Giant Cell Tumor Occurring in Familial Paget's Disease of Bone: Report of Clinical Characteristics and Linkage Analysis of a Large Pedigree
Giant Cell Tumor Occurring in Familial Paget's Disease of Bone: Report of Clinical Characteristics and Linkage Analysis of a Large Pedigree
复制标题
DOI：
10.1002/jbmr.1750
复制
发表时间：
2013-02-01
影响因子：
6.2
通讯作者：
Gennari, Luigi
中科院分区：
文献类型：
--
作者：
Gianfrancesco, Fernando;Rendina, Domenico;Gennari, Luigi
肿瘤变性是佩吉特骨病（PDB）的一种罕见但严重的并发症。虽然骨肉瘤在PDB病例中的发生率高达1%，但巨细胞瘤的发生率较低，主要发生在多发性骨质疏松症患者中。我们最近的特点是一个大的谱系与14个受影响的成员，其中四个开发巨细胞瘤在pagetic网站。多代受影响的受试者数量众多，使我们能够更好地表征临床表型并寻找可能的易感基因座。值得注意的是，所有受影响的成员都患有多骨性PDB，但发生巨细胞瘤的受试者显示疾病严重程度增加，对双膦酸盐治疗的临床反应降低，骨痛、畸形和骨折的患病率增加。除了常见的肺动脉并发症的发生率增加外，该家系的受累患者的冠状动脉疾病患病率也比未受累的家庭成员或来自同一地理区域的150例无关PDB病例的比较队列高5倍。这种关联在4例PDB和巨细胞瘤患者中进一步增强，他们都在60岁之前发生冠状动脉疾病。尽管发病较早且表型严重，但该谱系的PDB患者对SQSTM 1或TNFRSF11 A突变的存在呈阴性，而这些突变之前与疾病严重程度增加相关。全基因组连锁分析确定了染色体1，5，6，8，10和20上的六个可能的候选区域。由于8号和10号染色体位点与TNFRSF11B和OPTN基因相邻，我们将遗传筛查扩展到这两个基因，但我们未能在基因组和转录水平上鉴定出任何致病突变，这表明在该家系中，不同的遗传缺陷与PDB和潜在的骨巨细胞瘤相关。(C)2013年美国骨矿物质研究学会。
Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree. (C) 2013 American Society for Bone and Mineral Research.