婴儿型炎症性肠病48例临床特征及基因分析

Analysis of clinical features and genotype of 48 infantile-onset inflammatory bowel disease

目的总结婴儿型炎症性肠病(IO-IBD)患儿的临床和遗传学特征。方法回顾性分析首都医科大学附属北京儿童医院确诊的48例IO-IBD患儿的临床特征,采用目标基因捕获高通量测序方法对43例患儿行基因测序分析,比较基因突变组和非基因突变组IO-IBD患儿的临床特征。结果48例IO-IBD患儿中,克罗恩病(CD)41例,溃疡性结肠炎(UC)7例;起病中位年龄2.00(0.24~6.00)月龄,其中1月龄内起病患儿占45.8%(22/48例)。临床症状以腹泻(48/48例,100.0%)、发热(45/48例,93.8%)、便血(37/48例,77.1%)为主,肠外表现以肛周病变和皮疹最常见,均占43.8%(21/48例)。41例CD患儿病变部位以结肠(L2)型为主(30/41例,73.2%),疾病行为以非狭窄非穿透(B1)型为主(33/41例,80.5%);7例UC患儿病变范围以全结肠(E4)型为主(4/7例,57.1%)。48例IO-IBD患儿手术率12.5%(6/48例),临床缓解率50.0%(24/48例),病死率25.0%(12/48例)。43例IO-IBD患儿行基因检测,共有23例(53.5%)患儿存在有意义的基因突变,其中22例突变基因为白细胞介素-10受体A(IL-10RA),1例为TTC37。22例IL-10RA突变患儿中,共检测到11个突变位点,包括1例新发突变位点c.635G>C(p.R212P);c.301C>T(p.R101W)(19例)和c.537G>A(p.T179T)(8例)是最常见的突变位点。与非基因突变组患儿相比,基因突变组患儿起病年龄更早[0.3(0.1~1.0)月龄比(6.27±5.64)月龄,P<0.001],营养不良[14例(60.9%)比5例(25.0%),P=0.018]、口腔溃疡[14例(60.9%)比3例(15.0%),P=0.006]及肛周病变[17例(73.9%)比3例(15.0%),P<0.001]更常见,临床缓解率低[7例(30.4%)比15例(75.0%),P=0.004]。结论IO-IBD患儿的单基因突变阳性率较高,IL-10RA基因突变最为常见。基因突变IO-IBD患儿具有起病年龄早,更易合并营养不良、口腔溃疡、肛周病变,有临床缓解率较低的特点。

Objective To summarize clinical and genetic features of infantile-onset inflammatory bowel disease(IO-IBD)patients.Methods The clinical data of 48 IO-IBD patients from Beijing Children′s Hospital,Capital Medical University,including age of onset,family history,clinical manifestations and drug efficacy were retrospectively analyzed.Based on target gene panel,next generation sequencing(NGS)was performed for 43 patients,and further compared clinical features between gene mutation and non-gene mutation IO-IBD groups.Results Among the 48 IO-IBD patients,41 cases suffered from Crohn′s disease(CD)and 7 cases were ulcerative colitis(UC).The median age of onset was 2.00(0.24-6.00)months,and 45.8%(22/48 cases)of patients′onset age was within 1 month.Diarrhea(48/48 cases,100%),fever(45/48 cases,93.8%)and hematochezia(37/48 cases,77.1%)were the main clinical symptoms.Perianal lesions and rashes were common extraintestinal manifestations,accounting for 43.8%(21/48 cases)each.Among 41 CD patients,73.2%(30/41 cases)had predominantly colonic disease(L2 type),and disease behavior was mainly nonstricturing and nonpenetrating(B1 type)(33/41 cases,80.5%).Among 7 UC patients,57.1%(4/7 cases)had predominantly pancolonic(E4 type).The surgical rate of the 48 IO-IBD patients was 12.5%(6/48 cases),the clinical remission rate was 50.0%(24/48 cases),and the mortality rate was 25.0%(12/48 cases).Among the 43 IO-IBD patients,23(23/43 cases,53.5%)had meaningful gene mutations,of which 22 cases had mutations in interleukin-10 receptor A(IL-10RA)and 1 case with mutation in TTC37.A total of 11 mutation sites were detected in 22 patients with IL-10RA mutations,including one novel mutation site c.635G>C(p.R212P);19 cases c.301C>T(p.R101W)and 8 cases c.537G>A(p.T179T)that were common mutation sites.Compared with non-gene mutation IO-IBD group,patients in gene mutation IO-IBD group had earlier onset age[0.3(0.1-1.0)months vs.(6.27±5.64)months,P<0.001],higher proportion of malnutrition[14 cases(60.9%)vs.5 cases(25.0%),P=0.018],oral ulcers[14 cases(60.9%)vs.30 cases(15.0%),P=0.006]and perianal lesions[17 cases(73.9%)vs.3 cases(15.0%),P<0.001],and the lower rate of clinical remission[7 cases(30.4%)vs.15 cases(75.0%),P=0.004].Conclusions IO-IBD patients had a high rate of monogenic mutation,and IL-10RA gene mutation was the common mutation.IO-IBD patients developing with gene mutation were characterized by early age of onset,higher incidence of malnutrition,oral ulcers,perianal lesions,and the lower clinical remission rate.