Hypercalciuric hypophosphatemic rickets, mineral balance, bone histomorphometry, and therapeutic implications of hypercalciuria

A 14-year-old Turkish boy had severe rickets that had been clinically evident since he was 2 years of age. When he was 5 years of age, he had normal serum calcium and phosphorus levels and increased alkaline phosphatase activity. Treatment with modest dosages of vitamin D (5000 U/d for 3 weeks) resulted in hypercalcemia. At 10 years of age, high-dose vitamin D (40,000 U/d) plus phosphorus (1.1 g/d) therapy for 20 days resulted in symptomatic nephrolithiasis. When, 14 years of age, he had normocalcemia, hypophosphatemia, increased alkaline phosphatase activity, and normal circulating parathyroid hormone concentration. Levels of 25-hydroxyvitamin D were normal but those of 1,25-dihydroxyvitamin D were markedly increased. Rickets and osteopenia were evident on radiographs, and osteomalacia was present on trabecular bone obtained at biopsy. Balance study results showed increased intestinal absorption of calcium and phosphorus, hypercalciuria, and increased urinary phosphorus excretion. This patient manifests an unusual form of hypophosphatemic rickets in which hypercalciuria is a cardinal feature. In contrast with most varieties of hypophosphatemia, this disorder is characterized by appropriately increased production of 1,25-dihydroxyvitamin D in response to hypophosphatemia. It is recommended that urinary calcium excretion be assessed in all patients with hypophosphatemic rickets so that appropriate therapy will be instituted.     

Pathogenesis of rickets in chronic hepatobiliary disease in children.

To investigate whether hepatobiliary rickets is caused by defective intestinal absorption of vitamin D or by impaired hepatic hydroxylation of the vitamin, we studied three children who developed severe rickets, hypocalcemia, and hypophosphatemia, two despite having received 400 to 800 IU vitamin D per day by mouth, and one despite prolonged treatment with 10,000 IU daily. On oral vitamin D therapy, plasma vitamin D and 25-hydroxyvitamin D levels were low. When two children were treated with weekly intravenous doses of 3,000 IU vitamin D to approximate the recommended prophylactic allowance, their plasma calcium and phosphate values improved promptly, the radiographic lesions healed, and the plasma concentrations of vitamin D and 25-hydroxyvitamin D became normal. Our studies indicate that the primary cause of hepatobiliary rickets is intestinal malabsorption of vitamin D, not impairment of the hepatic metabolism of the vitamin.     

Aminoaciduria in calcium-deficiency rickets in northern Nigeria

Generalized aminoaciduria is associated with vitamin D-deficiency rickets in humans, but there is little information regarding aminoaciduria in rickets caused by primary calcium deficiency. In contrast to rickets in other parts of the world, this bone disease in Nigeria is caused primarily by inadequate intake of dietary calcium. We conducted a clinical trial in Jos, Nigeria in 10 children with radiographically and biochemically proven rickets; an equal number of non-rachitic healthy children from the same area served as controls. Serum and 24 h urine samples were obtained at baseline and at 24 h, 1 week, 4 weeks, and 12 weeks after initiation of calcium supplementation (1000 mg/day) and were analysed for their content of amino acids. Serum calcium, phosphorus, intact parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were also measured at each time point. In the rachitic subjects urinary amino acid concentrations were elevated from 2- to 16-fold at baseline, while serum amino acid levels increased 1.5- to 3.8-fold compared to controls. After 12 weeks of calcium supplementation, serum and urine amino acids decreased. There was no correlation between the degree of aminoaciduria and serum PTH or 1,25-dihydroxyvitamin D concentrations. We conclude that the aminoaciduria in these rachitic children was related to their calcium status and not to their vitamin D or PTH status.     

Prospective study of vitamin D supplementation and rickets in China.

To determine whether amounts of vitamin D lower than recommended doses are effective in preventing rickets, 256 term infants from two northern and two southern cities in China were studied in a randomized trial of vitamin D supplementation (100, 200, or 400 IU/day) during the first 6 months of life. Cord blood and 6-month blood samples were collected and radiographs were obtained at 3 to 5 days and at 6 months of age. Cord serum 25-hydroxyvitamin D concentrations were lower in the north than in the south (5 vs 14 ng/ml (12.5 vs 35.0 nmol/L); p less than 0.01). Wrist ossification centers were less likely to be present at birth in the northern children than in the southern children (p = 0.009) and were more likely to be present in infants born in the fall who had higher cord serum concentrations of 25-hydroxyvitamin D (p = 0.04). Serum 25-hydroxyvitamin D concentrations were lower in northern children 6 months of age than in southern children (p = 0.005) and were higher with an increasing supplemental dosage of vitamin D (p less than 0.001), particularly in infants in the north. None of the infants had rickets at 6 months of age. Because of the low serum 25-hydroxyvitamin D concentrations, especially among infants in the north, it may be prudent to supplement the diet with vitamin D at a dose of 400 IU/day.     

Effect of Long-Term Treatment with Massive Doses of 1α-Hydroxyvitamin D3 on Calcium-Phosphate Balance in Patients with Vitamin D-Dependent Rickets Type II

Three patients with vitamin D-dependent rickets type II were given massive doses of 1α-hydroxyvitamin D₃ for 29 to 36 months and their calcium-phosphate balance was studied during treatment and one month after cesation of treatment. During treatment fasting hypercalciuria was observed in patient 1 and an increased rate of calcium excretion after calcium loading in patients 1 and 2. In these patients, calcium excretion was parallel with the serum 24, 25-dihydroxyvitamin D. These findings suggested that the responsiveness to 1,25-dihydroxyvitamin D improved during long-term treatment of these two patients with vitamin D-dependent rickets type II.     

Nutritional rickets in ichthyosis and response to calcipotriene

Nutritional rickets has occasionally been described in children with lamellar ichthyosis, but their vitamin D endocrine status has not been described. We report 3 cases of vitamin D-deficiency rickets associated with ichthyosis in African children. A 13-month-old Nigerian boy with lamellar ichthyosis had rib beading, elevated alkaline phosphatase, and rachitic changes on radiographs. His rickets did not resolve with calcium therapy, and his 25-hydroxyvitamin D level was low. His rickets resolved with parenteral vitamin D treatment, but his skin did not improve. Topical 0.005% calcipotriene (an analog of 1,25-dihydroxyvitamin D that has been useful in treating adults with psoriasis) was similarly ineffective in improving the child's skin condition. An 8-year-old Nigerian boy with life-long skin findings consistent with lamellar ichthyosis had windswept deformity of the legs with rib beading and enlargement of the wrists and ankles. Radiographs showed active rickets, and the boy had an elevated alkaline phosphatase level and a decreased calcium level. Before knowing that his 25-hydroxyvitamin D level was low, he was treated with calcium and showed radiologic improvement. The skin did not improve with resolution of the rickets but did improve with unilateral topical application of 0.005% calcipotriene. A 7-year-old South African girl presented with progressive windswept deformities of the legs and a 4-year history of skin disease (and a skin biopsy consistent with X-linked ichthyosis). Radiographs and biochemical data confirmed active rickets. Her rickets improved dramatically with vitamin D treatment. Thus, 3 African children with ichthyosis developed vitamin D-deficiency rickets, probably because of a combination of impaired skin production and sunlight avoidance. This is consistent with previous findings of hypovitaminosis D in adults with ichthyosis and other disorders of keratinization. Measurement of 25-hydroxyvitamin D may be indicated in children with ichthyosis to identify those at risk for vitamin D-deficiency rickets, because it is possible that the cutaneous synthesis of vitamin D in such children is impaired. Although the ichthyosis did not improve with resolution of vitamin D deficiency and rickets, 1 of 2 children treated with topical calcipotriene showed improvement in the treated areas of skin. Calcipotriene does not seem to be effective in reversing systemic vitamin D deficiency but can be effective in improving the severity of skin disease in children with ichthyosis.     

Vitamin D metabolism in hypophosphatasia

A 4-month-old boy with the infantile form of hypophosphatasia was followed for 9 months with measurements of serum calcium, phosphate, alkaline phosphatase and various vitamin D metabolites, together with urinary excretion of cyclic AMP. During the initial hypercalcemic stage the serum concentration of 25-hydroxyvitamin D was normal. Urinary cyclic AMP was low and the serum concentration of the dihydroxymetabolites of vitamin D were appropriate to the high serum calcium with low 1,25-(OH)2D and relatively high 24,25(OH)2D and 25,26(OH)2D levels. Due to restrictions of the vitamin D intake and lack of exposure to sun he developed vitamin D-deficiency rickets at 9 months of age with very low serum concentration of 25-hydroxyvitamin D and markedly increased urinary excretion of cyclic AMP. Following vitamin D treatment the serum level of 1,25(OH)2D showed a brisk rise to a considerably elevated value. Initially the serum concentration of alkaline phosphatase was well below the normal range, rose markedly during the stage of active rickets and returned to the characteristic low levels of hypophosphatasia with healing of the rickets.     

Vitamin D dependent rickets: Decreased sensitivity to 1,25-dihydroxyvitamin D

A patient with vitamin D dependent rickets with decreased sensitivity to 1,25-Dihydroxyvitamin D was observed. She suffered from bone pain of two years duration beginning at 12 years of age and was found to be suffering from hypocalcemia, secondary hyperparathyroidism and osteomalacia. Laboratory findings revealed normal serum 25-hydroxyvitamin D (27 ng/ml) and markedly elevated serum 1,25-dihydroxyvitamin D (131.9 pg/ml). The hypocalcemia was refractory in spite of administration of 25,000 units of vitamin D₂, but therapy with high doses of oral 1-hydroxyvitamin D₃ resulted in significant elevation of the serum calcium level. The clinical findings and course of the patient's disease were quite different from those of other patients with vitamin D dependent rickets reported by other authors.     

VITAMIN D METABOLISM IN HYPOPHOSPHATASIA

ABSTRACT. A 4-month-old boy with the infantile form of hypophosphatasia was followed for 9 months with measurements of serum calcium, phosphate, alkaline phosphatase and various vitamin D metabolites, together with urinary excretion of cyclic AMP. During the initial hypercalcemic stage the serum concentration of 25-hydroxyvitamin D was normal. Urinary cyclic AMP was low and the serum concentration of the dihydroxymetabolites of vitamin D were appropriate to the high serum calcium with low 1,25(OH)₂D and relatively high 24, 25(OH)₂ and 25, 26(OH)₂D levels. Due to restrictions of the vitamin D intake and lack of exposure to sun he developed vitamin D deficiency rickets at 9 months of age with very low serum concentration of 25-hydroxyvitamin D and markedly increased urinary excretion of cyclic AMP. Following vitamin D treatment the serum level of 1,25(OH)₂D showed a brisk rise to a considerably elevated value. Initially the serum concentration of alkaline phosphatase was well below the normal range, rase markedly during the stage of active rickets and returned to the characteristic low levels of hypophosphatasia with healing of the rickets.     

Rickets in Nigerian children: response to calcium supplementation.

In a previous study of rachitic children in Jos, Nigeria we concluded that inadequate dietary intake of calcium was the primary contributing factor to the development of their rickets. The objective of the present study was to determine the effect of calcium supplementation in 10 children with radiographically and biochemically proven rickets from the same geographical area. Rachitic children were provided with calcium supplements of 1000 mg/day for a period of 3 months. Serum and urine samples were obtained at baseline and at 24 hours, 1 week, 4 weeks, and 12 weeks after initiation of supplementation. Serum calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at each time point. Dietary recalls obtained at two separate times were used to estimate usual daily intakes of calcium and phosphorus. Ten non-rachitic age-matched controls from the same geographical area were recruited for comparison. Nine of 10 rachitic subjects had radiographic evidence of healing after 3 months of calcium therapy. Although serum calcium concentrations returned to control levels, other biochemical data indicated that the rickets of these subjects may have been multifactorial in aetiology, pointing to a possible defect in the synthesis of 25-hydroxyvitamin D.     

Asymptomatic rickets in adolescent girls

Objective Inadequate sunlight exposure and calcium intake during rapid growth at puberty lead to hypocalcemia, hypovitaminosis D and eventually to overt rickets. To determine serum biochemical findings of rickets in healthy 11–15 yr old girls, the effect of sunlight exposure and oral vitamin D supplementation on serum 25-hydroxy vitamin D and calcium administration in girls with abnormal findings during December 2002 through March 2003 in Tehran, Iran. Methods Healthy middle school girls were selected for estimation of vitamin D, calcium and phosphorus intake by a three-day food recall. And measurement of serum calcium, phosphorus, parathyroid hormone, alkaline-phosphatase and 25-hydroxyvitamin D concentration. The girls with abnormal findings divided in two groups. Hypovitaminosis D girls subdivided into two groups, supplementary sunlight exposure and vitamin-D administrated for them and calcium administration for the second group for 20 days. Results Of 414 girls, the mean daily vitamin D acquirment and calcium intake were 119 ± 52 IU and 360 ± 350 mg among all girls respectively. Mean serum 25-hydroxyvitamin D with two or more abnormal biochemical findings in 15 (3.6%) girls (group I) were 7.8 ng/ml and alkaline phosphatse with normal or low calcium in 29 (7%) girls (group II) was 1187 IU/L. Mean serum calcium was 8.2 mg % in 8 of 29 girls. Serum 25-hydroxyvitamin D before and after sunlight exposure was 7.1 ± 1.9 ng/ml and 13.9 ± 2.4 ng/ml and vitamin D administration was 7.4 ± 1.8 ng/ml (group la) and 27.9 ± 4.2ng/ml (group lb) respectively. Serum alkaline phosphatase before and after calcium administration were 1187 IU/L and 666 IU/L respectively. Conclusion We conclude that low daily calcium intake, and vitamin D acquirement are two important problems in Iranian girls during rapid growth at puberty; therefore, for prevention of overt rickets calcium and vitamin D Supplementation appear to be necessary.     

Vitamin D-dependent rickets type I and type II

Two distinct hereditary defects, vitamin D-dependent rickets type I (VDDR I) and type II (VDDR II), have been recognized in vitamin D metabolism. VDDR I is suggested to be a deficiency of the renal 25-hydroxyvitamin D (25(OH)D)-1α-hydroxylase. Muscle weakness and rickets are the prominent clinical findings. A normal physiologic dose of 1α-hydroxyvitamin D₃ and 1,25-dihydroxyvitamin D₃ is sufficient to maintain remission of rickets in this disorder. VDDR II consists of a spectrum of intracellular vitamin D receptor (VDR) defects and is characterized by the early onset of severe rickets and associated alopecia. This can be attributed to mutations in the VDR gene. Massive doses of vitamin D analogs and calcium supplementation is usually required for the treatment; however, the response to therapy is sometimes variable.     

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.     

Unique form of rickets with low serum 25-hydroxyvitamin D in two normally nourished children

We present an unusual type of rickets involving two children: a 2 year old boy and a 15 month old boy, who presented with marked bowing of the lower extremities and bulging of costochondral junctions. Both children had normal growth, with their height and body weight greater than the 50th and 97th percentile for age. Roentgenograms of their extremities showed the typical changes of vitamin D refractory rickets. Serum alkaline phosphatase levels were elevated and serum levels of calcium and phosphate were both within the normal range. No primary cause for the rickets, including nutritional deficiencies, was found in the two patients. Characteristic findings were persistently low serum 25-hydroxyvitamin D (25-OH-D) and normal 1,25-dihydroxyvitamin D (1,25-(OH)2-D). Improvements in clinical and X-ray findings were observed after either oral administration of 1 α-(OH)-D3 (9–15 μg per day) or massive vitamin D2 therapy (600 000 IU single injection). The low serum levels of 25-OH-D did not increase unless massive vitamin D2 therapy was also given. These two cases represent a unique form of rickets that does not meet the criteria for any type of previously known rickets.     

Case-control study of factors associated with nutritional rickets in Nigerian children

OBJECTIVE: Because the causes of nutritional rickets in tropical countries are poorly understood, we conducted a case-control study to determine factors associated with rickets in Nigerian children. STUDY DESIGN: We compared 123 Nigerian children who had rickets with matched control subjects. Dietary, demographic, anthropometric, and biochemical data were collected to assess factors related to calcium and vitamin D status, which might predispose children to rickets. RESULTS: Mean (+/- SD) daily dietary calcium intake was low in both children with rickets and control children (217 +/- 88 mg and 214 +/- 77 mg, respectively; P =.64). Children with rickets had a greater proportion of first-degree relatives with a history of rickets (14.6% vs 3.1%; P <.001), a shorter mean duration of breast-feeding (16.0 vs 17.3 months; P =.041), and a delayed age of walking (14 vs 12 months; P <.001). Among children with rickets, biochemical features suggestive of calcium deficiency included hypocalcemia, extremely low calcium excretion, and elevated 1, 25-dihydroxyvitamin D and parathyroid hormone values. Median 25-hydroxyvitamin D concentrations were 32 and 50 nmol/L (13 and 20 ng/mL) in children with rickets and control children, respectively (P <.0001). Only 46 subjects with rickets (37%) had 25-hydroxyvitamin D values <30 nmol/L (12 ng/mL). CONCLUSIONS: Vitamin D deficiency appears unlikely to be the primary etiologic factor of rickets in African children. Moreover, low dietary calcium intake alone does not account for rickets. Insufficient dietary calcium probably interacts with genetic, hormonal, and other nutritional factors to cause rickets in susceptible children.     

Treatment of malabsorption vitamin D deficiency myopathy with intramuscular vitamin D

A nearly 5 year-old boy presented with proximal muscle weakness, reduced muscle bulk, a positive Gower sign and Trendelenburg gait. He was known to have cholestatic liver disease. Investigations revealed markedly low serum total calcium, elevated alkaline phosphatase, very low serum 25-hydroxyvitamin D, and radiographs consistent with active rickets despite the ongoing administration of a water-soluble preparation of vitamin D. Only i.v. calcitriol acutely corrected the hypocalcemia, despite trying several oral preparations, suggesting that malabsorption secondary to chronic liver disease was the cause of his rickets. Intramuscular calciferol quickly corrected his muscle weakness and X-ray findings. Myopathy secondary to vitamin D deficiency is an uncommon diagnosis in children. Intermittent calciferol is an inexpensive and practical treatment for vitamin D deficiency, especially if associated with malabsorption.     

Early response to vitamin D2 in children with calcium deficiency rickets

OBJECTIVE: To assess the effect of vitamin D(2) administration on serum vitamin D metabolite concentrations in calcium deficiency rickets. STUDY DESIGN: We administered vitamin D(2), 50,000 IU orally to 16 Nigerian children 15 to 48 months of age with radiographically active rickets. We measured calcium and vitamin D metabolites at baseline and at 1, 3, 7, and 14 days. RESULTS: At baseline, ranges of serum 25-hydroxyvitamin D (25(OH)D) concentrations were 18 to 40 nmol/L (7-16 ng/mL), and 1,25-dihydroxyvitamin D (1,25-(OH)(2)D) concentrations were 290 to 790 pmol/L (120-330 pg/mL). After vitamin D administration, serum 25(OH)D and 1,25(OH)(2)D concentrations rapidly rose and peaked at 2.8 and 1.9 times the baseline values (P < .001), respectively, at 3 days. Positive correlations between 1,25(OH)(2)D and 25(OH)D were strongest at day 3 (r = 0.84, P < .001) and weakest at day 14 (r = 0.41, P = .11). The relationship of 1,25(OH)(2)D with 25(OH)D at baseline and the increase in 1,25(OH)(2)D in response to vitamin D were similar to those described in children with vitamin D deficiency. However, unlike the pattern in vitamin D deficiency, 1,25(OH)(2)D remained positively correlated with 25(OH)D after administration of vitamin D. CONCLUSION: Dietary calcium deficiency increases the demand for 25(OH)D above that required in vitamin D deficiency to optimize 1,25(OH)(2)D concentrations. Assessment of vitamin D sufficiency in persons or communities may need to be adjusted for habitual dietary calcium intake.     

Comparison of low and high dose of vitamin D treatment in nutritional vitamin D deficiency rickets

In this study, we compared three different therapy modes (150,000 IU, 300,000 IU, and 600,000 IU vitamin D p.o.) in infants with nutritional vitamin D deficiency rickets (VDR). Our purpose was to determine the most effective dosage of vitamin D with least side effects for treating VDR. The study included 56 patients, 3-36 months of age, with nutritional VDR and 20 age-matched control infants. In all infants, serum calcium, phosphorus, alkaline phosphatase, magnesium, serum 25-hydroxycholecalciferol, plasma intact parathormone levels and urinary Ca/creatine ratio were determined. Of 56 patients, 52 were able to be followed long-term. These patients were reexamined on the 3rd day, 7-10th day, and 25-30th day after treatment. On the 30th day post-treatment, we did not find any difference between the doses in the improvement of rickets. However, hypercalcemia was present in eight infants who had been administered 300,000 IU (two infants) and 600,000 IU (six infants) of vitamin D. In conclusion, our findings showed that 150,000 IU or 300,000 IU of vitamin D was adequate in the treatment of VDR, but 600,000 IU of vitamin D may carry the risk of hypercalcemia.     

Serum concentrations of 25 hydroxyvitamin D in hospitalized infants. Relation to calciuria

In attempt to evaluate the vitamin D status of the infants of our area under the mode of prophylaxis of carential rickets actually used in France, serum 25 hydroxyvitamin D (25 OHD) levels were measured in 65 infants (age 3 - 32 months) during their hospitalisation for acute illness. Most infants were receiving vitamin D either in daily doses (1,200 - 1,600 u) or in unique loading doses (200,000 - 600,000 u every 4 - 6 months). With this prophylaxis serum concentrations of 25 OHD were elevated, i.e. above 75 nmol/l, in more than 50% of the infants, reaching 474 nmol/l in one case. Calciuria estimated by the calcium/creatinine urinary ratio tended to increase in parallel with the serum 25 OHD level. From these data it is concluded that the actual prophylaxis of carential rickets in France frequently uses excessive doses of vitamin D and that new rules have to be established.     

血清25-羟维生素D在佝偻病诊断中的应用价值

目的：探讨血清25 羟维生素D［25（OH）D］在维生素D缺乏性佝偻病早期诊断中的意义。方法：检测对照组（73例）、可疑组（45例）和佝偻病组（65例）的血清25（OH）D、钙、磷、碱性磷酸酶浓度,并通过ROC曲线对血清25（OH）D的诊断价值进行评价。结果：对照组、可疑组和佝偻病组的血清25（OH）D水平分别为112±37、83±30和72±31 nmol/L,后两者均显著低于对照组（F=26.174,P0.05）。可疑组和佝偻病组的维生素D缺乏率均显著高于对照组（χ2=33.346, P0.05）。结论：血清25(OH)D水平在可疑及确诊佝偻病的患儿中显著降低,可以反映维生素D的营养状况,适用于佝偻病的早期筛查。