基于新生儿期PTPN11基因相关Noonan综合征21例病例系列报告并文献复习提出的遗传筛查指征

Genetic screening indications of neonatal PTPN11 gene-related Noonan syndrome based on case series of 21 neonatal patients and literature review

目的探讨基因筛查用于新生儿PTPN11基因相关Noonan综合征早期识别的临床价值。方法纳入2016年1月至2017年12月复旦大学附属儿科医院NICU参与"新生儿基因组计划"、携带PTPN11基因已报道Noonan综合征相关致病变异的患儿,以及Pubmed、知网及万方数据库筛选出的具有新生儿期表型描述的,携带PTPN11基因致病变异的Noonan综合征患儿,总结其临床特征和基因变异特征,并与其他时期PTPN11基因相关Noonan综合征患儿表型进行对比。结果5280例参与"新生儿基因组计划"的患儿中,携带PTPN11基因已报道Noonan综合征相关致病变异的患儿共21例,均不能完全满足现有Noonan综合征的临床诊断标准。结合既往文献报道的37例PTPN11基因相关Noonan综合征的新生儿期临床表现,提出独立的新生儿PTPN11基因相关Noonan综合征基因筛查标准如下:①肺动脉狭窄/肺动脉瓣狭窄、肥厚型心肌病;②淋巴管发育不良所致的乳糜胸、胸腔积液、不明原因呼吸困难、产检异常;③血小板减少、白细胞增多、单核细胞增多;④隐睾等泌尿生殖系统畸形。结论新生儿PTPN11基因相关Noonan综合征应建立独立的遗传筛查指征和诊断标准。

Objective To investigate the clinical value of genetic screening for early diagnosis of neonatal PTPN11 gene-related Noonan syndrome. Methods We collected neonates with pathogenic variants related to Noonan syndrome in PTPN11 gene from patients of neonatal intensive care unit( NICU) of Children’s Hospital of Fudan University enrolled in the Neonatal Genome Project from January 2016 to December 2017 and patients with PTPN11 gene-related Noonan syndrome with neonatal manifestation descriptions from Pubmed,CNKI and Wanfang databases. We summarized their clinical characteristics and gene variants,and compared them with other PTPN11 gene-related Noonan syndrome patients. Results In 5,280 neonates enrolled in the Neonatal Genome Project,there were 21 patients carrying pathogenic variants related to Noonan syndrome in PTPN11 gene,but they cannot fully meet the clinical diagnostic criteria of Noonan syndrome. Combined with 37 cases having neonatal feature descriptions of PTPN11 gene-related Noonan syndrome in published articles,we proposed specific genetic screening indications of neonatal PTPN11 gene-related Noonan syndrome: a. pulmonary stenosis/pulmonary valve stenosis and hypertrophic obstructive cardiomyopathy;b. lymphatic dysplasia-related chylothorax, pleural effusion, unexplained dyspnea;c. thrombocytopenia,leukocytosis,monocytosis;d. cryptorchidism or other genitourinary system abnormality. Conclusion Specific genetic screening indications and diagnosis criteria of neonatal PTPN11 gene-related Noonan syndrome should be established.