Wiskott-Aldrich syndrome (WAS)

Wiskott-Aldrich syndrome (also termed WAS-related disorders, encompassing classic Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and X-linked neutropenia) usually presents in infancy with profound thrombocytopenia, reduced platelet volume, and a substantial bleeding tendency. Affected males typically develop eczema (in approximately 80%) and abnormal lymphocyte function with susceptibility to serious bacterial, viral, and fungal infections. The cumulative incidence of severe bleeding reaches 33% by age 15 years and 49% by age 30 years, contributing to 23% of mortality.

Roughly 25-40% of males surviving early complications develop one or more autoimmune conditions, including haemolytic anaemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated renal or hepatic injury.

Approximately 15% develop lymphoma at an average age of 30 years. Clinical severity varies widely, even within the same kindred, and the phenotype may worsen with age.

The estimated prevalence is 1 to 4 per 1,000,000 live male births.

Wiskott-Aldrich syndrome is caused by germline pathogenic variants in WAS (Xp11.23), which encodes the actin nucleation-promoting factor WASP, expressed exclusively in haematopoietic cells and responsible for organising the actin cytoskeleton in response to external stimuli. Loss-of-function variants in WAS underlie classic Wiskott-Aldrich syndrome and X-linked thrombocytopenia, whereas rare gain-of-function variants in the region encoding the GTPase-binding domain of WASP cause X-linked neutropenia.

Wiskott-Aldrich syndrome is inherited in an X-linked recessive manner. Affected males transmit the pathogenic variant to all daughters (obligate heterozygotes) and to none of their sons; female heterozygotes have a 50% risk of transmitting the variant to each child. About one third of affected males with no family history of the disorder carry a de novo pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis is supported by profound thrombocytopenia with characteristically small platelets (mean platelet volume greater than 2 SD below the laboratory mean), often accompanied by eczema and recurrent infections. Absent or decreased Wiskott-Aldrich syndrome protein (WASP) expression in haematopoietic cells, demonstrated by flow cytometry or western blotting, supports the diagnosis. Definitive confirmation is established by molecular genetic testing.

Main differential diagnoses include:

• WAS-2 (WIPF1-related Wiskott-Aldrich-like syndrome): recurrent infections, eczema and thrombocytopenia overlapping with Wiskott-Aldrich syndrome but with normal platelet volumes and autosomal recessive inheritance; WIPF1
• X-linked : recurrent infections, neutropenia, thrombocytopenia and haemolytic anaemia with high or normal IgM and severely deficient IgG/IgA/IgE; CD40LG
• : severe and persistent infections with T-B+NK- lymphocyte profile, agammaglobulinaemia and thymic atrophy, without persistent thrombocytopenia or small platelets; IL2RG

• Establishing the molecular diagnosis through identification of the underlying pathogenic variant.
• Enabling specific and individualised surveillance of haematologic, immunologic, autoimmune and malignancy-related complications, as a prerequisite for targeted medical care decided by the treating physicians in consultation with the affected individual.
• Allowing predictive testing of at-risk female relatives and reproductive counselling within affected families.

• Chandra S, Nagaraj CB, Sun M, Chandrakasan S, Zhang K. WAS-related disorders. 2024 Aug 15. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301357.
• Vallée TC, Glasmacher JS, Buchner H, Arkwright PD, Behrends U, Bondarenko A, et al. Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival. Blood. 2024;143(24):2504-16. doi:10.1182/blood.2023021411. PMID:.
• Mallhi KK, Petrovic A, Ochs HD. Hematopoietic stem cell therapy for Wiskott-Aldrich syndrome: improved outcome and quality of life. J Blood Med. 2021;12:435-47. doi:10.2147/JBM.S232650. PMID:.
• Hosahalli Vasanna S, Pereda MA, Dalal J. Clinical features, cancer biology, transplant approach and other integrated management strategies for Wiskott-Aldrich syndrome. J Multidiscip Healthc. 2021;14:3497-512. doi:10.2147/JMDH.S295386. PMID:.