中国性发育异常患儿临床表型与基因型分析  

Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development

作　　者：林胡[1] 杨浩 傅君芬[1] 袁金娜[1] 黄轲[1] 吴蔚[1] 董关萍[1] 田红娟[2] 吴德华[2] 唐达星[2] 吴鼎文[3] 孙莉颖[4] 皮亚雷[5] 刘丽君[6] 史丽萍[7] 顾威[8] 黄鲁刚[9] 汪治华[10] 陈临琪[11] 李洪英[12] 于旸[13] 卫海燕[14] 程昕然 单小鸥[16] 刘毓[17] 徐旭[18] 刘舒[19] 罗小平[20] 肖延风[21] 杨玉[22] 李桂梅[23] 冯梅[24] 马秀琦 潘道香[26] 唐家彦 陈瑞敏[28] 米热古丽·买买提[29] 刘德云[30] 崔新海[31] 苏喆[32] 董志巧[33] 邹莉[34] 刘燕玲[35] 吴瑾[36] 李坤霞[37] 李媛[38] Lin Hu;Yang Hao;Fu Junfen;Yuan Jinna;Huang Ke;Wu Wei;Dong Guanping;Tian Hongjuan;Wu Dehua;Tang Daxing;Wu Dingwen;Sun Liying;Pi Yalei;Liu Lijun;Shi Liping;Gu Wei;Huang Lugang;Wang Zhihua;Chen Linqi;Li Hongying;Yu Yang;Wei Haiyan;Cheng Xinran;Shan Xiaoou;Liu Yu;Xu Xu;Liu Shu;Luo Xiaoping;Xiao Yanfeng;Yang Yu;Li Guimei;Feng Mei;Ma Xiuqi;Pan Daoxiang;Tang Jiayan;Chen Ruimin;Maimaiti Mireguli;Liu Deyun;Cui Xinhai;Su Zhe;Dong Zhiqiao;Zou Li;Liu Yanling;Wu Jin;Li Kunxia;Li Yuan(department of Endocrinology,the Children's Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,National Children's Regional Medical Center,Hangzhou 310052,China;Department of Urology,the Children's Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,National Children's Regional Medical Center,Hangzhou 310052,China;Department of Genetics and Metabolism,the Children's Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,National Children's Regional Medical Center,Hangzhou 310052,China;Department of Children's Gynecology,the Children's Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,National Children's Regional Medical Center,Hangzhou 310052,China;Department of Pediatrics,the Second Hospital of Hebei Medical University,Shijiazhuang 050000,China;Department of Metabolism,Hebei Children's Hospital,Shijiazhuang 050031,China;Department of Urology,Hebei Children's Hospital,Shijiazhuang 050031,China;Department of Endocrinology,Children's Hospital of Nanjing Medical University,Nanjing 210008,China;Department of Pediatric Surgery,West China Hospital,Sichuan University,Chengdu 610041,China;Department of Endocrinology and Metabolism,Genetics,Xi'an Children^Hospital,Xi'an 710003,China;Department of Endocrinology and Metabolism,Genetics,Children's Hospital of Soochow University,Suzhou 215300,China;Department of Endocrinology,Jinan Children's Hospital,Jinan 250000,China;Depar

机构地区：[1]浙江大学医学院附属儿童医院内分泌科国家儿童健康与疾病临床医学研究中心国家儿童区域医疗中心,杭州310052 [2]浙江大学医学院附属儿童医院泌尿外科国家儿童健康与疾病临床医学研究中心国家儿童区域医疗中心,杭州310052 [3]浙江大学医学院附属儿童医院遗传代谢科国家儿童健康与疾病临床医学研究中心国家儿童区域医疗中心,杭州310052 [4]浙江大学医学院附属儿童医院小儿、青少年妇科国家儿童健康与疾病临床医学研究中心国家儿童区域医疗中心,杭州31OO52 [5]河北医科大学第二医院儿科,石家庄050000 [6]河北省儿童医院代谢科,石家庄050031 [7]河北省儿童医院泌尿外科,石家庄050031 [8]南京医科大学附属南京儿童医院内分泌科,南京210008 [9]四川大学华西医院小儿外科,成都610041 [10]西安市儿童医院内分泌遗传代谢科,西安710003 [11]苏州大学附属儿童医院内分泌遗传代谢科,苏州215300 [12]济南市儿童医院小儿内分泌科,济南250000 [13]济南市儿童医院小儿外科,济南250000 [14]郑州市儿童医院内分泌遗传代谢科,郑州450000 [15]成都市妇女儿童中心医院内分泌遗传代谢科,成都611731 [16]温州医科大学附属第二医院育英儿童医院儿童内分泌遗传代谢科,温州325000 [17]贵阳市妇幼保健院内分泌遗传代谢科,贵阳550003 [18]无锡市儿童医院内分泌科,无锡214023 [19]广东省妇幼保健院内分泌遗传代谢科,广州511442 [20]华中科技大学同济医学院附属同济医院儿科,武汉430030 [21]西安交通大学第二附属医院小儿内科,西安710004 [22]江西省儿童医院内分泌遗传代谢科,南昌330006 [23]山东大学附属省立医院儿科内分泌科,济南250014 [24]山西省儿童医院内分泌遗传代谢科,太原030013 [25]贵州省人民医院儿内科,贵阳550002 [26]严安徽医科大学第一附属医院儿科,合肥230022 [27]南方医科大学附属中山博爱医�

出　　处：《中华儿科杂志》2022年第5期435-441,共7页Chinese Journal of Pediatrics

基　　金：国家自然科学基金(81570759);国家重点研发计划(2016YFC1305300);中央高校基本科研业务费专项(2017xzzx001-01)。

摘　　要：目的探讨性发育异常(DSD)患儿临床表型及基因型的异质性及相关性。方法回顾性分析全国36家儿童医疗机构2017年1月至2021年5月临床拟诊DSD的1235例患儿的临床资料,对277个DSD相关候选基因进行捕获之后进行二代测序,结合临床表型分析其异质性及相关性。结果1235例临床拟诊为DSD的患儿初诊时社会性别男980例、女255例,初诊年龄为1日龄至17.92岁。通过基因分子学检测致病性变异患儿共443例,阳性检出率为35.9%。临床表型以小阴茎(455例)、尿道下裂(321例)、隐睾(172例)常见;基因检测发现常见变异为SRD5A2变异(80例),AR变异(53例)及CYP21A2变异(44例)。其中临床表型为单纯小阴茎和单纯尿道下裂患儿中,均表现为SRD5A2变异最常见(分别为33例及11例),而单纯隐睾患儿中,以AMH变异最常见(7例)。结论中国DSD患儿最常见的基因变异是SRD5A2变异,常见的临床表型是小阴茎、隐睾、尿道下裂。分子诊断可以提供有关DSD生物学基础的线索并指导临床医生进行特定的临床检查,目标序列捕获探针并二代测序技术能针对性地为DSD患儿提供有效而经济的遗传学诊断。Objective To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development(DSD).Methods A retrospective study of 1235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021.After capturing 277 DSD-related candidate genes,second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes.Results Among 1235 children with clinically proposed DSD,980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years.A total of 443 children with pathogenic variants were detected through molecular genetic studies,with a positive detection rate of 35.9%.The most common clinical phenotypes were micropenis(455 cases),hypospadias(321 cases),and cryptorchidism(172 cases)and common mutations detected were in SRD5A2 gene(80 cases),AR gene(53 cases)and CYP21A2 gene(44 cases).Among them,the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias,while the AMH mutation is the most common in children with simple cryptorchidism.Conclusions The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD,and micropenis,cryptorchidism,and hypospadias are the most common clinical phenotypes.Molecular diagnosis can provide clues about the biological basis of DSD,and can also guide clinicians to perform specific clinical examinations.Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

关 键 词：性分化障碍 诊断 遗传学 

分 类 号：R725.8[医药卫生—儿科]