FBN1基因杂合突变导致轻型Geleophysic发育不良2型/Acromicric发育不良中国家系及促生长治疗的探讨  

FBN1 gene mutation in a Chinese pedigree of mild Geleophysic dysplasia type 2/Acromicric dysplasia and the exploration of growth-promoting therapy

作　　者：黄梦甜 陈秋莉[1] 马华梅[1] 李燕虹[1] 张军[1] 郭松[1] Huang Mengtian;Chen Qiuli;Ma Huamei;Li Yanhong;Zhang Jun;Guo Song(Department of Pediatrics,the First Affiliated Hospital,Sun Yat-Sen University,Guangzhou 510080,China)

机构地区：[1]中山大学附属第一医院儿科,广州510080

出　　处：《中华内分泌代谢杂志》2023年第6期492-498,共7页Chinese Journal of Endocrinology and Metabolism

基　　金：广东省科技创新战略专项(2018A030310266)。

摘　　要：目的总结1个由原纤维蛋白1(fibrillin 1,FBN1)基因杂合突变导致轻型Geleophysic发育不良2型(Geleophysic dysplasia type 2,GD2)/Acromicric发育不良(Acromicric dysplasia,AD)的严重不匀称矮小中国家系7例患者的临床特征及诊治经验。方法回顾总结2017年8月至2022年5月在中山大学附属第一医院儿科内分泌专科就诊的1个通过全外显子基因测序确定FBN1基因杂合突变致轻型GD2/AD家系的临床资料,并进行文献复习。结果该家系三代13人中有7例患者,成年女性和男性各1例,儿童5例;均表现为出生后进行性生长衰竭,严重不匀称矮小,无典型面部特征。除Ⅱ-3外的6例患者(Ⅱ-1、Ⅲ-1~Ⅲ-5)经全外显子测序和Sanger测序验证提示FBN1基因第42号外显子中存在c.5099A>G(p.Tyr1700Cys)杂合错义突变,为致病突变,该突变曾出现于1个中国经典型AD家系。综合基因、临床特征及多系统评估,3例因合并心脏瓣膜异常诊断为轻型GD2,4例为轻型AD。对5例患儿(Ⅲ-1~Ⅲ-5)使用基因重组人生长激素(recombinant human growth hormone,rhGH;1.1~1.4 IU·kg-1·周-1)治疗,并将促性腺激素释放激素类似物(gonadotropin releasing hormone analogue,GnRHa)应用于青春后期的2例女性患儿(Ⅲ-1、Ⅲ-2),均取得了一定的促生长疗效。结论c.5099A>G(p.Tyr1700Cys)突变不仅可导致文献报道的经典型AD,还可引起本家系的非经典GD2型或AD(轻型GD2型/AD)。rhGH治疗的远期疗效值得进一步研究。Objective To summarize the clinical and genetic features of 7 patients with a mild form of Geleophysic dysplasia type 2(GD2)/Acromicric dysplasia(AD)induced by fibrillin 1(FBN1)gene mutation from one Chinese family.Methods A Chinese pedigree of mild GD2/AD treated at the Pediatric Endocrinology Department at the First Affiliated Hospital of Sun Yat-sen University between August 2017 and May 2022 was collected.Whole-exome genetic sequencing of the FBN1 gene were performed to establish the diagnosis.Additionally,a literature review was further conducted.Results In this family,among 13 individuals spanning three generations,there were 7 affected cases,including 1 adult female,1 adult male,and 5 children.All individuals exhibited postnatal growth failure,severe disproportionate short stature,and lacked typical facial features.Exome sequencing and Sanger sequencing confirmed the presence of a heterozygous missense mutation c.5099A>G(p.Tyr1700Cys)in exon 42 of the FBNI gene in 6 affected individuals(Ⅱ-1,Ⅲ-1 toⅢ-5),which was identified as a pathogenic mutation.This mutation was previously reported in a Chinese classical achondroplasia(AD)family.Based on comprehensive genetic analysis,clinical features,and multisystem evaluation,3 cases were diagnosed with mild type 2 growth hormone deficiency(GD2),and 4 cases were diagnosed with mild AD.Recombinant human growth hormone(rhGH;1.1-1.4 IU·kg-1·week-1)was applied to all the 5 children,and additional gonadotropin releasing hormone analogue(GnRHa)was administered to the 2 girls in late puberty,resulting in certain growth-promoting effect.Conclusions The c.5099A>G(p.Tyr1700Cys)mutation not only leads to the classical type of achondroplasia(AD)as reported in the literature but also causes the non-classical GD2 or AD(mild GD2/AD).Further research is warranted to investigate the long-term therapeutic effects of rhGH treatment.

关 键 词：FBN1基因 Geleophysic发育不良 Acromicric发育不良 肢端发育不良 矮小 治疗 

分 类 号：R725.8[医药卫生—儿科]