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Wiskott–Aldrich syndrome (WAS)

X-linked primary immunodeficiency disorder that is characterized by the classic triad of severe immunodeficiency, microthrombocytopenia, and eczema.

Introduction

Wiskott-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.

X-linked primary immunodeficiency disorder that is characterized by the classic triad of severe immunodeficiency, microthrombocytopenia, and eczema.

  • Type of primary immunodeficiencies (PID)
  • X-linked recessive disease (Xp11.23):
    • Mutation in WASP gene: Encodes Wiskott–Aldrich syndrome protein (WASP)

Salient features:

WAXTIE
  • Wiskott-Aldrich
  • X-linked recessive inheritance
  • Thrombocytopaenia
  • Repeated infections
  • Eczema
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History

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.

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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.

Pathophysiology

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.

fimmu-06-00047-g0031
Defects of T cell subsets and link to clinical manifestations. As WASP is required for many functions, its absence results in defects of cellular function. We have listed those impairments for human T cell subsets that have been described in the literature. Black arrows show the function exerted by each T cell types, with dotted arrows to point out unknown WASP implication. Red crosses point out the most prominent impairments described in WAS T cells. APC, antigen-presenting cell; pMHC, peptide/major histocompatibility complex; TCR, T-cell receptor, TGF-β, transforming growth factor β. | Cotta-de-Almeida, V., Dupré, L., Guipouy, D., & Vasconcelos, Z. (2015). Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott–Aldrich Syndrome . Frontiers in Immunology . Retrieved from https://www.frontiersin.org/article/10.3389/fimmu.2015.00047

Clinical features

Triad:

  1. Eczema (50%)
    • Resembles classical atopic dermatitis
  2. Microthrombocytopenia (M/C finding)
    • Bleeding complications (>80%)
      • Non-life-threatening: Epistaxis, ecchymoses, petechiae, etc
      • Life-threatening (30%): GI hemorrhage, intracranial hemorrhage (2%)
  3. Immunodeficiency → recurrent infections:
    • Recurrent infections by 3 months of age

Clinical phenotypes:

  • 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. 

Complications

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
  • Myelodysplasia
  • Leukaemia
  • Myeloproliferative disorders

Diagnosis

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)

Flow cytometry:

  • ↓ IgM
  • IgG usually normal
  • Paradoxical↑ IgA & IgE

Genetic sequencing:

  • 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

Management

Aspirin and other NSAIDs should be avoided, since these may interfere with platelet function which is already compromised.

Symptomatic treatment

  • Prophylactic antibiotics
  • IV Ig infusions
  • Severe bleeding:
    • Platelet transfusions
    • Splenectomy
  • Autoimmune conditions:
    • Immunosuppressive treatment

Hematopoietic stem cell transplant (HSCT)

Definitive treatment, performed through a umbilical cord blood or bone marrow transplant

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