骨质疏松症-假性胶质瘤综合征(OPPG)和LRP5高骨量(LRP5-HBM)是两种罕见的骨骼疾病,由LRP5的功能丧失和功能获得突变引起的临床症状相反。双膦酸盐是OPPG患者的有效治疗方法。LRP5-HBM有良性病程,在一名LRP5-HBM患者中发现与年龄相关的骨丢失。
目的:低密度脂蛋白受体相关蛋白5(LRP5)参与经典的Wnt信号通路。功能获得突变导致高骨量(LRP5-HBM),而功能缺失突变导致骨质疏松-假性胶质瘤综合征(OPPG)。在这项研究中,临床表现,致病突变,治疗,并对随访进行了总结,以提高对这两种疾病的认识。
方法:本研究包括两名OPPG患者和四名LRP5-HBM患者。临床特点,生化和放射学检查,致病性突变,并对结构分析进行了总结。此外,对患者进行随访,观察治疗效果和病情进展。
结果:先天性失明,持续性骨痛,低骨密度(BMD),OPPG的临床表现以多发脆性骨折为主。在两名OPPG患者中检测到复杂的杂合突变。首次报道了外显子7中的c.1455G>T突变。在后续行动中,2例患者经双膦酸盐治疗后BMD明显改善。相反,LRP5-HBM的典型临床特征包括极高的BMD而无骨折,圆环和正常视力。X线示为弥漫性骨硬化。在四名患者中检测到两个杂合错义突变。此外,1例LRP5-HBM患者随访12年后发现与年龄相关的骨丢失.
结论:这项研究加深了对临床特征的认识,治疗,以及OPPG和LRP5-HBM的随访;扩大了OPPG的致病基因谱;并证实双膦酸盐对OPPG有效。此外,研究发现Ala242Thr突变不能保护LRP5-HBM患者免于年龄相关性骨丢失.这一现象值得进一步研究。
Osteoporosis-pseudoglioma syndrome (OPPG) and LRP5 high bone mass (LRP5-HBM) are two rare bone diseases with opposite clinical symptoms caused by loss-of-function and gain-of-function mutations in LRP5. Bisphosphonates are an effective treatment for OPPG patients. LRP5-HBM has a benign course, and age-related bone loss is found in one LRP5-HBM patient.
OBJECTIVE: Low-density lipoprotein receptor-related protein 5 (LRP5) is involved in the canonical Wnt signaling pathway. The gain-of-function mutation leads to high bone mass (LRP5-HBM), while the loss-of-function mutation leads to osteoporosis-pseudoglioma syndrome (OPPG). In this study, the clinical manifestations, disease-causing mutations, treatment, and follow-up were summarized to improve the understanding of these two diseases.
METHODS: Two OPPG patients and four LRP5-HBM patients were included in this study. The clinical characteristics, biochemical and radiological examinations, pathogenic mutations, and structural analysis were summarized. Furthermore, several patients were followed up to observe the treatment effect and disease progress.
RESULTS: Congenital blindness, persistent bone pain, low bone mineral density (BMD), and multiple brittle fractures were the main clinical manifestations of OPPG. Complex heterozygous mutations were detected in two OPPG patients. The c.1455G > T mutation in exon 7 was first reported. During the follow-up, BMD of two patients was significantly improved after bisphosphonate treatment. On the contrary, typical clinical features of LRP5-HBM included extremely high BMD without fractures, torus palatinus and normal vision. X-ray showed diffuse osteosclerosis. Two heterozygous missense mutations were detected in four patients. In addition, age-related bone loss was found in one LRP5-HBM patient after 12-year of follow-up.
CONCLUSIONS: This study deepened the understanding of the clinical characteristics, treatment, and follow-up of OPPG and LRP5-HBM; expanded the pathogenic gene spectrum of OPPG; and confirmed that bisphosphonates were effective for OPPG. Additionally, it was found that Ala242Thr mutation could not protect LRP5-HBM patients from age-related bone loss. This phenomenon deserves further study.