Wiskott Aldrich syndrome
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Wiskott-Aldrich syndrome clinical features genetics pathophysiology
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Wiskott-Aldrich syndrome diagnosis management treatment hematopoietic stem cell transplant
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Wiskott-Aldrich Syndrome (WAS)
Overview
Wiskott-Aldrich Syndrome is a complex, X-linked recessive primary immunodeficiency with an incidence of approximately 1 in 200,000 live births, affecting almost exclusively males. It is caused by mutations in the WAS gene (Xp11.22), which encodes WASP (Wiskott-Aldrich Syndrome Protein) — a key regulator of actin cytoskeleton polymerization in hematopoietic cells (Harrison's, p. 9882).
Pathophysiology
WASP is expressed exclusively in hematopoietic stem cells and their progeny. It links cell surface receptor signaling to actin cytoskeleton reorganization, which is critical for:
- T and B lymphocyte activation, migration, and immune synapse formation
- NK cell cytotoxicity
- Platelet formation from megakaryocytes (explaining microthrombocytopenia)
- Dendritic cell function
Loss or dysfunction of WASP impairs all these cell lineages, creating a combined immunodeficiency with additional hematologic and inflammatory consequences.
Classic Triad
| Feature | Details |
|---|---|
| Eczema | Atopic-like, often severe; present in early infancy |
| Thrombocytopenia | Microplatelets (small platelets) — a hallmark; platelet count typically 20,000–80,000/µL |
| Recurrent infections | Bacterial, viral, and opportunistic; due to combined T + B cell dysfunction |
The classic triad is remembered as "EIT" — Eczema, Infections, Thrombocytopenia.
Genetics and Mutation Spectrum
- Gene: WAS (Xp11.22)
- Inheritance: X-linked recessive (males affected; females are carriers, usually asymptomatic)
- Mutation types: Missense, nonsense, frameshift, splice site — over 300 mutations identified
Genotype-Phenotype Correlation (Harrison's, p. 9882):
| Mutation Type | Phenotype |
|---|---|
| Missense (partial WASP expression) | Milder disease, often X-linked thrombocytopenia (XLT) only |
| Null mutations (no WASP) | Severe WAS: invasive infections, severe eczema, autoimmunity, lymphoma risk |
Clinical Manifestations
Immunologic
- Recurrent bacterial infections: sinopulmonary (encapsulated organisms — S. pneumoniae, H. influenzae)
- Viral infections: herpes simplex, CMV, EBV
- Opportunistic infections: Pneumocystis jirovecii pneumonia (PCP)
- Progressive decline in T cell numbers and function over time
Hematologic
- Microplatelets with thrombocytopenia — characteristic and present from birth
- Bleeding: petechiae, bloody diarrhea, intracranial hemorrhage (serious risk)
Autoimmune (especially with null mutations)
- Autoimmune hemolytic anemia, neutropenia
- Glomerulonephritis
- Vasculitis (including cerebral vasculitis)
- Inflammatory bowel disease-like colitis
- Arthritis, erythema nodosum
Malignancy
- Lymphoma (most common) — often EBV-driven or associated with HHV-8/Kaposi's sarcoma
- Leukemia
- Lifetime risk of malignancy ~13–22% in severe WAS
Diagnosis
Laboratory Findings
| Test | Finding |
|---|---|
| CBC | Thrombocytopenia with small platelets (MPV ↓) |
| Immunoglobulins | Variable: IgM ↓, IgA/IgE often ↑, IgG variable |
| Lymphocyte subsets | T cells (CD3+) progressively ↓; B cell function impaired |
| WASP expression | Flow cytometry of peripheral blood (screening) |
| Genetic testing | WAS gene sequencing — confirmatory |
- WASP protein expression by flow cytometry is a rapid screening tool
- Absent or reduced WASP expression + microthrombocytopenia in a male → strong diagnostic indicator
- Confirmed by molecular genetic testing (WAS sequencing)
Prenatal/Carrier Testing
- Carrier females identified by genetic testing; may show skewed X-inactivation
- Prenatal diagnosis possible via CVS or amniocentesis
Management
Supportive Care
- Prophylactic antibiotics: trimethoprim-sulfamethoxazole for PCP prophylaxis; penicillin for encapsulated organisms
- IVIG (intravenous immunoglobulin): to compensate for poor antibody responses
- Antifungal/antiviral prophylaxis as indicated
- Topical corticosteroids for eczema management
Vaccinations
- Live vaccines are contraindicated in severe WAS
- Patients with moderate-to-severe immunodeficiency (including WAS) require additional doses of inactivated vaccines and special revaccination schedules, especially post-HSCT (Immunization Schedule, p. 5)
Hematopoietic Stem Cell Transplantation (HSCT)
The only curative therapy:
- Best outcomes with HLA-matched sibling donor (overall survival >90%) or matched unrelated donor, performed before age 5
- Corrects both immune deficiency and thrombocytopenia
- Early transplantation is preferred before infectious complications and autoimmunity accumulate
Gene Therapy (Emerging)
- Lentiviral vector-based gene therapy inserting functional WAS cDNA into autologous stem cells has shown promising results in clinical trials
- Avoids graft-versus-host disease (GvHD) risk of allogeneic HSCT
- Not yet universally available but an active area of development
Splenectomy
- May increase platelet count temporarily (used cautiously in XLT/mild WAS)
- Increases infection risk with encapsulated organisms — requires lifelong penicillin prophylaxis if performed
Prognosis
| Factor | Impact |
|---|---|
| Null WAS mutations | Severe disease; early mortality without HSCT |
| Missense (XLT phenotype) | Near-normal lifespan possible with support |
| Successful early HSCT | Essentially curative; normal immune reconstitution |
| Without treatment | Median survival historically <15 years; causes of death: infection, bleeding, malignancy |
Key Differentials
- X-linked thrombocytopenia (XLT): allelic disorder (WAS missense), microplatelets + thrombocytopenia only, minimal immune deficiency
- Immune thrombocytopenia (ITP): normal platelet size; no immune deficiency or eczema
- Other combined immunodeficiencies: SCID, DiGeorge syndrome, ataxia-telangiectasia
- Atopic dermatitis + infection: consider WAS in male infants with eczema + unexplained thrombocytopenia
Bottom line: WAS is a complex X-linked primary immunodeficiency defined by the triad of eczema, microthrombocytopenia, and combined immunodeficiency. The severity is tightly linked to the nature of the WAS mutation. HSCT remains the cornerstone of curative treatment, ideally performed early in life before complications develop.
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