{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T17:49:16Z","timestamp":1789494556569,"version":"build-2803163510"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012554","name":"Hubei Provincial Department of Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency disorder caused by mutations in the Bruton tyrosine kinase (BTK) gene. This article presents a fatal case of a 20-year-old male with XLA complicated by septic shock due to <jats:italic>Pseudomonas aeruginosa<\/jats:italic> infection, highlighting two novel BTK insertion mutations in exon 15 (NM_000061.3 exon15:c.1561insG and c.1565insTAGAA). Concurrently, we provide a systematic review of XLA\u2019s genetic basis, clinical manifestations, diagnostic challenges, and therapeutic advancements. The patient\u2019s delayed diagnosis, lack of immunoglobulin replacement therapy, and fatal outcome underscore the importance of early genetic screening and standardized management. This case and review aim to enhance clinical awareness and emphasize the integration of genetic diagnostics into routine practice for primary immunodeficiencies.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1645337","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T10:33:30Z","timestamp":1755254010000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Fatal X-linked agammaglobulinemia complicated by septic shock: a case report and comprehensive review of novel BTK mutations"],"prefix":"10.3389","volume":"16","author":[{"given":"Piaopiao","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayue","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198608283150907","article-title":"Expression of the gene defect in X-linked agammaglobulinemia","volume":"315","author":"Conley","year":"1986","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1086\/301828","article-title":"Mutations in btk in patients with presumed X-linked agammaglobulinemia","volume":"62","author":"Conley","year":"1998","journal-title":"Am J Hum Genet"},{"key":"B3","article-title":"X-linked agammaglobulinemia","volume-title":"GeneReviews((R))","author":"Smith","year":"1993"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199611000-00001","article-title":"X-linked agammaglobulinemia. A clinical and molecular analysis","volume":"75","author":"Ochs","year":"1996","journal-title":"Med (Baltimore)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.1046","article-title":"Bruton\u2019s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell Malignancies","volume":"32","author":"Ponader","year":"2014","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/jimmunol\/188.7.2948","article-title":"The gene involved in X-linked agammaglobulinaemia is a member of the Src family of protein-tyrosine kinases","volume":"188","author":"Vetrie","year":"2012","journal-title":"1993. J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-879X2010007500079","article-title":"Mutations of Bruton\u2019s tyrosine kinase gene in Brazilian patients with X-linked agammaglobulinemia","volume":"43","author":"Ramalho","year":"2010","journal-title":"Braz J Med Biol Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev.immunol.021908.132649","article-title":"Primary B cell immunodeficiencies: comparisons and contrasts","volume":"27","author":"Conley","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01237-1","article-title":"X-linked agammaglobulinemia: infection frequency and infection-related mortality in the USIDNET registry","volume":"42","author":"O\u2019Toole","year":"2022","journal-title":"J Clin Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000004544","article-title":"Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015)","volume":"95","author":"Chen","year":"2016","journal-title":"Med (Baltimore)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(99)70246-5","article-title":"Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients","volume":"134","author":"Quartier","year":"1999","journal-title":"J Pediatr"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2021.04.070","article-title":"Crohn\u2019s-like enteritis in X-linked agammaglobulinemia: A case series and systematic review","volume":"9","author":"Khan","year":"2021","journal-title":"J\u00a0Allergy Clin Immunol Pract"},{"key":"B13","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1080\/1744666X.2018.1413349","article-title":"Delayed diagnosis in X-linked agammaglobulinemia and its relationship to the occurrence of mutations in BTK non-kinase domains","volume":"14","author":"Carrillo-Tapia","year":"2018","journal-title":"Expert Rev Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.10.1743","article-title":"Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia","volume":"3","author":"Hagemann","year":"1994","journal-title":"Hum Mol Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2023\/5797541","article-title":"BTKbase, bruton tyrosine kinase variant database in X-linked agammaglobulinemia: looking back and ahead","volume":"2023","author":"Schaafsma","year":"2023","journal-title":"Hum Mutat"},{"key":"B16","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1007\/s12016-021-08870-5","article-title":"Agammaglobulinemia: from X-linked to autosomal forms of disease","volume":"63","author":"Cardenas-Morales","year":"2022","journal-title":"Clin Rev Allergy Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2005.04.043","article-title":"A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia","volume":"116","author":"Lopez-Granados","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00464","article-title":"Multiplexed proteomic analysis for diagnosis and screening of five primary immunodeficiency disorders from dried blood spots","volume":"11","author":"Collins","year":"2020","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1039\/D4CB00312H","article-title":"Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK\/Tec double deficient X-linked agammaglobulinemia model","volume":"6","author":"Bestas","year":"2025","journal-title":"RSC Chem Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2025.02.026","article-title":"Gene therapy for inborn errors of immunity: Current clinical progress","volume":"134","author":"Wijeyesinghe","year":"2025","journal-title":"Ann Allergy Asthma Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1645337\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T10:33:31Z","timestamp":1755254011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1645337\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":20,"alternative-id":["10.3389\/fimmu.2025.1645337"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1645337","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,15]]},"article-number":"1645337"}}