DESCRIPTION

• Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disorder caused by mutations in the WAS gene that encodes for the WAS protein (WASP).
• Classically described as a triad of thrombocytopenia with small platelets, eczema, and recurrent infections
  • Increased risks of autoimmunity and malignancies
  • Increased bleeding tendency secondary to thrombocytopenia with impaired platelet production, increased turnover, and defective function
• Other variants in WAS gene can result in WAS-associated disorders including X-linked thrombocytopenia (XLT) and X-linked neutropenia (XLN).
• A number of innate and adaptive immune defects are found in WAS including impaired phagocytosis and chemotaxis, decreased number and function of T cells, disturbed B-cell homeostasis with defective antibody responses to vaccinations, impaired NK-cell cytotoxicity, and abnormal regulatory T-cell function.

EPIDEMIOLOGY

Incidence of classic WAS is ~1 to 10 per 1 million live births. The true incidence could be much higher when considering milder cases that are missed diagnosed.

ETIOLOGY

• Classic WAS
  • Mutations in WAS encoding for WASP
    • WASP is a cytoplasmic protein involved in cell mobility, immune regulation, cell signaling, cell-to-cell interactions, signaling, and cytotoxicity.
  • WASP is integral to linking signaling pathways with reorganization of the actin cytoskeleton in white blood cells and platelets.
    • Following activation of WASP, actin cytoskeleton reorganization results in polarization of cells.
    • Cells polarization function is important to form actin mesh in platelets for clotting, in macrophages for phagocytosis, and for orientation of T- and B-cells as well as other antigen-presenting cells to form immunology synapses and cross-talk.
  • Defects in WASP lead to dysfunction in adaptive and innate immunity, regulatory T-cell function and immune surveillance, and platelet homeostasis and function.
• WAS-associated disorders
  • XLT
    • Can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP) that does not carry an increased risk of malignancy
    • Testing for WASP expression and WAS gene variants is important in any male who is presenting with thrombocytopenia and small platelets.
  • XLN
    • Results from gain-of-function mutations in the Cdc42-binding domain of WAS gene leading to increased actin polymerization
    • Clinical features include profound neutropenia, with or without associated lymphopenia; decreased T-cell proliferation in vitro; and increased risk of myelodysplastic changes in bone marrow.

Genetics

• X-linked recessive disease
  • ~60% of cases have a positive family history of WAS.
  • Symptomatic females with heterozygous WAS mutations often have skewed X-chromosome inactivation.
• Caused by variants in WAS located on the short arm of chromosome X (p11.22-11.23)
  • Classic WAS results from loss-of-function variants.
  • XLT: chronic thrombocytopenia without other manifestations of WAS—caused by amino acid substitutions in the stabilization binding region of the same gene
• Genotype/phenotype correlation
  • Complete absence of WASP expression correlates with classic WAS phenotype (increased infections, severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies). Survival rate is significantly lower in patients with absence of WASP.
  • Patients with some expression of WASP often have nonfunctional mutated protein and express milder phenotypes.
  • ~50% of patients with variants in WAS present with classic WAS phenotype; the other half with milder XLT phenotype.

COMMONLY ASSOCIATED CONDITIONS

• Immunoglobulin A (IgA) nephropathy
• Autoimmune disorders (typically present in older age)
• Increased incidence of B-cell lymphomas (associated with Epstein-Barr virus [EBV])
• Atopy and allergy