Hyperphosphatemic Familial Tumoral Calcinosis: Genetic Models of Deficient FGF23 Action

Abstract

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.

Research Models for Studying Vascular Calcification

“…FGF23: Hyperphosphatemia often succeeds CKD, hypoparathyreoidism and vitamin D intoxication, but can also result from rare genetic disorders like hyperphosphatemic tumoral familial calcinosis (hFTC). In hFTC, the FGF23 receptor cannot be activated due to a mutation of either the FGF23, the α-Klotho or the GalNAc transferase 3 (GALNT3) gene [122]. FGF23 is an essential regulator of phosphate homeostasis and vitamin D metabolism promoting phosphaturia.…”

Dialysis as a Treatment Option for a Patient With Normal Kidney Function and Familial Tumoral Calcinosis Due to a Compound Heterozygous FGF23 Mutation

“…This autosomal recessive disorder is genetically heterogeneous and is caused by mutations in GALNT3, FGF23 , or KL (encoding Klotho). 10–14 …”

Pharmacological management of X‐linked hypophosphataemia

“…A single calcitonin injection decreased serum FGF23 and increased serum phosphorus transiently in patients with XLH, although not in healthy controls . To make the calcitonin story more confusing, case reports indicate calcitonin increases urinary phosphorus excretion in hyperphosphatemic tumoural calcinosis (a condition of FGF23 deficiency rather than excess) , which would be opposite of the goal of XLH management. A 3‐month‐long blinded randomized controlled clinical trial of monotherapy with nasal calcitonin 400 units daily for XLH failed to demonstrate improvements in serum phosphorus, TmP/GFR or FGF23 .…”