From T-cell defect to tumorigenesis: Epstein-Barr virus-associated smooth muscle tumors in ITK deficiency

Interleukin-2-inducible T-cell kinase (ITK) is critical for T-cell receptor signaling and antiviral immunity. ITK deficiency is a rare combined immunodeficiency, classically linked to Epstein-Barr virus (EBV)-driven lymphoproliferation, with only two previous reports of EBV-associated smooth muscle tumors (EBV-SMT). We report a 13-year-old boy with recurrent respiratory infections and bilateral adrenal masses. Immunophenotyping, targeted gene panel sequencing, histopathology, immunohistochemistry, and EBV in situ hybridization were performed to investigate underlying immunodeficiency and tumor etiology. Computational modeling assessed the functional impact of the identified ITK variant. The patient exhibited CD4+ T-cell lymphopenia and markedly reduced regulatory T cells. Histopathology and immunohistochemistry confirmed bilateral adrenal leiomyomas, and EBV in situ hybridization demonstrated EBV infection within tumor cells despite negative blood EBV serology, indicating tissue-restricted viral persistence. Genetic analysis revealed a novel homozygous ITK variant (c.1673C>T; p.Pro558Leu) in the kinase domain, predicted to destabilize the protein and impair T-cell receptor signaling. This represents the first African case of ITK deficiency complicated by EBV-SMT, expanding the recognized tumor spectrum and highlighting that EBV can remain localized within tissue despite negative systemic serology. The combination of CD4+ T-cell lymphopenia and Treg reduction underscores ITK's critical role in antiviral immunity and tumor surveillance. Tissue-based EBV detection is essential for accurate diagnosis in immunodeficient patients presenting with SMTs.