title: Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.
abstract: The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ichikawa@iupui.edu
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Geneviève
authors.initials: G
authors.lastname: Baujat
authors.forename: Aksel
authors.initials: A
authors.lastname: Seyahi
authors.forename: Anastasia G
authors.initials: AG
authors.lastname: Garoufali
authors.forename: Erik A
authors.initials: EA
authors.lastname: Imel
authors.forename: Leah R
authors.initials: LR
authors.lastname: Padgett
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Austin
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Sorenson
authors.forename: Zagorka
authors.initials: Z
authors.lastname: Pejin
authors.forename: Vicken
authors.initials: V
authors.lastname: Topouchian
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Michele
authors.initials: M
authors.lastname: Dechaux
authors.forename: Fotini Ch
authors.initials: FCh
authors.lastname: Malandrinou
authors.forename: Panagiotis N
authors.initials: PN
authors.lastname: Singhellakis
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002114:Calcinosis / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D009369:Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics*; D011859:Radiography; D055815:Young Adult; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000089703:Fibroblast Growth Factor-23; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human