The basic physiologic defect in XLH is impaired proximal renal tubular reabsorption of phosphate. This defect is due to reduced expression of sodium-phosphate cotransporters (NaPi-IIa and NaPi-IIc, members of the type II sodium-phosphate symporter family) on the apical surface of proximal renal tubule cells, as demonstrated in the syngenic murine model of the disease, the Hyp mouse (5
). The novel hormone, FGF23, suppresses transcription of the genes encoding NaPi-IIa and NaPi-IIc, and most patients with XLH (as well as Hyp mice) have elevated circulating levels of intact FGF23.
The genetic basis for XLH (and in Hyp mice) is loss-of-function of PHEX (P
hosphate regulating gene with H
omology to E
ndopeptidases located on the X
). PHEX is a member of the M13 family of neutral endopeptidases, which activate or degrade peptides, is expressed in bones and teeth, and localizes to the cell surface. PHEX is expressed in late embryonic development as skeletal mineralization begins (8
). FGF23 does not appear to be a physiologic substrate for PHEX and the mechanism by which PHEX disruption results in elevated circulating FGF23 levels remains unclear, however both are products of the osteocyte. Circulating FGF23 is increased in other, less frequent hypophosphatemic disorders including Autosomal Dominant Hypophosphatemic Rickets (due to activating mutations in FGF23) (9
), and Autosomal Recessive Hypophosphatemic Rickets (due to loss-of-function mutations in another osteocytic protein, dentin matrix protein 1 (DMP1) (10
). More recently recessive mutations in ectonucleotide pyrophosphatase/phophodiesterase 1 (ENPP1), can result in FGF23 mediated phosphate-wasting disorders (12
). This enzyme regulates local concentrations of pyrophosphate, a potent inhibitor of mineralization; loss of function of the encoding gene also been associated with the rare disorder, generalized arterial calcification of infancy (13
). Thus FGF23 mediates several inherited phosphate wasting disorders, of which XLH is the most common. In addition, ectopic production of FGF23 by mescenchymal tumors causes the paraneoplastic syndrome, Tumor-Induced Osteomalacia, an acquired variant of similar pathophysiology.
Another direct consequence of elevated FGF23 levels is the abnormally regulated vitamin D axis. FGF23 can down-regulate CYP271B (which encodes 25-OHD- 1α-hydroxylase), and up-regulate CYP24A1 (encoding the 24-hydroxylase) (14
), thereby resulting in inappropriate (low to normal) levels of 1,25(OH)2
D -- due to decreased synthesis and increased catabolism.
FGF23 acts through specific FGF receptors (FGFRs) on the basolateral surface of renal tubular cells. To transduce its signal, FGF23 must form a ternary complex with a cognate FGFR and the klotho protein (15
). The precise downstream pathway mediating the altered expression of NaPi-II and the vitamin D hydroxylases has not been clarified.
Thus, current therapy for XLH consists of phosphate and 1,25(OH)2
D, and serves as the basis for the treatment guidelines herein. Newer therapeutic strategies based on the molecular pathogenesis of XLH are under development. For example, treatment of Hyp mice with a neutralizing antibody to FGF23 results in correction of hypophosphatemia, an increased in serum 1,25(OH)2
D and marked improvement in skeletal abnormalities (18
). Other approaches have included directing therapy toward the suppression of PTH, using the calcium sensing receptor modulator, cinacalcet (19
). Hopefully such new approaches will lead to treatments with improved efficacy for this chronic and disabling disorder.