Wiskott-Aldrich Syndrome

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
  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

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 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.