Urinary saturation among phosphate-treated children with hypophosphataemic rickets.
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Adolescent↗
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Results for “HYPOPHOSPHATEMIA, FAMILIAL”
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Metabolism of 25-hydroxyvitamin D3 in renal slices from the X-linked hypophosphatemic (Hyp) mouse: abnormal response to fall in serum calcium.
The effect of the X-linked Hyp mutation on 25-hydroxyvitamin D3 (25-OH-D3) metabolism in mouse renal cortical slices was investigated. Vitamin D replete normal mice and Hyp littermates fed the control diet synthesized primarily 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3); only minimal synthesis of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) was detected in both genotypes and 1,25-(OH)2D3 formation was not significantly greater in Hyp mice relative to normal littermates, despite hypophosphatemia and hypocalcemia in the mutants. Calcium-deficient diet fed to normal mice reduced serum calcium (p less than 0.01), increased renal 25-hydroxyvitamin D3-1-hydroxylase (1-OHase) activity (p less than 0.05), and decreased 25-hydroxyvitamin D3-24-hydroxylase (24-OHase) activity (p less than 0.05). In contrast, Hyp littermates on the calcium-deficient diet had decreased serum calcium (p less than 0.01), without significant changes in the renal metabolism of 25-OH-D3. Both normal and Hyp mice responded to the vitamin D-deficient diet with a fall in serum calcium (p less than 0.01), significantly increased renal 1-OHase, and significantly decreased renal 24-OHase activities. In Hyp mice, the fall in serum calcium on the vitamin D-deficient diet was significantly greater than that observed on the calcium-deficient diet. Therefore the ability of Hyp mice to increase renal 1-OHase activity when fed the vitamin D-deficient diet and their failure to do so on the calcium-deficient diet may be related to the resulting degree of hypocalcemia. The results suggest that although Hyp mice can respond to a disturbance of calcium homeostasis, the in vivo signal for the stimulation of renal 1-OHase activity may be set at a different threshold in the Hyp mouse; i.e. a lower serum calcium concentration is necessary for Hyp mice to initiate increased synthesis of 1,25(-OH)2D3.
24,25-Dihydroxyvitamin D 3↗
Low levels of intestinal calbindin-D28K in X-linked hypophosphatemic mice.
Using our radioimmunoassay for chick intestinal calbindin-D28K, a protein homologous to that in the chick intestine on the basis of immuno-crossreactivity, molecular weight and charge properties was identified in mouse intestinal mucosa. No such protein, however, was found in the kidney, cerebellum, cerebrum, liver or myocardium of the mice. In X-linked hypophosphatemic mice (Hyp mice) maintained on a standard diet containing vitamin D, the basal level of intestinal calbindin-D28K was much lower (average 65.13 +/- 7.39%) than that in breeding pairs of normal mice maintained under the same conditions. Although the mean intestinal level of calbindin-D28K was as low as 118.23 +/- 20.08 (SD) ng/mg protein in vitamin D-deficient mice (-D), the level of this protein was markedly increased to the control level (198.68 +/- 9.98 vs. 198.49 +/- 14.29 ng/mg protein of control) (P less than 0.001) in response to the administration of vitamin D3 (1000 I.U. s.c. for 10 days) (+D). These results indicate that calbindin-D28K, biochemically indistinguishable from the chick intestinal calbindin-D28K, is present in the mouse intestine, and that the lower amount of this protein in the Hyp mouse intestine may, at least in part, be responsible for the resistance to the effects of vitamin D.
Animals↗
Effect of single oral phosphate loading on vitamin D metabolites in normal subjects and in X-linked hypophosphatemic rickets.
There have been several reports that document abnormal vitamin D metabolism in X-linked hypophosphatemic rickets (XLH). Those reports indicate a blunted renal 25-hydroxyvitamin D-1 alpha-hydroxylase response to a potent stimulator, phosphorus restriction. We examined here its response to phosphate supplementation. Seven normal volunteers and 12 patients with XLH were submitted to single oral phosphate loading. This treatment produced a marked elevation of the serum phosphorus level, with a mild reduction in the serum calcium level. In normal subjects, although the concentrations of intact parathyroid hormone and mid-region parathyroid hormone were increased, with two peaks at 2 and 8 h after treatment, there were no significant changes in vitamin D metabolites including 25-hydroxyvitamin D (25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)2D) and 1,25-dihydroxyvitamin D (1,25(OH)2D). On the other hand, in the patients with XLH, the serum 1,25(OH)2D level increased from 23.4 +/- 12.0 (mean +/- SD) pg/ml to 44.3 +/- 33.6 pg/ml 6 h after ingestion without any significant change in 25(OH)D or 24,25(OH)2D.
24,25-Dihydroxyvitamin D 3↗
Recent advances in pediatric metabolic bone disease: the consequences of altered phosphate homeostasis in renal insufficiency and hypophosphatemic vitamin D-resistant rickets.
Over the past decade our understanding of the pathogenesis of altered mineral homeostasis in chronic renal failure (CRF) and X-linked hypophosphatemic vitamin D-resistant rickets (XLH) has increased, and has provided a rational approach for the use of the 1 alpha-hydroxylated analogues of vitamin D in their therapy. Recent evidence suggests that intracellular phosphate (Pi) retention in CRF plays a major role in decreasing serum 1,25-dihydroxyvitamin D (1,25(OH)2D) levels, which are responsible for the progressive rise in serum parathyroid hormone (PTH) concentrations through the direct action of 1,25(OH)2D on the parathyroid gland. 1,25(OH)2D levels affect the number of intracellular 1,25(OH)2D receptors, preproPTH mRNA levels and the set point for calcium suppression of PTH release. Further in experimental CRF, the maintenance of normal 1,25(OH)2D levels prevents parathyroid gland hyperplasia. These studies indicate that depressed renal 1 alpha-hydroxylase activity due to Pi retention is a major factor in directly increasing PTH secretion, which in turn contributes significantly to the severity of renal osteodystrophy. Thus the aim of therapy in early CRF should be to maintain normal levels of 1,25(OH)2D which can be achieved by either dietary Pi restriction and oral Pi binders or by administering small doses of 1 alpha-hydroxylated metabolites. The long term consequences of these two different therapeutic regimens still need to be assessed. In XLH, evidence is rapidly accumulating that alterations in 1 alpha-hydroxylase activity secondary to impaired Pi handling by the proximal renal tubule, results in decreased serum 1,25(OH)2D levels, which might be responsible for a number of the associated abnormalities documented in both treated and untreated XLH patients. These abnormalities include decreased calcium and Pi absorption by the intestine and low normal serum calcium values. In vitamin D- and Pi-treated patients 1,25(OH)2D levels are further depressed, with a resultant increase in PTH values, and the development of tertiary hyperparathyroidism in a small number of patients. The use of 1 alpha-hydroxylated analogues rather than vitamin D together with Pi supplements decreases the severity of hyperparathyroidism, improves Pi absorption from the intestine and markedly ameliorates the degree of osteomalacia. Whether long-term therapy with these analogues will prevent the development of tertiary hyperparathyroidism in patients with XLH is unclear.
Animals↗
Decreased concentration of 1,25-dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with X-linked hypophosphatemic rickets: effect of phosphate supplementation.
Abnormal renal tubular phosphate transport is considered to be the primary defect in X-linked hypophosphatemic rickets (XLH). However, the resistance to vitamin D treatment in XLH cannot be explained by hypophosphatemia alone. Since most of the actions of vitamin D are mediated by its receptors (VDR), abnormalities of VDR have been postulated in XLH. In order to investigate this possibility, we measured the concentration of VDR in PHA-activated peripheral mononuclear cells from 10 XLH patients. Patients without phosphate supplementation showed significantly lower concentration (21.7 +/- 5.1 fmol/mg protein, mean +/- SEM) compared to the normal controls (60.7 +/- 4.0). On the contrary, there was no significant difference between the phosphate-supplemented patients (58.3 +/- 2.7) and controls. There was a significant positive correlation between VDR concentration and serum phosphate (P less than 0.05). In two patients, VDR was increased after daily phosphate supplementation was started. These results indicate that a decreased concentration of VDR secondary to persistent hypophosphatemia is one of the causes of vitamin D resistance in XLH.
Adolescent↗
Bone mineral density of the spine and radius shaft in children with X-linked hypophosphatemic rickets (XLH).
X-linked hypophosphatemic rickets (XLH) is characterized by inadequate skeletal mineralization. The bone mineral density (BMD) of the radius shaft and the lumbar spine was determined in 13 children with XLH. Ten patients were on treatment, whereas three patients had discontinued treatment 20-32 months prior to this study. Two of them had radiological evidence of rickets. The radius shaft BMD was significantly diminished: Z score was -1.33 +/- 0.89 (P less than 0.001), while the BMD of lumbar spine was significantly augmented (Z score +1.95 +/- 1.17, P less than 0.001). A positive correlation was found between the Z scores for the BMD of the radius shaft and spine. The two patients with overt rickets had lower radius shaft BMD values and a lesser increment of BMD of the spine. The BMD deficit of cortical bone may be related to the lack of efficacy of the treatment and/or to an intrinsic defect of the bone on this disease. On the other hand, the augmented BMD of the lumbar spine might reflect the overabundance of partially mineralized osteoid. The determination of the BMD of the radius shaft by SPA was a sensitive method for detecting abnormalities of the bone mass in XLH patients under treatment without radiological signs of rickets.
Absorptiometry, Photon↗
1,25-Dihydroxyvitamin D3 does not up-regulate vitamin D receptor messenger ribonucleic acid levels in hypophosphatemic mice.
The effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) administration on duodenal vitamin D receptor (VDR) mRNA levels in hypophosphatemic (Hyp) mice, a murine homologue of human X-linked hypophosphatemic rickets, was examined. Basal levels of VDR mRNA in Hyp mice were similar to those of normal littermates and, in normal mice, VDR mRNA levels were up-regulated 1.8-2.7-fold after injection of 1 microgram/kg 1,25(OH)2D3. In contrast, no significant change in VDR mRNA was observed in Hyp mice treated with 1,25(OH)2D3. To determine the effect of phosphate repletion on VDR mRNA levels, high-phosphate diet was fed to Hyp mice. Although plasma phosphorus concentration was restored to normal, up-regulation of VDR mRNA was not recovered with phosphate supplementation. These results indicate that the vitamin D-resistance in Hyp mice is not caused by hypophosphatemia, per se, and may result from a fundamental molecular defect in vitamin D action at the intestine which could be related to ineffective up-regulation of VDR mRNA by 1,25(OH)2D3.
Animals↗
Stimulation of cortical bone mineralization and remodeling by phosphate and 1,25-dihydroxyvitamin D in vitamin D-resistant rickets.
Besides rachitic and osteomalacic bone lesions specific disturbances of intracortical bone remodeling have been described in children with vitamin D-resistant rickets (VDRR). The effects of phosphate and 1,25-dihydroxyvitamin D3 [Pi + 1,25(OH)2D] on the abnormal cortical bone remodeling were assessed by static and dynamic histomorphometric analysis of dual labeled undecalcified iliac crest bone biopsies obtained from 12 young VDRR children. Bone mineralization was markedly improved as shown by reduction of the osteoid thickness, shortening of the mineralization lag time and of the osteon calcification period. In conjunction with improved bone mineralization the extent of dual labeled bone surface was increased together with the osteoblast population, indicating that normal bone calcification requires the presence of osteoblasts. At the tissue level the birthrate of new Basic Multicellular remodeling Units (BMU) was clearly enhanced; while at the cellular level, the low calcification rate remained unchanged in most cases. The data show that treatment with Pi + 1,25(OH)2D stimulates the bone turnover in young patients with VDRR by inducing creation of new BMU after restoration of bone mineralization. Unlike the increased recruitment of new BMU caused by treatment, the persistence of a low calcification rate may reflect the existence of a primary osteoblast defect in some VDRR patients.
Adolescent↗
Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia.
Vitamin D-resistant rickets (VDRR) in adults is characterized by low serum phosphorus and osteomalacia. Despite the disappearance of rickets after the closure of epiphyses, some adults with VDRR present with symptomatic bone disease while other are asymptomatic. In order to test the presumption that asymptomatic adults no longer have active bone disease, we have compared bone histology in 10 symptom-free adults to 6 age-comparable symptomatic adults presenting with bone pain and persistent deformities. Both groups had similar low serum phosphorus and increased serum alkaline phosphatase values. Serum calcium, parathyroid hormone, and vitamin D metabolite concentrations were not different in the two groups. Histomorphometric study of bone formation and resorption was made on undecalcified sections of iliac crest bone biopsies obtained after in vivo single or dual tetracycline labeling. Bone histology revealed that both groups of patients had comparable osteomalacia, as evidenced by increased amount of osteoid tissue, prolonged mineralization lag time, and reduced bone formation rate. Despite the presence of osteomalacia, the trabecular calcified bone volume was within or above normal values in the two groups, implying a remodeling imbalance between the rates of bone resorption and formation. The data show that despite the absence of symptoms and the disappearance of rickets, adults with VDRR still have active bone disease characterized by moderate to severe osteomalacia. The normal to increased trabecular bone mass implies that the occurrence of painful symptoms results from factors other than trabecular osteopenia. These observations thus lead one to question the utility of active medical treatment with vitamin D and/or phosphate in asymptomatic adults with VDRR.
Adolescent↗
Hereditary 1,25-dihydroxyvitamin D resistant rickets: molecular basis and implications for the role of 1,25(OH) 2D3 in normal physiology.
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Animals↗
Inheritance of hypophosphatasia.
A system of multiple, codominant alleles (HN, HC, HI) is proposed for the inheritance of hypophosphatasia. These alleles are associated with a single autosomal locus which determines the presence or absence of hypophosphatasia among human subjects. Either HC or HI conditions hypophosphatasia whereas HN conditions the absence of this disorder. Only one genotype, HNHN, produces the absence of hypophosphatasia. Either HNHC or HNHI produces adult hypophosphatasia. Either HCHC or HCHI produces childhood hypophosphatasia. Only HIHI produces infantile (neonatal) hypophosphatasia. HI is lethal only in a homozygous state. HN occurs at a much higher frequency in human populations than either HC or HI. Any one of the hypophosphatasic genotypes is thought to exert the same degree of epistatic effect on enzyme activity within the bone/liver/kidney complex of alkaline phosphatases. These alleles and genotypes are considered to be completely penetrant but show variable expressivity within each class of hypophosphatasia.
Adult↗
Giant nevocellular nevi with rickets and brainstem tumor.
A boy, 9 years, 8 months of age, with hairy pigmented nevi over the trunk, upper extremities, and face with bone deformities characteristic of rickets was admitted because of general weakness and poor appetite for 3 weeks. Repeated examinations demonstrated marked brainstem dysfunction; a brainstem tumor was visualized by computed tomography. The patient died 14 days after admission despite supportive treatment. The relationship between giant intradermal nevocellular nevi and brain tumor is discussed.
Arachnoid Cysts↗
The human glycine receptor: a new probe that is linked to the X-linked hypophosphatemic rickets gene.
We undertook linkage analysis in four large North Carolina kindreds with X-linked hypophosphatemic rickets (HYP) using a newly defined polymorphic probe, derived from the 5' untranslated portion of the human glycine receptor (GLR). Two-point linkage analysis established linkage between GLR and HYP [Z(theta) = 7.91 at theta = 0.07] and confirmed linkage between HYP and DXS41 [Z(theta) = 8.31 at theta = 0.06] and DXS43 [Z(theta) = 5.94 at theta = 0.05]. Additionally, we found GLR tightly linked to DXS43 [Z(theta) = 5.40 at theta = 0.0]. Multipoint analysis indicated that GLR is on the telomeric side of HYP with a map order of Xpcen-DXS41-HYP-(GLR/DSX43).
Female↗
Determination of a molecular map position for Hyp using a new interspecific backcross produced by in vitro fertilization.
We have established a Mus spretus/Mus musculus domesticus interspecific backcross segregating for two X-linked mutant genes, Ta and Hyp, using in vitro fertilization. The haplotype of the recombinant X chromosome of each of 241 backcross progeny has been established using the X-linked anchor loci Otc, Hprt, Dmd, Pgk-1, and Amg and the additional probes DXSmh43 and Cbx-rs1. The Hyp locus (putative homologue of the human disease gene hypophosphatemic rickets, HYP) has been incorporated into the molecular genetic map of the X chromosome. We show that the most likely gene order in the distal portion of the mouse X chromosome is Pgk-1-DXSmh43-Hyp-Cbx-rs1-Amg, from proximal to distal. The distance in centimorgans (mean +/- SE) between DXSmh43 and Hyp was 2.52 +/- 1.4 and that between Hyp and Cbx-rs1 was 1.98 +/- 1.39. Thus closely linked flanking markers for the Hyp locus that will facilitate the molecular characterization of the gene itself have been defined.
Alkaline Phosphatase↗
Oral phosphate supplements reverse skeletal muscle abnormalities in a case of chronic fatigue with idiopathic renal hypophosphatemia.
A 57-yr-old man presented with a long history of undiagnosed fatigue but no evidence of bone disease. He was noted to have hypophosphatemia due to an idiopathic phosphaturia. Marked abnormalities of exercising skeletal muscle detected by phosphorus magnetic resonance spectroscopy and by plasma metabolite measurements were consistent with mitochondrial dysfunction. Oral phosphate supplements restored plasma phosphate concentration and muscle biochemistry to normal and produced considerable improvement in symptoms and exercise tolerance, although the phosphate concentration in muscle was only marginally low and increased little by treatment. We conclude that hypophosphatemia should be excluded in unexplained fatigue.
Adenosine Diphosphate↗
Phospholipid changes in the bones of the hypophosphatemic mouse.
The mineral and lipid composition of the bones of 35 day old hypophosphatemic (Hyp/Y) and control (+/Y) mice were compared in order to test the hypothesis that phosphate status has an effect on the complexed acidic phospholipid content of developing bones. The Hyp/Y bones were found to be rachitic and osteomalacic, having significantly reduced mineral content. That mineral was shown by X-ray diffraction to consist of larger/more perfect crystals than that in +/Y animals, indicating either a preference for crystal growth rather than new mineral deposition, or an increased mineral turnover. The increased crystal perfection was confirmed by chemical analyses which showed an increased calcium to phosphorus ratio in the Hyp/Y bones. The bones of Hyp/Y animals had significantly reduced complexed acidic phospholipid contents relative to those of control animals. Since these complexes are believed to play a role in vitro and in vivo mineral deposition, it is suggested that the deficiency of these complexes contributes to the mineralization defect. The magnitude of the complexed acidic phospholipid deficiency in the Hyp/Y animals indicates the importance of phosphate for the formation of these lipids. Although the proportion of phosphatidylserine and phosphatidylinositol and lysophospholipids tended to be reduced in the Hyp/Y bones, the absence of other statistically significant phospholipid abnormalities in the bones and brains of these animals suggests that the lipid defect is not systemic, but is associated with a decrease in phosphate at the site of bone formation.
Animals↗
Abnormal response of osteoblasts from Hyp mice to 1,25-dihydroxyvitamin D3.
To further explore the hypothesis of an osteoblast inappropriate response to 1,25-(OH)2D3 in hypophosphatemic vitamin D-resistant rickets (HYP), osteoblasts were isolated from Hyp mice, the animal model for human HYP, and their response to a physiologic dose of 1,25-(OH)2D3 (10(-10) M) was investigated with respect to alkaline phosphatase (ALP) activity and cell proliferation, and compared to that of normal osteoblasts. Cells in secondary culture were incubated for 72 h while in log phase, with or without 1,25-(OH)2D3, at various medium phosphate (P) concentrations ranging from 0.5 to 4.5 mM. Stimulation of ALP activity and inhibition of cell proliferation was induced by 10(-10)M 1,25-(OH)2D3 in normal cells exposed to medium P concentration corresponding to serum levels observed in normal mice (2.1-2.7 mM P). By contrast, Hyp cells failed to respond to 1,25-(OH)2D3 in that range of P concentrations. Stimulation of ALP activity and inhibition of proliferation of mutant cells were evident at higher medium P concentrations (over 3 mM). 1,25-(OH)2D3 at the supraphysiologic level of 10(-9)M had no consistent effect on ALP activity in normal and Hyp mouse osteoblasts, but inhibited cell proliferation in cultures of both genotypes at all P concentrations tested. These results indicate that extracellular P modulates the action of 1,25-(OH)2D3 on osteoblasts, and that this modulation was altered in osteoblasts from Hyp mice. The failure of Hyp cells to respond to a physiologic dose of 1,25-(OH)2D3 upon normal P concentration may reflect the abnormal response of bone to 1,25-(OH)2D3 observed in Hyp mice and HYP patients.
Alkaline Phosphatase↗