Endocrine Abstracts

JOINT776

Introduction: Alterations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with primary bone fragility, leading to recurrent low-energy fractures. Heterozygous carriers typically exhibit a milder phenotype, with reduced bone mass observed early in childhood. This study aims to describe the clinical features and therapeutic outcomes of a pediatric cohort with heterozygous LRP5 gene variants.

Case Series: This retrospective study includes 7 pediatric patients (5 males, 2 females) from 3 Italian Pediatric Endocrinology Centers, aged 6 to 17 years (mean age at diagnosis: 9.1 years). Their height ranged from -1.2 to +1.3 SDS, and BMI from -0.7 to 3.0 SDS. Eight distinct heterozygous LRP5 variants were identified (6 missense, 2 nonsense), with most classified as variants of uncertain significance (VUS) and 2 deemed likely pathogenic. One patient carried the c.1709G>A; p.(Arg570Gln) variant, previously reported as pathogenic in the homozygous state. Before diagnosis, patients had between 0 and 4 low-trauma fractures, with 4 out of 7 presenting multiple spontaneous vertebral fractures. Bone and joint pain were reported by 5 out of 7 patients (71%) at presentation. All but two underwent bisphosphonate therapy (one is scheduled to start), and one patient also received denosumab. During a follow-up period ranging from 9 months to 4 years, none experienced new fractures. Bone mineral density (BMD) improved in all patients, with an observed increase ranging from 3% to 103% (mean increase: 51%). Those with vertebral compression fractures showed evidence of stabilization or partial reshaping. No adverse effects related to therapy were reported in this cohort.

Discussion and Conclusion: This case series highlights the clinical variability associated with LRP5 gene variants in pediatric patients and underscores the effectiveness of bisphosphonate therapy in improving BMD and reducing fracture risk. The identification of predominantly VUS variants provides valuable insight into the genetic landscape of LRP5-related bone disorders. Our findings contribute to the expanding knowledge of LRP5 mutations and their association with primary bone fragility in children, underscoring the critical role of molecular diagnostics. Understanding the genetic basis of the disease not only improves diagnosis but also offers deeper insights into its pathophysiology, potentially informing more targeted therapeutic approaches. While bisphosphonates remain the current standard of care, further research is needed to explore precision therapies targeting Wnt signaling and other pathways affected by LRP5 mutations. A personalized approach, tailored to the specific genetic variant and clinical presentation, may further optimize long-term bone health in affected children.