Department of Paediatric GastroenterologyHepatology and Nutrition, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France.
Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
Clin Transl Gastroenterol. 2018 Nov 2;9(10):201. doi: 10.1038/s41424-018-0064-x.
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.
Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3.
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).
The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.
免疫调节异常、多内分泌腺病、肠病、X 连锁（IPEX）综合征是一种自身免疫性疾病，由叉头框蛋白 3 基因（FOXP3）突变引起，该基因编码免疫耐受的关键调节因子。本研究旨在描述法国全国队列中该疾病的临床异质性。
对 FOXP3 突变引起的 IPEX 综合征患者进行多中心回顾性研究。
共纳入 26 个家系的 30 名儿童。疾病发病年龄（中位数[第一四分位数至第三四分位数]）为 1.5 个月[0-84]，死亡年龄为 3.5 岁[0-10.5]（n=15），表明存在高度异质性。首发表现为腹泻（68%）、1 型糖尿病（T1D；25%）、皮肤病变（7%）和肾病（3%）。在疾病过程中，观察到以下主要症状：腹泻（100%）、皮肤病变（85%）、T1DM（50%）、严重食物过敏（39%）、血液系统疾病（28%）、肾病（25%）、肝炎（14%）以及存在各种自身抗体。免疫抑制单药或联合治疗使 8 名儿童病情改善。3 名男孩未接受免疫抑制治疗，病情稳定。总体 10 年生存率为 43%（移植患者为 42%，接受免疫抑制治疗患者为 52%）。在 22 个鉴定的 FOXP3 突变中，有 5 个尚未描述：c.-23+1G>G、c.-23+5G>G、c.264delC、c.1015C>T 和 c.1091A>G。前两种产生非典型、衰减表型。影响叉头结构域的错义和移码突变与不良预后相关（Gehan-Wilcoxon p=0.002）。
IPEX 的广泛表型异质性引发了对修饰因子的质疑，并证明了在疑似病例中早期进行 FOXP3 测序的合理性。
