罕见遗传性多发性骨软骨瘤合并骨质疏松症一例研究并文献复习

Rare hereditary multiple exostoses with osteoporosis:A case study and literature review

目的 分析以多发骨性突起、骨密度下降为主要表现的一例罕见遗传性多发性骨软骨瘤(hereditary multiple exostoses, HME)患者的临床特点及致病基因突变。方法 评估临床特点,测量骨转换生化指标、骨密度、骨骼X线。采用二代靶向测序及Sanger测序技术检测并确定致病基因突变。通过文献复习,总结我国HME基因突变研究及HME合并骨质疏松症的国内外研究。结果 本例主要表现为多发骨性突起,X线检查提示长骨干骺端及右肩胛骨多发外生骨疣,骨转换生化指标正常,腰椎及全髋骨密度为0.973 g/cm^(2)(Z值-1.2)、0.613 g/cm^(2)(Z值-2.7),予阿仑膦酸钠、钙剂和维生素D治疗2年,骨密度明显增加。患者存在EXT1基因第3外显子c.1162C>T杂合无义突变,导致蛋白糖基转移酶活性结构域缺失。文献显示,我国HME患者主要病因为EXT1或EXT2杂合失活性突变,无明确热点突变,尚未见HME合并骨质疏松症的报道。结论 HME是罕见的常染色体显性遗传骨病,表型主要包括多发骨性突起、肢体畸形、疼痛等,主要病因为EXT1或EXT2突变,EXT1基因失活突变可能为本例患者HME合并骨质疏松症的原因,本研究丰富了HME致病基因突变谱和表型谱。

Objective To investigate the clinical features of a patient with hereditary multiple exostoses(HME)presented with multiple bony prominences and decreased bone mineral density(BMD),and to analyze its pathogenic mutation.Methods Clinical features,serum bone turnover biomarkers,BMD,and bone morphology were evaluated.Paneled sequencing and Sanger sequencing were performed to detect and confirm the pathogenic mutation.Domestic studies on gene mutational spectrum in HME patients and all studies on HME with osteoporosis were summarized by literature review.Results The main features of this patient were multiple bony prominences.Radiography revealed multiple exostoses in the metaphysis of long bones and right scapula.Bone turnover biomarker levels were normal,and BMD at lumbar spine and total hip was 0.973 g/cm^(2)(Z-score-1.2),0.613 g/cm^(2)(Z-score-2.7).After 2 years'treatment of alendronate,calcium,and vitamin D,BMD was obviously increased.The heterozygous nonsense mutation of c.1162C>T in exon 3 of EXTI was identified in this patient,which caused loss of the glycosyltransferase domain of EXT1 protein.Previous studies have shown that HME patients in China were usually caused by heterozygous LOF mutation in EXTI or EXT2,without clear hot-spot mutation.HME with osteoporosis has not been reported in China.Conclusions HME is a rare autosomal dominant bone disease,whose phenotypes include multiple bony prominences,limb deformity,pain,and so on,mainly due to mutations in EXTI or EXT2.The LOF mutation of EXTI may be the cause of HME complicated with osteoporosis in this patient.Our findings enrich both pathogenic mutation spectrum and phenotypic spectrum of HME.