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Results for “HYPOPHOSPHATEMIA, FAMILIAL”

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At least 559 records · Page 31Linked to original sources
PubMed2003

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

BACKGROUND: Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. METHODS: Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. RESULTS: Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. CONCLUSIONS: FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.

Adolescent↗
PubMed2001

Effect of growth hormone treatment on final height, phosphate metabolism, and bone mineral density in children with X-linked hypophosphatemic rickets.

OBJECTIVE: To evaluate the effect of growth hormone treatment on final height, phosphate metabolism, bone markers, and bone mineral density in children with X-linked hypophosphatemic rickets. STUDY DESIGN: Six patients (aged 7.8 +/- 1.8 years; height z score, -3.4 +/- 0.5) received conventional treatment (1,25-dihydroxyvitamin D(3) plus phosphate salts) combined with growth hormone (0.6-0.9 IU/kg per week, subcutaneously) (group A); 6 patients (aged 7.9 +/- 2.5 years; height z score, -2.1 +/- 0.6, P <.01 with respect to group A) received only conventional treatment (group B). RESULTS: Final height z score significantly improved in group A (-2.4 +/- 0.5, P <.03 with respect to the value at entry), whereas it did not change in group B (-2.8 +/- 0.5, P = NS). At final height, degree of body disproportion was similar between the groups (group A, 1.3 +/- 0.2; group B, 1.2 +/- 0.1; P = NS). Phosphate retention, bone markers, and radial bone mineral density increased only in group A. No adverse effects were observed. CONCLUSIONS: In poorly growing patients with X-linked hypophosphatemic rickets, growth hormone therapy combined with conventional treatment improves final height, phosphate retention, and radial bone mineral density, but it does not influence degree of body disproportion.

Adolescent↗
PubMed1986

The Gy mutation: another cause of X-linked hypophosphatemia in mouse.

An X-linked dominant mutation (gyro, gene symbol Gy) in the laboratory mouse causes hypophosphatemia, rickets/osteomalacia, circling behavior, inner ear abnormalities, and sterility in males and a milder phenotype in females. Gy maps closely (crossover value 0.4-0.8%) to another X-linked gene (Hyp) that also causes hypophosphatemia in the mouse. Gy and Hyp genes have similar quantitative expression in serum phosphorus values, renal excretion of phosphate, and impairment of Na+/phosphate cotransport by renal brush-border membrane vesicles. These findings indicate that independent translation products of two X-linked genes serve phosphate transport in mouse kidney and thereby control phosphate content of extracellular fluid. The Gy translation product, unlike the Hyp product, is also expressed in the inner ear. These findings have implications for our understanding of the human counterpart known as "X-linked hypophosphatemia."

Alkaline Phosphatase↗
PubMed2001

A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,25-dihydroxyvitamin D(3).

Hereditary vitamin D-resistant rickets (HVDRR) is caused by heterogeneous inactivating mutations in the vitamin D receptor (VDR). Treatment of HVDRR patients with high doses of oral calcium and supraphysiologic doses of 1 alpha,25-dihydroxyvitamin D(3) (1,25D(3)) has had limited success. In this study we explored the use of vitamin D analogs as a potential therapy for this disorder. The rationale for the use of vitamin D analogs is that they bind the VDR at different amino acid residues than 1,25D(3), and their ability to modulate VDR functions differs from that of the natural hormone. In this report, we examined the VDR from three HVDRR patients with mutations in the ligand-binding domain of the VDR (histidine 305 to glutamine, arginine 274 to leucine, and phenylalanine 251 to cysteine) for their responses to two vitamin D analogs, 20-epi-1,25D(3) and 1 beta-hydroxymethyl-3-epi-16-ene-26a,27a-bishomo-25D(3) (JK-1626-2). Our results reveal that vitamin D analogs partially or completely restore the responsiveness of the mutated VDR. Analog treatment seemed to be more successful when the mutation affects the amino acids directly involved in ligand binding rather than amino acids that contribute to a functional VDR interface with dimerization partners or coactivators of transcription.

Amino Acid Substitution↗
PubMed2003

The rapid effects of 1,25-dihydroxyvitamin D3 require the vitamin D receptor and influence 24-hydroxylase activity: studies in human skin fibroblasts bearing vitamin D receptor mutations.

If both rapid and genomic pathways may co-exist in the same cell, the involvement of the nuclear vitamin D receptor (VDR) in the rapid effects of 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) remains unclear. We therefore studied rapid and long term effects of 1,25-(OH)(2)D(3) in cultured skin fibroblasts from three patients with severe vitamin D-resistant rickets and one age-matched control. Patients bear homozygous missense VDR mutations that abolished either VDR binding to DNA (patient 1, mutation K45E) or its stable ligand binding (patients 2 and 3, mutation W286R). In patient 1 cells, 1,25-(OH)(2)D(3) (1 pm-10 nm) had no effect on either intracellular calcium or 24-hydroxylase (enzyme activity and mRNA expression). In contrast, cells bearing the W286R mutation had calcium responses to 1,25-(OH)(2)D(3) (profile and magnitude) and 24-hydroxylase responses to low (1 pm-100 pm) 1,25-(OH)(2)D(3) concentrations (activity, CYP24, and ferredoxin mRNAs) similar to those of controls. The blocker of Ca(2+) channels, verapamil, impeded both rapid (calcium) and long term (24-hydroxylase activity, CYP24, and ferredoxin mRNAs) responses in patient and control fibroblasts. The MEK 1/2 kinase inhibitor PD98059 also blocked the CYP24 mRNA response. Taken together, these results suggest that 1,25-(OH)(2)D(3) rapid effects require the presence of VDR and control, in part, the first step of 1,25-(OH)(2)D(3) catabolism via increased mRNA expression of the CYP24 and ferredoxin genes in the 24-hydroxylase complex.

Calcitriol↗
PubMed2000

Molecular mechanism of transcriptional control by nuclear vitamin receptors.

Nuclear receptors for vitamins A and D belong to the nuclear hormone receptor superfamily and act as ligand-inducible transcription factors. Therefore, most of the biological actions of vitamins A and D are now considered to be exerted through nuclear vitamin receptor-mediated gene expression. The vitamin A nuclear receptors compromise six members, three all-trans retinoic acid receptors (RARalpha, RARbeta, RARgamma) and three 9-cis retinoic acid receptors (RXRalpha, RXRbeta, RXRgamma) (Mangelsdorf et al. 1995). Unlike vitamin A receptors, only one member is identified for vitamin D. The present study investigating the vitamin D receptor function in gene expression in both cell culture and intact animals was undertaken to better understand the actions of the fat-soluble vitamin A and vitamin D at a molecular level.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2006

Deformity correction by external fixation and/or intramedullary nailing in hypophosphatemic rickets.

BACKGROUND: There are many modalities of treatment for complex lower extremity deformity in hypophosphatemic rickets. We evaluated the outcomes of deformity correction using an external fixation and/or intramedullary nailing in hypophosphatemic rickets. PATIENTS AND METHODS: 55 segmental deformities (20 femora, 35 tibiae) from 20 patients were examined retrospectively. There were 9 children and 11 adults. Distraction osteogenesis was used in 28 segments and acute deformity correction in 27. External fixation was applied in 24 segments, intramedullary nailing in 6, and external fixation and intramedullary nailing in 25. RESULTS: There were 18 major and 13 minor complications in 26 of 28 segments with distraction osteogenesis, and 13 major and 10 minor complications in 19 of 27 segments with acute correction. Recurrent deformity or refracture occurred in 10 of 21 segments with distraction osteogenesis by external fixation only, 4 of 6 with acute correction by intramedullary nailing, and 1 of 25 with distraction osteogenesis or acute correction by external fixation and intramedullary nailing. Nail-related complications occurred in 3 of 6 with intramedullary nailing and 2 of 25 with external fixation and intramedullary nailing. INTERPRETATION: External fixation and intramedullary nailing can be recommended to prevent complications during or after deformity correction in hypophosphatemic rickets.

Adolescent↗
PubMed1980

The vitamin d hormonal system: implications for bone diseases.

A half century ago, vitamin D was recognized as a vitamin. Now it has become clear that it is also a hormone--indeed the biochemical cornerstone of a major hormonal system involved in regulating the body's calcium economy. The active metabolite, calcitriol, produced in the kidney, acts on bone and intestine and has been found effective in therapy of osteodystrophy and perhaps other metabolic bone diseases.

Calcium↗