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Background <p>&#xa0;X-linked agammaglobulinemia (XLA) is an inborn error of immunity resulting from mutations in the&#xa0;<i>BTK</i>&#xa0;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 <i>BTK</i> variant and skewed X chromosome inactivation (XCI).</p> Case presentation <p>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&#xa0;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&#xa0;g/L, &lt; 0.10&#xa0;g/L, and 0.21&#xa0;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 <i>BTK</i> (c.862C &gt; 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.</p> Conclusions <p>Female carriers of pathogenic mutations in BTK may develop clinically important disease as a result of extreme random X inactivation.</p>

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

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  • 发表日期：

    2025年12月2日

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  • Sundus M. NoorSaeed,
  • Abdulaziz S. Alrafiaah,
  • Manar Alghamdi,
  • Adam J. Shapiro,
  • Christine McCusker

摘要

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.