Clinical And Genetic Analysis Of 8 Patients With Noonan Syndrome

Background and objectiveNoonan syndrome（NS）is a congenital hereditary disease with an incidence of1/2500～1/1000.The main clinical manifestations of NS are peculiar face and short stature,and can be accompanied by other systemic developmental abnormalities,such as congenital heart disease,mental retardation,skeletal malformation,male cryptorchidism and so on.NS is caused by variations in genes related to the signaling pathway of Mitogen-activated protein kinase（RAS-MAPK）.So far,16 pathogenic genes have been reported,of which,PTPN11 is the most common one and RIT1 is relatively rare.At present,there are few patients of NS reported in China.This paper reported 7 patients of NS,caused by PTPN11 gene and 1 patient of NS,caused by RIT1gene variation,and summarized the NS patients published in domestic and foreign journals,and analyzed their clinical and genetic features in order to improve clinicians’understanding of the disease.MethodsThe clinical data of 8 patients with NS were collected.Peripheral blood samples of the probands were extracted for whole exome sequencing（WES）,and Sanger sequencing was performed on the parents of the positive patients.Six patients were treated with recombinant human growth hormone（rh GH）.The key words"Noonan syndrome AND gene"and"Noonan syndrome AND Chinese"were used to search the Chinese databases,"Wanfang,Weipu,Zhiwang"and the English database"Pubmed"from January 2009 to February 2020.Results1.There were 8 NS patients,including 6 males and 2 females.The age of initial diagnosis ranged from 1.4 to 8.8 years old（mean 4.8 years old）.All of them had peculiar faces and short statures,congenital heart disease,mental retardation,facial freckles and skin cafe au lait spots were 3 patients respectively,feeding difficulty,abnormal vision and cryptorchidism were 2 patients respectively,the skeletal malformations were founded in 4 patients,including 2 patients with scoliosis,1 patient with pectus excavatum and 1 patients with deformity rib and brachydactyly,and 1patient with early puberty.2.Among the 8 patients,7 patients had PTPN11 gene variation and 1 patient had RIT1 gene variation.Among them,2 patients had the same PTPN11 gene variation site.There were 6 PTPN11 gene variation sites（c.1529A>G/p.Q510R,c.844A>G/p.I282V,c.184T>G/p.Y62D,c.794G>A/p.R265Q,c.1508G>A/p.G503E,c.188A>G/p.Y63C）and 1 RIT1 gene variation site（c.270G>A/p.M90I）.Among them,4variation sites in 5 patients（c.184T>G/p.Y62D,c.794G>A/p.R265Q,c.1508G>A/p.G503E,c.188A>G/p.Y63C）were new mutation（de novo）.3.Six patients were treated with recombined human growth hormone（rh GH）for 3months to 24 months（mean 9.7 months）,and the standard deviation of height by age(Ht SDS_CA)increased 0.15～1.11SDS（mean 0.51SDS）.No side effects occured.4.133 Chinese patients had been previously reported with gene diagnosis.With the new 8 patients adding,we summarized the phenotypic features of a total of 141Chinese NS patients as following:peculiar face（100%）,congenital heart disease（85.1%）,Short stature（60.3%）,male cryptorchidism（46.2%）,pectus carinatum or pectus excavatum（38.3%）.Conclusion1.In patients with peculiar face,congenital heart disease,short stature,male cryptorchidism,pectus carinatum and pectus excavatum,it should be considered that NS,and genetic testing can determine the etiology.2.This study found that hyperopia and deformity of rib were the first reported in Chinese NS patients.Moreover,NS with early puberty was not previously reported.This study extended the clinical spectra of NS.3.rh GH treatment was effective in NS patients with short stature and was safty during treatment.