Jiang Tao, Li Shuangjie, Tan Yanfang, Ouyang Wenxian
Center for Pediatric Liver Diseases, Hunan Children's Hospital, Changsha, Hunan 410007, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Apr 10;42(4):486-494. doi: 10.3760/cma.j.cn511374-20240620-00345.
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 literature.
Clinical data of a child with gastrointestinal hemorrhage with CRMCC 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 whole 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 the guardian of the child.
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: c.787G>A (p.Val263Met) in exon 5 and c.2930C>G (p.Ser977Cys) in exon 17, which were inherited from his 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. The child had continued to experience recurrent gastrointestinal bleeding episodes despite propranolol treatment, but the condition was 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. Pharmacological and endoscopic therapies play a certain role in the management of CRMCC children complicated with gastrointestinal bleeding.
The CTC1 gene c.787G>A and c.2930C>G variants probably underlay CRMCC in this child. This study has 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.
探讨1例患有胃肠道出血及伴有钙化和囊肿的脑视网膜微血管病变（CRMCC）患儿的临床特征及遗传病因，并进行文献复习。
收集2019年9月入住湖南省儿童医院肝病科的1例患有CRMCC并伴有胃肠道出血患儿的临床资料，采用全外显子组测序分析患儿及其父母的外周血DNA。通过Sanger测序验证候选变异，随后进行生物信息学分析、美国医学遗传学与基因组学学会（ACMG）序列变异致病性分类标准与指南以及蛋白质结构预测。以“Coats Plus综合征”或“伴有钙化和囊肿的脑视网膜微血管病变”为关键词，在PubMed、中国知网和万方数据库进行文献检索，纳入最近发表的研究（截至2023年12月）。本研究已获得湖南省儿童医院伦理委员会批准（伦理编号：KY2020 - 07）。获得了患儿监护人的临床研究知情同意书。
先证者为一名10岁10个月大的男孩。临床表现为宫内及出生后生长发育迟缓、胃肠道出血、肝纤维化、全血细胞减少、双侧渗出性视网膜病变、颅内病变及面部色素沉着。全外显子组测序和Sanger测序显示，CTC1基因存在两个新的杂合变异：外显子5中的c.787G>A（p.Val263Met）和外显子17中的c.2930C>G（p.Ser977Cys），分别遗传自其母亲和父亲。根据ACMG致病性分类，这两个错义变异均被分类为意义未明的变异（VUS）。蛋白质结构预测显示LIG_SH3_3基序缺失，且p.Ser977Cys突变可能影响CST（CTC1 - STN1 - TEN）复合物与DNA链之间的结合。尽管使用普萘洛尔治疗，患儿仍持续出现反复胃肠道出血发作，但肝移植后病情得到控制。根据本研究预先设定的文献检索策略，共检索到10篇关于儿童CRMCC患者的相关文章，涉及11例伴有胃肠道出血的患儿。药物治疗和内镜治疗在CRMCC合并胃肠道出血患儿的管理中发挥一定作用。
CTC1基因的c.787G>A和c.2930C>G变异可能是该患儿CRMCC的病因。本研究拓宽了CTC1相关疾病的变异谱，为遗传咨询提供了依据。对于药物和内镜治疗反应不佳的儿童胃肠道出血，肝移植可能是一种重要的治疗方法。
