These disorders usually manifest in childhood as rickets and hypophosphatemia, although they may first present in adults. In both X-linked and autosomal dominant hypophosphatemia, biologically active FGF23 accumulates, leading to phosphate wasting in the urine and hypophosphatemia. In autosomal dominant hypophosphatemia, mutations in the FGF23 gene replace an arginine required for proteolysis and result in increased FGF23 stability. X-linked hypophosphatemia is caused by mutations in the gene encoding the PHEX protein, an endopeptidase. Initially, it was thought that FGF23 was a direct substrate for PHEX, but this no longer appears to be the case. Tumor-induced osteomalacia is a phenotypically similar but acquired syndrome in adults that results from overexpression of FGF23 in tumor cells. The current concept for all of these diseases is that FGF23 blocks the renal uptake of phosphate and blocks 1,25(OH)2D production leading to rickets in children and osteomalacia in adults. Phosphate is critical to normal bone mineralization; when phosphate stores are deficient, a clinical and pathologic picture resembling vitamin D–dependent rickets develops. However, affected children fail to respond to the standard doses of vitamin D used in the treatment of nutritional rickets. A defect in 1,25(OH)2D production by the kidney contributes to the phenotype as 1,25(OH)2D levels are low relative to the degree of hypophosphatemia observed. This combination of low serum phosphate and low or low-normal serum 1,25(OH)2D provides the rationale for treating these patients with oral phosphate (1–3 g daily) and calcitriol (0.25–2 mcg daily). Reports of such combination therapy are encouraging in this otherwise debilitating disease, although prolonged treatment often leads to secondary hyperparathyroidism. More recently the use of FGF23 antibodies for children with X-linked hypophosphatemic (XLH) rickets has shown promise and may become the treatment of choice for these conditions.
These distinctly different autosomal recessive diseases present as childhood rickets that do not respond to conventional doses of vitamin D. Pseudovitamin D–deficiency rickets is due to an isolated deficiency of 1,25(OH)2D production caused by mutations in 25(OH)-D1α-hydroxylase (CYP27B1). This condition is treated with calcitriol (0.25–0.5 mcg daily). Hereditary vitamin D–resistant rickets (HVDRR) is caused by mutations in the gene for the vitamin D receptor. The serum levels of 1,25(OH)2D are very high in HVDRR but inappropriately low for the level of calcium in pseudovitamin D–deficient rickets. Treatment with large doses of calcitriol has been claimed to be effective in restoring normocalcemia in some HVDRR patients, presumably those with a partially functional vitamin D receptor, although many patients are completely resistant to all forms of vitamin D. Calcium and phosphate infusions have been shown to correct the rickets in some children, similar to studies in mice in which the VDR gene has been deleted. These diseases are rare.
Mutations in CYP24A1, the enzyme catabolizing 25(OH)D and 1,25(OH)2D, have recently been found to account for a number of cases of idiopathic infantile hypercalcemia. However, these mutations have also been described in adults with previously unexplained hypercalcemia and elevated 1,25(OH)2D levels. At this point no definitive therapy has been established, but vitamin D supplementation needs to be avoided. The diagnosis can be made by finding a reduced ratio of 24,25(OH)2D to 25(OH)D in the blood.