{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T13:00:57Z","timestamp":1780146057320,"version":"3.54.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Interleukin-2\u2013inducible 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\u2013Barr 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&amp;gt;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\u2019s critical role in antiviral immunity and tumor surveillance. Tissue-based EBV detection is essential for accurate diagnosis in immunodeficient patients presenting with SMTs.<\/jats:p>","DOI":"10.1093\/cei\/uxag028","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T11:38:07Z","timestamp":1778585887000},"source":"Crossref","is-referenced-by-count":0,"title":["From T-cell defect to tumorigenesis: Epstein\u2013Barr virus\u2013associated smooth muscle tumors in\n                    <i>ITK<\/i>\n                    deficiency"],"prefix":"10.1093","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6785-3281","authenticated-orcid":false,"given":"Khaoula","family":"Oussama","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Immunology, Infection and Autoimmunity LICIA, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadoua","family":"Idrissi Fawzi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Abderrahim Harouchi Hospital, Ibn Rochd University Hospital , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibtihal","family":"Benhsaien","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology, Infection and Autoimmunity LICIA, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca ,","place":["Morocco"]},{"name":"Department of Clinical Immunology and Infectious Pediatrics, Abderrahim Harouchi Hospital, Ibn Rochd University Hospital , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisrine","family":"Bennani Guebessi","sequence":"additional","affiliation":[{"name":"Department of Anatomopathology, CHU Ibn Rochd , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Aadam","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology, Infection and Autoimmunity LICIA, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahamada","family":"Elamine","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology, Infection and Autoimmunity LICIA, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siham","family":"Salam","sequence":"additional","affiliation":[{"name":"Department of Pediatric Radiology, Abderrahim Harouchi Children\u2019s Hospital, Ibn Rochd University Hospital Center , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Karkouri","sequence":"additional","affiliation":[{"name":"Department of Anatomopathology, CHU Ibn Rochd , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalila","family":"Elbakkouri","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology, Infection and Autoimmunity LICIA, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca ,","place":["Morocco"]},{"name":"Immunology Laboratory, Ibn Rochd University Hospital , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Aziz","family":"Bousfiha","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology, Infection and Autoimmunity LICIA, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca ,","place":["Morocco"]},{"name":"Department of Clinical Immunology and Infectious Pediatrics, Abderrahim Harouchi Hospital, Ibn Rochd University Hospital , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mounia","family":"Alzemmouri","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Abderrahim Harouchi Hospital, Ibn Rochd University Hospital , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Ailal","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology, Infection and Autoimmunity LICIA, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca ,","place":["Morocco"]},{"name":"Department of Clinical Immunology and Infectious Pediatrics, Abderrahim Harouchi Hospital, Ibn Rochd University Hospital , Casablanca ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026053008112438200_uxag028-B1","doi-asserted-by":"crossref","first-page":"a002287","DOI":"10.1101\/cshperspect.a002287","article-title":"T-cell signaling regulated by the Tec family kinase, ITK","volume":"2","author":"Andreotti","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2026053008112438200_uxag028-B2","doi-asserted-by":"crossref","first-page":"25401","DOI":"10.1074\/jbc.272.40.25401","article-title":"Lck phosphorylates the activation loop tyrosine of the ITK kinase domain and activates ITK kinase activity","volume":"272","author":"Heyeck","year":"1997","journal-title":"J Biol Chem"},{"key":"2026053008112438200_uxag028-B3","doi-asserted-by":"crossref","first-page":"11194","DOI":"10.1073\/pnas.89.23.11194","article-title":"ITK, a T-cell-specific tyrosine kinase gene inducible by interleukin 2","volume":"89","author":"Siliciano","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026053008112438200_uxag028-B4","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1182\/blood.V82.5.1561.1561","article-title":"Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q","volume":"82","author":"Gibson","year":"1993","journal-title":"Blood"},{"key":"2026053008112438200_uxag028-B5","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s00109-020-01958-z","article-title":"Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis","volume":"98","author":"Lechner","year":"2020","journal-title":"J Mol Med"},{"key":"2026053008112438200_uxag028-B6","doi-asserted-by":"crossref","first-page":"29882","DOI":"10.1074\/jbc.M109.003129","article-title":"The Tec family kinase ITK exists as a folded monomer in vivo","volume":"284","author":"Qi","year":"2009","journal-title":"J Biol Chem"},{"key":"2026053008112438200_uxag028-B7","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.4049\/jimmunol.178.6.3575","article-title":"Differential regulation of human NK cell-mediated cytotoxicity by the tyrosine kinase ITK","volume":"178","author":"Khurana","year":"2007","journal-title":"J Immunol"},{"key":"2026053008112438200_uxag028-B8","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.4049\/jimmunol.180.5.3007","article-title":"The Tec kinases ITK and RLK regulate NKT cell maturation, cytokine production, and survival","volume":"180","author":"Felices","year":"2008","journal-title":"J Immunol"},{"key":"2026053008112438200_uxag028-B9","doi-asserted-by":"crossref","first-page":"7688","DOI":"10.1038\/srep07688","article-title":"The tyrosine kinase ITK suppresses CD8+ memory T cell development in response to bacterial infection","volume":"5","author":"Huang","year":"2015","journal-title":"Sci Rep"},{"key":"2026053008112438200_uxag028-B10","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.jaci.2015.08.056","article-title":"Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide","volume":"137","author":"Huang","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"2026053008112438200_uxag028-B11","doi-asserted-by":"crossref","first-page":"6544","DOI":"10.4049\/jimmunol.180.10.6544","article-title":"Naive and innate memory phenotype CD4+ T cells have different requirements for active ITK for their development","volume":"180","author":"Hu","year":"2008","journal-title":"J Immunol"},{"key":"2026053008112438200_uxag028-B12","doi-asserted-by":"crossref","first-page":"256","DOI":"10.4049\/jimmunol.165.1.256","article-title":"TCR\/CD3-induced activation and binding of Emt\/ITK to linker of activated T cell complexes: requirement for the Src homology 2 domain","volume":"165","author":"Ching","year":"2000","journal-title":"J Immunol"},{"key":"2026053008112438200_uxag028-B13","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1021\/acs.jproteome.5b00340","article-title":"Vav1 regulates T-cell activation through a feedback mechanism and crosstalk between the T-cell receptor and CD28","volume":"14","author":"Helou","year":"2015","journal-title":"J Proteome Res"},{"key":"2026053008112438200_uxag028-B14","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1074\/jbc.275.3.2219","article-title":"Biochemical interactions integrating ITK with the T cell receptor-initiated signaling cascade","volume":"275","author":"Bunnell","year":"2000","journal-title":"J Biol Chem"},{"key":"2026053008112438200_uxag028-B15","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/S0962-8924(01)02154-7","article-title":"SH2 domains, interaction modules and cellular wiring","volume":"11","author":"Pawson","year":"2001","journal-title":"Trends Cell Biol"},{"key":"2026053008112438200_uxag028-B16","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1111\/j.1742-4658.2011.08072.x","article-title":"Tec family kinases ITK and Rlk\u200a\/\u200aTxk in T lymphocytes: cross-regulation of cytokine production and T-cell fates","volume":"278","author":"Gomez-Rodriguez","year":"2011","journal-title":"FEBS J"},{"key":"2026053008112438200_uxag028-B17","doi-asserted-by":"crossref","first-page":"10857","DOI":"10.1038\/ncomms10857","article-title":"ITK is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4","volume":"7","author":"Gomez-Rodriguez","year":"2016","journal-title":"Nat Commun"},{"key":"2026053008112438200_uxag028-B18","doi-asserted-by":"crossref","first-page":"979","DOI":"10.3389\/fimmu.2018.00979","article-title":"Interleukin-2-inducible T-cell kinase deficiency-new patients, new insight?","volume":"9","author":"Ghosh","year":"2018","journal-title":"Front Immunol"},{"key":"2026053008112438200_uxag028-B19","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1182\/blood-2014-03-564930","article-title":"Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia","volume":"124","author":"Serwas","year":"2014","journal-title":"Blood"},{"key":"2026053008112438200_uxag028-B20","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S1074-7613(00)80115-6","article-title":"Impaired NFATc translocation and failure of Th2 development in ITK-deficient CD4+ T cells","volume":"11","author":"Fowell","year":"1999","journal-title":"Immunity"},{"key":"2026053008112438200_uxag028-B21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.immuni.2006.05.012","article-title":"The Tec family tyrosine kinases ITK and RLK regulate the development of conventional CD8+ T cells","volume":"25","author":"Atherly","year":"2006","journal-title":"Immunity"},{"key":"2026053008112438200_uxag028-B22","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1097\/ACI.0000000000000008","article-title":"X-linked lymphoproliferative syndromes and related autosomal recessive disorders","volume":"13","author":"Veillette","year":"2013","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"2026053008112438200_uxag028-B23","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1084\/jem.20161846","article-title":"Human immunity against EBV-lessons from the clinic","volume":"214","author":"Tangye","year":"2017","journal-title":"J Exp Med"},{"key":"2026053008112438200_uxag028-B24","first-page":"241","article-title":"Primary immunodeficiencies associated with EBV disease","volume":"390","author":"Cohen","year":"2015","journal-title":"Curr Top Microbiol Immunol"},{"key":"2026053008112438200_uxag028-B25","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1172\/JCI37901","article-title":"Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation","volume":"119","author":"Huck","year":"2009","journal-title":"J Clin Invest"},{"key":"2026053008112438200_uxag028-B26","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/leu.2011.371","article-title":"Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases","volume":"26","author":"Linka","year":"2012","journal-title":"Leukemia"},{"key":"2026053008112438200_uxag028-B27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.jaci.2020.06.019","article-title":"ITK deficiency presenting as autoimmune lymphoproliferative syndrome","volume":"147","author":"Wallace","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"2026053008112438200_uxag028-B28","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1093\/cid\/ciy942","article-title":"Inherited interleukin 2-inducible T-cell (ITK) kinase deficiency in siblings with epidermodysplasia verruciformis and Hodgkin lymphoma","volume":"68","author":"Youssefian","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2026053008112438200_uxag028-B29","doi-asserted-by":"crossref","first-page":"e20220484","DOI":"10.1084\/jem.20220484","article-title":"Inherited human ITK deficiency impairs IFN-\u03b3 immunity and underlies tuberculosis","volume":"220","author":"Ogishi","year":"2023","journal-title":"J Exp Med"},{"key":"2026053008112438200_uxag028-B30","doi-asserted-by":"crossref","first-page":"1189219","DOI":"10.3389\/fped.2023.1189219","article-title":"Case report: multiple Epstein-Barr virus-associated smooth muscle tumours in a child with IL-2-inducible T-cell kinase mutation of undetermined clinical significance","volume":"11","author":"Wen","year":"2023","journal-title":"Front Pediatr"},{"key":"2026053008112438200_uxag028-B31","doi-asserted-by":"crossref","first-page":"106249","DOI":"10.1016\/j.ijscr.2021.106249","article-title":"Adrenal leiomyoma: a case report","volume":"85","author":"Sharma","year":"2021","journal-title":"Int J Surg Case Rep"},{"key":"2026053008112438200_uxag028-B32","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.21873\/invivo.12034","article-title":"Review of the literature on leiomyoma and leiomyosarcoma of the adrenal gland: a systematic analysis of case reports","volume":"34","author":"Sakellariou","year":"2020","journal-title":"In Vivo (Brooklyn)"},{"key":"2026053008112438200_uxag028-B33","doi-asserted-by":"crossref","first-page":"1283981","DOI":"10.3389\/fimmu.2023.1283981","article-title":"Changes in Treg and Breg cells in a healthy pediatric population","volume":"14","author":"Luo","year":"2023","journal-title":"Front Immunol"},{"key":"2026053008112438200_uxag028-B34","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1159\/000333472","article-title":"IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection","volume":"158","author":"Mansouri","year":"2012","journal-title":"Int Arch Allergy Immunol"},{"key":"2026053008112438200_uxag028-B35","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.3389\/fimmu.2019.02000","article-title":"Magnesium restores activity to peripheral blood cells in a patient with functionally impaired interleukin-2-inducible T cell kinase","volume":"10","author":"Howe","year":"2019","journal-title":"Front Immunol"},{"key":"2026053008112438200_uxag028-B36","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s10875-019-00632-5","article-title":"Genetic deficiency and biochemical inhibition of ITK affect human Th17, Treg, and innate lymphoid cells","volume":"39","author":"Eken","year":"2019","journal-title":"J Clin Immunol"},{"key":"2026053008112438200_uxag028-B37","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1097\/MPH.0000000000000366","article-title":"Atypical clinical course in pediatric Hodgkin lymphoma: association with germline mutations in interleukin-2-inducible T-cell kinase","volume":"37","author":"Alme","year":"2015","journal-title":"J Pediatr Hematol Oncol"},{"key":"2026053008112438200_uxag028-B38","doi-asserted-by":"crossref","first-page":"472","DOI":"10.3324\/haematol.2010.033910","article-title":"IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach","volume":"96","author":"Stepensky","year":"2011","journal-title":"Haematologica"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cei\/advance-article-pdf\/doi\/10.1093\/cei\/uxag028\/68284523\/uxag028.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/220\/1\/uxag028\/68284523\/uxag028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/220\/1\/uxag028\/68284523\/uxag028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T12:11:33Z","timestamp":1780143093000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/doi\/10.1093\/cei\/uxag028\/8678019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,6]]}},"URL":"https:\/\/doi.org\/10.1093\/cei\/uxag028","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"uxag028"}}