FGF23 – Familial Tumoral Calcinosis

Familial tumoral calcinosis (FTC) is an autosomal recessive disorder characterized by hyperphosphatemia (HP:0002905) and extensive periarticular and vascular ectopic calcifications (HP:0010766). Biallelic loss-of-function mutations in FGF23 underlie FTC, leading to disrupted phosphate homeostasis and pathological calcification.

Genetic analyses across three unrelated families identified 7 affected individuals homozygous for pathogenic FGF23 variants (c.211A>G (p.Ser71Gly), c.386C>T (p.Ser129Phe), c.199C>A (p.Gln67Lys)) segregating with disease phenotype (PMID:15687325; PMID:15961556; PMID:16030159; PMID:25378588). The c.211A>G (p.Ser71Gly) mutation was demonstrated homozygous in two sisters with hyperphosphatemia and periarticular calcifications, showing elevated C-terminal FGF23 fragments and absent intact hormone (PMID:15687325).

Segregation analysis confirmed co-segregation of each FGF23 variant with FTC in all affected members, with no unaffected carriers displaying clinical disease features (7 affected relatives). Multi-family co-segregation supports a recessive mode of inheritance and high penetrance for biallelic loss-of-function alleles.

Functional studies in HEK293 cells demonstrated that FTC-associated FGF23 mutants undergo enhanced furin-mediated proteolytic cleavage, resulting in severely diminished secretion of intact 251-amino-acid FGF23 and accumulation of inactive C-terminal fragments. Restoration of the RXXR cleavage motif or low-temperature rescue experiments reinstated intact FGF23 secretion, confirming a loss-of-function mechanism (PMID:15961556). Murine knockout models of Fgf23 phenocopy human FTC, exhibiting hyperphosphatemia and ectopic calcifications.

No conflicting evidence challenges the causative role of FGF23 biallelic mutations in FTC. The combined genetic and functional data fulfill ClinGen criteria for a Strong gene–disease association.

Key Take-home: Biallelic FGF23 loss-of-function mutations reliably cause autosomal recessive familial tumoral calcinosis by impairing hormone secretion and phosphate regulation, supporting genetic testing of FGF23 in patients with hyperphosphatemia and ectopic calcifications.

References

• Endocrinology • 2005 • Fibroblast growth factor-23 mutants causing familial tumoral calcinosis are differentially processed. PMID:15961556
• The Journal of clinical endocrinology and metabolism • 2005 • A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. PMID:15687325
• The Journal of clinical endocrinology and metabolism • 2005 • A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. PMID:16030159
• Nephrology, dialysis, transplantation • 2014 • Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing. PMID:25378588

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