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PubMed1983

Defective binding of macrophages to bone in rodent osteomalacia and vitamin D deficiency. In vitro evidence for a cellular defect and altered saccharides in the bone matrix.

In the osteomalacic as well as normal skeleton, few osteoclasts are associated with osteoid-covered bone surfaces. The reason for this particular cellular deficit is not clear, but may relate to the inability of osteoclasts and/or osteoclast precursors (monocyte-macrophages) to attach to immature, unmineralized bone matrix, a step apparently essential for normal resorptive activity and osteoclast differentiation. In this study, we have examined cell-bone binding using macrophages (M phi) and bone isolated from vitamin D-deficient rats and hypophosphatemic, osteomalacic mice and from their normal counterparts. The data show that M phi-bone attachment is greatly reduced (P less than 0.001) in both vitamin D deficiency and hypophosphatemia, but that the mechanisms responsible for this reduction are apparently different in the two disorders. In hypophosphatemia, the reduction in binding appears solely attributable to the absence or inaccessibility of bone matrix oligosaccharides or glycoproteins essential to the attachment process. In vitamin D deficiency, on the other hand, not only is the bone matrix defective as a binding substrate, but the M phi, per se, is limited in its capacity to attach to normal, vitamin D-deficient, and hypophosphatemic bone.

Animals↗
PubMed1983

Impaired stimulation of 25-hydroxyvitamin D-24-hydroxylase in fibroblasts from a patient with vitamin D-dependent rickets, type II. A form of receptor-positive resistance to 1,25-dihydroxyvitamin D3.

We describe studies of the molecular defect in 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] action in cultured skin fibroblasts from a patient previously reported to have vitamin D-dependent rickets, type II. Binding of [3H]1,25-(OH)2D3 in fibroblast cytosol was normal with a Bmax (amount of high affinity binding) of 26 fmol/mg protein and a half-maximal saturation of 0.2 nM. Nuclear binding of [3H]1,25-(OH)2D3 following whole cell uptake was 1.5 fmol/micrograms DNA in patient fibroblasts compared with a range of 0.5-2.9 fmol/micrograms DNA in five control strains. The size of the [3H]1,25-(OH)2D3-receptor complex on sucrose density gradients, 3.8 S, was the same as in normal cells. This patient, therefore, appeared to have a receptor-positive form of resistance to 1,25-(OH)2D3. To document resistance to 1,25-(OH)2D3 in the fibroblasts we developed a method for detection of 1,25-(OH)2D3 action in normal skin fibroblasts. Following treatment of normal cell monolayers with 1,25-(OH)2D3 there was more than a 20-fold increase of 25-hydroxy-vitamin D-24-hydroxylase (24-hydroxylase) activity. Treatment of 10 control cell strains with 1,25-(OH)2D3 for 8 h increased the formation of 24,25-dihydroxy-vitamin D3 from 25-hydroxyvitamin D3 in cell sonicates from less than 0.02 to 0.11-0.27 pmol/min per mg protein. When cells from the patient with vitamin D-dependent rickets, type II were treated with 1,25-(OH)2D3 in a similar manner, maximal 24-hydroxylase activity was only 0.02 pmol/min per mg protein, less than a fifth the lower limit of normal. 24-Hydroxylase activity in fibroblasts from the parents of the patient increased normally following treatment with 1,25-(OH)2D3. We conclude that impaired induction of 24-hydroxylase in the presence of normal receptor binding is evidence for postreceptor resistance to the action of 1,25-(OH)2D3.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1985

Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.

Adolescent↗
PubMed1985

Defective binding and function of 1,25-dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end-organ resistance to 1,25-dihydroxyvitamin D.

Lectin-induced DNA synthesis by peripheral mononuclear cells from 17 normal donors was inhibited (40-60%) by 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) at physiological concentrations (10(-10)-10(-9) M). The lymphocytes acquire specific receptors for 1,25(OH)2D3 upon activation by the lectins. This process precedes the inhibitory effect of 1,25(OH)2D3. We studied lymphocytes from six patients from four different kindreds with the syndrome of hereditary end-organ resistance to 1,25(OH)2D (the so-called vitamin D-dependent rickets type II). In five patients (three kindreds) peripheral blood mononuclear cells did not acquire receptors for 1,25(OH)2D3 upon phytohemagglutinin-induced activation. Moreover, in contrast to normal lymphocytes, the mitogenic stimulation of these patients' lymphocytes by phytohemagglutinin and concanavalin A was not inhibited by 1,25(OH)2D3. Activated lymphocytes of the sixth patient from a fourth kindred exhibited normal binding of [3H]1,25(OH)2D3 but the hormone failed to inhibit the mitogenic stimulation. A similar pattern of the vitamin D effector system was previously observed in fibroblasts cultured from skin biopsies of the same group of patients. The conclusions from these findings are: (a) the inhibition of mitogenic stimulation by 1,25(OH)2D3 is mediated by specific functional receptors to the hormone; and (b) the receptors for 1,25(OH)2D3 in mononuclear cells are probably controlled genetically by the same mechanisms as the effector system in well-characterized target organs of the hormone, such as intestine and kidney.

Adolescent↗
PubMed1986

Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism.

Abnormal regulation of vitamin D metabolism is a feature of X-linked hypophosphatemic rickets in man and of the murine homologue of the disease in the hypophosphatemic (Hyp)-mouse. We previously reported that mutant mice have abnormally low renal 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity for the prevailing degree of hypophosphatemia. To further characterize this defect, we examined whether Hyp-mouse renal 1 alpha-hydroxylase activity responds normally to other stimulatory and inhibitory controls of enzyme function. We studied stimulation by parathyroid hormone (PTH) using: (a) a calcium-deficient (0.02% Ca) diet to raise endogenous PTH; or (b) 24-h continuous infusion of 0.25 IU/h bovine PTH via osmotic minipump. In both cases enzyme activity of identically treated normal mice increased to greater levels than those attained by Hyp-mice. The relative inability of PTH to stimulate 1 alpha-hydroxylase activity is not a function of the hypophosphatemia in the Hyp-mouse since PTH-infused, phosphate-depleted normal mice sustained a level of enzyme activity greater than that of normal and Hyp-mice. In further studies we investigated inhibition of enzyme activity by using: (a) a calcium-loaded (1.2% Ca) diet to suppress endogenous PTH; or (b) 24-h continuous infusion of 0.2 ng/h 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The 1 alpha-hydroxylase activity of normal and Hyp-mice was significantly reduced to similar absolute levels following maintenance on the calcium-loaded diet. Further, infusion of 1,25(OH)2D3 caused a comparable reduction of 1 alpha-hydroxylase activity in normal, Hyp-, and phosphate-depleted normal mice. These observations indicate that the inhibitory control of 1 alpha-hydroxylase by reduced levels of PTH or increased 1,25(OH)2D3 concentrations is intact in the mutants. However, the inability of PTH and hypophosphatemia to stimulate enzyme activity in a manner analogous to that in normal and phosphate-depleted mice indicates that a generalized defect of 1 alpha-hydroxylase regulation is manifest in Hyp-mice.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1986

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

We report the beneficial effects of calcium infusions in a child with hereditary resistance to 1,25(OH)2D and alopecia. This patient after transient responsiveness to vitamin D derivatives became unresponsive to all therapy despite serum 1,25(OH)2D concentrations maintained at levels approximately 100-fold normal. A 7-mo trial with calcium infusions led to correction of biochemical abnormalities and healing of rickets. Bone biopsies (n = 3) showed a normal mineralization and the disappearance of the osteomalacia. Cultures of bone-derived cells demonstrated a lack of activation of 25-hydroxyvitamin D 24-hydroxylase and osteocalcin synthesis by 1,25(OH)2D3 (10(-9) and 10(-6) M). These results demonstrate that even in the absence of a normal 1,25(OH)2D3 receptor-effector system in bone cells, normal mineralization can be achieved in humans if adequate serum calcium and phosphorus concentrations are maintained; and calcium infusions may be an efficient alternative for the management of patients with this condition who are unresponsive to large doses of vitamin D derivatives.

Bone and Bones↗
PubMed1987

Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.

Hypophosphatemia (Hyp) mice have defective regulation of 25(OH)D-1 alpha-hydroxylase activity in response to hypophosphatemia, hypocalcemia, and parathyroid hormone (PTH) administration. However, recent observations support the existence of anatomically distinct, independently regulated renal 1 alpha-hydroxylase systems in mammalian proximal convoluted and straight tubules. To more completely define the extent of the 1 alpha-hydroxylase regulatory defect in Hyp-mice, we compared enzyme maximum velocity in normal and mutants after infusion of calcitonin. Upon stimulation, renal 1 alpha-hydroxylase activity increased to similar levels in normal and Hyp-mouse renal homogenates. Moreover, time-course and dose-dependence studies revealed similar patterns of response in the animal models. Subsequently, we examined whether PTH and calcitonin stimulatory effects on enzyme activity are mediated through different mechanisms. In both animal models administration of PTH and calcitonin increased enzyme activity to levels greater than those obtained after maximal stimulation by either hormone alone, consistent with additive effects. These observations indicate that a calcitonin-sensitive component of 1 alpha-hydroxylase is not compromised in the X-linked hypophosphatemic syndrome.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1987

Granulocyte-macrophage colony-stimulating factor. Sensitive and receptor-mediated regulation by 1,25-dihydroxyvitamin D3 in normal human peripheral blood lymphocytes.

We show that 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), the most hormonally active metabolite of vitamin D3, modulates sensitively and specifically both the protein and messenger RNA accumulation of the multilineage growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). The regulation of GM-CSF expression is seen in both normal human mitogen-activated T lymphocytes and T lymphocytes from a line (S-LB1) transformed with human T cell lymphotropic virus 1 (HTLV-1). In contrast, cells from a HTLV-1 transformed T lymphocyte line (Ab-VDR) established from a patient with vitamin D-resistant rickets type II with undetectable 1,25(OH)2D3 cellular receptors are resistant to the action of 1,25(OH)2D3. Inhibition of GM-CSF expression by 1,25(OH)2D3 can occur independently of interleukin 2 regulation and is probably mediated through cellular 1,25(OH)2D3 receptors. We conclude that 1,25(OH)2D3 may be important in the physiology of hematopoiesis.

Calcitriol↗
PubMed1988

Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets.

The hypophosphatemic (Hyp) mouse, a murine homologue of human X-linked hypophosphatemic rickets, is characterized by renal defects in brush border membrane phosphate transport and vitamin D3 metabolism. The present study was undertaken to examine whether elevated renal 25-hydroxyvitamin D3-24-hydroxylase activity in Hyp mice is associated with increased degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by side chain oxidation. Metabolites of 1,25(OH)2D3 were separated by HPLC on Zorbax SIL and identified by comparison with standards authenticated by mass spectrometry. Production of 1,24,25-trihydroxyvitamin D3, 24-oxo-1,25-dihydroxyvitamin D3, and 24-oxo-1,23,25-trihydroxyvitamin D3 was twofold greater in mitochondria from mutant Hyp/Y mice than from normal +/Y littermates. Enzyme activities, estimated by the sum of the three products synthesized per milligram mitochondrial protein under initial rate conditions, were used to estimate kinetic parameters. The apparent Vmax was significantly greater for mitochondria from Hyp/Y mice than from +/Y mice (0.607 +/- 0.064 vs. 0.290 +/- 0.011 pmol/mg per protein per min, mean +/- SEM, P less than 0.001), whereas the apparent Michaelis-Menten constant (Km) was similar in both genotypes (23 +/- 2 vs. 17 +/- 5 nM). The Km for 1,25(OH)2D3 was approximately 10-fold lower than that for 25-hydroxyvitamin D3 [25(OH)D3], indicating that 1,25(OH)2D3 is perhaps the preferred substrate under physiological conditions. In both genotypes, apparent Vmax for 25(OH)D3 was fourfold greater than that for 1,25(OH)2D3, suggesting that side chain oxidation of 25(OH)D3 may operate at pharmacological concentrations of substrate. The present results demonstrate that Hyp mice exhibit increased renal catabolism of 1,25(OH)2D3 and suggest that elevated degradation of vitamin D3 hormone may contribute significantly to the clinical phenotype in this disorder.

Animals↗
PubMed1990

Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets.

Hyp mice exhibit increased renal catabolism of vitamin D metabolites by the C-24 oxidation pathway (1988. J. Clin. Invest. 81:461-465). To examine the regulatory influence of dietary phosphate on the renal vitamin D catabolic pathway in Hyp mice, we measured C-24 oxidation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in renal mitochondria isolated from Hyp mice and normal littermates fed diets containing 0.03% (low-Pi), 1% (control-Pi), and 1.6% (high-Pi) phosphate. In normal mice the low-Pi diet led to a rise in serum 1,25(OH)2D (22.2 +/- 1.8 to 48.1 +/- 6.8 pg/ml, P less than 0.05) and no change in C-24 oxidation products (0.053 +/- 0.006 to 0.066 +/- 0.008 pmol/mg protein per min) when compared with the control diet. In Hyp mice the low-Pi diet elicited a fall in serum 1,25(OH)2D (21.9 +/- 1.2 to 8.0 +/- 0.2 pg/ml, P less than 0.05) and a dramatic increase in C-24 oxidation products (0.120 +/- 0.017 to 0.526 +/- 0.053 pmol/mg protein per min, P less than 0.05) when compared with the control diet. The high-Pi diet did not significantly alter serum levels of 1,25(OH)2D or C-24 oxidation products in normal mice. Hyp mice on the high-Pi diet experienced a rise in serum 1,25(OH)2D (21.9 +/- 1.2 to 40.4 +/- 7.3, P less than 0.05) and a fall in C-24 oxidation products (0.120 +/- 0.017 to 0.043 +/- 0.007 pmol/mg protein per min, P less than 0.05). The present results demonstrate that the defect in C-24 oxidation of 1,25(OH)2D3 in Hyp mice is exacerbated by phosphate depletion and corrected by phosphate supplementation. The data suggest that the disorder in vitamin D metabolism in the mutant strain is secondary to the perturbation in phosphate homeostasis.

Animals↗
PubMed1992

Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.

Although deranged phosphate transport is the fundamental abnormality in X-linked hypophosphatemic (XLH) rickets, it remains unknown if this defect is the consequence of an intrinsic kidney abnormality or aberrant production of a humoral factor. To discriminate between these possibilities, we examined phosphate homeostasis in normal and Hyp mice, subjected to renal crosstransplantation. We initially evaluated the effects of uninephrectomy on the indices of phosphate metabolism that identify the mutant biochemical phenotype. No differences were found in the serum phosphorus concentration, fractional excretion of phosphate (FEP), or tubular reabsorption of phosphate per milliliter of glomerular filtrate (TRP) in uninephrectomized normal and Hyp mice, compared with sham-operated controls. Subsequently, single kidneys from normal or Hyp mice were transplanted into normal and Hyp mouse recipients. Normal mice transplanted with normal kidneys and Hyp mice engrafted with mutant kidneys exhibited serum phosphorus, FEP, and TRP no different from those of uninephrectomized normal and Hyp mice, respectively. However, engraftment of normal kidneys in Hyp mice and mutant kidneys in normal mice affected neither serum phosphorus (4.69 +/- 0.31 and 8.25 +/- 0.52 mg/dl, respectively) nor FEP and TRP of the recipients. These data indicate that the Hyp mouse phenotype is neither corrected nor transferred by renal transplantation. Further, they suggest that the phosphate transport defect in Hyp mice, and likely X-linked hypophosphatemia, is the result of a humoral factor, and is not an intrinsic renal abnormality.

Animals↗
PubMed1994

Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization.

The X-linked Hyp mouse is characterized by a specific defect in proximal tubular phosphate (Pi) reabsorption that is associated with a decrease in Vmax of the high affinity Na(+)-Pi cotransport system in the renal brush border membrane. To understand the mechanism for Vmax reduction, we examined the effect of the Hyp mutation on renal expression of Na(+)-Pi cotransporter mRNA and protein. Northern hybridization of renal RNA with a rat, renal-specific Na(+)-Pi cotransporter cDNA probe (NaPi-2) (Magagnin et al. 1993. Proc. Natl. Acad. Sci. USA. 90:5979-5983.) demonstrated a reduction in a 2.6-kb transcript in kidneys of Hyp mice relative to normal littermates (NaPi-2/beta-actin mRNA = 57 +/- 6% of normal in Hyp mice, n = 6, P < 0.01). Na(+)-Pi cotransport, but not Na(+)-sulfate cotransport, was approximately 50% lower in Xenopus oocytes injected with renal mRNA extracted from Hyp mice when compared with that from normal mice. Hybrid depletion experiments documented that the mRNA-dependent expression of Na(+)-Pi cotransport in oocytes was related to NaPi-2. Western analysis demonstrated that NaPi-2 protein is also significantly reduced in brush border membranes of Hyp mice when compared to normals. The present data demonstrate that the specific reduction in renal Na(+)-Pi cotransport in brush border membranes of Hyp mice can be ascribed to a proportionate decrease in the abundance of Na(+)-Pi cotransporter mRNA and protein.

Animals↗
PubMed1997

Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness.

Mutations in the vitamin D receptor (VDR) result in target organ resistance to 1alpha,25-dihydroxyvitamin D [1,25(OH)2D3], the active form of vitamin D, and cause hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR). We analyzed the VDR of a patient who exhibited three genetic diseases: HVDRR, congenital total lipodystrophy, and persistent mullerian duct syndrome. The patient was treated with extremely high dose calcitriol (12.5 microg/d) which normalized serum calcium and improved his rickets. Analysis of [3H]1,25(OH)2D3 binding in the patient's cultured fibroblasts showed normal abundance of VDR with only a slight decrease in binding affinity compared to normal fibroblasts when measured at 0 degrees C. The patient's fibroblasts demonstrated 1,25(OH)2D3-induction of 24-hydroxylase mRNA, but the effective dose was approximately fivefold higher than in control cells. Sequence analysis of the patient's VDR gene uncovered a single point mutation, H305Q. The recreated mutant VDR was transfected into COS-7 cells where it was 5 to 10-fold less responsive to 1,25(OH)2D3 in gene transactivation. The mutant VDR had an eightfold lower affinity for [3H]1,25(OH)2D3 than the normal VDR when measured at 24 degrees C. RFLP demonstrated that the patient was homozygous for the mutation while the parents were heterozygous. In conclusion, we describe a new ligand binding domain mutation in the VDR that causes HVDRR due to decreased affinity for 1,25(OH)2D3 which can be effectively treated with extremely high doses of hormone.

Calcitriol↗
PubMed1997

Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13.

Autosomal dominant hypophosphatemic rickets (ADHR) is an inherited disorder of isolated renal phosphate wasting, the pathogenesis of which is unknown. We performed a genome-wide linkage study in a large kindred to determine the chromosome location of the ADHR gene. Two-point LOD scores indicate that the gene is linked to the markers D12S314 [Z(theta) = 3.15 at theta = 0.0], vWf [Z(theta) = 5.32 at theta = 0.0], and CD4 [Z(theta) = 3.53 at theta = 0.0]. Moreover, multilocus analysis indicates that the ADHR gene locus is located on chromosome 12p13 in the 18-cM interval between the flanking markers D12S100 and D12S397. These data are the first to establish a chromosomal location for the ADHR locus and to provide a framework map to further localize the gene. Such studies will permit ultimate identification of the ADHR gene and provide further insight into phosphate homeostasis.

Chromosomes, Human, Pair 12↗
PubMedDate not supplied

Audiologic findings in young patients with hypophosphatemic bone disease.

Audiometric tests were conducted on 19 subjects with hypophosphatemic bone disease to investigate whether auditory impairment like that reported in affected adults occurs in young patients. No hearing loss or significant auditory findings were noted among the children or young adult patients. However, sensorineural hearing loss of cochlear origin was identified in the three oldest subjects (40 to 58 years), although a history of noise exposure in two of them could explain the observations. The results indicate that if an association exists between hypophosphatemic bone disease and hearing impairment, the auditory signs will not develop until adulthood in treated patients. Additional studies of large populations of affected adults are needed to identify the incidence and mechanism(s) of the auditory system abnormalities and to assess any effect of medical therapy for the metabolic bone disease.

Adolescent↗