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A PHEX Gene Mutation Is Responsible for Adult-Onset Vitamin D-Resistant Hypophosphatemic Osteomalacia: Evidence That the Disorder Is Not a Distinct Entity from X-Linked Hypophosphatemic Rickets¹

Departments of Medicine (M.J.E.) and Radiology (J.A.S.), Indiana University, Indianapolis, Indiana 46202; Departments of Pediatrics (N.E.F.) and Medicine (M.C.S., B.E.L., H.B.), Duke University, Durham, North Carolina 27710; University College London (P.S.N.R.), London, United Kingdom NW3 2PF; Max-Planck Institut für Molekulare Genetik (F.F.), Berlin, Germany; Abteilung Medizinische Genetik, Kinderpoliklinik der Ludwig Maximilians Universität (T.M.S.), Munich 80336, Germany; IGBMC, Parc d’Innovation (C.O.), 67404 Illkirch, France; and the Department of Orthopedic Surgery, Medical College of Wisconsin (J.T.N.), Wisconsin 53226

Address all correspondence and requests for reprints to: Michael J. Econs, M.D., F.A.C.P., F.A.C.E., Indiana University School of Medicine, 975 W. Walnut Street, IB 445, Indianapolis, Indiana 46202. E-mail: mecons{at}iupui.edu

Previous investigators described a kindred with an X-linked dominant form of phosphate wasting in which affected children did not have radiographic evidence of rickets, whereas older individuals were progressively disabled by severe bowing. They proposed that this kindred suffered from a distinct disorder that they referred to as adult-onset vitamin D-resistant hypophosphatemic osteomalacia (AVDRR). We recently identified a gene, PHEX, that is responsible for the disorder X-linked hypophosphatemic rickets. To determine whether AVDRR is a distinct form of phosphate wasting, we searched for PHEX mutations in affected members of the original AVDRR kindred. We found that affected individuals have a missense mutation in PHEX exon 16 that results in an amino acid change from leucine to proline in residue 555. Clinical evaluation of individuals from this family indicates that some of these individuals display classic features of X-linked hypophosphatemic rickets, and we were unable to verify progressive bowing in adults. In light of the variability in the clinical spectrum of X-linked hypophosphatemic rickets and the presence of a PHEX mutation in affected members of this kindred, we conclude that there is only one form of X-linked dominant phosphate wasting.

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