Is fibroblast growth factor‑23 (FGF‑23) elevated in X‑linked hypophosphatemia?

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Last updated: September 22, 2026 • View editorial policy

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Yes, FGF-23 is Elevated in X-Linked Hypophosphatemia

FGF-23 levels are characteristically elevated (or inappropriately normal) in X-linked hypophosphatemia (XLH), and this excess FGF-23 is the primary driver of the disease pathophysiology. 1, 2

Pathophysiology

The elevated FGF-23 in XLH results from inactivating mutations in the PHEX gene, which normally regulates FGF-23 production and degradation. This leads to:

  • Increased FGF-23 secretion from bone that binds to the FGF receptor 1–alpha-Klotho co-receptor complex in the kidney 1
  • Downregulation of renal phosphate transporters (NPT2a and NPT2c), causing renal phosphate wasting 1
  • Suppression of 1,25-dihydroxyvitamin D synthesis and increased degradation 1
  • Resulting hypophosphatemia and hypovitaminosis D that drive the clinical manifestations 1

Diagnostic Significance

FGF-23 measurement is useful for differential diagnosis of hypophosphatemia 3:

  • In XLH and other FGF-23-mediated hypophosphatemic disorders, FGF-23 is high or inappropriately normal (should be suppressed in the setting of hypophosphatemia) 2
  • In chronic hypophosphatemia from other causes (e.g., vitamin D deficiency), FGF-23 is appropriately low 3
  • 100% of untreated XLH patients have intact FGF-23 levels above the normal mean, with 88% having levels >2 standard deviations above normal 4

Clinical Context

The biochemical profile of XLH includes 2:

  • Low serum phosphorus for age (due to renal phosphate wasting)
  • High or inappropriately normal FGF-23
  • Normal or inappropriately low 1,25-dihydroxyvitamin D
  • Elevated alkaline phosphatase
  • Normal or mildly elevated PTH (distinguishes from nutritional rickets)

Important Caveats

  • FGF-23 can be detected even in cord blood and early neonatal period (day 4-5) in affected offspring, making it a potential early predictor 5
  • When monitoring burosumab treatment (anti-FGF-23 antibody), measuring FGF-23 concentrations is NOT recommended because burosumab interferes with analytical assays 1
  • Intact FGF-23 assays are more sensitive than C-terminal FGF-23 assays for detecting XLH (100% vs 71% above normal mean) 4

References

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