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Submitted on February 9, 2006
Accepted on July 18, 2006
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Rheumatology, Southend General Hospital, Westcliff-on-Sea, Essex SS0 0RY, UK; Department of Endocrinology, Saint James's Hospital and Trinity College Dublin Medical School, Dublin 8, Ireland; and Division of Geriatric Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224
* To whom correspondence should be addressed. E-mail: kenewhit{at}iupui.edu.
Context. Familial tumoral calcinosis (TC) results from disruptions in phosphate metabolism and is characterized by high serum phosphate with normal or elevated 1,25(OH)2 vitamin D concentrations and ectopic and vascular calcifications. Recessive loss of function mutations in GalNAc transferase-3 (GALNT3) and fibroblast growth factor-23 (FGF23) result in TC.
Objective. To determine the relationship between GALNT3 and FGF23 in familial TC.
Design, Setting, and Patients. We assessed the major biochemical defects and potential genes involved in patients with TC.
Intervention. Combination therapy consisted of the phosphate binder Sevelamer and the carbonic anhydrase inhibitor acetazolamide.
Results. We report a patient homozygous for a GALNT3 exon 1 deletion which is predicted to truncate the encoded protein. This patient had high serum FGF23 concentrations when assessed with a C-terminal FGF23 ELISA, but low-normal FGF23 levels when tested with an ELISA for intact FGF23 concentrations. Matrix extracellular phosphoglycoprotein (MEPE) has been identified as a possible regulator of phosphate homeostasis. Serum MEPE levels, however, were normal in the family with GALNT3-TC and in a kindred with TC carrying the FGF23 S71G mutation. The tumoral masses of the patient with GALNT3-TC completely resolved following combination therapy.
Conclusions: Our findings demonstrate that GALNT3 inactivation in patients with TC leads to inadequate production of biologically active FGF23 as the most likely cause of the hyperphosphatemic phenotype. Furthermore, combination therapy may provide effective for reducing the tumoral burden associated with familial TC.
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