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<p>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 <i>LPR5</i> gene. Eight heterozygous variants of the <i>LRP5</i> 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&#xa0;months–4&#xa0;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 <i>LRP5</i> 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 <i>LRP5</i> gene alterations.</p>

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Clinical, Biochemical and Radiological Features of LRP5 Gene Variants in Children

  • 期刊论文

  • 发表日期：

    2025年8月12日

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  • Graziamaria Ubertini,
  • Danilo Fintini,
  • Francesco d’Aniello,
  • Flavia Urbano,
  • Mariangela Chiarito,
  • Alessia Angelelli,
  • Natascia Di Iorgi,
  • Maria Felicia Faienza

摘要

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.