消化系统遗传代谢病患儿临床和基因特征的病例系列报告

Clinical and genetic profiles of children with inherited metabolic diseases of the digestive system:A case series report

背景既往儿童消化系统疾病以感染性疾病为主,近年来遗传代谢性疾病的诊断率也逐渐升高。目的总结常见的消化系统遗传代谢病的临床表型和基因型。设计病例系列报告。方法纳入在单中心2015年1月1日至2019年12月31日因消化系统症状就诊且全外显子组基因检测结果异常的患儿。从病历系统中截取患儿的人口学资料、临床资料和基因检测结果。主要结局指标临床表型和基因型。结果320例行基因检测的消化科患儿中结果异常111例(34.7%),诊断时年龄(2.4±2.8)岁,男68例(61.3%)。主要疾病表型包括:遗传性肝病70例(63.1%),其中肝豆状核变性和糖原累积病各15例,Citrin缺乏症13例,Alagille综合征、进行性家族性肝内胆汁淤积症和胆红素代谢障碍各9例;极早发型炎症性肠病(VEO-IBD)8例(7.2%);进行性肌营养不良10例(9.1%)等。肝豆状核变性多表现为无症状的持续性转氨酶升高(53.3%),ATP7B基因c.2333G>T(p.R778L)是最常见的变异位点(53.3%)。糖原累积病患儿的临床表现主要为低血糖、肝肿大、肝功能异常(均为93.3%)以及TG升高(60.0%),亚型包括Ⅸa型6例,Ⅲ型5例,GSDⅠa、GSDⅡ、GSDⅥ和ⅩⅤ型各1例。9例Alagille综合征患儿均有肝功能异常,8例(88.9%)以“皮肤、巩膜黄染”就诊;8例(88.9%)为JAG1基因变异(Alagille综合征1型),1例为NOTCH2基因变异(Alagille综合征2型)。Citrin缺乏症患儿多因“皮肤黏膜黄染”入院(92.3%),多有肝酶异常、胆汁淤积和低血糖,13例均检出SLC25A13基因突变,以c.851_854del(38.5%)和c.852_855del(30.8%)位点最为常见。9例进行性家族性肝内胆汁淤积症患儿均有肝脏肿大,ALT、AST和总胆汁酸升高,分型包括2型(ABCB11基因变异)6例,3型(ABCB4基因变异)2例,1型(ATP8B1基因变异)1例。9例胆红素代谢障碍患儿主诉均为“黄疸和/或肝功能异常”,均检出UGT1A1基因突变,c.211G>A(p.G71R)(66.7%)和A(AT)6TAAinsTA(55.6%)是最常见的变异位点。8例VEO-IBD患儿均以“慢性腹泻”为主诉,均有血WBC计数和CRP水平升高,消化道内镜均显示结肠黏膜出现鹅卵石样改变和深度溃疡;7例为IL10-RA基因突变,最常见的为c.301C>T(p.R101W)(62.5%)和c.537G>A(p.T179T)(50%),1例为IL10-RB基因的杂合突变。结论基因检测在儿童消化系统遗传病的诊断及治疗中有重要作用。

Background Historically,infectious diseases have been the primary focus of pediatric gastrointestinal disorders.However,in recent years,the diagnosis rate of genetic metabolic diseases has gradually increased.Objective To summarize the clinical phenotypes and genotypes of common genetic metabolic diseases affecting the digestive system.Design Case series report.Methods This study included children who presented with gastrointestinal symptoms and had abnormal whole-exome sequencing results at a single center between January 1,2015,and December 31,2019.Demographic data,clinical information,and genetic testing results were extracted from the medical records system.Main outcome measures Clinical phenotypes and genotypes.Results Among the 320 children who underwent genetic testing in the gastroenterology department,111(34.7%)had abnormal results.The mean age at diagnosis was 2.4±2.8 years,and 68(61.3%)were male.The main disease phenotypes included hereditary liver diseases in 70 cases(63.1%),with Wilson's disease and glycogen storage diseases each accounting for 15 cases,Citrin deficiency for 13 cases,Alagille syndrome,progressive familial intrahepatic cholestasis(PFIC),and bilirubin metabolism disorders for 9 cases each.Other conditions included very early-onset inflammatory bowel disease(VEO-IBD)in 8 cases(7.2%)and progressive muscular dystrophy in 10 cases(9.1%).Wilson's disease commonly presented as asymptomatic persistent transaminase elevation(53.3%),with the ATP7B gene c.2333G>T(p.R778L)being the most common mutation site(53.3%).Glycogen storage disease patients mainly exhibited hypoglycemia,hepatomegaly,abnormal liver function(93.3%for all),and elevated triglycerides(60.0%).Subtypes included typeⅨa(6 cases),typeⅢ(5 cases),and one case each of GSDⅠa,GSDⅡ,GSDⅥ,and GSDⅩⅤ.Alagille syndrome was associated with abnormal liver function in all 9 cases,and 8(88.9%)visited the hospital due to yellowish discolouration of the skin and sclera.The JAG1 gene mutation(Alagille syndrome type 1)was found in 8 cases(88.9%),and the NOTCH2 gene mutation(Alagille syndrome type 2)was found in 1 case.Citrin deficiency patients were mostly admitted due to yellowish discolouration of the skin and mucous membrane(92.3%)and exhibited abnormal liver enzymes,cholestasis,and hypoglycemia.All 13 cases had mutations in the SLC25A13 gene,with c.851_854del(38.5%)and c.852_855del(30.8%)being the most common mutations.Progressive familial intrahepatic cholestasis(PFIC)was characterized by hepatomegaly,elevated ALT,AST,and total bile acids in all 9 cases.The subtypes included type 2(6 cases with ABCB11 gene mutations),type 3(2 cases with ABCB4 gene mutations),and type 1(1 case with ATP8B1 gene mutation).Bilirubin metabolism disorders were identified in 9 cases presenting with jaundice and/or abnormal liver function,all of which had UGT1A1 gene mutations.The most common mutation sites were c.211G>A(p.G71R)(66.7%)and A(AT)6TAAinsTA(55.6%).VEO-IBD was primarily characterized by chronic diarrhea in all 8 cases,with elevated WBC counts and CRP levels.Endoscopic findings showed cobblestone-like changes and deep ulcers in the colonic mucosa.Seven cases had IL10-RA gene mutations,with c.301C>T(p.R101W)(62.5%)and c.537G>A(p.T179T)(50%)being the most common,and one case had a heterozygous mutation in the IL10-RB gene.Conclusion Genetic testing plays a crucial role in the diagnosis and treatment of genetic metabolic diseases affecting the digestive system in children.