Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations.
BACKGROUND
Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-alpha-D-galactosamine:polypeptide N- acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes.


OBJECTIVE
Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient.


METHODS
Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA.


METHODS
A 5-year-old French boy with HHS and his family members participated.


RESULTS
The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC.


CONCLUSIONS
The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.
Ichikawa
Shoji
S
Department of Medicine, Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 459, Indianapolis, IN 46202-5121, USA.
Guigonis
Vincent
V
Imel
Erik A
EA
Courouble
Mélanie
M
Heissat
Sophie
S
Henley
John D
JD
Sorenson
Andrea H
AH
Petit
Barbara
B
Lienhardt
Anne
A
Econs
Michael J
MJ
D002114:Calcinosis / Q000378:metabolism; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D015576:Hyperostosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000502:physiology; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010710:Phosphates / Q000097:blood*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011877:Radionuclide Imaging; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D017350:N-Acetylgalactosaminyltransferases; D009363:Neoplasm Proteins; D010710:Phosphates; D012313:RNA; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human