45例结节性硬化症的临床表型及TSC1/TSC2基因变异分析  

Clinical characteristics and TSC1/TSC2 genetic variation analysis in 45 cases of tuberous sclerosis

作　　者：梅道启 张兵兵[1] 汤继宏[1] 王媛[2] 王莉[2] 梅世月 高超[4] 王潇娜 马远宁 董世杰 MEI Daoqi;ZHANG Bingbing;TANG jihong;WANG Yuan;WANG Li;MEI Shiyue;GAO Chao;WANG Xiaona;MA Yuanning;DONG Shijie(Department of Neurology,Children's Hospital of Soochow University,Suzhou 215025,Jiangsu,China;Department of Neurology,Children's Hospital Affiliated to Zhengzhou University,Henan Children's Hospital,Zhengzhou Children's Hospital,Zhengzhou 450018,Henan,China;Henan Provincial Key Laboratory of Childrens Genetics and Metabolic Diseases,Henan Engineering Research Center of Childhood Neurodevelopment,Zhengzhou 450018,Henan,China;Department of Rehabilitation Medicine,Children's Hospital Affiliated to Zhengzhou University,Henan Children's Hospital,Zhengzhou Children's Hospital,Zhengzhou 450018,Henan,China;Department of Radiological,Children's Hospital Affiliated to Zhengzhou University,Henan Children's Hospital,Zhengzhou Children's Hospital,Zhengzhou 450018,Henan,China)

机构地区：[1]苏州大学附属儿童医院神经内科,江苏苏州215025 [2]郑州大学附属儿童医院,河南省儿童医院,郑州儿童医院神经内科,河南郑州450018 [3]河南省遗传代谢性疾病重点实验室,河南省儿童神经发育工程研究中心,河南郑州450018 [4]郑州大学附属儿童医院,河南省儿童医院,郑州儿童医院康复医学科,河南郑州450018 [5]郑州大学附属儿童医院,河南省儿童医院,郑州儿童医院放射科,河南郑州450018

出　　处：《临床儿科杂志》2024年第11期935-941,共7页Journal of Clinical Pediatrics

基　　金：国家自然科学基金(No.81701125);科技部国际合作项目(No.G2021026025L);河南省科技厅科技攻关计划项目(No.232102310077);河南省医学科技攻关计划联合共建项目(No.LHGJ20200618,2018020633);苏州市科技计划项目(No.SKY2022007);疑难病、罕见病研究专项项目(No.2024YNHJ03)。

摘　　要：目的总结45例经基因诊断确诊的结节性硬化症(TSC)临床特点及TSC1/TSC2基因变异分析,提高对本病的认识。方法回顾性收集2018年1月至2021年10月确诊的45例TSC1/TSC2基因变异相关结节性硬化症合并癫痫患儿的临床资料进行总结及分析。结果45例患儿中44例患儿以癫痫起病,包括婴儿痉挛发作25例、全面强直-阵挛发作23例、肌阵挛发作8例、失神发作6例、失张力5例、局灶性发作20例。45例均有皮肤色素脱失斑,6例伴发颜面部血管纤维瘤。25例智力低下;12例有运动发育落后;6例心脏错构瘤;8例肾囊肿;1例多囊肾;8例视网膜错构瘤。15例患者检出TSC1基因杂合突变,其中8例新生突变,7例为遗传性突变;移码突变4例,无义突变7例,错义突变2例,剪切突变2例。30例患者检出TSC2基因杂合突变,其中21例为新生突变,9例为遗传性突变;移码突变7例,无义突变4例,错义突变7例,整码突变3例;剪切突变7例,大片段缺失1例,延长突变1例。1例TSC1基因变异与10例TSC2基因变异之前未见报道。结论结节性硬化症临床表现多样,基因型-表型关联复杂。临床上对于疑诊结节性硬化的患者应尽早行TSC1/TSC2基因分析以期及早诊断、对症治疗。Objective This study aims to summarize the clinical features and TSC1/TSC2 gene variation analysis of 45 cases of tuberous sclerosis complex(TSC)diagnosed through genetic analysis,thereby enhancing the understanding of the disease.Methods Retrospectively collected and summarized clinical data of 45 children diagnosed with TSC associated with TSC1/TSC2 gene mutations and epilepsy from January 2018 to October 2021.Results Of the 45 children,44 exhibited epilepsy,with 25 presenting with infantile spasms,23 with generalized tonic-clonic seizures,8 with myoclonic seizures,6 with atonic seizures,5 with dystonic seizures,and 20 with focal seizures.All patients showed skin depigmentation,with 6 presenting hemangiomas in the facial region.Cognitive impairment was observed in 25 cases,while 12 exhibited developmental delays.6 had cardiac rhabdomyomas,8 had renal cysts,1 had polycystic kidneys,and 8 had retinal hamartomas.Genetic analysis revealed 15 patients with heterozygous mutations in the TSC1 gene(8 de novo and 7 inherited),including 4 frameshift mutations,7 nonsense mutations,2 missense mutations,and 2 splice mutations.In addition,30 patients had heterozygous mutations in the TSC2 gene(21 de novo and 9 inherited),comprising 7 frameshift mutations,4 nonsense mutations,7 missense mutations,3 whole-gene mutations,7 splice sito mutations,1 largo segmental deletion,and 1 extended mutotion.Notably,1 TSC1 mutation and 10 TSC2 mutations were novel findings.Conclusion TSC presents with a diverse range of clinical symptoms,and the genotype-phenotype correlation is complex.Early genetic analysis of TSC1/TSC2 is essential for timely diagnosis and targeted treatment in suspected cases.

关 键 词：结节性硬化症 TSC1/TSC2基因 癫痫 新生变异 MTOR抑制剂 

分 类 号：R725.9[医药卫生—儿科]