{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:37:45Z","timestamp":1760060265679,"version":"build-2065373602"},"reference-count":73,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T00:00:00Z","timestamp":1754697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council for Humanities, Science and Technology","award":["10869\/2020","HIM-2020-017","SSA 1649"],"award-info":[{"award-number":["10869\/2020","HIM-2020-017","SSA 1649"]}]},{"name":"Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d Fondo de Apoyo a la Investigaci\u00f3n","award":["10869\/2020","HIM-2020-017","SSA 1649"],"award-info":[{"award-number":["10869\/2020","HIM-2020-017","SSA 1649"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Introduction: X-linked agammaglobulinemia (XLA) is a prototypical inborn error of immunity (IEI) caused by mutations in the BTK gene, leading to a profound deficiency of mature B cells and severe pan-hypogammaglobulinemia. The Epstein-Barr virus (EBV), which primarily infects B lymphocytes, is believed to be unable to establish persistence in these patients due to the lack of its natural reservoir. Indeed, current evidence supports that EBV infection is typically refractory in individuals with XLA. Methods: We describe the clinical and molecular characterization of a 10-year-old male patient with genetically confirmed XLA who developed EBV viremia, hemophagocytic lymphohistiocytosis (HLH), and EBV-positive cutaneous T cell lymphoma. Diagnosis was supported by flow cytometry, serology, quantitative PCR, EBER in situ hybridization, histopathology, and whole-exome sequencing. Results: Despite the complete absence of peripheral B cells, EBV was detected in leukocytes and multiple tissues, indicating active infection. The patient developed HLH and a T cell lymphoma with EBER-positive infiltrates. Genetic analysis revealed a nonsense mutation in BTK (1558C&gt;T, R520*), confirming XLA. The clinical course included multiple episodes of neutropenia, viral and bacterial infections, and severe systemic inflammation. Conclusions: This is the first documented case of an XLA patient with confirmed BTK mutation presenting with clinical features more consistent with chronic active EBV infection. These findings challenge the prevailing paradigm that XLA confers protection against EBV-related diseases and further support the possibility of EBV noncanonical reservoirs leading to immune dysregulation. EBV should also be considered in the differential diagnosis of XLA patients presenting with systemic inflammation or lymphoproliferative disease.<\/jats:p>","DOI":"10.3390\/jpm15080365","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T09:04:53Z","timestamp":1754903093000},"page":"365","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["EBV-Driven HLH and T Cell Lymphoma in a Child with X-Linked Agammaglobulinemia: A Genetically Confirmed Case Report and Literature Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0109-5606","authenticated-orcid":false,"given":"Jose Humberto","family":"Perez-Olais","sequence":"first","affiliation":[{"name":"Unidad de Investigaci\u00f3n en Virolog\u00eda y C\u00e1ncer, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1979-113X","authenticated-orcid":false,"given":"Elizabeth","family":"Mendoza-Coronel","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n en Virolog\u00eda y C\u00e1ncer, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Javier","family":"Moreno-Ortega","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n en Virolog\u00eda y C\u00e1ncer, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2715-6422","authenticated-orcid":false,"given":"Jes\u00fas","family":"Aguirre-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00f3mica, Gen\u00e9tica y Bioinform\u00e1tica, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5498-6739","authenticated-orcid":false,"given":"Gabriela","family":"L\u00f3pez-Herrera","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunodeficiencias, Instituto Nacional de Pediatr\u00eda, M\u00e9xico City 04530, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7609-3923","authenticated-orcid":false,"given":"Marco Antonio","family":"Yamazaki-Nakashimada","sequence":"additional","affiliation":[{"name":"Departamento de Inmunolog\u00eda Cl\u00ednica, Instituto Nacional de Pediatr\u00eda, M\u00e9xico City 04530, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Baeza-Capetillo","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00f3mica, Gen\u00e9tica y Bioinform\u00e1tica, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guadalupe Fernanda","family":"God\u00ednez-Zamora","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00f3mica, Gen\u00e9tica y Bioinform\u00e1tica, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9193-0091","authenticated-orcid":false,"given":"Omar Josue","family":"Saucedo-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Departamento de Alergia e Inmunolog\u00eda Pedi\u00e1trica, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura C.","family":"Bonifaz","sequence":"additional","affiliation":[{"name":"Coordinaci\u00f3n de Investigaci\u00f3n en Salud, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2872-0459","authenticated-orcid":false,"given":"Ezequiel M.","family":"Fuentes-Panan\u00e1","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n en Virolog\u00eda y C\u00e1ncer, Hospital Infantil de M\u00e9xico \u201cFederico G\u00f3mez\u201d, M\u00e9xico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e20250003","DOI":"10.70962\/jhi.20250003","article-title":"Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee","volume":"1","author":"Poli","year":"2025","journal-title":"J. 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