Clinical relevant Bruton’s X-linked tyrosine kinase deficiency in a female with extreme X-chromosome inactivation

Sep 30, 2026

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X-linked agammaglobulinemia (XLA) is an inherited BTK-gene immunodeficiency that mainly affects males, while females are typically carriers. A 14-year-old girl was diagnosed with XLA due to a pathogenic BTK variant together with markedly skewed X-chromosome inactivation, producing predominant expression of the mutant allele. Recurrent pneumonias, chronic sinusitis with polyposis, severely decreased IgG/IgA/IgM, and virtual absence of circulating B cells supported the diagnosis. The case highlights that extreme random X inactivation can make female carriers clinically affected.

LanguageEnglish

CategoryHealthcare

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Pages5

Reading Time13 min

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NoorSaeed et al. Allergy, Asthma & Clinical Immunology (2026) 22:4 [https://doi.org/10.1186/s13223-025-01002-0](https://doi.org/10.1186/s13223-025-01002-0) Allergy, Asthma & Clinical Immunology CASE REPORT Open Access Clinical relevant Bruton’s X-linked tyrosine kinase deficiency in a female with extreme X-chromosome inactivation Sundus M. NoorSaeed 1,2*, Abdulaziz S. Alrafiaah3,2, Manar Alghamdi2, Adam J. Shapiro4 and Christine McCusker2 Abstract Background X-linked agammaglobulinemia (XLA) is an inborn error of immunity resulting from mutations in the BTK gene. 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 BTK variant and skewed X chromosome inactivation (XCI) . Case presentation A 14-year-old female Ukrainian refugee was referred to the respirology clinic at the Montreal Children’s 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 years 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 g/L, < 0.10 g/L, and 0.21 g/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 BTK (c. 862C >T, 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. Conclusions Female carriers of pathogenic mutations in BTK may develop clinically important disease as a result of extreme random X inactivation. Keywords Agammaglobulinemia, BTK, X-chromosome inactivation, XLA, Immunodeficiency, Bronchiectasis, Bruton’s, IVIG, CVID, Chronic sinusitis *Correspondence: Sundus M. NoorSaeed [sundus.noorsaeed@mail.mcgill.ca](sundus.noorsaeed@mail.mcgill.ca) 1Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia 2Department of Pediatrics, Division of Allergy and Clinical Immunology and Dermatology, Montreal Children’s Hospital, Montreal, QC, Canada 3Department of Pediatrics, College of Medicine, Majmaah University, Majmaah 11952, Saudi Arabia 4Department of Pediatrics, Division of Respiratory Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, Canada © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ([http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/p

FAQs

What genetic and cellular mechanisms caused XLA in the female patient?

The patient had a pathogenic BTK variant and markedly skewed X-chromosome inactivation (99:1), leading to predominant expression of the mutant BTK allele.

What clinical and laboratory findings supported the diagnosis?

She developed recurrent pneumonias, chronic productive cough, and chronic sinusitis with polyposis. Laboratory tests showed severely reduced IgG/IgA/IgM and flow cytometry showed a complete absence of circulating B cells.

Why can female carriers of BTK mutations develop clinical disease?

Female carriers may develop disease when extreme random X inactivation results in clinically important expression of the mutant allele rather than balanced inactivation.

Sep 30, 2026

Uploaded by Connor