Etiology and Pathophysiology
Epidemiology
- 1 in 100,000 live male births in the United States
- 1–10 in 1,000,000 males worldwide
- Occurs much more commonly in boys due to its X-linked recessive inheritance pattern
Etiology
- Mutations in the WASp gene on the short arm of the X-chromosome (Xp11.22-23)
- The WASp gene encodes the WASp protein (Wiskott-Aldrich syndrome protein) that is mainly expressed in hematopoietic cells and leads to defective cytoskeleton-dependent activation signals in lymphocytes, defective antigen presentation, and leukocyte migration.
- X-linked thrombocytopenia and X-linked neutropenia are also linked to WAS mutations.
- Defects in the CD43 molecules are also associated with WAS.
Pathophysiology
- The WASp mutation leads to microthrombocytes in which defective platelets are removed by the spleen and/or liver, resulting in lower platelet counts → bleeding diathesis
- Defective antigen presentation and leukocyte signaling → higher susceptibility to infections by opportunistic pathogens, most commonly in the respiratory tract, gastrointestinal (GI) tract, and skin
Clinical Presentation
- Classic triad: present from birth in 30% of cases
- Eczema (80% of cases)
- Bleeding diathesis: petechiae, bruising, purpura, spontaneous nose bleeds, and bloody diarrhea resulting from low platelet count
- Recurrent opportunistic infections: usually by encapsulated organisms such as Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus influenzae, as well as candida, commonly in the respiratory tract, GI tract, or skin
- Increased risk of autoimmune diseases due to an elevated eosinophil count, including:
- Autoimmune hemolytic anemia
- Neutropenia
- Vasculitis
- Inflammatory bowel disease
- Renal disease
- Rheumatoid arthritis
- Higher risk of hematological malignancies (30% of cases) such as B-cell lymphoma

Young male patient with Wiskott–Aldrich syndrome presenting with multiple face petechiae and a hematoma under the right eye (A) and eczema of the foot (B)
Image: “Wiskott–Aldrich syndrome” by Michael H. Albert and Alexandra F. Freeman, on behalf of the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT). License: CC BY 4.0Diagnosis
- Check immunoglobulin levels:
- Normal or low levels of IgG and IgM (low specificity since IgG may also be elevated)
- Increased levels of IgE and IgA
- Check CBC: shows low platelet count of 20,000/mm3–50,000/mm3 and small platelet size (microthrombocytopenia)
- Genetic testing for mutated WASp confirms the diagnosis
- Additional optional tests:
- Serology: decreased T- and B-cell count
- Skin immunologic testing may reveal hyposensitivity.
- Decreased levels of WASp are observed
Management
- Hematopoietic stem cell transplantation (HSCT) is the only possible cure.
- General measures:
- Protective helmets should be worn to prevent cerebral bleeding in children.
- Patients may benefit from transfusions for severe thrombocytopenia.
- Iron supplements are recommended for anemia due to chronic blood loss.
- Topical or systemic steroids are recommended for severe eczema but should be used with caution due to immunosuppressive effects.
- Prophylactic antibiotics to prevent infection
- Immunoglobulin replacement therapy, with IV preferred over subcutaneous injection due to higher risk of bleeding
- Acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated due to their effects on platelet function.
- Prognosis:
- HSCT leads to an 80% survival rate.
- Without HSCT, the average life expectancy is 15–20 years.
Differential Diagnosis
The following conditions are differential diagnoses for Wiskott-Aldrich syndrome:
- Idiopathic thrombocytopenic purpura (ITP): a condition that develops secondary to immune-mediated destruction of platelets, resulting in thrombocytopenia (platelet count < 150 X 10⁹/L). The condition can be primary with an isolated decreased platelet count. Secondary causes are drug-induced or due to infections such as HIV or hepatitis C. Idiopathic thrombocytopenic purpura is usually a diagnosis of exclusion.
- Platelet alloimmunization in neonates: a condition characterized by a low platelet count occurring in infants due to maternal antibodies raised against alloantigens of the fetal platelets.
- Severe combined immunodeficiency (SCID): the most severe form of primary immunodeficiency, SCID is a genetic disorder that involves defective antibody response due to either direct involvement with B lymphocytes or through improper B-lymphocyte activation due to non-functional T-helper cells. Presents as severe and recurrent opportunistic infections and is diagnosed through quantitative polymerase chain reaction (PCR) and flow cytometry.
- Thrombotic thrombocytopenic purpura (TTP): a life-threatening condition due to either a congenital deficiency or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand Factor (vWF). These large multimers then aggregate excessive platelets, resulting in thrombosis plus increased usage of platelets that leads to thrombocytopenia.