Wiskott-Aldrich syndrome

Genetics and biology

• X-linked recessive. WAS gene at Xp11.22-23 encodes WASp (Wiskott-Aldrich syndrome protein) — a key regulator of actin polymerisation in haematopoietic cells.
• Null mutations cause classical severe phenotype; missense / hypomorphic mutations cause milder X-linked thrombocytopenia (XLT).
• Gain-of-function mutations cause X-linked neutropenia.

Clinical phenotype

Classic triad:

• Microthrombocytopenia — typical low MPV (mean platelet volume) distinguishes WAS from ITP. Bleeding from birth, petechiae, easy bruising.
• Eczema — refractory atopic-like eczema; often severe; co-existing food allergies common.
• Recurrent infections — encapsulated bacteria, PCP, viral (CMV, EBV, VZV, HSV), fungal.

Autoimmunity in up to 70% — AIHA, vasculitis, IBD, arthritis, nephritis. Paradoxical despite immunodeficiency.

Malignancy in ~13-22% of long-term survivors — most commonly EBV-driven B-cell lymphoma (often CNS), but also Hodgkin lymphoma, leukaemia, Kaposi sarcoma.

Diagnosis

• FBC: thrombocytopenia with low MPV (typically <5 fL); confirm on film — small platelets.
• Flow cytometry: absent or reduced WASp expression.
• Genetic confirmation: WAS sequencing.
• Defective T-cell, NK-cell and B-cell function on functional immunology; low IgM, raised IgE.

Management

• Allogeneic HSCT — definitive cure; matched-sibling-donor outcomes excellent.
• Gene therapy — lentiviral WAS gene therapy in trials; durable engraftment reported.
• Supportive: IVIG / SCIG, antimicrobial prophylaxis (co-trimoxazole, antifungals, antivirals).
• Platelet transfusion only for active bleeding; splenectomy historically used but increases sepsis risk.
• Eczema management with intensive emollients, topical corticosteroids, calcineurin inhibitors.
• Skin / lymph-node biopsy of any new mass — EBV-driven LPD risk.

Practical points

• Severe eczema with petechiae in a boy — check FBC and platelet morphology before assuming ITP.
• Any new cutaneous lymphoid infiltrate in a WAS patient warrants EBV staining (EBER).
• HSCT teams treat WAS as a malignancy-risk syndrome — close skin surveillance pre- and post-transplant.
• Pre-pregnancy genetic counselling — X-linked carrier daughters at risk of skewed Lyonisation.