Abstract: Objective To analyze the clinical phenotype and genetic characteristics of children with Noonan syndrome (NS), in order to provide theoretical evidence for early diagnosis and treatment of the disease. Methods A retrospective analysis of the clinical data and genetic testing results of 21 NS children diagnosed from January 2016 to January 2023 were performed. Therapeutic follow-up results of some of the shorter children were also included. Therapeutic follow-up results of some of the shorter children were also included. Results Among the 21 NS patients, there were 13 males and 8 females, with a diagnosis age ranging from 5 days to 14 years old and a mean age of 4.6 years old. Most common clinical features included special facial features (n=12), congenital heart disease (n=11), short stature (n=9), feeding difficulties (n=6), abnormal skeletal development (n=3), hearing disorder (n=3), and sparse hair (n=3). In addition to classic phenotypes, rare phenotypes such as sparse teeth, scoliosis, photophobia, hair follicle keratosis, epilepsy, and arrhythmias were also observed. Seven mutant genes were identified by genetic testing, including PTPN11(n=7), BRAF(n=4), LZTR1(n=3), SOS1(n=3), KRAS(n=2), RAF1(n=1), and SHOC2(n=1). Nine short stature children were treated with rhGH for an average of 16.6 months, with a mean height change from -3.62s to -3.21s. Conclusions Complete exome sequencing is helpful for early diagnosis of NS patients. In addition to the classic phenotype of NS, the RAF1 gene may be associated with frequent atrial arrhythmias, suggesting a new phenotype spectrum. Heterozygous variants in the LZTR1 gene may result in a mild phenotype with sparse hair, which is a rare phenotype of RAF1 and SHOC2 variants of NS. The short-term efficacy of rhGH treatment in NS patients is acceptable, but the correlation between rhGH efficacy and genotype was not clear.

Key words: Noonan syndrome, gene, phenotype, growth hormone

摘要： 目的 探讨努南综合征(NS)患儿的临床表型与基因学特征,为疾病的早期诊治提供理论依据。方法 回顾分析2016年1月—2023年1月诊断的21例NS患儿的临床资料及基因检测结果,并对伴有矮小的患儿身高进行随访。结果 21例NS患儿中,男性13例,女性8例,平均确诊年龄为4.6岁(5d~14岁)。21例患儿中,其中12例有特殊面容,11例患有先天性心脏病,9例伴矮身材,6例有喂养困难,3例伴骨骼系统发育异常,3例伴听力障碍,3例伴毛发稀疏,除经典表型外,部分患儿存在牙齿稀疏、脊柱侧弯、畏光、毛囊角化、癫痫、心律失常等少见表型。基因检测结果共发现7种变异基因,其中PTPN11 7例,BRAF 4例,LZTR1 3例,SOS1 3例,KRAS 2例,RAF1 1例,SHOC2 1例。其中发现1例合并频发房性心律失常患儿的基因为RAF1,3例伴毛发稀疏患儿中2例基因为RAF1、1例为SHOC2。3例携带LZTR1杂合变异患儿的临床表型仅表现为特殊面容、矮小。9例矮身材患儿给予rhGH治疗,平均治疗时间16.6月,平均身高由-3.62s提升到-3.21s。结论 全外显子组测序有助于NS患者的早期诊断;除了NS的经典表型外,频发房性心律失常可能是RAF1突变型NS的一个新的表型谱,毛发稀疏可能是RAF1和SHOC2变异型NS的一个表型谱,LZTR1杂合变异患儿的表型轻微。NS患者短期内rhGH治疗效果尚可,尚未发现rhGH疗效与基因型的明确相关性。

关键词: Noonan综合征, 基因, 表型, 生长激素