Further Evidence of Early-Onset Osteoporosis and Bone Fractures as a New -Related Phenotype.

Primary osteoporosis in children and young adults often suggests a monogenic disease affecting bone microarchitecture and bone mineral density. While Osteogenesis Imperfecta (OI) is the most recognized genetic cause of recurrent fractures, many other genes involved in bone metabolism may contribute to osteoporosis. Among them, FGFR2 plays a critical role in bone growth and development by regulating osteoblast differentiation and proliferation, as well as chondrogenesis. Germline pathogenic variants are typically associated with syndromic craniosynostosis, conditions not characterized by bone fragility or osteoporosis. A report recently identified FGFR2 as a potential cause of dominant early-onset osteoporosis and bone fractures in a family. We report the case of a child affected by severe osteoporosis with multiple fractures. We performed clinical exome sequencing in trio to investigate potential genetic causes of the observed phenotype and identified a likely mosaic pathogenic variant, absent in both parental samples. Our findings provide further evidence that pathogenic variants can lead to a novel non-syndromic bone mineralization disorder, reinforcing the role of FGFR2 in the pathogenesis of early-onset osteoporosis.