Tumoral Calcinosis Presenting with Eyelid Calcifications due to Novel Missense Mutations in the Glycosyl Transferase Domain of the GALNT3 Gene

• Published in: The journal of clinical endocrinology and metabolism Vol. 91; no. 11; pp. 4472 - 4475
• Main Authors: Ichikawa, Shoji, Imel, Erik A., Sorenson, Andrea H., Severe, Rebecca, Knudson, Paul, Harris, Gerald J., Shaker, Joseph L., Econs, Michael J.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.11.2006; Copyright by The Endocrine Society
• Subjects: Adult; Biological and medical sciences; Calcinosis - genetics; DNA Mutational Analysis; Endocrinopathies; Eyelids - pathology; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors - blood; Fundamental and applied biological sciences. Psychology; Glycosyltransferases - genetics; Humans; Medical sciences; Mutation, Missense; N-Acetylgalactosaminyltransferases - genetics; Neoplasm Proteins - genetics; Polypeptide N-acetylgalactosaminyltransferase; Protein Structure, Tertiary - genetics; Skin Diseases - genetics; Vertebrates: endocrinology; Eyelid; Skin disease; Tumoral calcinosis; Missense mutation; Gene; Enzyme; Transferases; Calcification; Genetics; Benign neoplasm; Endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2006-1247

Context: Familial tumoral calcinosis (TC) is a rare autosomal recessive disorder characterized by metastatic calcifications, often periarticular. Biochemical findings include hyperphosphatemia, high 1,25-dihydroxyvitamin D levels, and elevated tubular maximum for phosphate reabsorption per deciliter of glomerular filtrate (TmP/GFR). TC is caused by biallelic mutations of the genes encoding either fibroblast growth factor 23 (FGF23) or uridine diphosphate-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc transferase 3 or GALNT3). Objective: The objective was to identify mutations in FGF23 or GALNT3 responsible for a mild TC phenotype by DNA sequencing and to determine serum FGF23 levels by ELISA. Patients or Other Participants: The subject was a 25-yr-old Caucasian woman with eyelid calcifications and biochemical features of TC. Results: Eyelid biopsy revealed superficial dermis calcifications. There was no history of metastatic calcifications, mineral homeostasis abnormalities, or renal dysfunction. Biochemistry revealed normal levels of calcium, creatinine, PTH, and 25-hydroxyvitamin D, with elevated phosphorous, TmP/GFR, and high normal 1,25-dihydroxyvitamin D levels. Intact FGF23 was undetectable (<3 pg/ml), whereas C-terminal FGF23 was elevated (698.2 RU/ml). Mutation detection revealed compound heterozygosity for two novel mutations in the glycosyl transferase domain of the GALNT3 gene. Conclusion: Previously reported GALNT3 mutations in TC have been null mutations. This study shows that missense mutations affecting the glycosyl transferase domain of GalNAc transferase 3 also cause TC. Elevated C-terminal FGF23 fragments with undetectable intact FGF23 suggest that the mutant enzyme lacks the ability to glycosylate FGF23 and that glycosylation by GalNAc transferase 3 is necessary for secretion of functional full-length FGF23.