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Clin Transl Gastroenterol. 2018 Nov 2;9(10):201. doi: 10.1038/s41424-018-0064-x.

Clinical Heterogeneity of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A French Multicenter Retrospective Study.

Author information

1
Department of Paediatric GastroenterologyHepatology and Nutrition, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France. Remi.duclaux-loras@inserm.fr.
2
Université Paris Descartes-Sorbonne Paris Cité, Paris, France. Remi.duclaux-loras@inserm.fr.
3
INSERM, UMR1163, Laboratory of Intestinal Immunityand Imagine Institute, Paris, France. Remi.duclaux-loras@inserm.fr.
4
Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
5
INSERM, UMR1163, Laboratory of Intestinal Immunityand Imagine Institute, Paris, France.
6
Department of Pediatric, Gastroenterology Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.
7
Assistance Publique - Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paediatric Haemato-Immunology Unit, Paris, France.
8
Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland.
9
Department of Pathology, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France.
10
Hospices Civils de Lyon, Hôpital Edouard Herriot, Laboratory of Immunology, Lyon, France.
11
Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000, Grenoble, France.
12
CHU de Grenoble, UF de Biochimie Génétique et Moléculaire, Grenoble, F-38000, France.
13
Assistance Publique - Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Pediatric EndocrinologyDiabetology and Gynecology Department, Paris, France.
14
Department of Paediatric GastroenterologyHepatology and Nutrition, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France.
15
INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Paris, France.

Abstract

OBJECTIVE:

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort.

METHODS:

Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3.

RESULTS:

Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002).

CONCLUSION:

The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.

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