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

Area of Science:

• Genetics
• Pediatric Endocrinology
• Skeletal Biology

Background:

• Low-density lipoprotein receptor-related protein 5 (LRP5) gene alterations are linked to primary osteoporosis and recurrent fractures.
• Heterozygous LRP5 variants typically present with reduced bone mass from early childhood.

Purpose of the Study:

• To describe the clinical features and therapeutic outcomes of pediatric patients with LRP5 gene variants.
• To evaluate the efficacy of current therapies in managing osteoporosis associated with LRP5 alterations.

Main Methods:

• Retrospective analysis of clinical data from 7 pediatric patients (5 males) with identified LRP5 variants.
• Genetic sequencing to identify heterozygous and compound heterozygous variants in the LRP5 gene.
• Assessment of therapeutic outcomes including fracture incidence, bone mineral density (BMD), and adverse effects.

Main Results:

• Eight heterozygous LRP5 variants were identified (6 missense, 2 nonsense), with two deemed likely pathogenic.
• One patient with compound heterozygous variants exhibited a severe phenotype resembling Osteoporosis-Pseudoglioma Syndrome.
• All patients receiving bisphosphonate or denosumab therapy experienced no new fractures during follow-up.
• Significant increases in BMD (mean 55%) and partial vertebral reshaping were observed.

Conclusions:

• LRP5 gene variants present with significant phenotypic variability in children.
• Bisphosphonate therapy is effective in improving BMD and reducing fracture risk in pediatric LRP5-associated osteoporosis.
• Further research into precision therapies targeting Wnt signaling and LRP5-affected pathways is warranted.