Clinical phenotype and genotype characteristics of 17 cases of Noonan syndrome

Abstract:

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 11 years 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 PTPN11 gene，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 exome sequencing in the precise diagnosis is emphasized. Early diagnosis and treatment helps to improve the prognosis of NS.