D. A. S. Fraser

Pathogenesis of Hereditary Vitamin-D-Dependent Rickets

Abstract Requirements of vitamin D2, vitamin D3, 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 were studied in five patients with vitamin-D-dependent rickets, a recessively inherited form of v...

Pathogenesis of Hypocalcemia in Primary Hypomagnesemia: Normal End-Organ Responsiveness to Parathyroid Hormone, Impaired Parathyroid Gland Function

Hypocalcemia is a frequent feature of hypomagnesemia in man and several other species. To elucidate the cause of this hypocalcemia, we have studied a child with primary hypomagnesemia and secondary hypocalcemia during magnesium supplementation when he was normomagnesemic and normocalcemic and after magnesium restriction for 16 days when he quickly became hypomagnesemic (0.5 meq/liter) and hypocalcemic (3.4 meq/liter) and had positive Chvosteks and Trousseaus signs. Whether in the normomagnesemic or hypomagnesemic state, intravenous bovine parathyroid extract (PTE) 8 U. S. P. U/kg promptly caused transient increases in the urinary phosphate excretion, renal phosphate clearance and cyclic AMP excretion. The magnitudes of these responses were similar in the two states, and similar to those observed in a hypoparathyroid patient. When the patient was hypomagnesemic and hypocalcemic, intramuscular PTE, 8 U/kg at 8-h intervals for four doses promptly caused hypercalcemia. The findings indicate that the end-organs were responsive to parathyroid hormone. The concentrations of serum parathyroid hormone (PTH) were normal in the normomagnesemic state ranging from 0.15 ng/ml to 0.40 ng/ml. Serum PTH did not increase in the hypomagnesemic state in spite of hypocalcemia. Indeed, PTH became unmeasurable in four consecutive samples at the end of the period of magnesium restriction. The concentrations of serum calcitonin remained unmeasurable (< 0.10 ng/ml) throughout the study, implying that excess calcitonin was not the cause of hypocalcemia in magnesium depletion. The findings in this study support our thesis that magnesium depletion causes impaired synthesis or secretion of parathyroid hormone. This impairment would account for the hypocalcemia observed in the hypomagnesemic state.

The etiology of enamel hypoplasia: A unifying concept†

In a study of children with chronic disorders of calcium and phosphate homeostasis, enamel hypoplasia was found in hereditary vitamin D-dependency rickets and in hypoparathyroidism, conditions characterized by hypocalcemia, and was not found in X-linked hypophosphatemic rickets, a condition in which the plasma calcium concentration is normal. The occurrence of enamel hypoplasia bore no relation to the plasma phosphate concentration. Enamel hypoplasia has also been reported in other pediatric disorders in which hypocalcemia is a major sign (for example, vitamin D deficiency, prematurity, and neonatal tetany). The existence of enamel hypoplasia in a hypoparathyroid or rachitic patient, when correlated with the chronology of enamel mineralization, helps to establish the time of onset of hypocalcemia. The observations led us to the hypothesis that a low serum calcium concentration during enamel formation is a specific determinant of enamel hypoplasia. This hypothesis may be relevant to the etiology of linear enamel hypoplasia, an endemic lesion of primary teeth in children of many Third World countries that predisposes the teeth to dental caries. The hypothesis may therefore be relevant also in explaining the prevalence of caries in the primary teeth of children in many underdeveloped countries.

Hyperparathyroidism as the Cause of Hyperaminoaciduia and Phosphaturia in Human Vitamin D Deficiency

Extract: Thirty-nine infants with simple vitamin D deficiency were studied; three stages of deficiency were recognized. Stage I comprised hypocalcemia, usually as the sole important biochemical finding, while convulsions were a common clinical sign. Stage II revealed normocalcemia with hyperaminoaciduria, hypophosphatemia, and hyperphosphaturia; rickets was also in evidence. Stage III was comparable to stage II, but with recurrence of hypocalcemia and convulsions, the rickets was more severe. Patients progressed spontaneously from the early to the later stages of the deficiency syndrome; administration of parathyroid extract appeared to accelerate the rate of progression. Calcium infusion and vitamin D therapy each initially raised the serum calcium level in hypocalcemic patients; thereafter, aminoaciduria and hyperphosphaturia were suppressed.These diverse observations were interpreted in accordance with current knowledge of vitamin D and parathyroid hormone interrelations. The acquired excretory abnormality involving amino acid and phosphorus is the result of impaired tubular absorption; this defect is considered to be dependent on the development of endogenous reactive hyperparathyroidism, and not dependent on cellular deficiency of vitamin D per se. The stimulus for the hyperparathyroidism is hypocalcemia induced by deficiency of vitamin D. Normocalcemia is restored if sufficient vitamin D is present in cellular membranes to amplify the stimulative action of parathyroid hormone on intestinal transport of calcium and its release from bone. Severe deficiency of vitamin D blocks this regulatory effect upon calcium, but does not block the inhibitory effect of parathyroid hormone on renal tubular transport of amino acids and phosphorus.Speculation: An excess of parathyroid hormone rather than a simple deficiency of vitamin D at the renal tubular epithelial cell appears to cause the disturbance of transport affecting the absorption phosphorus, amino acids and other solutes. This impairment of function is the price paid in renal cellular economy for the conservation of calcium. The cellular mechanisms underlying this coexistent inhibitory effect of parathyroid hormone constitutes an important and fascinating subject for further investigation.

Treatment of Hypoparathyroidism and Pseudohypoparathyroidism with Metabolites of Vitamin D: Evidence for Impaired Conversion of 25-Hydroxyvitamin D to 1α,25-Dihydroxyvitamin D

In hypoparathyroidism and pseudohypoparathyroidism, pharmacologic doses of vitamin D correct hypocalcemia, but the mechanism is unknown. In two children with hypoparathyroidism and one with pseudohypoparathyroidism we tested the hypothesis that in these conditions there is a defect in synthesis of 1 alpha,25-dihydroxyvitamin D3, the principal active metabolite of vitamin D. In both conditions, minute doses of the metabolite (0.04 to 0.08 mug per kilogram of body weight per day) quickly corrected hypocalcemia and increased intestinal calcium absorption. On the other hand, the effective dose of 25-hydroxyvitamin D3 to maintain normocalcemia was 3 to 4 mug per kilogram per day in the two conditions. Thus, the dosage ratio of 25-hydroxyvitamin D3 to 1 alpha,25-dihydroxyvitamin D3 approximated 100:1. By contrast this ratio was approximately 3:1 in two infants with vitamin D deficiency, a condition in which optimal metabolism of vitamin D would be expected. These findings suggest an impaired conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D in both hypoparathyroidism and pseudohypoparathyroidism.

Rickets due to calcium deficiency

The importance of an adequate intake of calcium for normal skeletal growth and mineralization is well known. However, the dietary requirement for calcium is hard to define,1 2 3 4 5 6 and whether a...

Craniosynostosis in the rachitic spectrum

Premature closure of the cranial sutures can occur as an inherent mesenchymal defect.In addition, however, it can be secondary to metabolic bone disease. It is known to occur in hypophosphatasia and has been occasionally reported in vitamin D—refractory rickets. In order to ascertain the true incidence of craniosynostosis in all forms of rickets, a study was carried out on 59 children under 9 years of age, who were then or had previously been actively rachitic. Approximately one third of the children showed craniosynostosis and of these, 3 required craniectomies for decompression. The radiologic and biochemical findings have been examined in an attempt to explain why this metabolic type of craniosynostosis should occur so frequently in rachitic children. The only feature common to all cases was the presence at some time of inadequately mineralized osteoid.

Etiology of Enamel Hypoplasia and Interglobular Dentin: The Roles of Hypocalcemia and Hypophosphatemia

Abstract In the course of a long-term investigation of children with three well-defined disturbances of calcium and phosphate homeostasis - hereditary vitamin D dependency rickets, X-linked hypophosphatemia and hypoparathyroidism - we have observed distinctive distributions of enamel hypoplasia and interglobular dentin that provide a clue to the pathogenesis of these dental lesions. Each of the 25 patients with X-linked hypophosphatemia had extensive interglobular dentin in the primary and permanent teeth but no enamel hypoplasia; these patients were normocalcemic but very hypophosphatemic. Each of ten patients with vitamin D dependency rickets had severe enamel hypoplasia in the permanent teeth, and in the 7 patients whose teeth were examined histologically moderate interglobular dentin was observed in each; these patients were hypocalcemic and, because of secondary hyperparathyroidism, also hypophosphatemic. Fifteen of 21 children with hypo parathyroidism had severe enamel hypoplasia but none had interglobular dentin; these patients were hypocalcemic and hypopphosphatemic. From these observations we have formulated a unifying hypothesis that enamel hypoplasia, in disturbances of calcium and phosphate homeostasis; is caused by hypocalcemia and interglobular dentin is caused by hypophosphatemia.

Iatrogenic rickets in low-birth-weight infants

This report describes 4 premature infants, all with very low birth weights, whodeveloped nutritional rickets in a neonatal unit of a pediatric hospital. All infants were fed a proprietary milk formula containing vitamin D but no vitamin supplement. Because of their small size, the amount of formula ingested was small, resulting in a low daily vitamin D intake. A comparable group of infants who received a daily vitamin D supplement of 400 I.U. in addition to the enriched formula did not develop rickets. It is concluded that the rickets developed because the vitamin D intake was inadequate.

Randomization Tests for a Multivariate Two-Sample Problem

Abstract With few observations involving a large number of variables the T 2 test for the multivariate two-sample problem may not exist. Some alternative tests based on randomization methods are suggested and two of these are applied to an example. Also, valid randomization tests can be obtained by using subgroups of permutations; this provides a simple method for reducing computation which is desirable when the sample sizes are not small.