Adult X-linked hypophosphatemia: multisystem morbidity and no evidence of genotype–phenotype correlation – insights from a Brazilian cohort

Abstract Background X-linked hypophosphatemia (XLH) is a rare disorder caused by inactivating variants in the PHEX gene characterized by lifelong musculoskeletal and multisystemic complications. Despite its chronic nature, data on long-term outcomes in adults remain limited, and many patients may not receive appropriate care. This study aimed to describe the clinical and genetic profile of a cohort of Brazilian adults with XLH, providing real-world data on long-term disease manifestations across adulthood and exploring potential genotype-phenotype correlations. Methods We retrospectively reviewed medical records of adult individuals with XLH to assess musculoskeletal features and associated complications. For the genotype-phenotype analysis, clinical and biochemical parameters were compared between patients with nontruncating ( n = 6) variants and those with presumed truncating ( n = 22) variants using Mann-Whitney test and Fisher’s exact test. Results Twenty-eight patients (4 males) were included. The mean age at presentation to adult care unit was 32.5 ± 13.5 years, with a mean height of 142.7 ± 10.5 cm. Musculoskeletal pain, lower-limb deformities, and gait abnormalities were each documented in 82% of patients. Recurrent orthopedic interventions were common (75%), and 21% required the use of walking aids. Extra-skeletal manifestations included dental abnormalities (77%), hyperparathyroidism (43%), and renal complications (32%). Of the 25 patients not receiving pharmacological treatment at the time of adult care evaluation, 21 required medical therapy due to persistent osteomalacia. Among the 17 distinct PHEX variants that were identified, 4 variants had not been previously reported, and 13 variants were classified as presumed truncating variants. No significant differences in clinical or biochemical parameters were observed between presumed truncating and non-truncating variant groups. Conclusion Brazilian adults with XLH experience considerable musculoskeletal and extra-skeletal morbidity across their lives, with most requiring pharmacological intervention during adulthood. No evidence of correlation between disease severity and the type of PHEX variant was observed; however, the limited and uneven subgroup sizes preclude definitive conclusions. These results highlight the need for ongoing multidisciplinary care and tailored therapeutic strategies to mitigate disease burden.