5 years old), are thought to be at highest risk for increased morbidity and mortality related to their condition. As individuals can develop more WAS related symptoms (e. g. autoimmune disease, malignancy) with age, one's WAS score can increase over time. A lower WAS score may be more compatible with conservative management versus higher WAS scores that may favor intervention with treatments such as hematopoietic stem cell transplant. +WAS clinical scoreScoreDefinitionClinical syndrome0Neutropenia (low white blood cell count) or myelodysplasia onlyX linked neutropenia (XLN)0.5Intermittent thrombocytopenia (low platelet counts sometimes but not always)X linked thrombocytopenia (XLT)1Thrombocytopenia and small platelets (microthrombocytopenia)XLT2Microthrombocytopenia plus normally responsive eczema or occasional upper respiratory tract infectionsXLT2.5Microthrombocytopenia plus therapy responsive but severe eczema or airway infections requiring antibioticsXLT/Wiskott–Aldrich syndrome (WAS)3Microthrombocytopenia plus both eczema and airway infections requiring antibioticsWAS4Microthrombocytopenia plus eczema continuously requiring therapy and/or severe or life threatening infectionsWAS5Microthrombocytopenia plus autoimmune disease or malignancyXLT/WAS + autoimmune disease or cancer

The estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births. While still a rare disease, this makes it more common than many genetic immunodeficiency syndromes such as hyper IgM syndrome or SCID, which have an estimated incidence of about one in 1,000,000 live births, and Wiskott–Aldrich syndrome is thought to account for 1.2% of all inherited immunodeficiencies in the United States. WAS occurs worldwide and is not known to be more common in any particular ethnic group.

The syndrome is named after Dr. Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937, and Dr. Robert Anderson Aldrich (1917–1998), an American pediatrician who described the disease in a family of Dutch Americans in 1954.