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

doi:10.3969/j.issn.1006-7795.2018.06.025

首都医科大学学报 ›› 2018, Vol. 39 ›› Issue (6): 937-944.doi: 10.3969/j.issn.1006-7795.2018.06.025

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

胡旭昀¹, 吴迪², 李孟婷³, 陈佳佳², 李晓侨², 苏畅², 陈少科³, 沈亦平^3,4,5, 巩纯秀²

1. 国家儿童医学中心首都医科大学附属北京儿童医院-北京市儿科研究所医学遗传中心儿科重大疾病研究教育部重点实验室出生缺陷遗传学研究北京市重点实验室, 北京 100045;
2. 国家儿童医学中心首都医科大学附属北京儿童医院内分泌遗传代谢科儿科重大疾病研究教育部重点实验室出生缺陷遗传学研究北京市重点实验室, 北京 100045;
3. 广西壮族自治区妇幼保健院遗传代谢中心实验室, 南宁 530003;
4. 上海交通大学医学院附属上海儿童医学中心医学遗传科(分子诊断实验室), 上海 200127;
5. 哈佛医学院波士顿儿童医院遗传科, 美国波士顿 02115

收稿日期:2018-10-22 出版日期:2018-11-21 发布日期:2018-12-19
通讯作者: 巩纯秀 E-mail:chunxiugong@sina.com
基金资助:
国家自然科学基金（81570220）。

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

Hu Xuyun¹, Wu Di², Li Mengting³, Chen Jiajia², Li Xiaoqiao², Su Chang², Chen Shaoke³, Shen Yiping^3,4,5, Gong Chunxiu²

1. Beijing Key Laboratory for Genetics of Birth Defects, MOE Key Laboratory of Major Diseases in Children, Center for Medical Genetics, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China;
2. Beijing Key Laboratory for Genetics of Birth Defects, MOE Key Laboratory of Major Diseases in Children, Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China;
3. Genetic and Metabolic Central Laboratory, Guangxi Maternal and Child Health Hospital, Nanning 530003, China;
4. Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China;
5. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston 02115, USA

Received:2018-10-22 Online:2018-11-21 Published:2018-12-19
Supported by:
This study was supported by National Natural Science Foundation of China (81570220).

摘要/Abstract

摘要： 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。

关键词: 身材矮小, 短指(趾)畸形, 基因诊断, 二代测序, 生长激素治疗

Abstract: 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.

Key words: short, stature brachydactyly, genetic diagnosis, next generation sequencing, growth hormone therapy

中图分类号:

R725

胡旭昀, 吴迪, 李孟婷, 陈佳佳, 李晓侨, 苏畅, 陈少科, 沈亦平, 巩纯秀. 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[J]. 首都医科大学学报, 2018, 39(6): 937-944.

Hu Xuyun, Wu Di, Li Mengting, Chen Jiajia, Li Xiaoqiao, Su Chang, Chen Shaoke, Shen Yiping, Gong Chunxiu. Gene mutations and clinical phenotypes in three families with short stature and brachydactyly and review of literature[J]. Journal of Capital Medical University, 2018, 39(6): 937-944.

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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

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

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