论著

45例结节性硬化症的临床表型及TSC1/TSC2基因变异分析

  • 梅道启 ,
  • 张兵兵 ,
  • 汤继宏 ,
  • 王媛 ,
  • 王莉 ,
  • 梅世月 ,
  • 高超 ,
  • 王潇娜 ,
  • 马远宁 ,
  • 董世杰
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  • 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)

收稿日期: 2023-09-12

  网络出版日期: 2024-11-08

基金资助

国家自然科学基金(81701125);科技部国际合作项目(G2021026025L);河南省科技厅科技攻关计划项目(232102310077);河南省医学科技攻关计划联合共建项目(LHGJ20200618);河南省医学科技攻关计划联合共建项目(2018020633);苏州市科技计划项目(SKY2022007);疑难病、罕见病研究专项项目(2024YNHJ03)

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

  • Daoqi MEI ,
  • Bingbing ZHANG ,
  • jihong TANG ,
  • Yuan WANG ,
  • Li WANG ,
  • Shiyue MEI ,
  • Chao GAO ,
  • Xiaona WANG ,
  • Yuanning MA ,
  • Shijie DONG
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  • 1. Department of Neurology, Children's Hospital of Soochow University, Suzhou 215025, Jiangsu, China
    2. Department of Neurology, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, Henan, China
    3. Henan Provincial Key Laboratory of Childrens Genetics and Metabolic Diseases, Henan Engineering Research Center of Childhood Neurodevelopment, Zhengzhou 450018, Henan, China
    4. Department of Rehabilitation Medicine, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, Henan, China
    5. Department of Radiological,Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, Henan, China

Received date: 2023-09-12

  Online published: 2024-11-08

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。

本文引用格式

梅道启 , 张兵兵 , 汤继宏 , 王媛 , 王莉 , 梅世月 , 高超 , 王潇娜 , 马远宁 , 董世杰 . 45例结节性硬化症的临床表型及TSC1/TSC2基因变异分析[J]. 临床儿科杂志, 2024 , 42(11) : 935 -941 . DOI: 10.12372/jcp.2024.23e0885

Abstract

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.

参考文献

[1] Roebuck DJ, Chippington S, Berry BD, et al. Core needle biopsy and embolization of fat-poor renal tumors in children with tuberous sclerosis complex[J]. World J Pediatr, 2023, 19(6): 614-618.
[2] Liu T, Ding J, Zhang S, et al. Independent temporal lobe epilepsy in patients with tuberous sclerosis complex[J]. Pediatr Investig, 2022, 6(1): 23-28.
[3] Specchio N, Pavia GC, de Palma L, et al. Current role of surgery for tuberous sclerosis complex-associated epilepsy[J]. Pediatr Investig, 2022, 6(1): 16-22.
[4] 丁一峰, 周渊峰, 郁莉斐, 等. 结节性硬化症儿童智力障碍高危因素研究[J]. 临床儿科杂志, 2021, 39(7): 506-510.
[5] 禚志红, 王瑶, 靳培娜, 等. 以癫痫起病的儿童结节性硬化临床特点和遗传学分析[J]. 中国神经精神疾病杂志, 2021, 47(4): 228-233.
[6] 梅道启, 符娜, 秦炯. 结节性硬化症TSC1/TSC2基因型与临床表型相关性研究[J]. 中国实用儿科杂志, 2019, 34(4): 309-314.
[7] 梅道启, 梅世月, 王莉, 等. TSC2/PKD1邻接基因综合征临床表型与基因分析[J]. 中华神经科杂志, 2022, 55(10): 1135-1142.
[8] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405424.
[9] 张士德, 王占想, 林榕, 等. TSC1基因新突变导致的结节性硬化症家系的遗传学研究[J]. 中华医学遗传学杂志, 2019, 36(10): 961-964.
[10] 黄超, 张芹, 薛莹, 等. 一例结节性硬化症家系的TSC基因变异分析及产前诊断[J]. 中华医学遗传学杂志, 2021, 38(2): 154-157.
[11] Northrup H, Aronow ME, Bebin EM, et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations[J]. PediatrNeurol, 2021, 123: 50-66.
[12] 梅道启, 梅世月, 王潇娜, 等. 结节性硬化症二家系的临床表型及遗传学特点分析[J]. 中华神经医学杂志, 2020, 19(10) : 1040-1043
[13] 贺影忠, 李松, 姚如恩, 等. 结节性硬化伴难治性癫痫19例mTORC1信号通路活性检测及治疗[J]. 临床儿科杂志, 2022, 40(3): 196-201.
[14] Krishnan A, Kaza RK, Vummidi DR. Cross-sectional imaging review of tuberous sclerosis[J]. Radiol Clin North Am, 2016, 54(3): 423-440.
[15] 孙丹, 刘智胜, 胡家胜, 等. 结节性硬化症患儿TSC1/TSC2突变基因型与表型的相关性分析[J]. 中华实用儿科临床杂志, 2015, 30(6): 461-466.
[16] 田启龙. 结节硬化症相关性癫痫治疗进展[J]. 临床儿科杂志, 2022, 40(4): 311-315.
[17] Portocarrero LKL, Quental KN, Samorano LP, et al. Tuberous sclerosis complex: review based on new diagnostic criteria[J]. An Bras Dermatol, 2018, 93(3): 323-331.
[18] 梅道启, 符娜, 秦炯. 结节性硬化症TSC1TSC2基因型与临床表型相关性研究[J]. 临床儿科杂志, 2018, 36(9): 678-682.
[19] 费凌霞, 李恺煇, 胡湘蜀, 等. mTOR通路相关的难治性癫痫3例报告及文献复习[J]. 临床神经外科杂志, 2021, 18(5): 535-539.
[20] 邹丽萍. 结节性硬化症的治疗进展[J]. 中华儿科杂志, 2023, 61(8): 766-768.
[21] Nabbout R, Belousova E, Benedik MP, et al. Epilepsy in tuberous sclerosis complex: findings from the TOSCA study[J]. Epilepsia Open, 2019, 4(1): 73-84.
[22] 郭静, 张佩琪, 金洋, 等. 结节性硬化症伴癫痫发作患者基因突变类型与临床表型相关性研究[J]. 中风与神经疾病杂志, 2020, 37(9): 782-786.
[23] 贺晶, 周文静, 史洁, 等. 结节性硬化患者基因型与脑电图和临床表现的关系[J]. 中华医学杂志, 2020, 10(2): 136-140.
[24] Gao C, Zabielska B, Jiao F, et al. Subependymal giant cell astrocytomas in yuberous sclerosis complex-current views on their pathogenesis and management[J]. J Clin Med, 2023, 12(3): 956.
[25] 李花, 胡湘蜀, 费凌霞, 等. 结节性硬化症患者基因突变与临床表型的关系[J]. 中华神经科杂志, 2016, 49(5): 369-374.
[26] 刘林莉, 于春水, 杨和荣, 等. 一例结节性硬化症TSC2基因的新发变异分析[J]. 中华医学遗传学杂志, 2021, 38(9): 877-879.
[27] 朱思齐, 王纪文. 氨己烯酸治疗儿童结节性硬化症相关癫痫的疗效及安全性研究进展[J]. 国际儿科学杂志, 2023, 50(5): 302-305.
[28] 方雨, 廖建湘. 生酮饮食治疗结节性硬化症相关癫痫的研究进展[J]. 中华实用儿科临床杂志, 2021, 36(14): 1111-1114.
[29] 敦硕, 邹丽萍, 张梦娜, 等. 雷帕霉素对儿童结节性硬化症相关肾脏疾病的疗效观察[J]. 中华儿科杂志, 2019, 57(11): 852-856.
[30] 张世敏, 秦炯. 雷帕霉素及其衍生物治疗结节性硬化症研究进展[J]. 中国实用儿科杂志, 2019, 34(1): 67-70.
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