ESPE Abstracts

Background: X-Linked hypophosphatemic rickets (XLH) is a disorder of phosphate homeostasis, characterized by renal phosphate wasting and hypophosphatemia, with normal to low 1,25-dihydroxy vitamin D3 serum levels. PHEX is the gene defective in XLH and different mutations and genomic rearrangements have been described in different families affected by this disease.

Objectives: To detect inactivating mutations in the PHEX gene in a cohort of patients referred to genetic investigation of XLH.

Materials and Methods: 18 patients (12 females, 6 males), representing seven families, presented with suspected XLH from biochemical and clinical evidence. They were all referred for mutational analysis of the PHEX gene.

Results: Analysis of PHEX revealed mutations in 13 hypophosphatemic rickets patients. In 7 patients, in whom no PHEX mutation had been previously detected in 22 exons, MLPA (Multiplex Ligation-dependent Probe Amplification) analysis was carried out and large deletions in PHEX gene was found in 5 patients from the same family. No correlation was found between the severity of disease and the type or location of the mutation, even the ones with large deletions. However, among patients with a family history of hypophosphatemic rickets, there was a trend toward more severe skeletal disease in patients with truncating mutations. Family members in more recent generations had a more severe phenotype in 4 families, nevertheless even patients from the same kindred harboring the same mutation could show different phenotypes. Postpubertal males had a more severe dental phenotype.

Conclusion: Molecular genetic analysis confirms the clinical diagnosis of XLH and should include sequence analysis as well as the search for large deletions, which is facilitated by MLPA technique. Although identifying mutations in PHEX may have limited prognostic value, genetic testing may be useful for the early identification and treatment of affected individuals, in particular with advent of specific therapies with phocus in FGF23 metabolic pathway. Furthermore, this study suggests that other genes and environmental factors affect the severity of hypophosphatemic rickets.