From T-Cell Defect to Tumorigenesis: EBV-Associated Smooth Muscle Tumors in <i>ITK</i> Deficiency

Abstract

INTRODUCTION: 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 EBV (Epstein-Barr virus)-driven lymphoproliferation, with only two previous reports of EBV-associated smooth muscle tumors (EBV-SMT). METHODS: 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 (EBER-ISH) were performed to investigate underlying immunodeficiency and tumor etiology. Computational modeling assessed the functional impact of the identified ITK variant. RESULTS: The patient exhibited CD4+ T-cell lymphopenia and markedly reduced regulatory T cells. Histopathology and immunohistochemistry confirmed bilateral adrenal leiomyomas, and EBER-ISH 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 TCR signaling. CONCLUSION: 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 smooth muscle tumors.