Department of Medical Genetics and Skeletal Rare Diseases, Rizzoli Orthopaedic Institute, Bologna, Italy.
J Bone Joint Surg Am. 2011 Dec 21;93(24):2294-302. doi: 10.2106/JBJS.J.00949.
Multiple hereditary exostoses is an autosomal dominant skeletal disorder characterized by wide variation in clinical phenotype. The aim of this study was to evaluate whether the severity of the disease is linked with a specific genetic background.
Five hundred and twenty-nine patients with multiple hereditary exostoses from two different European referral centers participated in the study. According to a new clinical classification based on the presence or absence of deformities and functional limitations, the phenotype of the patients was assessed as mild (the absence of both aspects), intermediate, or severe (the concurrent presence of both aspects). An identical molecular screening protocol with denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification was performed in both institutions.
In our cohort of patients, variables such as female sex (odds ratio = 1.840; 95% confidence interval, 1.223 to 2.766), fewer than five skeletal sites with exostoses (odds ratio = 7.588; 95% confidence interval, 3.479 to 16.553), EXT2 mutations (odds ratio = 2.652; 95% confidence interval, 1.665 to 4.223), and absence of EXT1/2 mutations (odds ratio = 1.975; 95% confidence interval, 1.051 to 3.713) described patients with a mild phenotype; in contrast, a severe phenotype was associated with male sex (odds ratio = 2.431; 95% confidence interval, 1.544 to 3.826), EXT1 mutations (odds ratio = 6.817; 95% confidence interval, 1.003 to 46.348), and more than twenty affected skeletal sites (odds ratio = 2.413; 95% confidence interval, 1.144 to 5.091). Malignant transformation was observed in 5% of patients, and no evidence of association between chondrosarcoma onset and EXT mutation, sex, severity of disease, or number of lesions was detected.
The identified "protective" and "risk" factors, as well as the proposed classification system, represent helpful tools for clinical management and follow-up of patients with multiple hereditary exostoses; moreover, homogeneous cohorts of patients, useful for studies on the pathogenesis of multiple hereditary exostoses, have been identified.
多发性遗传性外生骨疣是一种常染色体显性骨骼疾病，其临床表现存在广泛的变异性。本研究旨在评估疾病的严重程度是否与特定的遗传背景有关。
本研究纳入了来自两个欧洲转诊中心的 529 名多发性遗传性外生骨疣患者。根据一种新的临床分类，根据有无畸形和功能受限，将患者的表型评估为轻度（无两个方面）、中度或重度（两个方面同时存在）。在两个机构中，采用相同的变性高效液相色谱和多重连接依赖性探针扩增的分子筛查方案。
在我们的患者队列中，女性（比值比=1.840；95%置信区间，1.223 至 2.766）、外生骨疣少于五个骨骼部位（比值比=7.588；95%置信区间，3.479 至 16.553）、EXT2 突变（比值比=2.652；95%置信区间，1.665 至 4.223）和无 EXT1/2 突变（比值比=1.975；95%置信区间，1.051 至 3.713）等变量与轻度表型相关；相反，严重表型与男性（比值比=2.431；95%置信区间，1.544 至 3.826）、EXT1 突变（比值比=6.817；95%置信区间，1.003 至 46.348）和二十多个受累骨骼部位（比值比=2.413；95%置信区间，1.144 至 5.091）相关。在 5%的患者中观察到恶性转化，未发现软骨肉瘤发病与 EXT 突变、性别、疾病严重程度或病变数量之间存在关联。
所确定的“保护”和“风险”因素以及提出的分类系统是多发性遗传性外生骨疣患者临床管理和随访的有用工具；此外，还确定了用于多发性遗传性外生骨疣发病机制研究的同质患者队列。
