先天性高胰岛素血症18例临床特征和遗传学分析

Clinical features and genetic analysis of 18 cases of congenital hyperinsulinemia

目的对先天性高胰岛素血症(CHI)的临床特征及致病基因携带情况进行总结及分析。方法选取2015年12月—2018年10月北京儿童医院内分泌遗传代谢科收治临床先天性高胰岛素血症患儿18例为研究对象,对患儿的临床特征、致病基因携带情况、诊疗经过和后期随访资料等进行回顾性分析。结果18例患儿中,男7例,女11例,起病年龄生后1 d~1岁2个月,中位起病年龄为45 d,出生体质量2.7~4.9(3.74±0.68)kg;足月胎龄儿10例,巨大儿8例。携带ABCC8基因或GULD1基因突变7例(38.9%),未发现已知CHI相关致病基因突变11例。3例患儿携带ABCC8基因突变:2例(1例为巨大儿,1例出生体质量正常,均于生后第1天起病,均对二氮嗪治疗无效)携带ABCC8基因复合杂合突变,突变均分别遗传自父亲或母亲;另1例患儿携带父系遗传ABCC8基因突变,患儿于生后第3天起病,出生体质量正常,对二氮嗪治疗无效。4例患儿携带GULD1基因新生杂合错义突变,起病年龄生后1 d~1岁2个月,对二氮嗪治疗均有效,经长期随访,其中2例患儿确诊为癫痫。结论中国CHI患儿中,ABCC8基因和GULD1基因突变可导致CHI的发生。携带ABCC8基因突变者通常起病较早,多对二氮嗪治疗无效。携带GLUD1基因突变的患儿起病相对较晚,均对二氮嗪治疗有效,有发生癫痫的倾向。

Objective To summarize and analyze the clinical features and pathogenic gene carriers of congenital hyperinsulinemia(CHI).Methods From December 2015 to October 2018,18 children with clinical congenital hyperinsulinemia admitted to the Department of Endocrinology,Genetics and Metabolism,Beijing Children's Hospital were selected as the research objects.The clinical characteristics,pathogenic gene carrying status,diagnosis and treatment process and later stages of the children were selected.Follow-up data and other retrospective analysis.Results Among the 18 children,7 were males and 11 were females.The age of onset was 1 d to 1 year and 2 months after birth,the median age of onset was 45 days,and the birth weight was 2.7 to 4.9(3.74±0.68)kg.10 cases of full-term infants were suitable for gestational age and 8 cases of giant infants.7 cases(38.9%)carried mutations of ABCC8 gene or GULD1 gene,and 11 cases of known CHI-related disease-causing gene mutations were not found.3 cases of children with ABCC8 gene mutation:2 cases(1 case was a giant baby,1 case was born with normal body weight,all onset on the first day after birth,and all were ineffective to diazoxide treatment)carrying ABCC8 gene compound heterozygous mutation.The mutations were all inherited from the father or mother.The other child had a paternal inheritance of the ABCC8 gene mutation.The child became ill on the 3rd day after birth and had a normal birth weight,which was ineffective to diazoxide treatment.Four cases of children with new heterozygous missense mutations in the GULD1 gene,age of onset from 1 day to 1 year and 2 months after birth,were effective for diazoxide treatment.After long-term follow-up,2 cases were diagnosed with epilepsy.Conclusion Among Chinese children with CHI,people with ABCC8 gene mutation usually have an early onset,and most of them are ineffective to diazoxide treatment.Children with mutations in the GLUD1 gene have a relatively late onset,are effective in diazoxide therapy,and tend to develop epilepsy.