The Journal of Bone and Joint Surgery (American). 2009;91:1190-1198.
doi:10.2106/JBJS.H.00783
© 2009 The Journal of Bone and Joint Surgery, Inc.
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A Novel Recessive Mutation of Fibroblast Growth Factor-23 in Tumoral Calcinosis

L. Masi, MD, PhD1, A. Gozzini, PhD1, A. Franchi, MD1, D. Campanacci, MD1, A. Amedei, MD1, A. Falchetti, MD1, F. Franceschelli, PhD1, G. Marcucci, MD1, A. Tanini, PhD1, R. Capanna, MD1 and M.L. Brandi, MD, PhD1

1 Departments of Internal Medicine (L.M., A.G., A.A., A. Falchetti, F.F., G.M., A.T., and M.L.B.), Human Pathology and Oncology (A. Franchi), Orthopedic Unit (D.C. and R.C.), and DeGene spin-off (M.L.B.), University Hospital of Florence, Viale Pieraccini n. 6, 50139 Florence, Italy. E-mail address for L. Masi: l.masi{at}dmi.unifi.it. E-mail address for A. Gozzini: alessiagozzini{at}alice.it. E-mail address for A. Franchi: franchi{at}unifi.it. E-mail address for D. Campanacci: campanaccid{at}ao-careggi.toscana.it. E-mail address for A. Amedei: amedei.antonietta{at}tiscali.it. E-mail address for A. Falchetti: a.falchetti{at}dmi.unifi.it. E-mail address for F. Franceschelli: f.franceschelli{at}dmi.unifi.it. E-mail address for G. Marcucci: gemma.marcucci{at}libero.it. E-mail address for A. Tanini: a.tanini{at}dmi.unifi.it. E-mail address for R. Capanna: capannar{at}ao-careggi.toscana.it. E-mail address for M.L. Brandi: m.brandi{at}dmi.unifi.it

Investigation performed at the Departments of Internal Medicine, Human Pathology and Oncology, and Orthopedics, University Hospital of Florence, Florence, Italy

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Fondazione Firmo-Fondazione Cassa di Risparmio, Ente Cassa di Risparmio di Firenze, and from F. I. R. M. O. Fondazione Raffaella Becagli. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Background: Tumoral calcinosis is a rare disease characterized by hyperphosphatemia due to hypophosphaturia and by ectopic calcifications. Phosphatonins are important hormones that regulate phosphorus homeostasis. Tumoral calcinosis is a rare congenital disorder in which the differential diagnosis from other syndromes associated with extraskeletal calcifications may be difficult. Mutations in the UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-3 (GALNT3) and fibroblast growth factor-23 (FGF23) genes have been described. Mutational analysis is important for the early recognition of the disorder, for prevention of its complications, and for family screening strategies. We examined two unrelated white patients affected by tumoral calcinosis.

Methods: The first patient was a woman with a history of an ectopic calcification in the left shoulder. The second patient was a man with a history of an ectopic calcification in the right buttock. Routine biochemistry and FGF-23 assays were performed on serum samples. Genomic DNA was extracted from peripheral blood. The FGF23 and GALNT3 genes were analyzed by direct sequencing.

Results: A new homozygous H41Q codon 41, C->A transversion at position 123 (c.123C>A) in exon 1 of the FGF23 gene was evidenced in both patients. No mutation of the GALNT3 gene was detected in these patients. As determined by an ELISA assay, intact FGF-23 circulating protein was low in both patients.

Conclusions: This is the fourth mutation of the FGF23 gene described in subjects with tumoral calcinosis.

Clinical Relevance: The biochemical and clinical profile of the two unrelated patients bearing the mutation reinforces the relevant role of FGF-23 in bone metabolism and in the pathogenesis of tumoral calcinosis.


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