{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T14:55:53Z","timestamp":1767711353525,"version":"3.48.0"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":35,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Allergy Asthma Clin Immunol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      \u00a0X-linked agammaglobulinemia (XLA) is an inborn error of immunity resulting from mutations in the\u00a0\n                      <jats:italic>BTK<\/jats:italic>\n                      \u00a0gene. It is an X-linked inherited disease that almost exclusively affects males, while females are usually carriers of the disease. However, certain genetic conditions can lead to XLA disease expression in females. We report a 14-year-old girl who was diagnosed with XLA from a pathogenic\n                      <jats:italic>BTK<\/jats:italic>\n                      variant and skewed X chromosome inactivation (XCI).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      A 14-year-old female Ukrainian refugee was referred to the respirology clinic at the Montreal Children\u2019s Hospital with an abnormal chest radiograph found during her immigration medical screening process in Canada. She was reported to be previously well until the age of 11\u00a0years when she was diagnosed with pneumonia following SARS-CoV-2 infection. She subsequently developed recurrent pneumonias, persistent productive cough, and chronic sinusitis with polyposis. Laboratory investigations showed severely reduced serum immunoglobulin G, A, and M concentrations of 0.78\u00a0g\/L,\u2009&lt;\u20090.10\u00a0g\/L, and 0.21\u00a0g\/L, respectively. Flow cytometry for lymphocyte subsets showed a complete absence of circulating B cells in peripheral blood. Next-generation sequencing panel for inborn errors or immunity revealed a heterozygous pathogenic variant in\n                      <jats:italic>BTK<\/jats:italic>\n                      (c.862C\u2009&gt;\u2009T, p.Arg288Trp). Analysis of XCI revealed markedly skewed inactivation (99:1), resulting in predominant expression of the mutant pathogenic BTK allele. These findings support the clinical diagnosis of X-linked agammaglobulinemia manifesting in a female patient due to skewed XCI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Female carriers of pathogenic mutations in BTK may develop clinically important disease as a result of extreme random X inactivation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13223-025-01002-0","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T02:03:33Z","timestamp":1764641013000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical relevant Bruton\u2019s X-linked tyrosine kinase deficiency in a female with extreme X-chromosome inactivation"],"prefix":"10.1186","volume":"22","author":[{"given":"Sundus M.","family":"NoorSaeed","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulaziz S.","family":"Alrafiaah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manar","family":"Alghamdi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam J.","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"McCusker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"issue":"6","key":"1002_CR1","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1542\/peds.9.6.722","volume":"9","author":"OC Bruton","year":"1952","unstructured":"Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722\u20138.","journal-title":"Pediatrics"},{"key":"1002_CR2","unstructured":"Smith CIE, Bergl\u00f6f A. X-Linked Agammaglobulinemia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(\u00ae). Seattle (WA): University of Washington, Seattle. Copyright \u00a9 1993\u20132025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993"},{"key":"1002_CR3","unstructured":"Basta M, Pandya AM. Genetics, X-Linked Inheritance. StatPearls, editor. Treasure Island (FL): StatPearls Publishing; 2023 2023 May 1."},{"issue":"3","key":"1002_CR4","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/humu.9219","volume":"23","author":"M Fiorini","year":"2004","unstructured":"Fiorini M, Franceschini R, Soresina A, Schumacher RF, Ugazio AG, Rossi P, et al. BTK: 22 novel and 25 recurrent mutations in European patients with X-linked agammaglobulinemia. Hum Mutat. 2004;23(3):286.","journal-title":"Hum Mutat"},{"issue":"12","key":"1002_CR5","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1110\/ps.9.12.2377","volume":"9","author":"SR Tzeng","year":"2000","unstructured":"Tzeng SR, Pai MT, Lung FD, Wu CW, Roller PP, Lei B, et al. Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia. Protein Sci. 2000;9(12):2377\u201385.","journal-title":"Protein Sci"},{"issue":"3","key":"1002_CR6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1006\/clim.2002.5241","volume":"104","author":"A Plebani","year":"2002","unstructured":"Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. 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Blood. 2004;103(1):185\u20137.","journal-title":"Blood"},{"issue":"2","key":"1002_CR15","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/s10875-024-01659-z","volume":"44","author":"M Garcia-Prat","year":"2024","unstructured":"Garcia-Prat M, Batlle-Mas\u00f3 L, Parra-Mart\u00ednez A, Franco-Jarava C, Martinez-Gallo M, Aguil\u00f3-Cucurull A, et al. Role of skewed X-chromosome inactivation in common variable immunodeficiency. J Clin Immunol. 2024;44(2):54.","journal-title":"J Clin Immunol"},{"key":"1002_CR16","doi-asserted-by":"publisher","first-page":"1391807","DOI":"10.1155\/2022\/1391807","volume":"2022","author":"Z Sun","year":"2022","unstructured":"Sun Z, Fan J, Wang Y. X-Chromosome inactivation and related diseases. Genet Res (Camb). 2022;2022:1391807.","journal-title":"Genet Res (Camb)"}],"container-title":["Allergy, Asthma &amp; Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13223-025-01002-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13223-025-01002-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13223-025-01002-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T14:54:39Z","timestamp":1767711279000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13223-025-01002-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":16,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1002"],"URL":"https:\/\/doi.org\/10.1186\/s13223-025-01002-0","relation":{},"ISSN":["1710-1492"],"issn-type":[{"type":"electronic","value":"1710-1492"}],"subject":[],"published":{"date-parts":[[2025,12,2]]},"assertion":[{"value":"31 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors\u2019 institution does not require ethical approval for publication of a case report. Written informed consent was obtained from the patient.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The patient\u2019s legal guardian gave written informed consent for participation in this case report and publication of her clinical details and images.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4"}}