Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations

• Published in: American journal of medical genetics. Part A Vol. 152A; no. 4; pp. 896 - 903
• Main Authors: Ichikawa, Shoji, Baujat, Geneviève, Seyahi, Aksel, Garoufali, Anastasia G., Imel, Erik A., Padgett, Leah R., Austin, Anthony M., Sorenson, Andrea H., Pejin, Zagorka, Topouchian, Vicken, Quartier, Pierre, Cormier-Daire, Valerie, Dechaux, Michele, Malandrinou, Fotini Ch, Singhellakis, Panagiotis N., Le Merrer, Martine, Econs, Michael J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-04-2010; Wiley-Liss
• Subjects: Adolescent; Adult; Base Sequence; Biological and medical sciences; Calcinosis - complications; Calcinosis - diagnostic imaging; Calcinosis - enzymology; Calcinosis - genetics; Child; Child, Preschool; Dermatology; DNA Mutational Analysis; Family; Female; FGF23; Fibroblast Growth Factor-23; GALNT3; Humans; hyperostosis-hyperphosphatemia syndrome; Male; Medical genetics; Medical sciences; Molecular Sequence Data; Mutation - genetics; N-Acetylgalactosaminyltransferases - genetics; Neoplasms - complications; Neoplasms - diagnostic imaging; Neoplasms - enzymology; Neoplasms - genetics; phosphate; Polypeptide N-acetylgalactosaminyltransferase; Radiography; tumoral calcinosis; Tumors of the skin and soft tissue. Premalignant lesions; Young Adult; Phosphates; Skin disease; Hydroelectrolytic balance disorder; GALNT3; Family study; Variability; hyperostosis―hyperphosphatemia syndrome; Diseases of the osteoarticular system; phosphate; Phosphorus; Hyperostosis; Inorganic element; Metabolic disorder; Tumoral calcinosis; Calcification; Hyperphosphatemia; Benign neoplasm; Mutation; FGF23
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.33337

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)2D] 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. © 2010 Wiley‐Liss, Inc.