Comprehensive clinical and immunologic characterization of Wiskott-Aldrich syndrome in Iran: a 10-year cohort study.
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BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and a heightened risk of autoimmunity and malignancy. Although its genetic basis is well understood, the clinical expression varies across populations, underscoring the need for region-specific data. This study represents the first comprehensive national report of WAS in Iran and highlights novel immunological patterns not previously described in global cohorts. METHODS: This retrospective cohort study analyzed 41 genetically and clinically confirmed WAS patients diagnosed between 2014 and 2024 across tertiary immunology centers in Iran. Clinical, laboratory, and immunological data were extracted from hospital records, including infection history, immunoglobulin levels, lymphocyte subsets, and complement factors. RESULTS: Of 41 patients, 87.8% were male and 12.2% female, including symptomatic female carriers. The mean age at diagnosis was 11.6 ± 8.7 years. Initial manifestations included bleeding (31.7%), fever (17.1%), and cough (17.1%). Skin involvement was prominent (78%), with eczema most common. Recurrent infections affected 78%, notably pneumonia (43.9%) and otitis media (36.6%). Autoimmunity was observed in 56.1%, and thrombocytopenia in 63.4%. Female patients had milder but notable immune symptoms, including higher autoimmunity and organomegaly. Immunoglobulin profiling revealed normal IgG in most, low-to-normal IgA/IgM, and elevated IgE in 58.3%. Lymphocyte subset analysis showed CD4 + T-cell reductions in 29.4% and CD19+/CD20 + B-cell deficiencies in 21.4%. Complement testing identified abnormalities in C3, C4, and CH₅₀ in approximately one-third of patients, a novel finding not previously reported in WAS literature, suggesting an additional layer of immune dysregulation. CONCLUSION: Our findings expand the immunopathological spectrum of WAS by reporting complement pathway abnormalities for the first time. Male patients exhibited the classical triad, while female carriers showed milder phenotypes with prominent autoimmunity and organomegaly. The immunologic profile revealed a mixed antibody pattern, with IgE elevation, selective IgA/IgM reduction, and frequent T- and B-cell deficiencies. Although all patients were genetically confirmed, the retrospective design may limit generalizability; prospective nationwide screening and longitudinal follow-up are warranted to improve early diagnosis, carrier detection, and timing of HSCT/gene therapy.