Novel familial mutation of LRP5 causing high bone mass: Genetic analysis, clinical presentation, and characterization of bone matrix mineralization.

The Wnt signalling pathway is a critical regulator of bone mass and quality. Several heterozygous mutations in the LRP5 gene, a Wnt co-receptor, causing high bone mass (LRP5-HBM) have been described to date. The pathogenic mechanism is thought to be a gain-of-function caused by impaired inhibition of the canonical Wnt signalling pathway, thereby leading to increased bone formation. We report the cases of two affected family members, a 53-year-old mother and her 23-year-old daughter, with high bone mass (T-scores mother: lumbar spine 11.4, femoral neck 10.5; T-scores daughter: lumbar spine 5.4, femoral neck 8.7), increased calvarial thickness, and thickened cortices of the long bones but no history of fractures. Whereas the mother did not show any indications of the mutation, the daughter suffered from congenital hearing impairment resulting in cochlear implantation, recurrent facial palsy, and migraine. In addition, she had stenosis of the foramen magnum. In both individuals, we detected a novel heterozygous duplication of six basepairs in the LRP5 gene, resulting in an insertion of two amino acids, very likely associated with a gain-of-function. When the daughter had part of the occipital bone surgically removed, the bone sample was used for the visualization of bone lamellar structure and bone cells as well as the measurement of bone mineralization density distribution (BMDD). The bone sample revealed two distinctly different regions: an intra-cortical region with osteonal remodeling, typical osteonal lamellar orientation, associated with relatively higher heterogeneity of bone matrix mineralization, and another periosteal region devoid of bone remodeling, with parallel bone lamellae and lower heterogeneity of mineralization. In conclusion, we present data on bone tissue and material level from an LRP5-HBM patient with a novel mutation in the LRP5 gene. Our findings indicate normal morphology of osteoclasts and osteoblasts as well as normal mineralization in skull bone in LRP5-HBM.