17例Noonan综合征临床表型与基因型特点  

Clinical phenotype and genotype characteristics of 17 cases of Noonan syndrome

作　　者：张文 林云婷 李端 李秀珍 陶春燕 梅慧芬 程静 江敏妍 刘丽 Zhang Wen;Lin Yunting;Li Duan;Li Xiuzhen;Tao Chunyan;Mei Huifen;Cheng Jing;Jiang Minyan;Liu Li(Department of Genetics and Endocrinology,Guangzhou Women and Children’s Medical Center)

机构地区：[1]广州市妇女儿童医疗中心遗传与内分泌科,广州510623

出　　处：《重庆医科大学学报》2022年第3期300-305,共6页Journal of Chongqing Medical University

基　　金：广州市科技计划资助项目(编号:202102080028);广州市妇女儿童医疗中心内科部内部基金资助项目(编号:NKE-PRE-2019-003)。

摘　　要：目的:为了增进对Noonan综合征(Noonan syndrome,NS)的认识,本文分析和总结了17例NS患儿的临床特点及基因分析结果。方法:回顾性分析2015年10月至2021年2月在广州市妇女儿童医疗中心诊断的17例NS患儿临床资料,通过全外显子联合Sanger测序分析基因变异类型。结果:17例NS患儿中男11例、女6例,诊断中位年龄4岁(5个月~11岁10个月)。17例患儿均具有典型特殊面容,伴有不同程度的精神运动发育迟缓;16例患儿就诊时身高身高标准差评分(standard deviation scores,SDS)<-2;3例有隐睾,3例有漏斗胸,3例有鸡胸,2例有头发卷曲。8例检出心脏结构异常,其中肺动脉瓣狭窄伴房间隔缺损3例,房间隔缺损2例,肺动脉瓣狭窄1例,动脉导管未闭伴二尖瓣脱垂并轻度关闭不全1例,室间隔与左室壁不均匀增厚1例。5例检出PTPN11基因突变;4例检出BRAF基因突变;3例检出KRAS基因突变;2例检出SHOC2基因突变,1例检出RAF1基因突变,1例检出CBL基因突变,1例检出SOS1基因突变。其中4个为新突变:PTPN11基因突变p.R4G和p.H426R、RAF1基因突变p.V263G及CBL基因突变p.R631Dfs*17,其余13个突变均为已知致病突变。1例为母源性,其余16例均为自发突变。3例接受重组人生长激素治疗,身高明显改善,定期随访无不良反应发生;1例因心肌肥厚给予美托洛尔治疗。结论:NS临床表现有很多共性也有明显的异质性,临床诊断仍有一定难度,建议借助基因测序尤其是二代测序以明确诊断,早期诊断、早期干预有助于改善预后。Objective:To analyze and summarize the clinical characteristics and genetic analysis results of 17 children with Noonan syndrome(NS),and to improve the diagnosis and expand the knowledge of the disease. Methods:The clinical data of 17 patients with NS who were diagnosed in Guangzhou Women and Children’s Medical Center from October 2015 to February 2021 were retrospec-tively analyzed. Gene analysis was performed using whole exome sequencing and Sanger sequencing. Results :Seventeen children including 11 boys and 6 girls were diagnosed with Noonan syndrome in our hospital and the median age was 4 years(5 months to 11years and 10 months). All cases had typical facial features of Noonan syndrome,accompanied by different degrees of psychomotor retardation,with 16 cases of short stature(SDS<-2),3 cases of cryptorchidism,3 cases of pectus carinatum,3 cases of pectus excavatum and 2 cases of curly hair. Abnormal cardiac structure was founded in 8 cases,including 3 cases of pulmonary valve stenosis with atrial septal defect,2 case of atrial septal defect,1 case of pulmonary valve stenosis,1 case of patent ductus arteriosus with mitral valve prolapse and 1 case of ventricular hypertrophy. Among 17 cases,we identified 17 different mutations:5 missense mutations of PTPN11gene,4 missense mutations of BRAF gene,3 missense mutations of KRAS gene,2 missense mutations of SHOC2 gene,1 missense mutation of RAF1 gene,1 small deletion of CBL gene and 1 missense mutation of SOS1 gene. Four novel pathogenic mutations were detected,including PTPN11 gene mutation p.R4G and p.H426R,RAF1 gene mutation p.V263G and CBL gene mutation p.R631Dfs*17,and the remaining 13 mutations were known pathogenic mutations. One was maternal,and 16 were de novo mutations. Three patients were treated with recombinant human growth hormone,and their height was significantly improved,without adverse events during the regular follow-up. One case had metoprolol because of cardiac hypertrophy. Conclusion:NS presents divergent phenotypes and the utility of whole e

关 键 词：NOONAN综合征 临床表型 基因分析 

分 类 号：R725.8[医药卫生—儿科]