セミナー要旨

　Rickets is mainly caused by the abnormal metabolism of calcium and/or Vitamin D resulting in hypocalcemia or hypophosphatemia. The causes of rickets include; (1) inadequate diet or poor UV exposure, (2) inability to produce calcitriol (Vitamin D dependent rickets type I (VDDR-I)), (3) inability to respond to calcitriol (hereditary Vitamin D resistant rickets (HVDRR or VDDR-II)), (4) phosphaturic diseases [tumor induced osteomalacia (TIO), X-linked hypophosphatemia (XLH), autosomaldominant hypophosphatemic rickets (ADHR)].
　VDDR-I is caused by mutations in the gene that codes for 1α-hydroxylase, the enzyme that produces the active hormone calcitriol. Defective enzyme results in deficiency of calcitriol and gives rise to hypocalcemia and hypophosphatemia and causes rickets. The disease can be treated by the administration of calcitriol which bypasses the defect.
　HVDRR is caused by mutations in the gene that codes for the Vitamin D receptor (VDR). Defective VDR causes resistance to the action of calcitriol. However, long term intravenous administration of calcium is effective in treating HVDDR by bypassing the abnormality in absorption of calcium at the small intestine. Children treated in this way show restoration of hypocalcemia to normal and resolution of their rickets. Alopecia is another interesting manifestation of HVDDR. Mutations causing defective DNA binding or premature stops cause the alopecia presumably through the inhibition of the interactions between the VDR, RXR and the vitamin D response element in target genes. In contrast, several patients with mutations in the ligand-binding domain of the VDR do not show alopecia. The findings suggest that the presence of the VDR may prevent alopecia, even if calcitrol cannot bind the VDR and induce transactivation of target genes.
　Fibroblast growth factor (FGF)-23 action has been demonstrated to be cause phosphaturia and hypophosphatemia and is now called a "phosphatonin". TIO, ADHR and XLH are all caused by an excess of FGF-23. TIO is due to over-production of FGF-23 by a tumor, ADHR is due to mutations of the FGF-23 gene that prevent its inactivation, and XLH is due to mutations of PHEX, which is the enzyme that cleaves FGF-23 to inactivate it. However, evidence suggests that there may be other phosphatonins in addition to FGF-23.