Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.
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.
Ichikawa
Shoji
S
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ichikawa@iupui.edu
Baujat
Geneviève
G
Seyahi
Aksel
A
Garoufali
Anastasia G
AG
Imel
Erik A
EA
Padgett
Leah R
LR
Austin
Anthony M
AM
Sorenson
Andrea H
AH
Pejin
Zagorka
Z
Topouchian
Vicken
V
Quartier
Pierre
P
Cormier-Daire
Valerie
V
Dechaux
Michele
M
Malandrinou
Fotini Ch
FCh
Singhellakis
Panagiotis N
PN
Le Merrer
Martine
M
Econs
Michael J
MJ
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
D000089703:Fibroblast Growth Factor-23; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human