Ubertini Graziamaria, Fintini Danilo, d'Aniello Francesco, Urbano Flavia, Chiarito Mariangela, Angelelli Alessia, Di Iorgi Natascia, Faienza Maria Felicia
Endocrinology and Diabetology Unit, IRCCS 'Bambino Gesù' Children's Hospital, Rome, Italy.
Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, 70124, Bari, Italy.
Calcif Tissue Int. 2025 Aug 12;116(1):108. doi: 10.1007/s00223-025-01412-7.
Alterations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been associated with primary osteoporosis, leading to recurrent low-trauma fractures. Heterozygous carriers typically show a milder phenotype, with reduced bone mass starting in early childhood. In this paper, we described the clinical features and therapeutic outcomes of a cohort of 7 children (5 males) harboring different variants in the LPR5 gene. Eight heterozygous variants of the LRP5 gene were identified (6 missense, 2 nonsense), two of which were likely pathogenic. One male patient was compound heterozygous, carrying two different variants, including p.(Arg570Gln), previously reported as pathogenic in homozygous form, and exhibited a more severe phenotype consistent with Osteoporosis-Pseudoglioma Syndrome, including vitreoretinal abnormalities. At initial presentation, most patients had a history of low-trauma long bone fractures, or spontaneous vertebral fractures, and bone/joint pain. Five of them received bisphosphonate therapy and one patient also received denosumab. No new fractures occurred during follow-up (9 months-4 years). Bone mineral density (BMD) increased in all patients (3-103%, mean: 55%), and partial vertebral reshaping was described. No adverse effects were reported. This pediatric case series highlights the phenotypic variability of LRP5 gene variants, and underscores the efficacy of bisphosphonate therapy in improving BMD and reducing fracture risk. However, while bisphosphonates remain the standard of care, further research is needed on precision therapies that target Wnt signaling and other pathways affected by LRP5 gene alterations.
低密度脂蛋白受体相关蛋白5（LRP5）基因的改变与原发性骨质疏松症相关，可导致反复发生低创伤性骨折。杂合子携带者通常表现出较轻的表型，从幼儿期开始骨量就会减少。在本文中，我们描述了一组7名儿童（5名男性）的临床特征和治疗结果，这些儿童携带LPR5基因的不同变异。共鉴定出8种LRP5基因的杂合变异（6种错义变异、2种无义变异），其中2种可能具有致病性。一名男性患者为复合杂合子，携带两种不同变异，包括p.(Arg570Gln)，该变异先前报道为纯合形式致病，其表现出更严重的表型，符合骨质疏松-假性胶质瘤综合征，包括玻璃体视网膜异常。初诊时，大多数患者有低创伤性长骨骨折或自发性椎体骨折病史，以及骨/关节疼痛。其中5名患者接受了双膦酸盐治疗，1名患者还接受了地诺单抗治疗。随访期间（9个月至4年）未发生新的骨折。所有患者的骨密度（BMD）均增加（3% - 103%，平均：55%），并描述有部分椎体重塑。未报告不良反应。该儿科病例系列突出了LRP5基因变异的表型变异性，并强调了双膦酸盐治疗在改善骨密度和降低骨折风险方面的疗效。然而，虽然双膦酸盐仍然是标准治疗方法，但仍需要对靶向Wnt信号通路和受LRP5基因改变影响的其他途径的精准治疗进行进一步研究。
