Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, IMD2, or immunodeficiency 2, is a rare genetic mixed disorder of B- and T-cell deficiency that follows an X-linked recessive inheritance pattern. It is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses.
Wiskott-Aldrich syndrome presents as a classic triad of eczema, bleeding diathesis, and recurrent opportunistic infections, but also carries a high risk of development of autoimmunity and malignancy. Management includes hematopoietic stem cell transplantation (HSCT), immunoglobulin replacement therapy, prophylactic and therapeutic antibiotics, and systemic steroids. Without HSCT, prognosis is poor and life expectancy is shortened.

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Etiology and Pathophysiology

Epidemiology

  • 1 in 100,000 live male births in the United States 
  • 110 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
    1. Eczema (80% of cases)
    2. Bleeding diathesis: petechiae, bruising, purpura, spontaneous nose bleeds, and bloody diarrhea resulting from low platelet count
    3. 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
Wiskott-Aldrich syndrome: petechiae, hematoma and eczema

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 4.0

Diagnosis

  • 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 1520 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.

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