Several Mendelian hypophosphatemias have been described. Each has a decrease in net renal tubular phosphate reabsorption as a major underlying abnormality and is associated with rickets and osteomalacia. The disorders differ from one another in their mode of inheritance, clinical features, metabolism of vitamin D, and response to therapy. This chapter describes three Mendelian hypophosphatemias as well as an acquired disorder, oncogenic hypophosphatemic osteomalacia, because of its phenotypic similarities to X-linked hypophosphatemia.
The most prevalent of the familial hypophosphatemias is inherited as an X-linked dominant trait and referred to as X-linked hypophosphatemia (XLH) (MIM 307800, 307810). It is characterized by reduced TmP/GFR, hypophosphatemia, normocalcemia, normal to low plasma 1,25-dihydroxyvitamin D levels, normal parathyroid gland function, and elevated plasma alkaline phosphatase activity. These changes are associated with growth retardation, lower extremity deformity, radiologic and histomorphometric evidence of rickets and osteomalacia, but no muscle weakness or tetany. This disease appears to result from combined renal defects in tubular phosphate reabsorption and vitamin D metabolism, as well as a functional disorder in bone and teeth. XLH results from inactivating mutations in the PHEX gene, a member of the zinc metallopeptidase family of type II integral membrane glycoproteins. PHEX is expressed in bone and teeth and to a lesser extent in lung, ovary, and testis but not in kidney. Nonetheless, the function of PHEX is not understood. The most effective treatment for XLH consists of a combination of oral phosphate (1.0–2.0 g/day in four divided doses) and 1,25-dihydroxyvitamin D3 (1.0–3.0 μg/day). A specific therapy for XLH has yet to be discovered, and the current modalities are not ideal.
X-linked Hyp and Gy mice serve as useful models to study the pathophysiology of XLH. Hyp and Gy mice harbor large deletions in 3′ and 5′ region of the Phex gene, respectively. Both mutants exhibit a defect in renal brush-border membrane Na+-dependent phosphate transport that is secondary to decreased expression of the type II renal-specific, high-affinity, low-capacity Na+-phosphate cotransporter Npt2. Hyp and Gy mice also are characterized by defects in renal vitamin D metabolism and bone mineralization. Studies in Hyp mice provide evidence in support of the view that the mutant renal phenotype is humorally mediated, presumably by a factor that is not appropriately processed or degraded by Phex protein. The Gy mutation also involves a deletion in the spermine synthase gene that lies upstream of Phex and thus is a contiguous gene syndrome. The latter likely accounts for the circling behavior and inner ear abnormalities in Gy mice that are not apparent in Hyp mice.
Oncogenic hypophosphatemic osteomalacia (OHO) is an acquired form of isolated phosphate wasting. Clinical and biochemical features of the disease are similar to XLH, except that OHO patients typically exhibit weakness, fatigue, and fractures. Evidence suggests that the phenotypic features in OHO result from the secretion of a humoral factor, since removal of the tumor results in complete correction of the clinical and biochemical manifestations and transplantation of the tumors in mice elicits renal phosphate wasting. The tumors are frequently small and difficult to locate. Therapy consists of oral phosphate and 1,25-dihydroxyvitamin D3.
There are two autosomal dominant forms of phosphate wasting, autosomal dominant hypophosphatemic rickets (ADHR; MIM 193100) and hypophosphatemic bone disease (HBD; MIM 146350), that may be a forme fruste of ADHR. While most of the clinical and laboratory features of ADHR are similar to those of XLH, ADHR displays incomplete penetrance and variable age of onset. ADHR may present during childhood, with clinical and biochemical features similar to XLH patients, or after puberty, with the additional features of weakness, fatigue, and fracture. Although the pathogenesis of ADHR is unknown and there is no animal model of the disorder, linkage studies in a large kindred have localized the disease gene locus to chromosome 12p13. Therapy for ADHR is the same as therapy for XLH and consists of a combination of oral phosphate and 1,25-dihydroxyvitamin D3.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH; MIM 241530) is inherited as an autosomal codominant trait. It is characterized by a reduced TmP/GFR, hypophosphatemia, an elevated plasma 1,25-dihydroxyvitamin D concentration, hypercalciuria, a low plasma parathyroid hormone concentration, and elevated plasma alkaline phosphatase activity. These abnormalities are associated with growth retardation, bone pain, muscle weakness, lower extremity deformity, and radiologic and histomorphometric evidence of rickets and osteomalacia. A primary defect in renal phosphate transport, linked to a secondary stimulation of the renal 25-hydroxyvitamin D3-1α-hydroxylase, appears to account for all the biochemical manifestations of the condition. Indeed, disruption of the type II renal Na+-Pi cotransporter gene Npt2 by targeted mutagenesis elicits a similar phenotype in mice. Treatment with oral phosphate alone (1.0–2.5 g/day in divided doses) reduces bone pain, heals rickets, and stimulates skeletal growth. Family members with milder degrees of hypophosphatemia have been found to have hypercalciuria and elevated plasma 1,25-dihydroxyvitamin D, without bone disease.