Jae Hyon Park1, Keum Hwa Lee2, Bokyoung Jeon3, Hans D Ochs4, Joon Suk Lee5, Heon Yung Gee5, Seeun Seo2, Dongil Geum1, Ciriaco A Piccirillo6, Michael Eisenhut7, Hans J van der Vliet8, Jiwon M Lee9, Andreas Kronbichler10, Younhee Ko11, Jae Il Shin12. 1. Yonsei University College of Medicine, Seoul, Republic of Korea. 2. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea. 3. Yonsei University Wonju College of Medicine, Wonju, Republic of Korea. 4. Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA. 5. Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03772, Republic of Korea. 6. Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada; The Research Institute of the McGill University Health Center, Montréal, QC, Canada; FOCiS Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada. 7. Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton LU4ODZ, United Kingdom. 8. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands. 9. Department of Pediatrics, Chungnam National University College of Medicine, Daejeon, Republic of Korea. 10. Department of Internal Medicine IV, Medical University Innsbruck, Innsbruck, Austria. 11. Division of Biomedical Engineering, Hankuk University of Foreign Studies, Gyeonggi-do, Republic of Korea. 12. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: shinji@yuhs.ac.
Abstract
BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. OBJECTIVES: In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. METHODS: We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. RESULTS: A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). CONCLUSIONS: We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.
BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. OBJECTIVES: In this systematic review, we focus on both clinical and demographic characteristics of IPEXpatients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. METHODS: We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. RESULTS: A total of 75 articles (195 patients) were identified. All IPEXpatients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). CONCLUSIONS: We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEXpatients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.
Authors: Jingchun Fan; Ya Gao; Na Zhao; Runjing Dai; Hailiang Zhang; Xiaoyan Feng; Guoxiu Shi; Jinhui Tian; Che Chen; Brett D Hambly; Shisan Bao Journal: Front Public Health Date: 2020-08-14