Hypophosphatemic nonrachitic bone disease: An entity distinct from X‐linked hypophosphatemia in the renal defect, bone involvement, and inheritance

Abstract

We have identified 5 patients with a condition which we call hypophosphatemic bone disease (HBD). The clinical findings, appearing during late infancy include modest shortening of stature, bowing of the lower limbs, and nonrachitic bone changes. The concentrations of calcium, parathyroid hormone (PTH), and vitamin D in serum and the basal excretion of cyclic AMP in urine are all normal. The serum phosphorus level is constantly depressed; impaired reclamation of phosphate anion by kidneys explains this finding.Net tubular reabsorption of phosphate anion is "normal" at the low endogenous levels of filtered phosphate anion, yet below normal at elevated levels. The phosphaturic response t o PTH infusion is abnormal in qualitative aspects. The characteristics of phosphate transport by kidney in HBD differ considerably from those described in X-linked hypophosphatemia (XLH). The transport defect is not expressed in the (nonepithelial) membrane of the erythrocyte.Since the severity of bone disease is quite different in HBD and XLH, and yet serum (extracellular) phosphorus concentration is similarly low in both diseases, we propose that some process regulates the distribution of phosphorus between serum and bone, and that this process is affected in different ways in HBD and XLH.

Conserved loci on the X chromosome confer phosphate homeostasis in mice and humans

“…(ii) Periosteocytic lesions in XLH compact bone (Marie & Glorieux, 1983) and in cultured or transplanted Hyp calvarial bone (Glorieux & Ecarot-Charrier, 1987;Ecarot-Charrier et al 1988) that were unrelated to environmental phosphate concentration, (iii) Lower bone mineral content in Hyp/Y mice relative to Hyp/ + mice although serum phosphorus values were similar in the sexes (Kay et al 1985). (iv) Milder bone disease (Scriver et al 1977) and tooth abnormalities (Schwartz et al 1988) in patients with autosomal dominant hypophosphatemia (McKusick 14635) than in patients with XLH, even though serum phosphorus values are similar in the two diseases. New observations on tooth development in XLH patients now provide evidence for extrarenal expression of the HPDR gene; it is based on evidence for a normal gene dose effect on teeth (Shields et al 1990).…”

Loss of Renal Phosphate Wasting in a Child with Autosomal Dominant Hypophosphatemic Rickets Caused by a <i>FGF23</i> Mutation

“…Isolated renal phosphate wasting may result from several hereditary disorders including X-linked hypophosphatemic rickets (XLH) [1], hereditary hypophosphatemic rickets with hypercalciuria (HHRH) [2], hypophosphatemic bone disease (HBD) [3]or autosomal dominant hypophosphatemic rickets (ADHR) [4, 5, 6]. XLH, the most common form, is characterized by rachitic and osteomalacic bone disease, growth retardation, hypophosphatemia with normal parathyroid hormone (PTH) levels and inappropriately normal 1,25-dihydroxyvitamin D concentrations [1, 7].…”

Hereditary hypophosphatemias: New genes in the bone–kidney axis (Review Article)

“…Hypophosphatemia due to isolated renal phosphate wasting is a genetically heterogeneous disease. It may result from several hereditary disorders, including X‐linked hypophosphatemic rickets (XLH), 1 autosomal dominant hypophosphatemic rickets (ADHR), 2–4 or a related disorder known as hypophosphatemic bone disease, 5 or hereditary hypophosphatemic rickets with hypercalciuria (HHRH) 6 . XLH is the most common form, and is characterized by rachitic and osteomalacic bone disease, growth retardation hypophosphatemia with normal parathyroid hormone (PTH) levels and inappropriately normal 1,25‐dihydroxyvitamin D concentrations for serum phosphorus levels 1,7 .…”

“…Inactivating mutations in the phosphate‐regulating gene with homologies to endopeptidases on the X‐chromosome (PHEX) has been found responsible for XLH 8 . ADHR is a less common form of hypophosphatemic rickets with similar biochemical disturbances but, in contrast with XLH, with variable and incomplete penetrance 2–4 . Fibroblast growth factor 23 (FGF23) missense mutations have been identified in several ADHR families 9…”

“…8 ADHR is a less common form of hypophosphatemic rickets with similar biochemical disturbances but, in contrast with XLH, with variable and incomplete penetrance. [2][3][4] Fibroblast growth factor 23 (FGF23) missense mutations have been identified in several ADHR families. 9 Mineralization of extracellular matrix and the renal handling of phosphate appear to be two interrelated processes, and some or a group of factors could provide a mechanism for the skeleton to communicate with the kidney to coordinate them.…”