Clinical and genetic profiles of children with inherited metabolic diseases of the digestive system:A case series report
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 type Ⅸa(6 cases),type Ⅲ(5 cases),and one case each of GSD Ⅰa,GSD Ⅱ,GSD Ⅵ,and GSD ⅩⅤ.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.
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