Hypophosphatemic Rickets: Lessons from Disrupted FGF23 Control of Phosphorus Homeostasis

Abstract

Fibroblast growth factor-23 (FGF23) regulates phosphate reabsorption in the kidney and therefore plays an essential role in phosphate balance in humans. There is a host of defects that ultimately lead to excess FGF23 levels and thereby cause renal phosphate wasting and hypophosphatemic rickets. We describe the genetic, pathophysiologic, and clinical aspects of this group of disorders with a focus on X-linked hypophosphatemia (XLH), the best characterized of these abnormalities. We also discuss autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR) and tumor-induced osteomalacia (TIO) in addition to other rarer FGF23-mediated conditions. We contrast the FGF23-mediated disorders with FGF23-independent hypophosphatemia, specifically hypophosphatemic rickets with hypercalciuria (HHRH). Errant diagnosis of hypophosphatemic disorders is common. This review aims to enhance the recognition and appropriate diagnosis of hypophosphatemia and to guide appropriate treatment.

FGFR Inhibitor Ameliorates Hypophosphatemia and Impaired Engrailed‐1/Wnt Signaling in FGF2 High Molecular Weight Isoform Transgenic Mice

“…Although the specific FGFR that mediates FGF23 actions in the kidney has not been fully defined, FGFR1 functions as an essential co‐receptor with α‐Klotho that interacts with FGF23 to form a heteromeric complex to initiate MAPK/ERK signaling, resulting in reduced Npt2a [Kurosu et al, ]. Increased serum level of FGF23 was found in the Hyp mouse (a homologue of XLH), the Fgf23 transgenic mouse (a model of ADHR) and the Dmp1 null mouse (a model of ARHR; [Bergwitz and Juppner, ; White et al, ; Goldsweig and Carpenter, ]). NVP‐BGJ398 treatment caused a further increase in serum FGF23 in HMWTg mice at 24 h. These results are in contrast to a previous report in which short‐term in vivo treatment for 7 h with NVP‐BGJ398 caused a transient decrease in serum FGF23 in Hyp mice and Dmp1‐null mice [Wöhrle et al, ]; however, the same study reported that long‐term treatment caused a significant increase in FGF23 which was interpreted, based on pharmokinetic studies of the drug, to reflect the clearance of NVBP398 by the kidneys at 24 h. Interestingly, using another pan‐specific inhibitor, the same group reported a significant reduction in serum FGF23 reduction at 8 h followed by a significant increase at 24 h [Wöhrle et al, ].…”

Rare, genetically conditioned forms of rickets: Differential diagnosis and advances in diagnostics and treatment

“…Mutation of at least 10 genes underlying this disease entity has been described by now. 10 Research on the pathogenesis of hypophosphatemic rickets and the role of a phosphaturic factor that was found to be FGF-23 made it possible to distinguish between FGF-23-dependent and FGF-23independent hypophosphatemic rickets. 10,14 The genetic background of hypophosphatemic rickets is shown in Table 1.…”

Tumor-induced osteomalacia: A sherlock holmes approach to diagnosis and management

“…Patients with adult-onset ADHR may present severe bone pain, pseudofractures, and weakness. [224] The absence of family history, as well the severity and rapid progression of symptoms, made this unlikely. Moreover, identification of a facial mass, a common location of TIO, strengthened our suspicion of latter condition.…”