Overview
Wiskott–Aldrich syndrome is a rare X-linked recessive primary immunodeficiency caused by mutations in the WAS gene, leading to defective actin cytoskeleton regulation in hematopoietic cells. It presents with the triad of eczema, recurrent infections, and thrombocytopenia with small platelets. Patients are prone to autoimmunity and malignancy. Incidence is ~1 in 100,000 live male births. Without curative therapy (HSCT), prognosis is poor.
Definition
Thrombocytopenia: Low platelet count; in WAS, platelets are also characteristically small.
Immunodeficiency: Impaired immune defence; in WAS both humoral and cellular immunity are defective.
Eczema: Chronic, pruritic, inflammatory skin condition.
X-linked recessive inheritance: Mutations passed via the maternal X chromosome, affecting males.
Anatomy & Physiology
- Normal WAS protein (WASP): Cytoskeletal regulator in hematopoietic cells, essential for immune synapse formation, migration, phagocytosis, and signal transduction.
- In WAS: Defective WASP → impaired T-cell receptor signalling, defective actin remodelling, poor immune synapse → impaired T-cell and B-cell interactions → defective adaptive immunity.
- Small, dysfunctional platelets due to abnormal megakaryocyte development.
Remember
WAS is the only immunodeficiency with small platelets (microthrombocytopenia).
Aetiology and Risk Factors
Aetiology
- Genetics: Mutations in WAS gene (Xp11.23), encoding WASP.
- Inheritance: X-linked recessive (males affected, carrier females usually asymptomatic).
Risk Factors
- Family history of affected males.
- Maternal carrier status.
Pathophysiology
- WAS gene mutation → defective WASP.
- Impaired actin cytoskeleton → defective immune synapse formation.
- T-cell and B-cell dysfunction → impaired antibody responses, poor memory cell formation.
- Small, dysfunctional platelets → thrombocytopenia and bleeding.
- Immune dysregulation → increased risk of autoimmunity and malignancy.
Think
“Cytoskeleton defect = immune + platelet dysfunction.”
Clinical Manifestations
- Classic Triad:
- Eczema (often severe, early onset).
- Recurrent infections (sinopulmonary, viral, fungal).
- Thrombocytopenia with small platelets → petechiae, bruising, epistaxis, GI bleeding.
- Other features:
- Autoimmunity (hemolytic anaemia, vasculitis, arthritis).
- Malignancy (lymphoma, leukemia).
- Failure to thrive in severe cases.
Remember
Petechiae + eczema + recurrent infections = WAS until proven otherwise.
Diagnosis
- CBC: Thrombocytopenia with small platelets (low mean platelet volume, MPV).
- Immunology:
- Low IgM.
- Normal/↑ IgA and IgE.
- Variable IgG.
- Flow cytometry: Absent/reduced WASP expression in lymphocytes.
- Genetic testing: Confirms WAS gene mutation.
- Family history: X-linked inheritance pattern.
Differential Diagnosis
| Condition | Differentiating Feature |
| Atopic dermatitis | Eczema but no thrombocytopenia or recurrent severe infections |
| ITP (immune thrombocytopenia) | Thrombocytopenia but normal platelet size and no immunodeficiency |
| SCID | Severe infections but no thrombocytopenia or eczema |
| Hyper-IgE syndrome | Eczema + infections but normal/large platelets |
Treatment
- Curative: Haematopoietic stem cell transplantation (HSCT).
- Emerging: Gene therapy (trials ongoing).
- Supportive:
- IVIG for antibody deficiency.
- Prophylactic antibiotics.
- Platelet transfusions if severe bleeding.
- Eczema management (topical therapy, infection control).
- Avoid aspirin/NSAIDs.
Think
HSCT = only definitive cure; supportive care buys time.
Complications & Prognosis
- Life-threatening bleeding (GI, intracranial).
- Severe recurrent infections.
- Autoimmune disease (20–40%).
- Lymphoma/leukaemia risk markedly increased.
- Prognosis: Poor without HSCT (death in childhood); greatly improved survival with early HSCT.
Remember
Poor prognosis without HSCT, most die before age 10.
Discussion