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

Department of Medicine (S.I., E.A.I., A.H.S., M.J.E.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pediatrics (E.A.I.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Division of Endocrinology (R.S., P.K.), Medical College of Wisconsin, Milwaukee, Wisconsin 53226; The Eye Institute (G.J.H.), Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Endocrine-Diabetes Center (J.L.S.), St. Luke’s Medical Center, Milwaukee, Wisconsin 53215; and Department of Medical and Molecular Genetics (M.J.E.), Indiana University School of Medicine, Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Michael J. Econs, M.D., Department of Medicine, Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 459, Indianapolis, Indiana 46202-5121. E-mail: mecons{at}iupui.edu.

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--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.

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