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Clinical Features of Female Taiwanese Carriers with X-linked Chronic Granulomatous Disease from 2004 to 2019

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Abstract

Purpose

Female carriers with X-linked chronic granulomatous disease (XL-CGD) who have < 10% reactive oxygen species (ROS) production due to profound X-chromosome inactivation (XCI or lyonization) are more susceptible to infections. We assessed ROS production in Taiwanese female carriers with XL-CGD to investigate whether the level of ROS correlated to their clinical features of infection, autoimmunity, and autoinflammation.

Methods

Clinical course, ROS production, flavocytochrome b558 (Cyto b558) expression, and genetic analysis in carriers were investigated after identifying their index cases between 2004 and 2019.

Results

A total of 19 mothers (median 27 years; range 25–60 years) and three of four girls (range 4–6 years) relative to 22 male index XL-CGD cases from 19 unrelated families were enrolled. Approximately half (8/19, 42%) of the mothers had novel one-allele mutations. Twenty-two of the 23 females were carriers. One carrier with de novo [Arg290X]CYBB who suffered from refractory salmonella sepsis and chorioretinitis as an XL-CGD phenotype had extreme XCI, absent Cyto b558 expression, and only 8% ROS production. The remaining carriers had bimodal patterns of Cyto b558 expressions (median 40.2%, 26.8–52.4%) and ROS production (38.3%, range 28.2–54.2%) sufficient to prevent significant infections, although neck lymphadenitis recurred in one mother and sister who had ROS expressions of 28.2% and 38.0%, respectively. However, none of the carriers had manifestations of autoimmunity or autoinflammation (e.g., photosensitivity, aphthous stomatitis, or joint disorders), of which each was seen in approximately one-third of XL-CGD carriers from the Western world.

Conclusion

One carrier had undetectable Cyto b558 expression and an extremely low ROS production, and consequently presented with an XL-CGD phenotype. One mother and her daughter experienced recurrent neck lymphadenitis despite having sufficient ROS production. Significant autoimmunity/autoinflammation did not develop in any of the carriers. Studies with a longer follow-up period are needed to validate our findings.

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Acknowledgements

The authors wish to thank all of the patients and their families for their kind cooperation, as well as their physicians for the referrals.

Funding

This study is funded by the Chang-Gung Medical Research Progress (Grant CMRPG 3G0441 and CMRPG 3K0261), the National Science Council (Grants NSC 102–2314-B-182A-039-MY3, MOST 106–2314-B-182A-147, MOST 109–2314-B-182A-109, NMRPG 3G0381, and PMRPG 3H0051), and the Taiwan Foundation for Rare Disorders (TFRD).

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Author notes

  1. Chao-Yi Wu and Yi-Ching Chen contributed equally to this work.

Authors and Affiliations

  1. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Chao-Yi Wu, Wen-I Lee, Liang-Shiou Ou & Tsung-Chieh Yao

  2. Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kwei-Shan, #5 Fu-Shing St. (Pediatric Office 12 L), Taoyuan, Taiwan

    Chao-Yi Wu, Wen-I Lee, Chi-Jou Liang & Chen-Chen Kang

  3. Division of Infection, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Yi-Ching Chen & Cheng-Hsun Chiu

  4. Department of Pediatrics, New Taipei Municipal TuChen Hospital, New Taipei, Taiwan

    Jing-Long Huang & Li-Chen Chen

  5. Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Tang-Her Jaing & Shih-Hsiang Chen

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Contributions

Wu CY, Chen YC, and Lee WI carried out the molecular genetic studies, analyzed the sequence alignment, and drafted the manuscript. Wu CY, Lee WI, and Chiu CH performed the immunoassays. Lee WI and Chiu CH designed the study and the statistical analysis. Chen LC, Yao TC, Ou LS, Jaing TH, Chen SH, and Huang JL participated in the study to care for the critical patients. All authors read and approved the final manuscript.

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Correspondence to Wen-I Lee or Cheng-Hsun Chiu.

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Wu, CY., Chen, YC., Lee, WI. et al. Clinical Features of Female Taiwanese Carriers with X-linked Chronic Granulomatous Disease from 2004 to 2019. J Clin Immunol 41, 1303–1314 (2021). https://doi.org/10.1007/s10875-021-01055-x

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