Tumoral calcinosis: Identification of a novel recessive mutation in fibroblast growth factor-23 (FGF-23)

Tumoral calcinosis (TC) is a rare genetic disorder characterized by periarticular cystic and solid tumorals calcifications. It is characterized by hyperphospatemia and an elevated serum of calcitriol concentration in every patients. The hyperphosphatemia results form an increase in capacity of renal tubular phosphate reabsorption. The identification of phosphotonin family hormones suggest that mutations of these molecules could be involved in the pathogenesis of TC. One of these molecules is represented by FGF-23. The TC phenotype is similar to that described in the FGF-23 knockout mice. In the present study we described a new FGF-23 mutation in a subject affected by TC.A Caucasian women (years 67) was examined for a history ofectopic calcification. Biochemical exams showed and hyperphosphathemia and hyperphosphaturia with normal value ofPTH and inappropriately normal level of 1–25 (OH)2 D3. The patient presented a big shoulder calcification and also a calcification of femoral artery. We expanded the family tree through detailed family histories, which importantly revealed that parents were consanguineous. Hystologically the mass was characterized by calcium deposition and granulomatous reaction around the mass. Genomic DNA was extracted from blood collected from the patient, her daughter and her grandchild by standard procedure. DNA was not available from her parents. All three FGF-23coding exons, as well as conserved splice sites, were amplified by standard PCR procedure. Nucleotide sequences were determined by direct sequencing with a DNA kit and an automated DNA sequencer (ABI PRISM 3100 - Perkiln-Elmer Corp). We discovered a new homozygous codon 41, His/Gln (CAC-CAA) substitution in exon 1 of FGF-23 gene in the affected patient. A heterozygous substitution was present in the daughter. No mutation were found in the two children. FGF-23 gene mutation was not found in the SNP database (www.ncbi.nih.gov/snp). In summary, a recessive mutation in FGF 23 causes TC. Understanding the functional significance and molecular physiology of this novel mutation will reveal critical information regarding the role of FGF-23 in states of normal and of disorder of phosphate homeostasis