Osteoporosis is characterized by reduced bone density and abnormal bone microarchitecture, leading to bone fragility and increased risk for fractures [1]. It is a complex disorder and can be secondary to other diseases with several risk factors having a role in the pathogenesis [2]. When occurring in childhood or young adulthood in absence of an underlying causative condition, osteoporosis can be related to a monogenic bone disease [3]; in fact, bone fragility is a key finding in several skeletal dysplasias [4]. In particular, the paradigm of skeletal dysplasia with bone fragility is Osteogenesis Imperfecta (OI), a group of hereditary connective tissue disorders with recurrent fractures as main clinical manifestation [5]. COL1A1 and COL1A2 mutations account for about 85-90% of cases of OI; despite this, many other genes (involved in collagen biosynthesis, bone mineralization, and osteoblast differentiation) have been identified as causative of OI or hereditary early onset osteoporosis, thus expanding the molecular mechanisms of bone fragility [6,7,8]. Recently, Dantsev and colleagues [2023] reported the case of a 13-year-old boy affected by osteoporosis and multiple fractures, with a family history of abnormal bone mineralization and fractures, carrying a heterozygous variant in the FGFR2 gene [9]. Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor belonging to a family that includes four high affinity receptors with a similar structure [10]. It is expressed in various tissues, and regulates many biological processes as cell proliferation, migration, survival and differentiation [11,12,13] with a key role in the development and growth of the skeleton [14]. In particular, FGFR2 is involved in osteogenesis of cranial and long bones [15,16]. Moreover, studies in mice models revealed a critical role of both gain and loss-of-function FGFR2 variants in balancing the proliferation and differentiation of osteoprogenitor cells [17,18,19].