FGF23 – Autosomal Dominant Hypophosphatemic Rickets

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare phosphate‐wasting disorder characterized by renal phosphate loss, hypophosphatemia, and inappropriately normal 1,25‐dihydroxyvitamin D levels, leading to rickets in childhood and osteomalacia, osteoporosis, and fatigue in adults. ADHR is caused by heterozygous gain‐of‐function mutations in FGF23 that impair proteolytic cleavage of the hormone, increasing its circulating bioactivity and causing phosphate loss (PMID:19655082).

ADHR follows an autosomal dominant inheritance pattern. Initial reports described a Tunisian kindred with one parent and three children harboring a heterozygous c.526C>T (p.Arg176Trp) mutation in FGF23, all exhibiting phosphate wasting and clinical ADHR features (PMID:19655082). Subsequent families include a Chinese pedigree with a c.527G>A (p.Arg176Gln) mutation in three members (PMID:21710177), an 85-year-old woman and her son with R176Q (PMID:23174215), and various sporadic cases in a 22-year-old female, a 26-month-old girl and her father, a 13-year-old boy, and an 18-month-old male, each with heterozygous RXXR‐motif mutations, totaling seven unrelated probands and segregation in seven additional affected relatives.

The mutational spectrum comprises predominantly missense variants at the subtilisin‐like proprotein convertase cleavage site (RXXR motif): c.526C>T (p.Arg176Trp), c.527G>A (p.Arg176Gln), c.535C>T (p.Arg179Trp), c.536G>A (p.Arg179Gln), and the first variant outside the motif, c.540G>T (p.Ser180Ile) (PMID:38493780). These six pathogenic alleles underscore the critical role of the R176–R179 site in FGF23 regulation and confirm autosomal dominant transmission across diverse ethnic backgrounds.

Functional assays demonstrate that ADHR mutations confer protease resistance: mutant FGF23 (R176Q, R179W, R179Q) is secreted predominantly as intact 32 kD protein versus wild‐type cleavage products (PMID:11737582), and in vivo overexpression of R176Q in mice induces more severe hypophosphatemia, reduced 1,25(OH)₂D, rickets, osteomalacia, and secondary hyperparathyroidism compared to wild‐type FGF23 (PMID:12519781). The novel S180I variant exhibits similar proteolysis resistance, confirming impaired cleavage as the pathogenic mechanism (PMID:38493780).

Gene‐environment interactions modulate ADHR. Iron deficiency triggers onset or relapse by upregulating FGF23 transcription and stabilizing intact hormone, while oral iron supplementation restores phosphate homeostasis, normalizes FGF23 levels, and allows discontinuation of phosphate/vitamin D therapy in children (PMID:26186302). In R176Q knock‐in mice, low‐iron diet elevates bone Fgf23 mRNA and circulating intact Fgf23, leading to hypophosphatemic osteomalacia, whereas wild‐type animals maintain normal intact Fgf23 and phosphate (PMID:22006328).

No studies have refuted the FGF23–ADHR link. Integrated genetic and experimental evidence supports a Strong ClinGen classification. Genetic testing for heterozygous RXXR‐motif mutations in FGF23 is indicated in unexplained hypophosphatemic rickets, and management should include iron status evaluation and optimization to mitigate disease expression.

Key take-home: Gain‐of‐function missense mutations in FGF23 impair proteolytic cleavage, causing autosomal dominant hypophosphatemic rickets with variable penetrance influenced by iron status. Genetic confirmation informs diagnosis and guides phosphate and iron‐based therapy.

References

• Journal of bone and mineral metabolism • 2010 • An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation. PMID:19655082
• Journal of bone and mineral metabolism • 2012 • FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets. PMID:21710177
• Bone • 2013 • Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood. PMID:23174215
• Hormone research in paediatrics • 2024 • A novel pathogenic variant in fibroblast growth factor 23 outside the furin-recognizing RXXR motif in an autosomal dominant hypophosphatemic rickets patient. PMID:38493780
• Kidney international • 2001 • Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. PMID:11737582
• The Journal of biological chemistry • 2003 • The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. PMID:12519781
• The Journal of clinical endocrinology and metabolism • 2015 • Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets. PMID:26186302
• Proceedings of the National Academy of Sciences of the United States of America • 2011 • Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. PMID:22006328

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