Wiskott-Aldrich Syndrome

Basics

An X-linked primary immunodeficiency caused by a mutation in the Wiskott-Aldrich syndrome (WAS) gene
Originally described as clinical triad of thrombocytopenia with small platelets, eczema, and recurrent infections with opportunistic and pyogenic organisms
Increased bleeding tendency secondary to thrombocytopenia likely results from impaired platelet production, increased turnover, and defective function.
Disease variants also resulting from WAS gene mutations include X-linked thrombocytopenia (XLT) and X-linked neutropenia (XLN).
Classic WAS is characterized by broad immunodeficiency, decreased number and function of T cells, disturbed marginal B-cell homeostasis, and skewed immunoglobulin isotypes, with defective antibody responses to vaccinations, impaired NK-cell cytotoxicity, and abnormal regulatory T-cell function as well as reduced phagocyte chemotaxis.

Presents in infancy with serious bleeding episodes secondary to thrombocytopenia (such as circumcision with increased bleeding, bloody diarrhea, ecchymoses)
Recurrent infections usually start after 6 months of age:
- Bacterial: otitis media, sinusitis, meningitis, sepsis and pneumonia
- Viral infections: herpes simplex virus, varicella with systemic complications
Milder phenotypes may lack history of recurrent infections.
Decline in T- and B-cell numbers with time
Eczema is usually present by 1 year of age (may be resistant to therapy, sometimes requiring systemic antibiotics).

X-linked recessive disease
Defective WAS protein gene located on X p11.22p–11.23
~60% of cases will have a positive family history for WAS.
XLT without the other findings is caused by mutations of the same gene.
Genotype/phenotype correlation
- Lack of WAS protein (WASP) expression correlates with classic WAS phenotype: increased infections, severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies
- Survival rate significantly lower in WASP-negative patients
- WASP-positive patients have expression of mutated protein and often have XLT phenotype.

Mutations in the gene for the WASP
WASP is involved in the reorganization of the actin cytoskeleton in hematopoietic cells:
- Following activation of WASP, reorganization of actin cytoskeleton results in polarization of cells (e.g., polarized actin mesh in platelets for clotting and in macrophages for phagocytosis, and polarization of T or B cells to form immunologic synapses).
WASP is a cytoplasmic protein involved in cell mobility, immune regulation, cell signaling, cell-to-cell interactions, signaling, and cytotoxicity.
Defects in WASP can lead to dysfunction in adaptive and innate immunity, immune surveillance, and platelet homeostasis and function as well as neutropenia.
“Classic” WAS and XLT result from loss-of-function mutations.
XLT can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP) that does not carry increased risk of malignancy, so testing for WASP expression and WAS gene mutation is important in any male with thrombocytopenia and small platelets.
XLN results from “activating” mutations in WAS that lead to increased actin polymerization; profound neutropenia, with or without associated lymphopenia; decreased T-cell proliferation in vitro; and increased risk of myelodysplastic changes in bone marrow.
WASP is also important for regulatory T-cell function.

There's more to see -- the rest of this topic is available only to subscribers.