Management and prevention of vitamin D deficiency rickets in captive-born juvenile chimpanzees (Pan troglodytes).

Vitamin D deficiency rickets was diagnosed in three juvenile chimpanzees (Pan troglodytes) raised indoors under skylights and consuming only breast milk. Two cases detected early had mild but characteristic radiographic changes. More advanced disease presented with florid x-ray features of rickets and pathologic fractures, as well as hypocalcemia, hypophosphatemia, and low serum 25-hydroxyvitamin D levels. Treatment by a single injection of vitamin D2 in sesame oil (slow release) followed by daily oral supplementation with vitamin D2 corrected the condition. On the basis of experience with these cases and comparison with rickets in humans, a prevention protocol for mother-reared, inside-housed, chimpanzee juveniles was developed. Injection with slow release vitamin D2 (5,000 IU i.m. once) at 4 mo of age, followed by oral supplementation of 400 IU vitamin D2 daily until weaning, prevents rickets in juvenile chimpanzees raised indoors.

Sequence analysis of 139 kb in Xp22.1 containing spermine synthase and the 5' region of PEX.

Human Xp22.1 contains genes involved in mineral balance that are implicated in X-linked hypophosphatemia (XLH) in humans, its murine homologue (Hyp), and another distinct murine hypophosphatemic disorder (Gy). In XLH, a gene, PEX, has been found to be mutated in up to 83% of patients but the sequences of the promoter and 5' end have not been characterized. To further the understanding of this genomic region, 139,454 bp in Xp22.1 have been sequenced. Our analysis confirms the three most 5' published exons of PEX and extends through a putative PEX promoter region. The 5' untranslated sequence of PEX and the mouse and rat equivalents are very highly homologous, implying a conserved functional significance. In addition, we mapped and analyzed another gene 5' of PEX, spermine synthase (SpS), which encodes a ubiquitous enzyme of polyamine metabolism that may contribute to the pathophysiology of Gy. SpS consists of 11 exons spread over 54 kb. The definition of the locations of SpS and the putative promoter region of PEX will facilitate functional analysis of these genes.

Expression and cloning of the human X-linked hypophosphatemia gene cDNA.

X-linked hypophosphatemia (XLH), which is a heritable metabolic bone disease characterized biochemically by selective renal phosphate (Pi) wasting, is associated with mutations in the PEX (Phosphate-regulating gene with homologies to Endopeptidases on the X-chromosome) gene. To further explore the physiologic role of PEX and define its effect in XLH we have determined the expression and tissue distribution. Northern analysis found abundant PEX mRNA in a restricted pattern, predominantly in adult ovary and fetal lung. In addition, PEX expression was also found in adult lung and fetal liver. A PEX cDNA of 2550 basepairs, which contains the full PEX coding region, was isolated from a human ovary cDNA library. The PEX cDNA shows high homology to other membrane-bound zinc metallopeptidases. The presence of PEX in nonosseous tissues strongly suggests features of a systemic role, rather than a unique function in bone development.

X-linked hypophosphatemia: normal renal function despite medullary nephrocalcinosis 25 years after transient vitamin D2-induced renal azotemia.

Nephrocalcinosis (NC) detected by ultrasound is a recognized abnormality for some patients with X-linked hypophosphatemia (XLH) who received vitamin D2 and inorganic phosphate therapy, but is commonly observed in XLH patients treated with 1,25-dihydroxyvitamin D3 and inorganic phosphate supplementation. Nevertheless, long-term follow-up of kidney function in XLH patients with NC detected ultrasonographically has not been reported. We investigated two women with XLH, ages 31 (patient 1) and 39 (patient 2) years, each of whom had suffered at least one documented episode of vitamin D2-induced hypercalcemia and renal azotemia during childhood. Patient 2 had also been treated with inorganic phosphate. No medications for XLH had been taken during adulthood. Renal ultrasonography at our institution demonstrated marked bilateral medullary NC in both women. No other explanation was found for their NC that apparently occurred several decades earlier from medical therapy for XLH. Detailed studies (including creatinine clearance, beta2-microglobulin excretion, and fasting urinary osmolality and acidification) revealed no impairment of kidney function in either patient. Our findings indicate that subradiographic medullary NC acquired during medical therapy for XLH may persist for decades, but with no adverse renal sequelae. Definitive (long-term) assessment of kidney function in the XLH population with NC, however, will be necessary to fully understand the risk of current medical treatment for this most common heritable form of rickets.

Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.

Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.

Hypercalcemic hyperparathyroidism complicating oncogenic osteomalacia. Effect of successful tumor resection on mineral homeostasis.

Described herein is a case of oncogenic osteomalacia that ran a course of at least 16 years before curative resection of a mixed mesenchymal tumor. Hypercalcemic hyperparathyroidism developed in the patient, and review of the literature indicated that this occurs in about 10 percent of reported cases. Changes in serum parathyroid hormone levels with and without phosphate supplement therapy and before and after tumor resection suggested that both the high intake of phosphate and the effect of the neoplasm on vitamin D bioactivation engendered the parathyroid overactivity. Despite marked hyperparathyroidism, serum 1,25-dihydroxyvitamin D levels were subnormal preoperatively but showed a sevenfold increase within 48 hours of tumor resection. Thereafter, a gradual increase in the maximal tubular reabsorption of phosphate occurred during several months. Biopsy of the iliac crest confirmed that tumor removal was followed by resolution of osteomalacia, but there was no accompanying increase in vertebral mineral density as assessed by quantitative computed tomography or in total-body bone mineral as measured with dual-photon absorptiometry. The findings presented are consistent with secretion by the tumor of a factor with a short half-life that is potent enough to inhibit renal 25-hydroxyvitamin D-1 alpha-hydroxylase despite hyperparathyroidism. The resulting subnormal circulating 1,25-dihydroxyvitamin D levels may have secondarily contributed to decreased renal tubular reabsorption of phosphate.

Cystinosis presenting with features suggesting Bartter syndrome. Case report and literature review.

Features suggestive of Bartter syndrome (hypokalemia, hypochloremic metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism) were found in a 5-year-old black child with cystinosis and Fanconi syndrome. Review of his medical records revealed that these abnormalities had probably been present when he first became clinically ill at 2 years of age. Sodium and potassium chloride supplementation lead to improved growth and strength, partial correction of his electrolyte abnormalities, and a decrease in markedly elevated plasma renin activity. Literature review disclosed a similar presentation in four Caucasian children with cystinosis. Biochemical findings compatible with Bartter syndrome can occur together with evidence of generalized proximal renal tubular dysfunction (Fanconi syndrome) in nephropathic cystinosis.

Effect of the menstrual cycle on calcium-regulating hormones in the normal young woman.

To examine the effect of estrogens on circulating levels of calcium-regulating hormones, total serum calcium, ionized calcium, inorganic phosphate, immunoreactive parathyroid hormone, calcitonin, 1,25-dihydroxyvitamin D, and estradiol (E2) levels were assayed on menstrual cycle days 3 and 13 in 12 healthy young women. Despite a 3-fold increase in serum E2 levels by midcycle, no differences in the other factors were observed. Furthermore, iv infusion of calcium (3 mg/kg over a 10-min period) produced similar changes in the serum levels of immunoreactive parathyroid hormone and calcitonin on days 3 and 13 in 8 women. Our findings suggest that in normal menstruating women, endogenous increases in E2 neither directly nor indirectly stimulate 1,25-dihydroxyvitamin D production, nor do they affect circulating levels of the hormones known to influence calcium homeostasis in man.