1、成骨不全症基因型—表现型的关联研究 2、阿仑膦酸钠、唑来膦酸治疗成骨不全症的疗效对比 3、Gorham-Stout综

发布时间：2018-05-02 13:07

本文选题：成骨不全症 + 双膦酸盐　；参考：《北京协和医学院》2015年硕士论文

【摘要】：第一部分成骨不全症基因型-表现型的关联研究研究背景：成骨不全症是一组以骨强度下降、骨折风险增加为特点的遗传异质性骨病,最常见的致病基因为编码Ⅰ型胶原的COL1A1、COL1A2。此外还有约15种基因可引起成骨不全症。通过传统Sanger测序的方式对成骨不全症进行基因诊断费时费力。研究目的：探究二代测序平台诊断成骨不全症的敏感性、特异性,同时对明确基因诊断的成骨不全症进行基因型-表现型关联的分析。研究方法：我们设计了包含12种成骨不全症致病基因在内的二代测序平台,检测临床诊断为成骨不全症的患者,通过Sanger测序对检测结果进行验证,并对COL1A1、COL1A2所致成骨不全症的基因型表现型进行进一步分析。研究结果：二代测序的平均测序深度为每个碱基200X。经Sanger测序验证,二代测序平台检测成骨不全症的敏感性约为90.2%,特异性为100%,检测到46个新突变位点。在COL1A1、 COL1A2基因所致OI中,COL1A1单倍剂量不足所致的OI表型比a三螺旋结构改变所致的表型较轻,其中身高Z值的改变有显著差异(单倍剂量不足组为-0.6±1.1,COL1A1 a三螺旋结构改变者为-6.5±6.1,COL1A2 a三螺旋结构改变者为-5.5±4.6,P=0.007)。未发现氨基酸替换、a三螺旋结构位置与表现型之间的关系。研究结论：二代测序平台是诊断成骨不全症的有效手段。COL1A1单倍剂量不足引起的成骨不全症较其他类型COLIA1?COL1A2改变临床表现更轻。第二部分阿仑膦酸钠、唑来膦酸盐治疗成骨不全症的疗效对比摘要研究背景：成骨不全症是一种以骨密度、骨强度下降,骨折风险增高为主要表现的遗传代谢性骨病。目前,双膦酸盐为最常用的治疗成骨不全症的药物,其中阿仑膦酸钠、唑来膦酸是较常见的强有效的双膦酸盐类药物。研究目的：评估阿仑膦酸钠、唑来膦酸治疗成骨不全症的疗效及安全性。研究方法：在这一单中心、随机、对照临床试验中,2-16岁成骨不全症患者按照2：1的比例进行分组,分别接受口服阿仑膦酸钠70mg/周或者静脉注射唑来膦酸5mg/年的治疗。每隔6月对患者进行骨密度(Bone mineral density, BMD)、X线、血清学检测、药物不良反应的评估。主要研究终点为腰椎骨密度(]Lumbar spine BMD, LS BMD)变化率,次要研究终点为LS BMD Z值、股骨颈B MD(Femoral neck BMD,FN BMD)变化率、FN BMDZ值、骨转换指标变化率、再次发生骨折率。主要研究终点采用协方差方法计算,固定因子为治疗方式,协变量为年龄及基线水平。分析基于意向性分析人群。研究结果：共有161例患者纳入研究,其中随机分配至阿仑膦酸钠组107例,唑来膦酸组54例。136例患者完成了2年的治疗与随访。经过2年治疗,阿仑膦酸钠组LS BMD的变化率为60.01%±7.08%,唑来膦酸组变化率为62.04%±5.9%,两组之间无显著性差异(0.951)。唑来膦酸组能够显著降低骨折发生率(危险比0.23,95%置信区间0.118-0.431,P0.001)。随访6月时,唑来膦酸组的FN BMD增长率(32.23%±4.43%)及FN BMD Z值(0.631±0.065)均显著高于阿仑膦酸钠组(22.64%±3.69%,P=0.025)(0.436±0.054,P=0.025)。随访24个月时,唑来膦酸组的LSBMD Z值(0.706±0.006)显著高于阿仑膦酸钠组(0.499±0.051)的LS BMD Z值(P=0.013)。两组均能显著降低骨转换指标碱性磷酸酶及Ⅰ型胶原羧基肽,但组间无显著性差异。研究结论：口服阿仑膦酸钠及静脉输注唑来膦酸均能显著提高成骨不全症患者的骨密度。在降低骨折风险方面,唑来膦酸优于阿仑膦酸钠。两种药物的耐受性均较好。第三部分Gorham-Stout综合征的临床分析摘要研究背景：Gorham-Stout综合征(Gorham-Stout syndrome,GSS)又称为大块骨溶解症,是一种极为罕见的以骨溶解性破坏为主要表现的疾病。研究目的：探究GSS可能的发病机制,探索双膦酸盐(Bisphosphonates, BPs)对GSS的疗效。研究方法：分析在北京协和医院就诊的GSS患者的临床、影像学、病理学表现。对取了骨组织活检的患者进行淋巴管特异标记物D2-40、血管标记物CD 31、CD 34及血管内皮生长因子(Vascular endothelial growth factor, VEGF),血管内皮生长因子受体Vascular endothelial growth factor receptor, VEGF-R)等染色。通过影像学、骨密度等指标评估BPs对于GSS的疗效。研究结果：在12例就诊的GSS患者中,11例为多发骨骼受累,1例为单一骨骼受累。4例患者合并其他部位的淋巴管瘤。4例合并乳糜胸3的患者出现反复呼吸困难。骨骼活检显示病变部位的内皮细胞有CD31、CD34及D2-40的阳性表达。此外,还发现有VEGF、VEGF-R的弱阳性表达。研究结论：GSS是一种极为罕见的淋巴管来源的疾病。合并乳糜胸时提示预后较差。
[Abstract]:The first part of the genotype - phenotype association study background: osteogenesis imperfecta is a group of genetic heterozygous bone diseases characterized by decreased bone strength and increased fracture risk. The most common pathogenetic gene is COL1A1 encoding type I collagen, and COL1A2. in addition to about 15 genes can cause osteogenesis imperfecta. Through traditional San Ger sequencing is time-consuming for gene diagnosis of osteogenesis imperfecta. Objective: To explore the sensitivity and specificity of the two generation sequencing platform to diagnose osteogenesis imperfecta, and to analyze the genotype phenotype association of osteogenesis imperfecta in the diagnosis of gene diagnosis. Research methods: we designed to include 12 types of osteogenesis imperfecta. The two generation sequencing platform, which was diagnosed as osteogenesis imperfecta, tested the results by Sanger sequencing, and further analyzed the genotype phenotype of COL1A1, COL1A2 induced osteogenesis imperfecta. The results showed that the average sequencing depth of the two generation sequencing was verified by Sanger sequencing for each base base 200X., The sensitivity of the two generation sequencing platform to detect osteogenesis imperfecta was about 90.2%, the specificity was 100%, and 46 new mutation sites were detected. In the COL1A1, the COL1A2 gene induced OI, the OI phenotype caused by the inadequacy of COL1A1 double dose was lighter than the a three spiral structure change, and there was a significant difference in the height Z value of the phenotype. 0.6 + 1.1, COL1A1 a three spiral structural changes were -6.5 + 6.1, COL1A2 a three spiral structure was -5.5 4.6, P=0.007). No amino acid replacement, the relationship between the position of the spiral structure of a three and the relationship between the phenotype. The study concluded that the two generation sequencing platform was an effective means to diagnose osteogenesis imperfecta caused by the lack of single dose of.COL1A1. Total disease is lighter than other types of COLIA1? COL1A2 changes. Second alendronate, zoledronate in the treatment of osteogenesis imperfecta: a summary of the summary of the effect of osteogenesis: osteogenesis imperfecta is a genetic metabolic bone disease characterized by bone density, reduced bone strength, and increased fracture risk. Drugs for the treatment of osteogenesis imperfecta, of which alendronate and zoledronic acid are the most common potent bisphosphonates. Purpose: To evaluate the efficacy and safety of alendronate and zoledronic acid in the treatment of osteogenesis imperfecta. Methods: 2-16 year old osteogenesis imperfecta in this single center, random, controlled clinical trial. The patients were divided into groups according to the proportion of 2:1, receiving oral alendronate 70mg/ weeks or intravenous zoledronic acid for 5mg/ years. Every June, the patients were treated with bone mineral density (Bone mineral density, BMD), X-ray, serological examination, and evaluation of adverse drug reactions. The main research end was lumbar bone mineral density (]Lumbar spine BMD, LS BM). D) rate of change, the secondary end point was LS BMD Z, B MD (Femoral neck BMD, FN BMD), FN depreciation, bone conversion index, and fracture rate. The main endpoint was calculated by covariance method, the fixation factor was the treatment method, the covariance was age and baseline level. Analysis based on intentional analysis population. Results: a total of 161 patients were randomly assigned to 107 cases of alendronate group and 54 cases of zoledronic acid group (.136) were treated and followed up for 2 years. After 2 years of treatment, the change rate of LS BMD in alendronate group was 60.01% + 7.08%, and the change rate of zoledronic acid group was 62.04% + 5.9%, and there was no significant difference between the two groups (0.951). Zoledronic acid group could significantly reduce the incidence of fracture (0.23,95% confidence interval 0.118-0.431, P0.001). In June, the FN BMD growth rate (32.23% + 4.43%) and FN BMD Z (0.631 + 0.065) in the zoledronic acid group were significantly higher than that in the alendronate group (22.64% + 3.69%, P=0.025) (0.436 + 0.054, P=0.025). The follow-up was 24 months, zoledronic acid The LSBMD Z value of the group (0.706 + 0.006) was significantly higher than the LS BMD Z value (P=0.013) of the alendronate group (0.499 + 0.051). The two groups could significantly reduce the bone conversion index alkaline phosphatase and type I collagen carboxyl peptide, but there was no significant difference between the groups. Bone mineral density. Zoledronic acid is better than alendronate in reducing fracture risk. The two drugs are well tolerated. The clinical analysis of the third part of the Gorham-Stout syndrome is a summary of the clinical summary: the Gorham-Stout syndrome (Gorham-Stout syndrome, GSS), also known as massive osteolysis, is an extremely rare osteolysis The purpose of the study is to explore the possible pathogenesis of GSS and explore the effect of bisphosphonates (Bisphosphonates, BPs) on GSS. Methods: to analyze the clinical, imaging, and pathological manifestations of GSS patients in Peking Union Medical College Hospital, and to perform lymphatic specific marker D2-4 for patients who have taken bone tissue biopsy. 0, vascular markers CD 31, CD 34 and vascular endothelial growth factor (Vascular endothelial growth factor, VEGF), vascular endothelial growth factor receptor Vascular endothelial growth factor receptor, and other staining. The case was multiple skeletal involvement. 1 cases of.4 patients with single bone involvement were combined with other parts of the lymphangioma.4 cases with chylothorax and 3 of the patients with recurrent dyspnea. The bone biopsy showed that the endothelial cells in the lesion site had CD31, CD34 and D2-40 positive expression. Furthermore, the weak positive expression of VEGF and VEGF-R was found. Conclusion: GSS It is a rare disease of lymphatic origin. When combined with chylothorax, the prognosis is poor.

【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R681.1

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