身材矮小合并短指(趾)畸形3例家系的基因突变与表型分析并文献复习

目的 研究3例身材矮小合并短指（趾）畸形中国家系中患者的临床表型和基因突变谱。方法 利用二代测序技术对来自首都医科大学附属北京儿童医院的3例临床诊断为身材矮小合并短指（趾）畸形的患者及其父母进行分子诊断。结果 在家系1中鉴定出IHH基因突变（c.283_285delGAG/p.E95del），在家系2中鉴定出ROR2基因突变（c.2625dupC/p.T876fs*20），在家系3中鉴定出PTHLH基因突变（c.413delA/p.K138fs*11），故各家系分别诊断为短指（趾）畸形A1型、短指（趾）畸形B1型和短指（趾）畸形E2型。对患儿进行生长激素治疗后身高改善明显（+0.99 SD、+0.64 SD及+2.69 SD）。结论 身材矮小合并短指（趾）畸形有较大的遗传异质性，二代测序技术可以有效地对短指（趾）畸形患者进行分子确诊。本研究分别报道了ROR2基因和PTHLH基因的两个新发变异，并在中国人群中鉴定出一个以往报道过的IHH基因热点突变，同时3例患儿生长激素治疗效果显著。

Gene mutations and clinical phenotypes in three families with short stature and brachydactyly and review of literature

Objective To evaluate the clinical phenotypes and genetic variations of three Chinese patients with familial short stature and brachydactyly. Methods Three patients with short stature and brachydactyly from Beijing Children's Hospital were molecularly confirmed with specific subtypes of brachydactyly via next generation sequencing. Their parents were also sequenced for segregation information. Growth hormone therapy was initiated after diagnosis. Results c.283_285delGAG/p.E95del in IHH, c.2625dupC/p.T876fs*20 in ROR2 or c.413delA/p.K138fs*11 in PTHLH was identified in every family, thus the patients from these three families were diagnosed as brachydactyly A1, brachydactyly B1 and brachydactyly E2, respectively. After growth hormone therapy, the heights of three patients were significantly improved (+0.99 SD,+0.64 SD and+2.69 SD respectively). Conclusion The genetic heterogeneity of brachydactyly combined with short stature can be uncovered by next generation sequencing. In this study, we reported two novel pathogenic variants in ROR2 and PTHLH genes, as well a previously reported IHH hotspot mutation which was identified in Chinese population for the first time. Growth hormone therapy was effective for all three patients.