Endocrine Abstracts

Osteoporosis causes bone fragility usually affecting the elderly. Genetic susceptibility plays a crucial role in determining the risk of fragility fractures and is involved in early-onset osteoporosis. When fragility fractures or low bone mineral density (BMD) occur in young adults without evident secondary osteoporosis, an underlying monogenetic bone disease should be assessed. The list of genes related to low BMD and their mutations is increasing. Nevertheless, little is known about the role of Variants of Uncertain Significance (VUS). We retrospectively evaluated 65 adult patients undergoing Next Generation Sequencing analysis for osteogenesis imperfecta/lowBMD panel including the following genes: COL1A1, COL1A2, BMP1, CRTAP, FKBP10, IFITM5, P3H1, PLOD2, PLS3, PPIB, SERPINF1, SERPINH1, WNT1, LRP5. The indication for genetic analysis was prompted by multiple fragility fractures or low BMD in premenopausal/perimenopausal women and in men aged less than 55 years, in the absence of a clear phenotype of monogenetic bone disease and after exclusion of secondary causes of osteoporosis. Gene variants were detected in 37 (57%) out of 65 enrolled patients: 3 patients, mean aged 47.3 years, had pathogenic mutations in COL1A1 and COL1A2, therefore being diagnosed with osteogenesis imperfecta. They denied dental diseases, while two of them had moderate-severe scoliosis and hearing loss, and one reported ligament laxity; each reported a mean of 5 fractures, more commonly appendicular. One patient had densitometric osteoporosis. The remaining 34 patients harboured VUS: they did not significantly differ from wild-type patients regarding age, sex, age at first fracture, presence of low BMD and circulating markers of mineral metabolism and C-terminal telopeptide. Of note, though the prevalences of dental disease and hearing loss were similar, VUS patients had more commonly a family history of fragility fractures (56.2 versus 24.0%, P=0.015), and a higher number of axial fractures (2.9 versus 1.0%, P=0.01), whereas the number of appendicular fractures was comparable with wild-type subjects. Moreover, moderate-severe scoliosis showed a trend to be more common in the VUS group (20.6 versus 3.6%, P=0.087), and the median levels of alkaline phosphatase and its bone isoenzyme were higher in VUS patients (81.8 versus 55.0 U/l, P=0.01; 20.3 versus 9.8 μg/l; P=0.02, respectively). In conclusion, VUS in low BMD related genes may associate with a family history of fragility fractures, moderate-severe scoliosis, high number of axial fractures and relatively high bone turnover. These findings suggest the need to extend genetic diagnosis and to investigate the role of VUS.