Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A systematic review.

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.

• Authors: Jae Hyon Park, Keum Hwa Lee, Bokyoung Jeon, Hans D Ochs, Joon Suk Lee, Heon Yung Gee, Seeun Seo, Dongil Geum, Ciriaco A Piccirillo, Michael Eisenhut, Hans J van der Vliet, Jiwon M Lee, Andreas Kronbichler, Younhee Ko, Jae Il Shin
• Journal: Autoimmunity reviews (Autoimmun Rev) Vol. 19 Issue 6 Pg. 102526 (Jun 2020) ISSN: 1873-0183 [Electronic] Netherlands
• PMID: 32234571 (Publication Type: Journal Article, Systematic Review)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• FOXP3 protein, human
• Forkhead Transcription Factors

Topics

• Forkhead Transcription Factors (genetics)
• Genetic Diseases, X-Linked (immunology, pathology)
• Humans
• Immune System Diseases (immunology, pathology)
• Intestinal Diseases (immunology, pathology)
• Mutation
• Polyendocrinopathies, Autoimmune (immunology, pathology)
• Syndrome
• T-Lymphocytes, Regulatory (immunology)