Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets

J Clin Endocrinol Metab. 2001 Aug;86(8):3889-99. doi: 10.1210/jcem.86.8.7761.


PHEX is the gene defective in X-linked hypophosphatemic rickets. In this study, analysis of PHEX revealed mutations in 22 hypophosphatemic rickets patients, including 16 of 28 patients in whom all 22 PHEX exons were studied. In 13 patients, in whom no PHEX mutation had been previously detected in 17 exons, the remaining 5 PHEX exons were analyzed and mutations found in 6 patients. Twenty different mutations were identified, including 16 mutations predicted to truncate PHEX and 4 missense mutations. Phenotype analysis was performed on 31 hypophosphatemic rickets patients with PHEX mutations, including the 22 patients identified in this study, 9 patients previously identified, and affected family members. No correlation was found between the severity of disease and the type or location of the mutation. 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 milder phenotype. Postpubertal males had a more severe dental phenotype. In conclusion, although identifying mutations in PHEX may have limited prognostic value, genetic testing may be useful for the early identification and treatment of affected individuals. Furthermore, this study suggests that other genes and environmental factors affect the severity of hypophosphatemic rickets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Substitution
  • Bone Diseases / genetics
  • Child
  • DNA Mutational Analysis
  • Exons
  • Family
  • Female
  • Genotype
  • Humans
  • Hypophosphatemia, Familial / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Mutation, Missense
  • Nuclear Family
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • Phenotype
  • Proteins / genetics*
  • Sequence Deletion
  • Tooth Diseases / genetics


  • Proteins
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • PHEX protein, human