Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency with the triad of thrombocytopenia, eczema and infections that affects both B and T lymphocytes. A clinically milder form is X-linked thrombocytopenia (XLT). The incidence of WAS is probably underestimated at 1-10:1,000,000. Clinically, petechiae, hematomas and bloody stools may already be noticeable at birth. Later, eczema similar to atopic dermatitis occurs in approximately 80% of patients. In addition to thrombocytopenia, the platelets are smaller than normal and have a reduced aggregation capacity. Life-threatening bleeding can occur in around 30% of patients. Bacterial infections such as otitis media, sinusitis, pneumonia, sepsis and meningitis as well as severe, sometimes recurrent viral infections with herpes simplex are common. Around 40% of patients suffer from autoimmune diseases such as hemolytic anemia, polyarthritis, inflammatory bowel disease and IgA nephritis, while malignancies, especially EBV-associated B-cell lymphomas, occur in over 10%. Laboratory diagnostic findings include thrombocytopenia in small platelets with impaired aggregation, abnormal B and T cell function and abnormalities in immunoglobulins and antibody tests. Lymphopenia becomes apparent with increasing age. The treatment of choice is blood stem cell transplantation or symptomatic therapy with antibiotics, immunoglobulins and, if necessary, platelet concentrates.

The cause is pathogenic variants in the WAS gene, which plays a role in the organization of the actin cytoskeleton, signal transduction, phagocytosis and apoptosis. Known pathogenic variants are distributed throughout the gene, with approximately 45% located in the P4/WH1 domain. Variants that completely suppress WAS expression are associated with WAS, partially inactivating variants lead to XLT. X-linked neutropenia (XLN) is also caused by pathogenic variants in the WAS gene. Carriers show non-random X-inactivation.

References

Chandra et al. 2016, GeneReviews® [Internet] https://www.ncbi.nlm.nih.gov/books/NBK1178/ / Gulácsy et al. 2011, Mol Immunol 48:788 / Albert et al. 2010, Blood 115:3231 / Ochs et al. 2006, J Allergy Clin Immunol 117:725 / Imai et al. 2004, Blood 103:456 / Jin et al. 2004, Blood 104:4010