摘要
目的探讨合并消化道出血的伴钙化和囊变的脑视网膜微血管病(CRMCC)患儿的临床特征、遗传学病因。方法选择2019年9月在湖南省儿童医院肝病科就诊的1例合并消化道出血CRMCC患儿(患儿1,先证者)为研究对象。采集患儿1及其父母外周血DNA进行全外显子组测序(WES),对候选基因变异进行Sanger测序验证、生物信息学分析、美国医学遗传学与基因组学学会(ACMG)《遗传变异分类标准与指南》的致病性评级和蛋白质结构预测。以"Coats Plus综合征"或者"伴钙化和囊变的脑视网膜微血管病"为关键词检索PubMed数据库、中国期刊全文数据库和万方医学文献数据库建库至2023年12月报道的CRMCC患儿研究相关文献,并进行文献复习。本研究获得湖南省儿童医院伦理委员会批准(批准号:KY2020-07),并与患儿1监护人签署临床研究知情同意书。结果患儿1为男性,10岁10个月,有宫内外生长发育迟缓史,以消化道出血、肝纤维化、全血细胞减少、双侧渗出性视网膜病变、颅内病变和面部色素沉着等收入本院治疗。WES和Sanger测序结果表明患儿1,保守端粒成分1(CTC1)双等位基因错义变异新发突变,分别位于第5号外显子c.787G>A(p.Val263Met)和第17号外显子c.2930C>G(p.Ser977Cys),分别遗传自患儿的母亲和父亲,根据ACMG致病性评级结果显示这2个错义变异为意义不明变异。CTC1蛋白质结构预测显示:LIGSH33motif的消失,p.Ser977Cys变异可能会影响CST(CTC1-STN1-TEN)复合物与DNA链之间的结合。本研究对患儿1合并的消化道出血采取普萘诺尔治疗后,出血仍反复复发,进行肝移植后,消化道出血得到控制。根据本研究设定的文献检索策略,共计检索到关于CRMCC患儿研究相关文献为10篇,涉及伴消化道出血的CRMCC患儿为11例。目前药物和内镜下治疗在合并消化道出血CRMCC患儿治疗中发挥着一定作用。结论CTC1基因c.787G>A和c.2930C>G错义变异,可能为CRMCC的遗传学病因。由此拓宽了CTC1基因相关疾病的变异谱,为家系遗传咨询提供了基础;对药物和内镜治疗效果欠佳的患儿,采取肝移植措施,可能使其胃肠道系统出血得到有效控制。
Objective To explore the clinical characteristics and genetic cause of a child with gastrointestinal hemorrhage and Cerebroretinal microangiopathy with calcifications and cysts(CRMCC)and to review the literatuve.Methods Clinical data of a child with gastrointestinal hemorrhage with CRMCC(patient 1,proband)admitted to the Hepatology Department of Hunan Children's Hospital in September 2019 were collected,and peripheral blood DNA of the child and his parents were analyzed by whol-exome sequencing.Candidate variants were validated by Sanger sequencing,followed by bioinformatics analysis,American College of Medical Genetics and Genomics(ACMG)Standards and Guidelines for the Interpretation of Sequence Variants pathogenicity classification,and protein structure prediction.A literature search with"Coats Plus syndrome"or"Cerebroretinal microangiopathy with calcifications and cysts"as keywords was conducted at PubMed,China National Knowledge Infrastructure and Wanfang databases to include recently published studies(up to December 2023).This study has been approved by the Ethics Committee of Hunan Children's Hospital(Ethics No.KY2020-07).Informed consent for clinical research was obtained from one guardian of the child.Results The proband was a 10-year-10-month-old boy.The clinical manifestations were intrauterine and postnatal growth retardation,gastrointestinal hemorrhage,liver fibrosis,panhemopenia,bilateral exudative retinopathy,intracranial lesions and facial pigmentation.WES and Sanger sequencing revealed two novel heterozygous variants in the CTC1 gene of the patient:c.787G>A(p.Val263Met)in exon 5 and c.2930C>G(p.Ser977Cys)in exon 17,inherited from the mother and father,respectively.According to ACMG pathogenicity classification,both missense variants were classified as variants of uncertain significance(VUS).Protein structure prediction showed the absence of LIG_SH3_3 motif and LIG_SH3_3 motif,and the p.Ser977Cys mutation may affect the binding between CST(CTC1-STN1-TEN)complex and DNA strand.In this study,the child had continued to experience recurrent gastrointestinal bleeding episodes despite propranolol treatment,but the condition was successfully controlled after liver transplantation.According to the predefined literature search strategy of this study,a total of 10 relevant articles on pediatric CRMCC patients were retrieved,involving 11 children with gastrointestinal bleeding.Current Pharmacological and endoscopic therapies play a certain role in the management of CRMCC children complicated with gastrointestinal bleeding.Conclusions The CTC1 gene c.787G>A and c.2930C>G variants probably underlay CRMCC in this child.This study had broadened the variation spectrum of CTC1-related diseases and provided a basis for genetic counseling.Liver transplantation may be an important treatment for gastrointestinal hemorrhage in children who do not respond well to medication and endoscopic therapy.
作者
姜涛
李双杰
谭艳芳
欧阳文献
Jiang Tao;Li Shuangjie;Tan Yanfang;Ouyang Wenxian(Center for Pediatric Liver Diseases,Hunan Children's Hospital,Changsha,Hunan 410007,China)
出处
《中华医学遗传学杂志》
2025年第4期486-494,共9页
Chinese Journal of Medical Genetics
关键词
伴钙化和囊变的脑视网膜微血管病
胃肠出血
失血
手术
CTC1基因
端粒
等位基因
错义变异
肝移植
Cerebroretinal microangiopathy with calcifications and cysts
Gastrointestinal hemorrhage
Blood loss,surgical
CTC1 gene
Telomere
Allele
Missense variant
Liver transplantation
