FGF23 – Familial Hyperphosphatemic Tumoral Calcinosis/Hyperostosis Syndrome

Familial hyperphosphatemic tumoral calcinosis (HFTC) and its variant hyperostosis-hyperphosphatemia syndrome are rare autosomal recessive disorders marked by elevated serum phosphate and progressive periarticular and visceral calcifications (PMID:16151858). FGF23 encodes a bone-derived phosphaturic hormone that binds renal FGF receptors, reducing phosphate reabsorption. Loss-of-function variants in FGF23 disrupt circulating intact hormone levels and lead to unregulated phosphate retention and ectopic mineral deposition.

Biallelic FGF23 pathogenic variants have been reported in ≥10 unrelated probands across >5 families, consistent with autosomal recessive inheritance (PMID:16151858, PMID:19188744). A representative variant, c.287T>C (p.Met96Thr), affects a highly conserved residue and was identified homozygously in a patient with widespread visceral calcifications (PMID:16151858). Other recurrent missense changes include c.211A>G (p.Ser71Gly) in two consanguineous families and c.471C>A (p.Phe157Leu) in multiple Iranian cases, all presenting with hyperphosphatemia and soft-tissue calcification.

Segregation analysis in consanguineous and non-consanguineous pedigrees confirms co-segregation of biallelic FGF23 variants with disease in at least three additional affected siblings (PMID:19188744, PMID:15687325). Across these reports, at least three affected relatives beyond the probands exhibit characteristic HFTC manifestations and carry the same homozygous or compound heterozygous FGF23 mutations.

The FGF23 variant spectrum in HFTC comprises predominantly missense substitutions (e.g., p.Ser71Gly, p.Met96Thr, p.Gly123Trp, p.Phe157Leu, p.Gln54His, p.Gln54Lys, p.His41Gln) and occasional in-frame deletions. No truncating or splice-site variants have been recurrently reported in FGF23-linked HFTC, underscoring missense-driven destabilization as the principal mechanism.

Functional assays consistently demonstrate that HFTC-associated FGF23 mutants have impaired O-glycosylation and enhanced proteolytic processing by furin-like convertases, yielding elevated C-terminal fragments but markedly reduced intact hormone secretion (PMID:15961556, PMID:18682534). In vitro expression of c.287T>C (p.Met96Thr) and other TC mutants produce minimal intact FGF23 and confirm loss of phosphaturic activity in cellular assays.

No studies to date dispute the association of biallelic FGF23 inactivation with AR HFTC. Alternative genetic etiologies (GALNT3, KL) are acknowledged but do not weaken the FGF23 linkage in reported families.

In summary, clinical, genetic, and functional data robustly support a strong autosomal recessive association between FGF23 loss-of-function and familial hyperphosphatemic tumoral calcinosis/hyperostosis syndrome. Genetic confirmation enables precise diagnosis, family counseling, and informs combined medical and surgical management of phosphate overload. Key take-home: biallelic FGF23 testing is recommended in AR HFTC to enable early intervention and tailored phosphate-lowering therapy.

References

• Human genetics • 2005 • A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification. PMID:16151858
• Hormone research • 2009 • Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer. PMID:19188744
• American journal of medical genetics. Part A • 2014 • Hyperostosis-hyperphosphatemia syndrome (HHS): report of two cases with a recurrent mutation and review of the literature. PMID:25153226
• Journal of clinical research in pediatric endocrinology • 2022 • The Successful Treatment of Deep Soft-tissue Calcifications with Topical Sodium Thiosulphate and Acetazolamide in a Boy with Hyperphosphatemic Familial Tumoral Calcinosis due to a Novel Mutation in FGF23. PMID:33685073
• Endocrinology • 2005 • Fibroblast growth factor-23 mutants causing familial tumoral calcinosis are differentially processed. PMID:15961556
• American journal of physiology. Endocrinology and metabolism • 2008 • Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis. PMID:18682534

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