GPC3基因变异致新生儿Simpson-Golabi-Behmel综合征Ⅰ型一例并文献复习

Simpson-Golabi-Behmel syndrome type Ⅰ in neonates caused by GPC3 gene mutation: a case report and literature review

目的:探讨磷脂酰肌醇蛋白聚糖3(glypican-3,GPC3)基因变异致Simpson-Golabi-Behmel综合征(Simpson-Golabi-Behmel syndrome,SGBS)Ⅰ型患者的临床特征及遗传学特点。方法:对南方医科大学附属深圳妇幼保健院新生儿科收治的1例SGBSⅠ型患儿的临床资料进行回顾性分析。并以“Simpson-Golabi-Behmel综合征Ⅰ型”“磷脂酰肌醇蛋白聚糖3”“Simpson-Golabi-Behmel syndrome typeⅠ”“GPC3”为关键词,分别对中国知网、维普数据库和万方数据库、PubMed数据库自2010年1月至2021年4月收录的文献进行检索,总结GPC3基因变异致SGBSⅠ型患者的临床特征及遗传学特点。结果:本例患儿男性,4 h,因“腹胀1 h”入院,主要表现为异常面部特征(大头、面容粗陋、鼻梁宽、大嘴、舌有中央纵沟)、巨体、多余的乳头、尿道下裂;全外显子组高通量测序分析发现位于X染色体的GPC3基因存在c.720delC移码变异,患儿为半合子,母亲该位点杂合变异,为未曾报道过的变异,确诊SGBSⅠ型。随访发现患儿存在过度生长、合并神经母细胞瘤及运动发育迟缓。文献检索共收集31篇文献包括本例共93例患者,其中男89例(95.7%),女4例(4.3%);主要临床表现为颅面异常、出生前/后过度生长及伴多系统畸形,多合并语言障碍、运动发育迟缓和不同程度的智力障碍,且易罹患胚胎性肿瘤;合并肿瘤11例(11.8%);宫内终止21例,余72例娩出者中存活63例、死亡9例。提供具体基因变异类型有80例,其中无义变异25例(31.2%),DNA片段缺失21例(26.2%),移码变异16例(20.0%),片段重复8例(10.0%),错义变异5例(6.2%),剪接突变5例(6.2%)。结论:SGBSⅠ型为X连锁隐性遗传病,临床表型谱广,生后有颅面异常、过度生长及伴多系统畸形时需高度怀疑本病可能,基因检测有助于早期诊断,治疗需多学科合作并长期随访,尤其是对肿瘤的监测。

Objective To investigate the clinical and genetic characteristics of Simpson-Golabi-Behmel syndrome(SGBS)typeⅠcaused by glypican-3(GPC3)gene mutations.Methods Data of one neonate with SGBS typeⅠfrom Shenzhen Maternity and Child Healthcare Hospital Affiliated to Southern Medical University was reviewed retrospectively.Literature was retrieved to summarize the clinical and genetic characteristics of SGBS typeⅠcaused by GPC3 mutations,using terms of"Simpson-Golabi-Behmel typeⅠ","GPC3"and"glypican-3"from China National Knowledge Infrastructure,VIP database,Wanfang database,and PubMed from January 2010 till April 2021.Results The male infant was admitted to the hospital at 4 h after birth due to"abdominal distension for 1 h",presenting with dysmorphic facial features,including macrocephaly,coarse face,broad nasal bridge,macrostomia,tongue with a groove in the middle,as well as macrosomatia,supernumerary nipples,and hypospadias.Whole exome sequencing revealed a novel frameshift mutation(c.720delC)in GPC3 gene of the patient and his mother for hemizygous and heterozygous variation,respectively,based on which SGBS typeⅠwas confirmed.During the follow-up,overgrowth,neuroblastoma,and motor development retardation were found in the boy.In addition to the index patient,92 cases of SGBS typeⅠreported in 31 articles were analyzed,including 89(95.7%)males and 4(4.3%)females.The main clinical features were craniofacial dysmorphism,pre/postnatal overgrowth with multiple congenital anomalies.Most patients were combined with language disorders,motor retardation,and various degrees of dysnoesia,and were more likely to develop embryonic tumors.Among the 93 cases,11(11.8%)suffered from tumors.Apart from 21 cases of termination,63 cases were born alive and nine cases died after birth.Pathogenic variants in GPC3 gene were reported in 80 cases,which were nonsense mutation in 25 cases(31.2%),DNA fragment deletion in 21 cases(26.2%),frameshift mutation in 16 cases(20.0%),large duplications in eight cases(10.0%),missense mutation in five cases(6.2%),and splice site mutation in five cases(6.2%).Conclusions SGBS typeⅠis an X-linked recessive genetic disease with various phenotypes.Patients with postnatal craniofacial dysmorphism,overgrowth,and multiple congenital anomalies should be highly suspected of SGBS typeⅠ.Genetic testing is conducive to its early diagnosis.Treatment requires multidisciplinary cooperation and long-term follow-up,especially for those with tumors.