Wen-I Lee1,2, Cheng-Hsun Chiu3, Chao-Yi Wu4,5, Yi-Ching Chen6, Jing-Long Huang7, Li-Chen Chen7, Liang-Shiou Ou4, Tsung-Chieh Yao4, Tang-Her Jaing8, Shih-Hsiang Chen8, Chi-Jou Liang5, Chen-Chen Kang5. 1. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. wen2707@gmail.com. 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. wen2707@gmail.com. 3. Division of Infection, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. chchiu@cgmh.org.tw. 4. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. 5. 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. 6. Division of Infection, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. 7. Department of Pediatrics, New Taipei Municipal TuChen Hospital, New Taipei, Taiwan. 8. Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
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.
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.
Authors: Donald B Kohn; Claire Booth; Elizabeth M Kang; Sung-Yun Pai; Kit L Shaw; Giorgia Santilli; Myriam Armant; Karen F Buckland; Uimook Choi; Suk See De Ravin; Morna J Dorsey; Caroline Y Kuo; Diego Leon-Rico; Christine Rivat; Natalia Izotova; Kimberly Gilmour; Katie Snell; Jinhua Xu-Bayford Dip; Jinan Darwish; Emma C Morris; Dayna Terrazas; Leo D Wang; Christopher A Bauser; Tobias Paprotka; Douglas B Kuhns; John Gregg; Hayley E Raymond; John K Everett; Geraldine Honnet; Luca Biasco; Peter E Newburger; Frederic D Bushman; Manuel Grez; H Bobby Gaspar; David A Williams; Harry L Malech; Anne Galy; Adrian J Thrasher Journal: Nat Med Date: 2020-01-27 Impact factor: 53.440
Authors: M Cazzola; F Sacchi; A Pagani; M Marconi; M M Ciriello; A Fietta; A Clivio; E Ascari Journal: Haematologica Date: 1985 Jul-Aug Impact factor: 9.941
Authors: Fabian Hauck; Sibylle Koletzko; Christoph Walz; Horst von Bernuth; Anne Klenk; Irene Schmid; Bernd H Belohradsky; Christoph Klein; Philip Bufler; Michael H Albert Journal: J Crohns Colitis Date: 2015-10-13 Impact factor: 9.071
Authors: Orathai Jirapongsananuruk; Harry L Malech; Douglas B Kuhns; Julie E Niemela; Margaret R Brown; Mindy Anderson-Cohen; Thomas A Fleisher Journal: J Allergy Clin Immunol Date: 2003-02 Impact factor: 10.793
Authors: David C Thomas; Louis-Marie Charbonnier; Andrea Schejtman; Hasan Aldhekri; Eve L Coomber; Elizabeth R Dufficy; Anne E Beenken; James C Lee; Simon Clare; Anneliese O Speak; Adrian J Thrasher; Giorgia Santilli; Hamoud Al-Mousa; Fowzan S Alkuraya; Talal A Chatila; Kenneth G C Smith Journal: J Allergy Clin Immunol Date: 2018-10-09 Impact factor: 10.793