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

Abstract

ObjectiveImmune 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.MethodsMulticenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3.ResultsThirty 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).ConclusionThe broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.

IPEX Syndrome: Improved Knowledge of Immune Pathogenesis Empowers Diagnosis

“…In the latter cases, evolution over time may help to raise suspicion, since the majority of IPEX patients develop additional autoimmune diseases. Studies on the largest cohorts of IPEX patients ( 6 , 56 , 57 ) report delayed onset above 1 year of age in a limited number of cases ranging from 6% (2/30) ( 57 ) to 10.4% (10/96) ( 6 ). According to our cohort study ( 6 ), the majority of patients with onset between 1 month and 1 year share a clinical picture similar to that of babies below 1 month of age displaying the “classical triad” of symptoms.…”

New Findings of Immunodysregulation, Polyendocrinopathy, and Enteropathy X-linked Syndrome (IPEX); Granulomas in Lung and Duodenum

“…However, this treatment regimen does not provide complete recovery and increases the risk of severe and opportunistic infections. 8 , 21 HSCT is the only curative treatment found effective in IPEX. 1 , 8 The best results of HSCT occur when performed at younger ages and at the early stage of the disease.…”

Nueva mutación identificada en el gen FOXP3 en lactante menor con diarrea crónica como manifestación de enteropatía autoinmune - Síndrome IPEX

“…Duclaux-Loras y cols, realizaron un estudio multicéntrico retrospectivo con 30 pacientes con Síndrome IPEX. De estos, 19 fueron llevados a endoscopia diagnóstica, encontrándose inflamación severa del tracto gastrointestinal superior y del colon 11 . Los hallazgos histológicos clásicos son: atrofia severa de vellosidades, hiperplasia de la lámina propia con infiltrado inflamatorio mononuclear e hiperplasia de las criptas con evidencia de cuerpos apoptóticos, como se evidenció en el paciente.…”