神经纤维瘤病1型患儿22例临床特点及NF1基因变异分析  

Clinical characteristics of and NF1 gene mutation analysis in 22 patients with neurofibromatosis type 1

作　　者：高莹[1] 王建才[1] 朱芸 张建昭[2] 仪晓立[3] 白晋丽[4] 瞿宇晋[4] Gao Ying;Wang Jiancai;Zhu Yun;Zhang Jianzhao;Yi Xiaoli;Bai Jinli;Qu Yujin(Department of Dermatology,Children′s Hospital,Capital Institute of Pediatrics,Beijing 100020,China;Department of Neurology,Children′s Hospital,Capital Institute of Pediatrics,Beijing 100020,China;Department of Radiology,Children′s Hospital,Capital Institute of Pediatrics,Beijing 100020,China;Capital Institute of Pediatrics,Beijing 100020,China)

机构地区：[1]首都儿科研究所附属儿童医院皮肤科,北京100020 [2]首都儿科研究所附属儿童医院神经内科,北京100020 [3]首都儿科研究所附属儿童医院放射科,北京100020 [4]首都儿科研究所,北京100020

出　　处：《中华皮肤科杂志》2024年第7期637-644,共8页Chinese Journal of Dermatology

基　　金：国家自然科学基金(81703106)。

摘　　要：目的探讨神经纤维瘤病1型患儿的临床特点及NF1基因变异的遗传学特点。方法收集并分析2022年1月至2023年9月就诊于首都儿科研究所附属儿童医院皮肤科门诊的22例神经纤维瘤病1型患儿的临床资料,采用二代测序方法对先证者进行致病基因检测,对家系成员应用Sanger测序进行基因突变位点验证,利用同源建模软件对蛋白三维结构进行预测,分析基因突变特点。结果22例神经纤维瘤病1型患儿中男14例,女8例,就诊年龄3个月至12岁。22例患儿均有多发的牛奶咖啡斑,发病年龄为出生时至2岁。9例伴腋窝或腹股沟区雀斑,2例伴皮肤神经纤维瘤,2例伴幼年黄色肉芽肿,2例伴学习障碍,伴虹膜lisch结节、中枢性性早熟和脊柱侧弯各1例,5例头颅磁共振成像显示有神经纤维瘤表现。22例患儿中共检测到5种类型的NF1基因变异,1例为NF1基因整体杂合缺失,4例为错义变异(其中1例携带2种错义变异),8例为移码变异,6例为无义变异,3例为经典剪接位点变异。其中有7种为未报道变异:c.758T>A(p.Val253Glu)、c.2360dupC(p.Thr788Asnfs*5)、c.5513T>G(p.Leu1838*)、c.2774dupT(p.Leu925Phefs*11)、c.6894dupT(p.Val2299Cysfs*7)、c.6882_6883delCT(p.Phe2295Leufs*10)和c.6448A>T(p.Lys2150*);6种为移码变异或者无义变异导致蛋白表达截短,严重影响蛋白功能;而错义变异c.758T>A(p.Val253Glu)经蛋白三维结构预测分析显示,不确定是否影响蛋白构象。2例患儿的NF1变异遗传自母亲;1例同时携带2个NF1错义变异,其中1个可能致病性变异为自发变异,另1个致病性不明的变异遗传自表型正常的患儿父亲;其余19例患儿的变异均为自发变异。结论神经纤维瘤病1型在儿童早期主要表现为多发牛奶咖啡斑,可在早期出现皮肤神经纤维瘤、幼年黄色肉芽肿、虹膜lisch结节等特征性表现;NF1基因发生致病性变异复杂多样,本研究鉴定22个变异,新变异丰富了NF1基因变异谱。Objective To investigate clinical characteristics of and genetic variants in the NF1 gene in children with neurofibromatosis type 1(NF1).Methods Clinical data were collected from 22 children with NF1,who were admitted to the Department of Dermatology,Children′s Hospital,Capital Institute of Pediatrics from January 2022 to September 2023,and were analyzed.Next-generation sequencing was performed to detect NF1 mutations in the probands,and the variants were verified in the family members by Sanger sequencing.A homology modeling software was used to predict the three-dimensional protein structure,and analyze the characteristics of gene mutations.Results Among the 22 children with NF1,there were 14 males and 8 females,and they were aged from 3 months to 12 years at the clinic visit.All the 22 children presented with multiple café-au-lait spots,and their age at onset ranged from birth to 2 years.Nine patients were accompanied by freckles in the axillary or inguinal regions,2 by cutaneous neurofibromas,2 by juvenile xanthogranuloma,2 by learning disabilities,and Lisch nodules of the iris,central precocious puberty and scoliosis occurred in 1 case each;5 cases showed characteristic manifestations of neurofibroma on brain magnetic resonance imaging.A total of 5 types of NF1 gene variants were identified in the 22 patients,including complete heterozygous deletion of the NF1 gene(1 patient),missense variants(4 patients,one of whom carried 2 types of missense variants),frameshift variants(8 patients),nonsense variants(6 patients),and classical splicing variants(3 patients).Among the 22 variants,7 were unreported variants,including c.758T>A(p.Val253Glu),c.2360dupC(p.Thr788Asnfs*5),c.5513T>G(p.Leu1838*),c.2774dupT(p.Leu925Phefs*11),c.6894dupT(p.Val2299Cysfs*7),c.6882_6883delCT(p.Phe2295Leufs*10),and c.6448A>T(p.Lys2150*).Of the unreported variants,6 were frameshift or nonsense variants leading to different degrees of truncated protein expression,and severely affecting protein function;based on the three-dimensional protein

关 键 词：神经纤维瘤病1型 基因 神经纤维瘤病1型 突变 表型 皮肤表现 多发牛奶咖啡斑 

分 类 号：R739.41[医药卫生—肿瘤]