儿童重症监护病房234例怀疑遗传病的死亡病例遗传病因分析

Analysis of genetic etiology of 234 deaths in the pediatric intensive care unit with suspected genetic diseases

目的探索儿童重症监护病房(PICU)死亡病例的遗传病因并总结其临床特征。方法回顾性队列研究。选择2017年1月至2021年12月复旦大学附属儿科医院PICU怀疑遗传病入院后7 d内死亡的234例患儿为研究对象,收集临床诊断、实验室检查等临床信息和基因检测结果,根据基因检测结果分为致病性基因变异阳性(PGVP)组和致病性基因变异阴性(PGVN)组,采用Mann-WhitneyU检验和Pearsonχ^(2)检验或Fisher确切概率法比较组间的临床特征差异。结果234例死亡病例中男139例(59.4%)、女95例(40.6%),死亡年龄为1.0(0.4,3.7)岁,住院时长为16(6,33)d。其中PGVP组62例(26.5%),变异的致病性基因包括免疫基因[23例(37.1%)]、代谢基因[11例(17.7%)]、神经肌肉基因[11例(17.7%)]、心血管基因[4例(6.5%)]和其他系统基因[13例(21.0%)]。PGVP组的死亡年龄低于PGVN组[0.6(0.3,1.4)比1.3(0.5,4.3)岁,Z=3.85,P<0.001];存在家族史和慢性复杂疾病(CCC)的情况均多于PGVN组[6.5%(4/62)比0.6%(1/172)、93.5%(58/62)比76.2%(131/172),χ^(2)=8.87,P=0.018、0.003]。PGVP组患儿入院存在重症感染、精神反应差或昏迷、中重度贫血、血小板减少、迁延性腹泻、肌力或肌张力异常的比例均高于PGVN组[74.2%(46/62)比45.9%(79/172)、50.0%(31/62)比35.5%(61/172)、32.3%(20/62)比18.0%(31/172)、21.0%(13/62)比10.5%(18/172)、25.8%(16/62)比4.1%(7/172)、16.1%(10/62)比5.2%(9/172),χ^(2)=14.63、4.04、5.41、4.37、24.30、7.25,均P<0.05]。出现2次以上的致病基因包括IL2RG(5例)、SMN1(4例)、SH2D1A(3例,包括2例单基因变异和1例拷贝数变异)。结论PICU死亡病例的遗传基因主要为免疫、代谢和神经肌肉遗传病基因。对存在家族史、CCC和入院时存在重症感染、精神反应差或昏迷、中重度贫血、血小板减少、迁延性腹泻、肌力或肌张力异常等特征的患儿应重点关注并尽早行基因检测。

Objective:To explore the genetic etiology of pediatric intensive care unit(PICU)mortality cases and summarize their clinical characteristics.Methods:This was a retrospective cohort study.The study population consisted of 234 children who died within 7 d after admitted to the PICU of Children′s Hospital of Fudan University from January 2017 to December 2021.The clinical diagnoses,laboratory test results,and genetic testing results were collected.These patients were divided into the pathogenic gene variation positive(PGVP)group and the pathogenic gene variation negative(PGVN)group according to the results of genetic testing.The Mann-Whitney U test and Pearson′s chi-square test or Fisher′s exact probability method were used to compare the clinical characteristics between the groups.Results:A total of 234 cases were enrolled,including 139(59.4%)males and 95(40.6%)females.The age at death was 1.0(0.4,3.7)years old and the length of PICU stay was 16(6,33)days.There were 62 cases(26.5%)PGVP,and the mutated pathogenic genes included immune genes(23 cases(37.1%)),metabolic genes(11 cases(17.7%)),neuromuscular genes(11 cases(17.7%)),cardiovascular genes(4 cases(6.5%)),and genes of other systems(13 cases(21.0%)).The age at death in PGVP cases was significantly lower than in PGVN cases(0.6(0.3,1.4)vs.1.3(0.5,4.3)years old,Z=3.85,P<0.001).Compared with the PGVN group,the PGVP group had a higher incidence of family history and chronic complex conditions(CCC)than the PGVN group(6.5%(4/62)vs.0.6%(1/172)and 93.5%(58/62)vs.76.2%(131/172),χ^(2)=8.87,P=0.018 and 0.003,respectively).Children in the PGVP group were admitted with higher incidence of severe infection,decreased consciousness or coma,moderate-to-severe anemia,thrombocytopenia,protracted diarrhea,and abnormalities in muscle strength or tone than those in the PGVN group(74.2%(46/62)vs.45.9%(79/172),50.0%(31/62)vs.35.5%(61/172),32.3%(20/62)vs.18.0%(31/172),21.0%(13/62)vs.10.5%(18/172),25.8%(16/62)vs.4.1%(7/172),16.1%(10/62)vs.5.2%(9/172),χ^(2)=14.63,4.04,5.41,4.37,24.30,7.25,all P<0.05).Pathogenic genes that occurred more than twice included IL2RG(5 cases),SMN1(4 cases),and SH2D1A(3 cases,including 2 single gene varients and 1 copy number varient).Conclusions:Among the deceased cases in the PICU,the main genetic causes are immune-related,metabolic,and neuromuscular genetic disorders.Critically ill children with a family history,CCC,and early features such as severe infections,decreased consciousness or coma,moderate to severe anemia,thrombocytopenia,protracted diarrhea,or abnormalities in muscle strength or tone should be closely monitored and undergo early genetic testing.