X-Linked Hypophosphatemia: New Horizons

X-linked hypophosphatemia (XLH) is a hypophosphatemic rachitic disorder, which occurs in one of 20,000 live births. The disease phenotype is quite variable, and many patients do not have profound signs or symptoms including rickets. Thus, XLH is sometimes called "XLH rickets without rickets". Such phenotypic variability makes a genetic examination of potentially affected patients inevitable for definite diagnosis. In most of the patients, hypophosphatemia, elevated serum alkaline phosphatase, and a lowered level of active vitamin D, as well as abnormalities in the bone mineralization, are seen. In hyp-mice, the model mouse of XLH, a hormonal abnormality that affects the Npt2 protein mediates the abnormal Na-dependent Pi transport in the renal tubules. The defect in vitamin D metabolism is the result of diminished 25(OH)D-1α-hydroxylase activity due to a post-transcriptional abnormality. There is a genetic abnormality of the PHEX gene causal of XLH. PHEX codes a protein from the cell membrane-bound endopeptidase family, which causes hypophosphatemia by decreasing the Npt2 in the kidneys; however, the localization of PHEX is limited to the bones and teeth. To clarify the pathophysiology of XLH, therefore, identification of the mechanism by which the diseased gene functions is urgently required.