ORF43-01 - Double Trouble in Bone: Osteopetrosis Associated with Concurrent CLCN7 and LRP5 Mutations

Osteopetrosis is most commonly caused by genetic mutations that disrupt normal bone remodeling, resulting in skeletal fragility despite high bone mass. Mutations in CLCN7, a gene encoding CIC-7 protein, impair the osteoclast’s ability to acidify and dissolve bone mineral, leading to reduced bone resorption and abnormally dense but brittle bone. Conversely, gain-of-function mutations in LRP5 cause osteopetrosis by upregulating the Wnt/β-catenin pathway and thus increasing osteoblast action and bone formation. The co-existence of mutations in both of these genes is rare and has not been frequently reported.

An 83-year-old male presented to our outpatient clinic with a history of osteopetrosis and multiple (>15) fragility fractures mostly in adulthood. He was diagnosed with abnormal skeletal findings on chest X-ray in childhood during a hospitalization for pneumonia. At that time, his family declined additional work up, and he was empirically treated with fluoride for 2 weeks. In 2014, after sustaining repeated fractures, he underwent a bone biopsy revealing findings consistent with osteopetrosis. Serial imaging revealed patchy skeletal sclerosis, and a "rugger-jersey" spine on X-ray. A dual-energy X-ray absorptiometry scan revealed a spine BMD of 1.782 g/cm²/ T-score 6.3, left femoral neck BMD of 1.544 g/cm²/ T-score 4.5, and left total hip BMD of 1.691 g/cm²/ T-score 4.4, with a relatively low left distal radius BMD of 0.601 g/cm²/ T-score -4.1. Biochemical evaluation revealed normal serum phosphorus, parathyroid hormone, alkaline phosphatase, 25-hydroxyvitamin D, and calcium levels. Genetic testing was performed and revealed that he was heterozygous for a pathogenic missense mutation in CLCN7 (c.857G>A/p.Arg286GIn) and for mutation of uncertain significance in LRP5 (c.3887C>G/p.Pro1296Arg).

This case describes a rare genetic combination of a heterozygous pathogenic CLCN7 mutation and an LRP5 variant of uncertain significance. The patient’s clinical features are most consistent with autosomal dominant osteopetrosis due to the pathogenic CLCN7 mutation. The presence of an LRP5 variant raises the possibility of additional effects on bone remodeling; however a causal role cannot be determined. Reporting this case may help expand understanding of combined genetic variants in high bone mass disorders, as further functional studies of LRP5 become available.