Hyperphosphatemic Familial Tumoral Calcinosis: Genetic Models of Deficient FGF23 Action

• Published in: Current osteoporosis reports Vol. 13; no. 2; pp. 78 - 87
• Main Authors: Folsom, Lisal J., Imel, Erik A.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-04-2015
• Subjects: Calcinosis - genetics; Calcinosis - metabolism; Calcinosis - therapy; Diet Therapy; Diphosphonates - therapeutic use; Epidemiology; Fibroblast Growth Factor-23; Fibroblast Growth Factors - deficiency; Fibroblast Growth Factors - genetics; Glucuronidase - genetics; Humans; Hyperostosis, Cortical, Congenital - genetics; Hyperostosis, Cortical, Congenital - metabolism; Hyperostosis, Cortical, Congenital - therapy; Hyperphosphatemia - genetics; Hyperphosphatemia - metabolism; Hyperphosphatemia - therapy; Klotho Proteins; Medicine; Medicine & Public Health; Models, Genetic; Mutation - genetics; N-Acetylgalactosaminyltransferases - genetics; Orthopedics; Phosphates - metabolism; Polypeptide N-acetylgalactosaminyltransferase; Rare Bone Disease (CB Langman and E Shore; Section Editors; Topical Collection on Rare Bone Diseases; Vitamin D - analogs & derivatives; Vitamin D - metabolism; Hyperphosphatemia; Tumoral calcinosis; Fibroblast growth factor 23; FGF23; Hyperphosphatemic familial tumoral calcinosis
• ISSN: 1544-1873; 1544-2241
• DOI: 10.1007/s11914-015-0254-3

Hyperphosphatemic familial tumoral calcinosis (hFTC) is a rare disorder of phosphate metabolism defined by hyperphosphatemia and ectopic calcifications in various locations. To date, recessive mutations have been described in three genes involving phosphate metabolism:
FGF23
,
GALNT3
, and
α-Klotho
, all of which result in the phenotypic presentation of hFTC. These mutations result in either inadequate intact fibroblast growth factor-23 (FGF23) secretion (
FGF23
or
GALNT3
) or resistance to FGF23 activity at the fibroblast growth factor receptor/α-Klotho complex (
α-Klotho
). The biochemical consequence of limitations in FGF23 activity includes increased renal tubular reabsorption of phosphate, hyperphosphatemia, and increased production of 1,25-dihydroxyvitamin D. The resultant ectopic calcifications can be painful and debilitating. Medical treatments are targeted toward decreasing intestinal phosphate absorption or increasing phosphate excretion; however, results have been variable and generally limited. Treatments that would increase FGF23 levels or signaling would more appropriately target the genetic etiologies of this disease and perhaps be more effective.