白细胞介素10受体A基因突变导致的极早发型炎症性肠病临床特点及基因分析

Clinical features and genetic analysis of very early-onset inflammatory bowel disease caused by interleukin-10 receptor A gene mutation

摘要

目的  总结白细胞介素10受体A（interleukin 10 receptor A, IL-10RA）基因突变导致的极早发型炎症性肠病（very early onset inflammatory bowel disease,VEO-IBD）患儿临床特点和遗传学特征。方法回顾性分析2007年3月到2019年5月在首都医科大学附属北京儿童医院院消化科住院的慢性腹泻的患儿中，确诊为VEO-IBD的患儿，其中病因为IL-10RA基因突变的患儿15例，对照组为15例非IL-10RA突变所致VEO-IBD患儿，统计分析其临床特点及基因报告。结果  IL-10RA基因突变所致的VEO-IBD患儿，克罗恩病（Crohn's disease,CD)11例，溃疡性结肠炎(ulcerative colitis, UC)4例，临床症状以慢性腹泻（15/15例，100.0%）、便血(15/15例，100.0%)为主，肠外表现依次为口腔黏膜溃疡（6/15例，40.0%）、皮肤红斑（5/15例，33.3%）；肛周表现依次为直肠会阴瘘5例（5/15，33.3%），肛瘘4例（4/15，26.7%)，肛裂3例(3/15，20.0%)，直肠会阴瘘、皮赘并存1例（1/15，6.7%）；全身表现为IL-10RA基因突变组营养不良13例（13/15例，86.7%），肛周病变13例（13/15例，86.7%）；对照组营养不良6例（6/15例，40.0%），肛周病变5例（5/15例，33.3%)，此两项指标与IL-10RA基因突变组相比，差异有统计学意义(P<0.05)。15例IL-10RA突变患儿中，共检测到9个突变位点，其中c.301c>T（ｐ．R101W）和c.537G>A(p.T179T)为最常见的突变位点。IL-10RA突变导致炎症因子增高，引起肠道炎症反应。凝血酶原时间和部分凝血活酶时间均明显延长。结论  IL-10RA基因突变导致的VEO-IBD患儿发病年龄早，除消化道症状外，肠外表现和肛周病变较为常见，结肠镜下病变特点以结肠多发溃疡最常见，其次为炎性息肉。c.301c>T（ｐ．R101W）和c.537G>A(p.T179T)为最常见的基因突变位点。IL-10RA突变导致炎症因子增高，引起肠道炎症反应。

Abstract

To summarize the clinical features and genetic characteristics of children with very early onset inflammatory bowel disease (VEO-IBD) caused by mutations in the interleukin 10 receptor A gene (IL10RA). Methods  Retrospective analysis was conducted on the children with chronic diarrhea hospitalized in the  Department of Gastroenterology Beijing Children's Hospital,Capital Medical University,from March 2007 to May 2019,who were diagnosed as very early onset inflammatory bowel disease (IBD). Among them,15 cases were diagnosed because of IL-10RA gene mutation,and 15 cases with VEO-IBD caused by non IL-10RA mutations in the control group. Clinical characteristics and gene reports were statistically analyzed. Results  Children with VEO-IBD caused by IL-10RA gene mutations,11 cases of Crohn's disease (CD) and 4 cases of ulcerative colitis (UC). The clinical symptoms  were mainly chronic diarrhea (15/15 cases,100.0%) and hematochezia (15/15 cases,100.0%),Extraintestinal manifestations were oral mucosal ulcers (6/15 cases,40.0%),skin erythema (5/15 cases,33.3%),and perianal manifestations were recto-perineal fistula in 5 cases (5/15,33.3%),4 cases of anal fistula (4/15,26.7%), 3 cases of anal fissure (3/15,20.0%),1 case of coexistence of recto-perineal fistula and skin tag (1/15,6.7%), and systemic manifestations of IL-10RA mutation group, malnutrition 13 cases （13/15 cases, 86.7%） perianal diseae 13 cases (13/15 cases, 86.7%). The control group had malnutrition 6 cases (6/15 cases, 40.0%) and perianal disease 5 cases (5/15  cases,33.3%).Compared with the IL-10RA mutation group，  the difference was statistically significant (P<0.05). Among 15 children with IL-10RA mutations,a total of 9 mutation sites were detected,with c.301c>T (p.R101W) and c.537G>A (P.T179T) being the most common mutation sites. The IL-10RA mutation led to an increase in inflammatory factors,leading to intestinal inflammatory response. Both prothrombin time and partial thromboplastin time were significantly prolonged.Conclusion  Children with very early-onset inflammatory bowel disease caused by IL-10RA gene mutations have an earlier age of onset. In addition to gastrointestinal symptoms,extraintestinal manifestations and perianal lesions are more common. The most common lesions under colonoscopy are multiple ulcers in the colon,followed by inflammatory polyps. The most prevalent mutation sites were c.301c>T (p.R101W) and c. 537G>A (P.T179T). The IL-10RA mutation led to an increase in inflammatory factors,leading to intestinal inflammatory response. 

关键词

极早发型炎症性肠病 / 白细胞介素10受体A基因 / 儿童 / 慢性腹泻 / 炎症因子

Key words

very early onset inflammatory bowel disease / interleukin 10 receptor A gene / children / chronic diarrhea / inflammatory factors