Wiskott-Aldrich Syndrome — Pediatric Gastroenterology Review

Definition and core features

Definition: X‑linked primary immunodeficiency caused by mutations in the WAS gene, with variable severity characterized by thrombocytopenia with small platelets, eczema, combined immunodeficiency, autoimmunity, and an increased risk of malignancy (notably lymphoma).

Thrombocytopenia: Small, dysfunctional platelets leading to mucocutaneous bleeding.
Immunodeficiency: Recurrent infections affecting bacterial, viral, and fungal pathogens.
Eczema: Severe atopic dermatitis frequently complicates care.
Autoimmunity and malignancy: Autoimmune cytopenias, IBD, renal disease, and markedly increased risk of hematologic malignancy.

Molecular biology

The WAS protein (WASp), encoded on Xp11.22‑p11.23, is expressed in hematopoietic cells and links membrane signals to actin cytoskeleton remodeling via interactions with CDC42 and the Arp2/3 complex, supporting platelet production, lymphocyte function, and T‑regulatory cell activity.

Presentation and epidemiology

Age at presentation: Symptoms commonly manifest in infancy, often before 2 years of age.
Typical signs: Epistaxis, petechiae, easy bruising, bloody stools, and recurrent otitis media, sinusitis, and pneumonia. Eczema and severe allergies are common.
GI involvement: Approximately one‑third of patients have GI manifestations including GI bleeding, infectious diarrhea (~25%), and IBD‑like disease (~10%).

Laboratory and immunophenotype

Hematology: Thrombocytopenia with small platelets; may have anemia from chronic blood loss or autoimmune hemolysis.
Immunoglobulins: Classically elevated IgE, increased IgA in some, and reduced IgM with relatively preserved IgG and IgA in many patients.
Flow cytometry: Mild T‑cell lymphopenia may be present; B‑cell numbers often normal; NK cells normal or elevated; WASp expression can be assessed for diagnostic support.

Management

Definitive therapy: Allogeneic hematopoietic stem cell transplantation is curative for severe disease and recommended early in classic WAS; gene therapy is an evolving curative option with promising results.
Supportive care: IV immunoglobulin for infection prevention, prophylactic antibiotics as indicated, prompt treatment of infections, and careful management of bleeding with platelet transfusions when needed.
Splenectomy: May normalize platelet counts in select patients but increases infection risk and is used selectively with vaccination and prophylaxis planning.
Autoimmunity and IBD: Manage per standard gastroenterology approaches with close coordination with immunology; immunosuppressive therapy requires risk‑benefit assessment due to infection susceptibility.

Clinical pearls

Suspect WAS in male infants with early bleeding (petechiae, bloody stools) plus eczema and recurrent infections.
Assess platelet size and count, immunoglobulin profile, and consider WASp testing or genetic sequencing to confirm diagnosis.
Refer early to immunology and transplant centers to discuss HSCT or gene therapy, especially for patients with severe immune dysfunction or progressive complications.