Vitamin D-dependent Rickets Research Articles

Factors causing rickets in institutionalised handicapped children on anticonvulsant therapy.

An epidemiological study on vitamin D-dependent rickets was carried out in severely handicapped institutionalised children on long-term anticonvulsant therapy. Nine (10%) of 94 patients had overt rickets on the basis of roentgenological bone changes and biochemical indices, but 46 patients in hospital without medication, and 50 epileptic patients attending an outpatient clinic and taking anticonvulsants had no sign of rickets. Causative factors for the development of rickets were evaluated. Administration of anticonvulsive drugs depressed the serum 25-hydroxyvitamin D (25-OHD) level, but this was not the major factor in the development of rickets. Vitamin D intake seemed to be about average in these patients and its supplementation increased their serum 25-OHD level. This serum 25-OHD level was not maintained by supplemental vitamin D, unless the children were exposed to sunlight. These results indicate that although several factors--such as anticonvulsants, low vitamin D intake, and inactivity--are concerned in the development of rickets, the main cause is lack of sun in institutionalised handicapped children.

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.

Vitamin D metabolism: update for the clinician.

Vitamin D3 must undergo two hydroxylation steps before it becomes fully active: 25-hydroxylation in the liver and 1- or 24-hydroxylation in the kidney. Parathyroid hormone, serum phosphate, and serum calcium are important in regulation of renal production of 1,25-dihydroxy vitamin D3 (1,25-[OH]2D3) and 24,25-dihydroxy vitamin D3. An enzyme involved in renal hydroxylation is deficient or defective in patients with chronic renal failure, the Fanconi syndrome, vitamin D-dependent rickets, hypoparathyroidism, and pseudohypoparathyroidism. Altered vitamin D metabolism also occurs in various hepatic diseases, postmenopausal osteoporosis, and anticonvulsant osteomalacia. Recently, 1,25-(OH)2D3 was approved for treatment of renal osteodystrophy. In physiologic doses, it predictably corrects many of the clinical and biochemical abnormalities associated with this disorder.

Hypertension in the neonate following closure of abdominal wall defects

6. Steichen JJ, Tsang RC, Graton TL, Hamstra A, and DeLuca HF: Vitamin D homeostasis in the perinatal period. 1,25 dihydroxyvitamin D in maternal cord and neonatal blood, N Engl J Med 302:315, 1980. 7. Rosen JF, and Finberg L: Vitamin D-dependent rickets, Pediatr Res 6:552, 1972. 8. Eisman JA, Hamstra AJ, Kream BE, and DeLuca HF: 1,25 dihydroxyvitamin D in biologic fluids: a simplified and sensitive assay, Science 193:1021, 1976. 9. Chesney RW, Rosen JF, Hamstra AJ, and DeLuca HF: Serum 1,25 dihydroxyvitamin D in normal children and in disorders of vitamin D metabolism, Am J Dis Child 134:135, 1980. 10. Rosen JF, Chesney RW, Hamstra A, DeLuca HF, and Mahaffey KR: Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption, N Engl J Med 302:1128, 1980.

Vitamin D-dependent rickets in the pig: renal handling of amino acids.

Vitamin D-dependent rickets in the pig: renal handling of amino acids.

Regulatory hyperparathyroidism in a pig breed with vitamin D dependency rickets.

A radioimmunoassay for porcine parathyroid hormone has been developed and applied to measure immunoreactive parathyroid hormone (PTH) in plasma of pigs with hereditary vitamin D dependency rickets (VDDR) (pseudovitamin D deficiency rickets). Levels of 25-hydroxycholecalciferol (25-(OH)-D3) in plasma were measured by a protein binding assay. Both plasma concentrations of PTH and 25-(OH)-D3 showed an approximately 4-fold increase compared to normal pigs. PTH levels increased with duration of the disease. Daily dosing of the animals with 1--4 micrograms of 1,25-dihydroxycholecalciferol (1,25-(OH)2-D3) reduced PTH concentrations and resulted in clinical healing. Iv administration of 10 micrograms of 25-(OH)-D3/day did not alter PTH concentrations nor the clinical symptoms. The results suggest that these animals suffer from regulatory hyperparathyroidism. The metabolic defect could be due to a failure of the kidney to convert 25-(OH)-D3 to 1,25-(OH)2-D3.

Vitamin D preparations: alfacalcidol (one-alpha) and others

Since we last discussed vitamin D therapy1 the synthetic vitamin D analogue 1α-hydroxyvitamin D3 has become available as alfacalcidol (One-Alpha - Leo). It is recommended for treatment of hypoparathyroidism, renal bone disease, vitamin D-dependent rickets, vitamin D-resistant hypophosphataemic rickets and osteomalacia. Peri-operative treatment is also recommended to reduce the risks of hypocalcaemia after parathyroidectomy.

A Familial Syndrome of Decrease in Sensitivity to 1,25-Dihydroxyvitamin D*

Typical features of hereditary vitamin D-dependent (pseudovitamin D-deficient) rickets were observed beginning at ages 20 and 5 months in a brother and sister. Both had calcium malabsorption correctable with high doses of 25-hydroxyvitamin D. During periods of hypocalcemia they both manifested secondary hyperparathyroidism with hypophosphatemia and high serum concentrations of endogenously produced 1,25-dihydroxyvitamin D. In each, normalization of serum calcium concentration and resolution of osteomalacia were obtained with continuous administration of high doses of ergocalciferol or high doses of 1,25-dihydroxycholecalciferol. Chemical features of vitamin D deficiency were corrected in the presence of high circulating concentrations of 1,25-dihydroxyvitamin D2, produced endogenously, or of 1,25-dihydroxyvitamin D3, administered by mouth. Serum concentrations of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal in five first degree relatives. We conclude that in these five first degree relatives. We conclude that in these siblings, rickets and osteomalacia resulted from a hereditary decreased sensitivity to 1,25-dihydroxyvitamin D at the intestine and perhaps other vitamin D target tissues.

140: Epidemiology of inherited disorders of calcium/phosphate metabolism

In the years 1973 to 1975 a systematic screening for clinically recognisable disorders of calcium/phosphate metabolism was carried out among 55,000 children, 0-14 years of age. Besides, serum alkaline phosphatase activity was determined in an unselected sample of 1070 children, and urinary calcium output was measured in 529 subjects. Detailed family investigation was performed in each of the positive cases. As a result of this programme 19 anomalies were discovered: 2 vitamin D-resistant hypophosphataemic rickets, 5 vitamin D-dependent rickets, 2 juvenile hypophosphatasia, 3 idiopathic hypercalcaemia, 7 idiopathic hypercalciuria. Considering only the index patients of the affected families, the following minimum estimate figures of prevalence could be calculated:

Vitamin D Endocrinology

Current status of our understanding of the metabolism of vitamin D and its implications in metabolic bone disease is reviewed. The details of metabolism of vitamin D3 to 25-hydroxyvitamin D3 in the liver and its further conversion in the kidneys to either 1,25-dihydroxyvitamin D3 or 24,25-dihydroxyvitamin D3 are presented. The latter conversions are regulated by the vitamin D status, serum calcium through the parathyroid gland system, and serum inorganic phosphorus concentration. The 1,25-dihydroxyvitamin D3 can now be regarded as a calcium- and a phosphate-mobilizing hormone and must be considered as one of the most important serum calcium-regulating hormones. Disruption of the vitamin D metabolic sequence or the signal system for 1,25-dihydroxyvitamin D3 results in several bone and calcium metabolism disorders such as renal osteodystrophy, hypoparathyroidism, pseudohypoparathyroidism, and vitamin D-dependency rickets. The use of the synthetic analogs of 1,25-dihydroxyvitamin D3 as well as 1,25-dihydroxyvitamin D3 itself in the management of these disease states is discussed.

Abstracts of the Eighth Annual Meeting of the Japanese Society for Bone Metabolism Research

Abstracts of the Eighth Annual Meeting of the Japanese Society for Bone Metabolism Research

Vitamin D-dependency rickets in institutionalized, mentally retarded children on long term anticonvulsant therapy. II. The response to 25-hydroxycholecalciferol and to vitamin D2.

Extract: Eight mentally retarded children with vitamin D-dependency rickets associated with long term anticonvulsant medication are reported. All had been institutionalized for most of their lives, and had marked cerebral palsy. Their ages ranged from 3.5–9.5 years. All suffered from a chronic convulsive disorder and had been treated for 3 years or more with various combinations of Dilantin, Mysoline, and phenobarbital. They had no alterations in hepatic, renal, or intestinal functions.Rickets ensued in these children despite an intake of conventional doses of oral vitamin D2 taken prophylactically throughout life. Three patients failed to respond to treatment with doses of up to 6,000 IU/24 hr given orally. In one instance, 2,000 IU vitamin D2 was given for 7 months, with no response. However, in three patients, healing was induced with higher doses of vitamin D2; one healed with 15,000 IU vitamin D2 daily for 10 weeks, and two responded to a single oral dose of vitamin D2 of 600,000 IU. Another patient did not improve after one single oral dose of 0.5 mg dihydrotachysterol. In contrast, 50 IU 25-hydroxycholecalciferol daily by mouth induced rapid healing in five patients. There was a rapid rise in serum PC4 levels within the 1st week of this therapy, with radiographic healing apparent after 1 month. However, the serum calcium levels remained low throughout 4–5 months of therapy. When the dose of 25-hydroxycholecalciferol (25-OH-D3) was increased to 100 IU/24 hr, the hypocalcemia was corrected. In some of these patients there was an amelioration of convulsions after rickets was treated. It is suggested that children who reside in institutional care centers, who are on long term anticonvulsant drugs, be given vitamin D supplements greater than the usual prophylactic dose, and also (perhaps more appropriately) that serial serum calcium, phosphate, and alkaline phosphatase estimations be performed regularly in such children as well as long bone radiographs when indicated.Speculation: The rapid response to small dosages of 25-OH-D3 is evidence suggestive that the mechanism for rickets induction in patients on long term anticonvulsant therapy is one of interference of vitamin D metabolism at the stage of hepatic conversion from cholecalciferol to its 25-hydroxy metabolite. Other factors such as levels of sunlight exposure, relative inactivity, and chronic recurrent infections, may also play a role in the development of rickets in these patients.

Vitamin D-dependent rickets in institutionalized, mentally retarded children receiving long-term anticonvulsant therapy. I. A survey of 288 patients

In 288 institutionalized mentally retarded children, fasting serum values of calcium, phosphorus, alkaline phosphatase, sodium, potassium, magnesium, and osmolality, and random urinary values of calcium, phosphorus, sodium, potassium, magnesium, creatinine, and amino acid nitrogen were measured. Roentgenograms of long bones were obtained from 75 patients. Of the 288 patients, 134 had received anticonvulsants of various types, combinations, and dosages for more than one year. All had a daily vitamin D 2 intake of 800 to 1,200 I.U. Patients who received anticonvulsants had lower values for both serum and urinary calcium and phosphorus and higher values for serum alkaline phosphatase and urinary amino acids than those who received no anticonvulsants. These changes were correlated with the duration of therapy but not with the dosage of the drug. The 68 patients receiving combinations of anticonvulsants had the most marked reductions of calcium and phosphorus and increases of alkaline phosphatase. Nine of them had biochemical and roentgenologic evidence of rickets, and 20 had severe osteoporosis. Neither rickets nor alterations in calcium metabolism were found in patients who were not receiving anticonvulsant medication. The serum calcium and phosphorus values of patients who were nonambulatory and confined indoors were lower than those of patients who were ambulatory and participated in normal outdoor activities. Vitamin D-dependent rickets associated with long-term anticonvulsant therapy may occur in patients who receive a combination of medication for more than one year. In our survey rickets was found in nonambulatory patients who were confined indoors and in whom chronic recurrent infections were common.

Vitamin D-dependent rickets: actions of parathyroid hormone and 25-hydroxycholecalciferol.

Extract: During active rickets, the increase in 3′,5′-adenosine monophosphate (3′,5′-AMP) excretion after infusion of parathyroid hormone (PTH) can be claimed as a demonstration of PTH responsiveness, at least as far as the kidney is concerned (Table II). In patients with vitamin D-dependent rickets, following 25-HCC therapy, the basal excretion ratios of nanomoles 3′,5′-AMP/milligrams creatinine fall within the normal range, and, although the basal ratios of milligrams phosphate/milligrams creatinine excretion decrease to normal (Tables III, IV, and V), a phosphaturic response to PTH is still not evident. The high basal ratios of nanomoles 3′,5′-AMP/ milligrams creatinine and milligrams phosphate/milligrams creatinine suggest underlying hyperparathyroidism during a phase of this syndrome marked by hypocalcemia and hyperaminoaciduria. During 2-day PTH challenges, while rickets was active, the peak increases in serum calcium above base line were 1.92, 1.80, and 1.86 mg/100 ml. After treatment with 25-hydroxycholecalciferol (25-HCG), no further significant increases in serum calcium above base line could be elicited (Tables VI, VII, VIII). It would seem, therefore, that, while these patients were untreated, small but sufficient amounts of 25-HCC or another metabolite of vitamin D were available to permit the calcium-mobilizing action of PTH on bone. The observed hypocalcemia in vitamin D-dependent rickets, then, is most likely secondary to a defect in gastrointestinal absorption. Mineral balance studies during active rickets revealed an absorptive defect for calcium, phosphorus, and magnesium—a defect completely reversible after 25-HCC treatment. Speculation: We suggest that the small intestine represents the prime target organ site for impaired vitamin D action in this disease by differential failure in the biologic formation of 1,25-dihydroxycholecalciferol from 25-HCC. Similarly, we postulate that a variable hydroxylating deficiency may be present in the transformation of vitamin D3 to 25-HCC. Genetic heterogeneity, therefore, may ultimately explain common responses in these three patients to contrasting doses of dihydrotachysterol (DHT) and 25-HCC.

Effect of treatment of calcium kinetics in metabolic bone disease

The effect of treatment on calcium kinetic and balance studies was investigated on six patients with osteoporosis (group A). The results were compared with data obtained from similar studies on four patients with calcium abnormalities secondary to steatorrhea and on one infant with vitamin D-dependent rickets (group B). The studies were carried out before treatment and subsequently at various periods up to 2 yr after the onset of treatment. The effect of treatment on bone calcium kinetics differed significantly between the two groups. In osteoporosis (group A), accretion rates of calcium to bone were lower as compared to pretreatment values. In contrast, in four of the five subjects of group B, accretion rates increased from pretreatment values. The results show that in osteoporosis changes in bone calcium metabolism were observed for as long as 2 yr on treatment, despite the fact that the balance data were normal at this time.

Type II Vitamin D Dependent Rickets: A Case Report

Vitamin D-dependent rickets Type II is a rare autosomal recessive disorder. Alopecia of the scalp or the body is seen in some families with Vitamin D-dependent rickets Type II. We report a child with this disease, and review the salient features of this disease with emphasis on the associated alopecia. Due to lack of facilities for estimation of 1, 25(OH)2 D and parathyroid hormone, alopecia remains the only clue to the diagnosis of this rare syndrome in association with resistant rickets. Key words: Rickets, Vitamin D metabolism DOI: 10.3126/jnps.v30i1.2460 Journal of Nepal Paediatric Society Vol.30(1) 2010 46-49