身材矮小伴多发性骨骼发育不良1例患儿的临床表型与遗传学分析

Clinical phenotype and genetic analysis of a child with short stature and multiple skeletal dysplasia

目的探讨1例身材矮小患儿的临床表型及遗传学特征。方法选择2021年10月7日因"生长迟缓伴鸡胸"就诊于湖州市妇幼保健院的1例患儿为研究对象,回顾性分析患儿临床资料。患儿进行全外显子组测序(WES),并对候选变异进行Sanger测序验证。结果患儿为1岁男性,主要临床特点为轻度身材矮小(Z值为-2.03)、面中部发育不良及多发性骨骼发育不良,包括鸡胸、椎体形态欠规则及腰椎前缘骨缺损等。患儿的母亲、外祖母、曾外祖父均身材矮小。WES结果显示患儿ACAN基因存在母源性c.2858dupA(p.Asp953GlufsTer476)杂合移码变异。根据美国医学遗传学与基因组学学会(ACMG)变异相关指南,c.2858dupA(p.Asp953GlufsTer476)评级为可能致病性变异(PVS1+PM2Supporting)。患儿从出生后20月龄开始接受约11个月的人重组生长激素治疗,身高明显改善。结论ACAN:c.2858dupA(p.Asp953GlufsTer476)考虑为该身材矮小患儿的致病原因。

Objective To analyze the clinical phenotype and genetic basis for a child featuring familial short stature.Methods A child who was admitted to Huzhou Maternal and Child Health Care Hospital on October 7,2021 for growth retardation and pectus carinatum was selected as the study subject.Physical exam and medical imaging was performed.The child was subjected to whole exome sequencing,and candidate variants were verified by Sanger sequencing and bioinformatic analysis.Results The child,a 1-year-old male,had manifested with slightly short stature(Z=-2.03),midfacial dysplasia,and multiple skeletal dysplasia such as pectus carinatum,irregular vertebral morphology,and defect of lumbar anterior bones.His mother,maternal grandmother and great-maternal grandfather also had short stature.WES revealed that the child has harbored a heterozygous c.2858dupA(p.Asp953GlufsTer476)frameshifting variant of the ACAN gene,which was inherited from his mother.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.2858dup(p.Sp953Glufster476)variant was classified as likely pathogenic(PVS1+PM2_Supporting).The patient has shown marked improved height after receiving 11 months of treatment with human recombinant growth hormone(supplemental dose)starting from 20 months of age.Conclusion The ACAN:c.2858dup(p.Asp953GlufsTer476)variant probably underlay the pathogenesis of short stature in this child.