IntroductionWiskott-Aldrich syndrome is a disease of the immune system. It’s genetically inherited in an X-linked recessive manner, so it mostly affects males. The classic triad of findings include microthrombocytopenia, repeated infections, and eczema. It’s caused by a mutation of Wiskott-Aldrich syndrome protein, which is produced by all of the hematopoietic cells. Treatment is focused on controlling the symptoms and hematopoietic stem cell transplantation is currently the only potentially curative treatment.
- Type of primary immunodeficiencies (PID)
- X-linked recessive disease (Xp11.23):
- Mutation in WASP gene: Encodes Wiskott–Aldrich syndrome protein (WASP)
- X-linked recessive inheritance
- Repeated infections
The syndrome is named after Dr Robert Anderson Aldrich (1917–1998), an American paediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott (1898–1978), a German paediatrician who first noticed the syndrome in 1937.
Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006, a German research group analysed family members of Wiskott’s three cases and surmised they probably shared a novel frameshift mutation of the first exon of the WASp gene.
Progressive loss of T lymphocytes in the peripheral blood and in the T-cell zones (paracortical areas) of the lymph nodes, with variable defects in cellular immunity.
- Eczema (50%)
- Resembles classical atopic dermatitis
- Microthrombocytopenia (M/C finding)
- Bleeding complications (>80%)
- Non-life-threatening: Epistaxis, ecchymoses, petechiae, etc
- Life-threatening (30%): GI hemorrhage, intracranial hemorrhage (2%)
- Bleeding complications (>80%)
- Immunodeficiency → recurrent infections:
- Recurrent infections by 3 months of age
- Classic Wiskott-Aldrich syndrome (M/severe):
- Present in early childhood with a hemorrhagic diathesis due to thrombocytopenia; recurrent bacterial, viral and fungal infections; and extensive eczema.
- Complications: Autoimmune disorders and lymphoma or other malignancies
- X-linked neutropenia (XLN)
- Presents mainly as congenital neutropenia with infections characteristic for neutropenia but may also develop infections associated with lymphocyte dysfunction.
- Complications: Myelodysplasia
- X-linked thrombocytopenia (XLT)
- Presents as congenital thrombocytopenia that is sometimes intermittent (IXLT) with mild eczema and a benign disease course and good long-term survival.
Autoimmunity (40% cases):⅔ develop multiple autoimmune disorders
- Autoimmune hemolytic anaemia (M/C, 14%)
- Vasculitis (13%)
- Renal disease (12%)
- Chronic arthritis (10%)
Malignancy (13% cases):Poor prognosis (> 95% mortality)
- Lymphoma (M/C): Non-Hodgkin’s lymphoma (NHL) > Hodgkin’s lymphoma
- Myeloproliferative disorders
Jin et al. (2004): numerical grading of severity:
- 0.5: intermittent thrombocytopenia
- 1.0: thrombocytopenia and small platelets (microthrombocytopenia)
- 2.0: microthrombocytopenia + normally responsive eczema or occasional upper respiratory tract infections
- 2.5: microthrombocytopenia + therapy-responsive but severe eczema or airway infections requiring antibiotics
- 3.0: microthrombocytopenia + both eczema & airway infections requiring antibiotics
- 4.0: microthrombocytopenia + eczema continuously requiring therapy and/or severe or life-threatening infections
- 5.0: microthrombocytopenia + autoimmune disease or malignancy
Peripheral blood smear (PBS):
- Microthrombocytopenia (thrombocytopenia + small platelets)
- ↓ IgM
- IgG usually normal
- Paradoxical↑ IgA & IgE
- Wiskott-Aldrich gene
Differential diagnosis:Other primary immunodeficiencies (PIDs)
- Hyper Ig syndrome
- Omenn syndrome
- Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)
- Atopic dermatitis
- Immune thrombocytopenic purpura
- Congenital neutropenia
Aspirin and other NSAIDs should be avoided, since these may interfere with platelet function which is already compromised.
- Prophylactic antibiotics
- IV Ig infusions
- Severe bleeding:
- Platelet transfusions
- Autoimmune conditions:
- Immunosuppressive treatment
Hematopoietic stem cell transplant (HSCT)Definitive treatment, performed through a umbilical cord blood or bone marrow transplant