Alessandra Guzzo

Hajdu–Cheney syndrome (HCS) is a rare genetic skeletal disorder caused by truncating variants of NOTCH2, characterized by progressive bone resorption and marked phenotypic heterogeneity. Despite advances in understanding Notch signaling in skeletal biology, longitudinal clinical data tracking disease evolution from early childhood through adolescence are lacking. Here, we report a rare longitudinal intrafamilial observation of HCS in a mother and her son carrying the same NOTCH2 pathogenic variant, providing novel insights into disease evolution and therapeutic response. Over extended follow-up, the son exhibited early vertebral fragility despite preserved or supranormal bone mineral density (BMD), whereas the mother developed severe osteoporosis, progressive acro-osteolysis, and multiple vertebral fractures. Longitudinal analysis revealed a dissociation between vertebral fragility and densitometric decline, challenging the paradigm that low BMD is the primary driver of skeletal morbidity in HCS. Treatment responses differed between the two patients, with bisphosphonate therapy in the son associated with stabilized BMD without altering vertebral structural progression, and denosumab in the mother associated with increased BMD, but not preventing progression of acro-osteolysis. Additionally, the emergence of extra-skeletal features during adolescence expands the phenotypic spectrum of HCS and suggests previously unrecognized systemic involvement. These data highlight intrinsic limitations of current therapeutic strategies and emphasize the need for targeted interventions addressing sustained Notch2 activation. Our findings contribute to the understanding of the natural history and therapeutic challenges of HCS, providing the framework for future mechanistic and translational research.

Osteogenesis imperfecta (OI) type XIV is a rare recessive disorder caused by TMEM38B pathogenic variants that disrupt an endoplasmic reticulum protein essential for calcium homeostasis and bone mineralization. This leads to severe bone fragility, early-onset fractures, skeletal deformities, low bone mass, scoliosis, and variable features like blue sclerae or dental abnormalities. We present a case report of a 21-year-old Italian male with a novel homozygous TMEM38B splice variant (c.112 + 1G > T), detailing the clinical presentation, genetic findings, and therapeutic outcomes. The patient exhibited multiple skeletal deformities and showed a moderate response to bisphosphonate therapy (neridronate). In addition, a systematic review of PubMed and Scopus identified 12 relevant studies from an initial set of 82 publications, encompassing data from 56 patients diagnosed with OI type XIV. Unlike classical collagen-related OI, TMEM38B-related OI necessitates genetic screening beyond classical collagen genes (COL1A1 and COL1A2). While bisphosphonates provide some clinical benefit, persistent fractures underscore the need for long-term management and innovative therapies. This case report and systematic review enhance understanding of OI type XIV and underscore the clinical importance of TMEM38B variants in bone fragility disorders.

Osteogenesis Imperfecta (OI) is a heterogeneous group of inherited skeletal dysplasias characterized by bone fragility. The study of bone metabolism, in these disease, is problematic in terms of clinical and genetic variability. The aims of our study were to evaluate the importance of Vitamin D levels in OI bone metabolism, reviewing studies performed on this topic and providing advice reflecting our experience using vitamin D supplementation. A comprehensive review on all English-language articles was conducted in order to analyze the influence of vitamin D in OI bone metabolism in pediatric patients. Reviewing the studies, contradictory data were found on the relationship between 25OH vitamin D levels and bone parameters in OI, and in several studies the baseline levels of 25OH D were below the threshold value of 75 nmol/L. In conclusion, according to the literature and to our experience, we highlight the importance of adequate vitamin D supplementation in children with OI.