title: Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens.
abstract: BACKGROUND
  The most common form of familial hypophosphatemic rickets is X-linked. PHEX has been identified as the gene defective in this phosphate wasting disorder leading to decreased renal phosphate reabsorption, hypophosphatemia and inappropriate concentrations of 1,25-dihydroxyvitamin D in regard to hypophosphatemia. Clinical manifestation are skeletal deformities, short stature, osteomalacia, dental abscesses, bone pain, and loss of hearing.
  
  
  METHODS
  We report 3 cases of hypophosphatemic rickets with genetic mutational analysis of the PHEX gene. In 1 male patient an unknown nonsense mutation was found in exon 7, codon 245 (c.735T>G, Tyr245Term, Y245X). In both female patients known mutations were found: c.682delTC (exon 6, codon 228) and c.1952G>C (exon 19, codon 651, R651P). Age at diagnosis ranged from early childhood to the age of 35 years. Clinical complications were hip replacement in 1 patient, mild nephrocalcinosis in 2 patients and loss of hearing in 1 patient. All 3 patients have been treated with phosphate supplements and receive 1,25-dihydroxyvitamin D. Under this regimen all patients show stable biochemical markers with slight hyperparathyreoidism. In all patients at least one family member is affected by rickets, as well.
  
  
  CONCLUSIONS
  We report a novel nonsense mutation of PHEX that has not been identified so far. The recent discovery of FGF23 and MEPE has changed our understanding of the kidney-bone metabolism, but also raises concerns about the efficacy of current therapeutic regimens that are reviewed in this context.
authors.affiliation: Department of Clinical Endocrinology, Charité University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kienitz
authors.forename: M
authors.initials: M
authors.lastname: Ventz
authors.forename: E
authors.initials: E
authors.lastname: Kaminsky
authors.forename: M
authors.initials: M
authors.lastname: Quinkler
mesh_terms: D000293:Adolescent; D000328:Adult; D019644:Arthroplasty, Replacement, Hip; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D002114:Calcinosis / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002117:Calcitriol / Q000008:administration & dosage*; D018389:Codon, Nonsense; D005091:Exons; D053098:Familial Hypophosphatemic Rickets / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D000089703:Fibroblast Growth Factor-23; D040181:Genetic Diseases, X-Linked; D034381:Hearing Loss; D006801:Humans; D008297:Male; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D018389:Codon, Nonsense; C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; D002117:Calcitriol