Clinical features of Italian adult individuals with X-linked hypophosphatemia: a multicenter retrospective study

Objective: X-linked hypophosphatemia (XLH) is the most common congenital phosphate disorder affecting individuals throughout the lifespan. We investigated the skeletal burden, the cardiovascular involvement, the diagnostic performance and the therapeutic management in a cohort of Italian adults with XLH. Design: Cross-sectional study involving 15 Italian tertiary centers. Methods: Retrospective study. Results: In total, 170 adults (110 females and 60 males), aged 44.6 ± 14.6 (19-83) years, were identified. i) Skeletal deformities were detected in 87.1% of individuals, fractures/pseudofractures in 44.7%, osteophytosis in 65.4% and enthesopathies in 57.6%. Dental disease affected 72.4% of individuals. The skeletal burden was heavier in males than in females. ii) Hypertension occurred in 14.7% of individuals and was associated with elevated plasma intact FGF23 levels; dyslipidemia, diabetes and cerebrovascular events occurred in very few individuals. iii) FGF23 levels were measured in 30.0% of individuals; they were >30 pg/mL (nv 23-95) in nearly all individuals but overtly elevated in 58.8%. Genetic analysis has been performed in 86.5% of the cohort, and PHEX mutations were identified in 95.2% of the individuals without evidence of genotype/phenotype correlation. iv) 44.2% of individuals were on conventional therapy, 32.5% were on burosumab, and 23.3% were untreated. Individuals having received diagnosis in the adulthood (n = 14) were neither medically nor surgically treated during their childhood. Conclusion: The burden of XLH disease in adulthood is determined by skeletal manifestations and dental disease and may be more severe in males. Additionally, cardiometabolic impairment may not be common. The disease burden impacts most of the individuals, beyond those presenting the criteria for burosumab reimbursement. Significance statement: Data from a consistent cohort of adults with XLH highlighted that skeletal and dental disease-related complications significantly affect XLH individuals during adulthood and aging. Skeletal features associated with aging occur earlier in adults with XLH, being more evident when untreated or poorly treated with conventional therapy. The disease burden impacts most of individuals, beyond those presenting the criteria for burosumab reimbursement. The study contributes in increasing awareness toward adult XLH individuals and provides data for implementing the disease management and the health policy planning.