48例原因不明矮身材儿童临床特征和致病基因分析  

Clinical and Genetic Study on 48 Children with Short Stature of Unknown Etiology

作　　者：侯乐乐[1] 林少汾 李晓娟[2] 刘祖霖[1] 欧辉[1] 张丽娜[1] 孟哲[1] 梁立阳[1] HOU Lele;LIN Shaofen;LI Xiaojuan;LIU Zulin;OU Hui;ZHANG Lina;MENG Zhe;LIANG Liyang(Children’s Medical Center,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510289,China;Cellular and Molecular Diagnostics Center,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou510289,China)

机构地区：[1]中山大学孙逸仙纪念医院儿童医学中心,广东广州510289 [2]中山大学孙逸仙纪念医院细胞分子诊断中心,广东广州510289

出　　处：《中山大学学报（医学科学版）》2024年第1期127-135,共9页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：中华国际医学交流基金会儿科内分泌中青年医师成长科研基金(Z-2019-41-2201)。

摘　　要：【目的】总结原因不明矮身材儿童的临床特征并探讨其致病基因,为临床精准诊疗提供依据。【方法】收集我院儿科内分泌专科2018年1月至2022年8月就诊的未能明确诊断的矮身材儿童临床表现、实验室检查及全外显子组测序(WES)结果进行回顾性分析,根据不同作用机制对致病基因进行归纳总结。【结果】纳入患儿48例(男性30例,女性18例),年龄(7.73±3.97)岁,身高标准差分值为-3.63±1.67;临床表现:特殊面容33例(68.8%),体型或骨骼系统异常31例(64.6%),围产期异常26例(54.2%,其中61.5%为小于胎龄儿),内分泌系统异常24例(50.0%,其中87.5%生长激素(GH)峰值低于正常),矮身材家族史21例(43.8%);实验室检查:GH激发试验峰值(9.72±7.25)ng/mL,IGF-1标准差分值为-0.82±1.42,骨龄与年龄差值(-0.93±1.39)岁;WES共发现相关基因变异者25例,其中14例(56.0%)为致病变异,6例(24.0%)为可能致病变异,5例(20.0%)为意义未明变异;评价为致病及可能致病变异的基因共14个,其中影响细胞内信号通路10个(PTPN11、RAF1、RIT1、ARID1B、ANKRD11、CSNK2A1、SRCAP、CUL7、SMAD4和FAM111A),影响细胞外基质(ECM)4个(ACAN、FBN1、COL10A1和COMP)。【结论】临床上表现为严重矮身材伴特殊面容、非匀称体型、骨骼系统异常、小于胎龄儿、GH峰值低于正常和矮身材家族史等特征的儿童,其病因需考虑罕见单基因疾病的可能,WES是提高单基因性矮小症诊断效能的重要手段。本组患儿致病基因中,主要致病机制是影响细胞内信号通路和ECM组分或功能,进一步研究有助于发现和研究新的矮小症致病变异和基因功能。【Objective】To explore the clinical features and causative genes of short stature children with unknown etiology,providing evidence for precise clinical diagnosis and treatment.【Methods】The study recruited children with suspected but undiagnosed short stature from the pediatric endocrinology department in our hospital between January 2018 and August 2022.A retrospective analysis was performed on the clinical manifestations,laboratory test and whole exome sequencing(WES)results.Causative genes were classified and analyzed according to different pathogenic mechanisms.【Results】A total of 48 children(30 boys and 18 girls)were enrolled,aged 7.73±3.97 years,with a height standard deviation score(HtSDS)of-3.63±1.67.Of the patients,33(68.8%)suffered from facial anomalies,31(64.6%)from skeletal abnormalities,26[54.2%,61.5%of whom born small for gestational age(SGA)]from perinatal abnormalities,24[50.0%,87.5%of whom with growth hormone(GH)peak concentration below normal]from endocrine disorders and 21(43.8%)had a family history of short stature.Laboratory tests showed that GH peak concentration following stimulation test was(9.72±7.25)ng/mL,IGF-1 standard deviation score was-0.82±1.42,the difference between bone age and chronological age was-0.93±1.39 years.Of the 25 cases with mutant genes found by WES,14(56.0%)had pathogenic mutation,6(24.0%)likely pathogenic mutation,and 5(20.0%)mutation of uncertain significance.Pathogenic and likely pathogenic variants were identified in 14 genes,including 10 affecting intracellular signaling pathways(PTPN11,RAF1,RIT1,ARID1B,ANKRD11,CSNK2A1,SRCAP,CUL7,SMAD4 and FAM111A)and 4 affecting extracellular matrix(ECM)components or functions(ACAN,FBN1,COL10A1 and COMP).【Conclusions】A rare monogenic disease should be considered as the possible etiology for children with severe short stature accompanied by facial anomalies,disproportionate body types,skeletal abnormalities,SGA,GH peak concentration below normal and a family history of short stature.WES played an important rol

关 键 词：矮身材 儿童 临床特征 全外显子组测序 基因变异 致病基因 

分 类 号：R725.8[医药卫生—儿科]