Vitamin D is a pro-hormone characterized by an intricate metabolism and regulation. It is well known for its role in calcium and phosphate metabolism, and in bone health. However, several studies have assessed a huge number of extra-skeletal functions, ranging from cell proliferation in some oncogenic pathways to antioxidant and immunomodulatory functions. Vitamin D exerts its role by binding to VDRs (vitamin D receptors), which are located in many different tissues. Moreover, VDRs are able to bind hundreds of genomic loci, modulating the expression of various primary target genes. Interestingly, plenty of gene polymorphisms regarding VDRs are described, each one carrying a potential influence against gene expression, with relapses in several chronic diseases and metabolic complications. In this review, we provide an overview of the genetic aspects of vitamin D and VDR, emphasizing the gene regulation of vitamin D, and the genetic modulation of VDR target genes. In addition, we briefly summarize the rare genetic disease linked to vitamin D metabolism.

Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on pathophysiology of XLH. Particular attention was given to the interaction between systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of alteration of calcium-phosphate metabolism, systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH.

Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on the pathophysiology of XLH. Particular attention was given to the role of systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH.

Background: The relationship between diet and body composition in people with HIV (PWH) is still not well defined. Therefore, our primary objective was to assess the association between Mediterranean diet (MD) adherence and body composition measured by whole-body dual-energy X-ray absorptiometry (DXA). Secondly, we aimed to assess differences between people living in the north (Padua, Veneto Region, Italy) vs. those living in the south of Italy (Catanzaro, Calabria Region, Italy) and with respect to ethnicity. Methods: In this cross-sectional study, adults with HIV with a confirmed virological suppression were enrolled at two Italian HIV clinics. MD adherence was assessed using the validated MedDiet Score, with high adherence being defined as a score ≥ 25. All participants underwent whole-body DXA. Anthropometric and DXA-derived measures were compared between people with high vs. low adherence to MD, and multivariable linear regression adjusted for age, sex, and CD4⁺ count at nadir was performed. Results: Among 130 participants (81.5% male; median age 57 years), 105 (80.8%) showed high MD adherence. High adherence to MD was more common among participants from Southern Italy than among those from Northern Italy and was associated with Caucasian ethnicity, higher education, higher CD4⁺ count and CD4/CD8 ratio, and a lower prevalence of obesity and neurological disorders. DXA analyses showed lower total and trunk fat mass and higher lumbar spine bone mineral density in highly adherent individuals. After adjustment, high MD adherence remained independently associated with lower BMI (β −5.3, 95% CI −7.3 to −3.4; p < 0.001). Conclusions: In ageing PWH, high MD adherence was associated with a more favourable clinical profile and healthier body composition, particularly lower central adiposity and BMI. Prospective and interventional studies are needed to clarify the role of this type of diet in PWH.

Skeletal fragility is a major, yet still under-recognized, complication of endogenous Cushing’s syndrome, with a prevalence of densitometric osteoporosis of approximately 30-50% and fragility fractures reported in 11-76% of patients across published series. Chronic cortisol excess impairs bone strength through a complex network of direct and indirect mechanisms that collectively produce a deterioration of bone quality extending well beyond what is captured by standard densitometry. Therefore, fragility fractures occur in a substantial proportion of patients at bone mineral density values in the osteopenic or even normal range, underscoring the central role of bone microarchitectural impairment. Emerging tools, including the Trabecular Bone Score, high-resolution peripheral quantitative computed tomography, and bone marrow fat assessment by MRI, provide complementary information on bone quality and fracture risk. Following successful treatment of hypercortisolism, spontaneous skeletal recovery occurs but is slow, site-specific, and incomplete, with fracture risk remaining elevated for years after remission. Despite the clinical relevance of these complications, no CS-skeletal specific guidelines exist for their management, the evidence base for bone-active agents in endogenous CS is extremely limited, and real-world data confirm that bone health is systematically under-assessed in routine practice. This review provides a comprehensive and updated overview of the epidemiology, pathophysiology, risk assessment, and treatment of skeletal fragility in endogenous CS, with the aim of raising awareness and highlighting the urgent need for dedicated diagnostic and therapeutic strategies in this high-risk population.

Purpose: This study investigates the role of CASR gene polymorphisms (A986S, R990G, Q1011E) in PHPT genetic susceptibility and its clinical variability. The aim is to evaluate the prevalence of these polymorphisms in patients with sporadic PHPT and their impact on clinical course, biochemistry, and histological features. Methods: 106 patients underwent clinical and anamnestic evaluations, focusing on major PHPT complications, as well as biochemical analyses of blood and urine. Genetic testing was conducted for CASR gene polymorphisms. Histological data were available for 68 patients who underwent parathyroidectomy. Results: The sample included 83 women and 23 men; mean age at diagnosis was 54.5 years. 55 patients carried CASR gene polymorphisms, while 51 were wild-type. Prevalence rates of polymorphisms were consistent with data for the Caucasian population, with A986S being the most common (31%). No significant associations were found between polymorphisms and increased levels of ionized calcium or other blood phospho-calcium metabolism parameters. However, 24-h urinary calcium levels were higher in patients with polymorphisms (p = 0.0185), particularly in those older than 50 years (p = 0.030) and with the A986S variant. Hypercalciuria was predictive of CASR polymorphism presence (OR = 2.76, p = 0.003). No significant association with PHPT complications, such as renal calculi or bone involvement, was confirmed. Histological data revealed no clear links between polymorphisms and more aggressive variants. Conclusions: CASR gene polymorphisms are associated with hypercalciuria but do not significantly influence age of onset or clinical phenotype in PHPT. Genetic analysis may be useful in selected cases to better understand individual clinical profiles.