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Mutational Analysis and Genotype-Phenotype Correlation of the PHEX Gene in X-Linked Hypophosphatemic Rickets

Division of Endocrinology, Department of Medicine (I.A.H.), Children’s Hospital, Boston, Massachusetts 02115; Cancer Genetics Department (A.E.N., B.G.R., R.S.M., D.J.M.), Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney 2065, Australia; Department of Physiology and Institute for Biomedical Research (A.E.N., R.S.M.), University of Sydney, Sydney 2006, Australia; Department of Medicine (B.G.R., D.J.M.), University of Sydney, Sydney 2006, Australia; The New Children’s Hospital (C.T.C.), Westmead 2145, Australia; and Department of Pediatrics (Endocrinology) (T.O.C.), Yale University School of Medicine, New Haven, Connecticut 06520-8064

Address all correspondence and requests for reprints to: Ingrid A. Holm, M.D., Division of Endocrinology, Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail: ingrid.holm{at}tch

Abstract

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.

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