Insight into Natural History and Phenotype in Untreated Adults with X-Linked Hypophosphatemia.

X-linked hypophosphatemia (XLH) is a rare genetic rachitic/osteomalacic and dental disorder caused by pathogenic variants in PHEX gene resulting in fibroblast growth factor 23 (FGF23) excess leading to hypophosphatemia by renal phosphate wasting and decreased 1,25-dihydroxyvitamin D production. The aim of the study was to provide insight into natural history and phenotype in untreated adults with XLH (no phosphate supplements and active vitamin D metabolites or burosumab). Clinical, biochemical, skeletal features, co-morbidities, and patient-reported outcomes (PROs) were examined in 52 patients (51.5 ± 12.2 years; 18 men and 34 women). Mean height Z-score and mean leg length Z-score were lower than normal (P < 0.0001) and were lower (P < 0.01) in men (-3.8 ± 1.2 and -4.2 ± 1.2, respectively) than in women (-2.9 ± 0.8 and -3.4 ± 0.9, respectively). BMI was in the range of overweight in 30 patients (57.7%) and in the range of obesity in 15 patients (28.8%). Most of patients had severe skeletal deformities and dental-periodontal abnormalities. Pseudofractures were documented in 17 patients (33%). Mean concentration of intact FGF23, osteocalcin, PINP, CTX, and BALP was higher in men compared to women (P < 0.05-P < 0.001). PROs ranged from moderate to severe scores, with no difference (P = NS) between sexes. The phenotype in adult individuals with XLH was characterized by severe and disproportionate short stature, overweight/obesity, severe skeletal deformities with difficulty walking, osteoarticular pain, poor dental health, and reduced quality of life. Stature and biochemical markers of bone turnover were more compromised in men than in women.

© 2026. The Author(s).