Li Haichong,Yao Ziming,Guo Ruolan,et al.Genotypes and clinical intervention of patients with neurofibromatosis type 1 associated dystrophic scoliosis[J].Journal of Clinical Pediatric Surgery,2025,(04):312-319.[doi:10.3760/cma.j.cn101785-202410023-003]
儿童Ⅰ型神经纤维瘤病脊柱畸形的遗传学特点及手术治疗效果研究
- Title:
- Genotypes and clinical intervention of patients with neurofibromatosis type 1 associated dystrophic scoliosis
- Keywords:
- Neurofibromatosis Type1; Spinal Deformities; Genetic Testing; Genetic Research; Surgical Procedures; Operative; Treatment Outcome; Child
- 摘要:
- 目的 探究Ⅰ型神经纤维瘤病(neurofibromatosis type 1,NF1)脊柱畸形的遗传学特点,并分析生长棒技术和后路脊柱融合手术对于该病的治疗效果。方法 回顾性分析2006年9月至2022年6月首都医科大学附属北京儿童医院收治的临床诊断为营养不良性NF1脊柱畸形患儿临床资料,利用全外显子组测序技术(whole exome sequencing,WES)、多重连接探针扩增技术(multiplex ligation-dependent probe amplification analysis,MLPA)以及全基因组测序技术(whole genome sequencing,WGS)对NF1脊柱畸形患儿进行基因检测,查找基因突变位点,并对患儿的基因突变类型进行分类。测量并对比患儿术前及术后末次随访时的主弯Cobb角、顶椎偏距、冠状面偏移及矢状面偏移等影像学参数变化,分析手术疗效。结果 本研究共纳入临床诊断为NF1脊柱畸形患儿47例,其中男性23例、女性24例。共明确NF1基因突变43例,未明确4例。WES的基因诊断率为76.6%(36/47),WES联合MLPA及WGS的诊断率为91.5%(43/47)。NF1脊柱畸形患儿的突变类型包括:NF1基因无义突变16例,移码突变13例,剪接位点突变9例,缺失/重复突变3例,错义突变2例。首次手术方式包括:生长棒技术30例,后路脊柱融合手术17例;初次手术年龄7.8(4.6,9.9)岁。术前及术后末次随访时,患儿主弯Cobb角分别为56.0(43.0,65.0)° 、17.0(8.0,25.0)°,差异有统计学意义(Z=-7.577,P＜0.001);主弯矫正率为(68.6±17.5)%。随访时间为3.6(2.0,6.3)年,随访期间9例(9/47,19.1%)出现并发症。结论 NF1脊柱畸形患儿的基因突变类型复杂多样,缺乏明确的基因突变热点。NF1脊柱畸形存在明显的表型异质性,即使相同NF1基因突变位点的患儿,其脊柱畸形的临床表型也可存在明显的个体差异。生长棒技术和后路脊柱融合手术安全有效,对于控制儿童期NF1脊柱侧凸畸形的病情进展具有良好效果。
- Abstract:
- Objective To explore the genotypic characteristics of children with neurofibromatosis type 1 (NF1) associated dystrophic scoliosis and summarize the outcomes of surgery.Methods Whole exome sequencing (WES),multiplexligation-dependent probe amplification (MLPA) and whole genome Sequencing (WGS) was utilized for genotypic identification.A total of 47 children were operated for spinal deformities and the outcomes of surgery summarized by examining the clinical and imaging parameters before and after surgery.Results Twenty-three boys and 24 girls were clinically diagnosed as NF1 associated scoliosis with common symptoms including café-au-lait spots and scoliosis.NF1 mutations were detected in 43(91.5%) children,including 16 nonsense mutations,9 splicing mutations,13 frame shift mutations,2 missense mutation,2 exon deletions and 1 exon duplication.Initial surgical procedures included growing-rod surgery (n=30) and posterior spinal fusion (n=17).The follow-up duration was 3.6 years and Cobb angle of main curve improved from 56.0(43.0,65.0)° pre-operatively to 17.0(8.0,25.0)° at the last follow-up with an average correction rate of (68.6±17.5)%.The complications occurred in 9 patients during follow-ups.Conclusions In children with scoliosis fulfilling the clinical diagnostic criteria for NF1,the mutation detection rate of WES,MLPA,WGS was 91.5%.There is no mutation hotspot in NF1 gene.Molecular diagnosis may offer information about genetic counseling,prenatal diagnosis and eugenics.Surgery based upon patient age and severity may effectively correct spinal deformities.
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备注/Memo
收稿日期:2024-10-11。
基金项目:国家重点研发计划资助(2023YFC2507701);北京市自然科学基金-海淀原始创新联合基金资助项目(L222095)
通讯作者:张学军,Email:zhang-x-j04@163.com;郝婵娟,Email:hchjhchj@163.com