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The radiological diagnosis of rickets is mainly based on the widened appearance of actively developing epiphyseal growth plates. In the adolescent with rickets the secondary iliac and ischial ossification centres may be abnormally wide when most other epiphyses have fused. The appearance of the iliac crest is of use both in helping to make the diagnosis and in monitoring the results of treatment.
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.
We describe a 15-year-old boy with hemangiomatosis of bone and hypophosphatemic rickets. The rickets was ameliorated by irradiation of the skeletal lesions.
In children with extrahepatic biliary atresia, impaired hydroxylation and defective intestinal absorption of cholecalciferol may lead to a deficiency of vitamin D and rickets. The data presented herein demonstrate that in such patients serum levels of vitamin D measured as 25-hydroxycalciferol are reduced. A moderate therapeutic oral dose of 25-hydroxycholecalciferol, by circumventing the hepatic conversion of cholecalciferol to 25-hydroxycholecalciferol, will replete vitamin D stores and maintain the serum concentration of 25-hydroxycalciferol required to prevent or heal rickets in these patients.
Elevated 1,25 dihydroxyvitamin D concentrations were found in five VLBW infants who developed rickets at two to three months postnatal age or term postconceptual age; 25 hydroxyvitamin D concentrations were low. Bone mineralization was found to be extremely low as measured by infant-adapted direct photon absorptiometry. After treatment with a formula supplemented with additional Ca and P, there was a rapid improvement in bone mineralization with a concomitant decrease of 1,25(OH)2D to normal adult values, whereas 250HD values increased and parathyroid hormone values decreased. In the VLBW infants studied, we suggest that rickets may be caused by Ca and P deficiency rather than by a deficiency of vitamin D metabolism.
The incidence of rickets was found to be 32% (39/125) in a retrospective review of consecutive survivors of very low birth weight in whom serial radiographic and biochemical data were obtained. A higher proportion of these infants were black, had a greater initial weight loss, and had a longer hospitalization; there was a prevalence of births in the spring. Soy formula, supplemented with calcium and vitamin D but not phosphorus, was used predominantly in both groups; cumulative calcium, phosphorus, vitamin D, and caloric intakes were the same. We believe that the etiology of rickets in VLBW infants is multifactorial; however, nutritional deficiency is of central importance. Soy isolate formula, as well as human milk and many other commercially available formulas, do not provide sufficient calcium and phosphorus to keep pace with rates of intrauterine accretion. Supplementation with calcium, phosphorus, and vitamin D, beginning as soon as possible after birth, is indicated.
Renal ultrasonography was performed on 23 patients with X-linked hypophosphatemic rickets (XLH) and 11 patients with autosomal recessive vitamin D-dependent rickets (ARVDD). A pattern of increased echogenicity of the renal pyramids (ERP) was identified in 11/23 patients with XLH and 3/11 patients with ARVDD; this ultrasonographic finding has previously been associated with medullary nephrocalcinosis. Patients with XLH and ERP had significantly higher mean serum calcium and phosphate concentrations, more frequent episodes of hypercalcemia, and higher doses of oral vitamin D and phosphate during the first 3 years of therapy. Episodes of hypercalcemia were more frequent when patients received higher doses of vitamin D2 (greater than 4000 IU/kg/day) or 1,25-dihydroxycholecalciferol (greater than 40 ng/kg/day). Episodes of hypercalciuria were significantly increased at doses of greater than 20 ng/kg/day 1,25-dihydroxycholecalciferol. In patients with ARVDD, ERP was also correlated with vitamin D dose and frequency of hypercalcemia episodes. ERP was not associated with an elevation of serum creatinine or loss of urinary concentrating ability in either patient group.
OBJECTIVE: To improve understanding of the biochemical events in vitamin D-deficiency rickets (VDR). METHODS: We investigated 51 untreated patients, 2 to 36 months of age, during three stages of VDR. Nineteen of these patients were also studied during therapy with 5000 to 10,000 U vitamin D3 (cholecalciferol) and 0.5 to 1 gm calcium. Together with calcium and inorganic phosphate in serum and urine, we measured (1) parathyroid hormone (PTH) secretion (intact serum PTH) and action on the kidney (urinary adenosine 3',5'-cyclic monophosphate (cAMP)/creatinine ratio; (2) serum alkaline phosphatase level; (3) urinary hydroxyproline/creatinine ratio; and (4) serum 1,25-dihydroxyvitamin D (1,25(OH)2D) level. RESULTS: The untreated patients had secondary hyperparathyroidism (high serum PTH and urinary cAMP/creatinine ratio), low calcium and phosphate concentrations in serum, and increased bone turnover (elevated serum alkaline phosphatase and OHP/creatinine ratio), whereas serum 1,25(OH)2D was low, normal, or even slightly elevated. Serum calcium level was positively correlated to serum 1,25(OH)2D and to OHP/creatinine ratio, indicating that normocalcemia in untreated rickets (stage 2) is at least partially maintained by 1,25(OH)2D-induced calcium mobilization from bone. There was no correlation between serum calcium and serum PTH, or between serum PTH and urinary cAMP/creatinine ratio or serum phosphate, indicating disturbed regulation and action of PTH. During vitamin D treatment, serum 1,25(OH)2D values increased to supranormal concentrations in association with the restoration of the physiologic relationship of PTH to serum calcium and phosphate concentrations and urinary cAMP/creatinine ratio. CONCLUSION: Circulating 1,25(OH)2D has an important role in the pathophysiology of VDR before and during treatment, mainly by influencing the bone and kidney response to endogenous PTH.
To study the 'in vivo' importance of vitamin D on the natural killer (NK) activity, rats were submitted to privational rickets induced by a diet deficient in vitamin D and phosphorus (D-P-). Thirty days after the beginning of treatment the animals showed low body weight, changes in the bone development, and decreased levels of 25-hydroxyvitamin D(3) (25-OH D(3)). NK activity, evaluated using a cytotoxicity assay against 51Cr-labeled Yac.1 target cells, was not modified by the rickets-inducing treatment during the first 30 days. Following a long-term treatment (60 days) the rachitic rats (D-P-) exhibited higher NK activity than control animals (D+P+) (P<0.05). On the other hand, D-P+ animals showed higher cytotoxic activity than D-P- and D+P+ groups. Feed replacement to the rachitic rats by a complete diet (D-P-/D+P+) led to a partial recuperation of growth, bone development, and 25-OH D(3) serum levels. The NK activity was also influenced by vitamin D intake, decreasing after treatment.
A 17-month-old black girl presented to the pediatric emergency department with sudden onset of her hands and feet "drawing up." A diagnosis of vitamin D deficiency rickets with tetany was made on a history of exclusive breast-feeding, low serum calcium, phosphorus, and 25-hydroxyvitamin D levels, and bone radiographs. Nutritional rickets should be considered in the differential diagnosis of acute hypocalcemia.
Vitamin D is deeply involved in a wide variety of biological events such as calcium homeostasis, bone formation and cellular differentiation. An active form of vitamin D, 1alpha,25(OH)2D3, serves as a vitamin D receptor (VDR)-specific ligand to activate the expression of a particular set of target genes. 1Alpha,25(OH)2D3, is biosynthesized from cholesterol, and at the final biosynthesis step, 25-hydroxyvitamin D3 1alpha-hydroxylase [1alpha(OH)ase] in kidney conducts 1alpha-hydroxylation of 25(OH)2D3. This enzymatic activity is under multihormonal regulation and critical for the biosynthesis. Molecular cloning of 1alpha(OH)ase from several species has revealed that this enzyme belongs to a member of the cytochrome P450 enzyme superfamily, with highest homologies to the P450 hydroxylases for vitamin D derivatives. The renal gene expression is strictly regulated at the transcriptional level through its gene promoter by PTH and calcitonine (positive) and 1alpha,25(OH)2D3 (negative). Most importantly in clinical aspects, genetic mutations in this gene to abolish the enzymatic activity are now shown to cause the one of three kinds of hereditary rickets, vitamin D-dependent rickets type I.
The piglets examined suffer from rickets and have symptoms similar to those of classic pseudo vitamin D-deficiency rickets, type I (PVDRI), including plasma concentrations of 1 alpha, 25-dihydroxyvitamin D3 considerably lower than in healthy control piglets. It has been suggested that the rachitic piglets have a defective renal 1 alpha,25-dihydroxyvitamin D3 production. The present study shows that partially purified mitochondrial and microsomal cytochrome P450 from kidney and liver of both rachitic and control animals is able to catalyze 1 alpha-hydroxylation of 25-hydroxyvitamin D3. The renal mitochondrial 1 alpha-hydroxylase activity was higher in the rachitic piglets whereas the renal microsomal 1 alpha-hydroxylase activity was decreased. The immunodetectable levels in kidney of a mitochondrial 1 alpha-hydroxylase (CYP27) and a microsomal 1 alpha-hydroxylase (vitamin D3 25-hydroxylase) were correlated with the 1 alpha-hydroxylase activities. The results suggest that the renal microsomal 1 alpha-hydroxylase is affected by the rachitic condition. It is concluded that the primary genetic defect of systemic 1 alpha,25-dihydroxyvitamin D3 deficiency in the rachitic PVDRI piglets does not reside in a defective function or absence of renal mitochondrial 25-hydroxyvitamin D3 1 alpha-hydroxylase. From this, it may also be concluded that PVDRI in man and pig appear to be two different forms of the disease.
BACKGROUND: Cow's milk allergy is one of the most common allergies in infancy. It has an excellent prognosis since most cases resolve by 4 years of age. The complications associated with milk allergy include delayed growth and atopic conditions, such as asthma, allergic rhinitis, atopic dermatitis, and other food allergies. OBJECTIVE: To report a case of vitamin D deficiency rickets in a 2-year-old boy with cow's milk allergy. METHODS: We describe a patient with clinical and biochemical evidence of rickets, including decreased serum calcium, phosphate, and 25-hydroxy vitamin D levels and an elevated alkaline phosphatase level. A dietary history revealed the prolonged absence of dietary vitamin D because the child did not tolerate cow's milk. Skin prick testing and measurement of specific IgE to cow's milk were performed to determine whether there was an allergy to cow's milk. RESULTS: Results of skin prick testing and measurement of specific IgE to cow's milk confirmed an IgE-mediated sensitivity to cow's milk. Introduction of appropriate supplementation into the child's diet resulted in complete resolution of his symptoms. CONCLUSIONS: This case emphasizes that the management of cow's milk allergy involves strict avoidance of the allergenic food while also ensuring that essential dietary requirements are met. A dietary history is crucial at all pediatric visits, and inquiry about supplementation of vitamins and minerals is important, especially in children with food allergies.
[formula: see text] Vitamin D3-resistant rickets (VDRR) is associated with mutations to the Vitamin D receptor (VDR) which effect ligand-dependent transactivation. Some VDRR associated mutants directly disrupt ligand binding. Using the reported VDR-1,25-dihydroxy vitamin D3 (1,25(OH)2D3) cocrystal structure, three 1,25(OH)2D3 analogues were designed to uniquely complement the rickets associated mutant VDR(Arg274-->Leu). The three analogues were 17 to 286 times more potent than 1,25(OH)2D3 with the mutant in cell-based assays and did not substantially activate cellular calcium influx.
Bone accretion is a two-stage process, with the osteoblasts laying down osteoid, which is then mineralized. Mineralization of osteoid requires vitamin D to be available in its active form (1,25(OH) 2 D); in addition, mineralization also requires normal levels of serum calcium, phosphorus, and alkaline phosphate. Deficiencies of any of these will result in defective mineralization of bone, in which the mineral-osteoid ratio is reduced (a qualitative abnormality). In the juvenile skeleton deficiencies particularly affect enchondral ossification at the growth plates, giving the characteristic clinical and radiological features of rickets. The bone may be soft, leading to deformity. In this article the causes of rickets in childhood are reviewed, together with the clinical and radiological features and strategies for prevention and treatment.
We studied a new hereditary syndrome of hypophosphatemic rickets and hypercalciuria in six affected members of one kindred. In all patients, the manifestations of disease began in early childhood. The characteristic features are rickets, short stature, increased renal phosphate clearance (the ratio between the maximal tubular reabsorption rate for phosphorus and the glomerular filtration rate [TmP/GFR] is 2 to 4 S.D. below the age-related mean), hypercalciuria (8.6 mg of urinary calcium per kilogram of body weight per 24 hours vs. the upper normal value of 4.0), normal serum calcium levels, increased gastrointestinal absorption of calcium and phosphorus, an elevated serum concentration of 1,25-dihydroxyvitamin D (390 +/- 99 pg per milliliter vs. the upper normal value of 110), and suppressed parathyroid function (an immunoreactive parathyroid hormone level of 0.33 +/- 0.1 ng per milliliter and a cyclic AMP level of 1.39 +/- 0.12 nmol per deciliter of glomerular filtrate vs. the lower normal values of 0.3 and 1.5, respectively). Long-term phosphate supplementation as the sole therapy resulted in reversal of all clinical and biochemical abnormalities except the decreased TmP/GFR. We propose that the pivotal defect in this syndrome is a renal phosphate leak resulting in hypophosphatemia with an appropriate elevation of 1,25-dihydroxyvitamin D levels, which causes increased calcium absorption, parathyroid suppression, and hypercalciuria. This syndrome may represent one end of a spectrum of hereditary absorptive hypercalciuria. Our observations support the importance of phosphate as a mediator in controlling 1,25-dihydroxyvitamin D production in human beings.
Missense mutations in fibroblast growth factor 23 (FGF23) are the cause of autosomal dominant hypophosphatemic rickets (ADHR). The mutations (R176Q, R179W, and R179Q) replace Arg residues within a subtilisin-like proprotein convertase (SPC) cleavage site (RXXR motif), leading to protease resistance of FGF23. The goals of this study were to examine in vivo the biological potency of the R176Q mutant FGF23 form and to characterize alterations in homeostatic mechanisms that give rise to the phenotypic presentation of this disorder. For this, wild type and R176Q mutant FGF23 were overexpressed in the intact animals using a tumor-bearing nude mouse system. At comparable circulating levels, the mutant form was more potent in inducing hypophosphatemia, in decreasing circulating concentrations of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), and in causing rickets and osteomalacia in these animals compared with wild type FGF23. Parameters of calcium homeostasis were also altered, leading to secondary hyperparathyroidism and parathyroid gland hyperplasia. However, the raised circulating levels of parathyroid hormone were ineffective in normalizing the reduced 1,25(OH)(2)D(3) levels by increasing renal expression of 25(OH)D(3)-1alpha-hydroxylase (Cyp40) to promote its synthesis and by decreasing that of 25(OH)D(3)-24-hydroxylase (Cyp24) to prevent its catabolism. The findings provide direct in vivo evidence that missense mutations from ADHR kindreds are gain-of-function mutations that retain and increase the protein's biological potency. Moreover, for the first time, they define a potential role for FGF23 in dissociating parathyroid hormone actions on mineral fluxes and on vitamin D metabolism at the level of the kidney.
1. Review of the evidence of the Irish Nutrition Survey concerning a market rise in the incidence of rickets in Dublin in 1942 concludes that a rise in the extraction rate of the national flour from 70 to 100% was principally responsible. 2. This rise and subsequent decrease in incidence as the extraction rate of flour was reduced is not explained by changes in the proportion of children protected by vitamin D supplements or by small changes in dietary vitamin D intake. 3. The evidence suggests that nutritional rickets in man cannot be explained on the basis of deficient vitamin D intake alone, whether derived from diet or u.v. radiation.