December 1975

1144

TheJournalofPEDIATRICS

Rickets then and now

Since the introduction of irradiated ergosterol into our food supply, nutritional vitamin D deficiency rickets has become an uncommon disease. However, skeletal disorders due to abnormalities o f vitamin D function still occur. These disorders can now be classified more exactly into two groups: those in which there is a deficiency o f the active metaboBte o f vitamin D, 1,25-dihydroxyvitamin D, and those in which there is an abnormality of renal tubular function resulting in renal hypophosphatemia despite normal vitamin D metabolism. The various entities o f these two groups are described and the theoretical basis o f their treatment given.

Harold E. Harrison, M.D., and Helen C. Harrison, Ph.D., Baltimore, Md.

WHEN HORACE HODES entered the discipline of pediatrics, rickets was still one of the major interests of his teachers; it was also one of the diseases which was in the process of being conquered by the combined investigative talents of biologists, biochemists, organic chemists, physicians, and epidemiologists. Despite the transformation of this problem from one of the most common disorders of childhood to a relatively rare disease, some investigators have continued to be fascinated by the physiology of vitamin D as an example of a biologic problem which continues to develop in complexity and interest even though the original mission of prevention and cure of rickets has been apparently accomplished. The original focus of attention was the interrelation of an antirachitic factor in cod liver oil and in the radiant energy of sunshine or artificial ultraviolet light. This was solved by the discovery of a provitamin D activated by the energy of shortwave ultraviolet light. The first "activated" sterol, vitamin D2, produced by the irradiation of ergosterol is still the basis of the effective prevention of rickets by its addition to milk or other infant feeding preparations. Continued investigation has shown, however, that the "activated" sterols produced by irradiation of ergosterol or 7-dehydrocholesterol are not in fact the active physiologic principles, but are converted to the active factor by a somewhat complex metabolic cycle. Our current concept of the vitamin D cycle is shown in Fig. 1. The product of ultraviolet activation of provitamin From the Baltimore City Hospitals and Johns Hopkins University School o f Medicine.

VoL 87, No. 6, part 2, pp. 1144-1151

D, whether it is 7-dehydrocholesterol produced in the intestinal mucosa and transported to the skin or ergosterol produced in the laboratory, must be acted upon by a liver microsomal system to form 25-hydroxyvitamin D. This compound is then the substrate of a kidney mitochondrial system which adds a hydroxyl group at the 1 carbon position in the A ring to form 1,25-dihydroxyvitamin D; this is the active physiologic agent operating on intestinal mucosal transport of calcium and phosphate, on renal tubular transport of phosphate, and, in cooperation with parathyroid hormone, on bone cell metabolism leading to solubilization of bone mineral and release of calcium and phosphate into the extracellular fluid. The physiologic justification for such a cycle is that it permits regulation of rates at a number of steps controlling the concentration of the final active product, 1,25-di OH vitamin D, and thus the role of this compound in calcium homeostasis. 25-Hydroxylation in the liver cell is controlled to some extent by product concentration and 1-hydroxylation in the kidney by parathyroid hormone, either directly or through tissue phosphate or calcium concentration? ~ Stimulation of 1-hydroxylation by parathyroid hormone permits adaptation to a low-calcium diet by increase of parathyroid hormone output; this results in increase of the concentration of 1,25-di OH vitamin D in plasma at constant intake of vitamin D or constant exposure of skin to sunshine. Control at two stages of the rate of formation of the active vitamin D hormone, 1,25-di OH vitamin D, presumably prevents vitamin D toxicity in individuals heavily exposed to sunshine, and still permits adequate vitamin D activity with relatively limited skin

Volume 87 Number 6, part 2

exposure to the ultraviolet energy spectrum of sunlight. Another control mechanism not shown in this cycle is skin pigmentation which absorbs the energy of ultraviolet light before it reaches the 7-dehydrocholesterol in the deeper layers of the skin. This is presumably the cause of the increased susceptibility of dark-skinned individuals to vitamin D deficiency when diet sources are limited and exposure to sunshine must be relied upon. This is also postulated to be the basis of the evolution of light-skinned people in the northern latitudes of Europe. The control mechanisms fail, unfortunately, when a large excess of vitamin D is taken orally. This may be due to physiologic activity in high concentration of the unmetabolized vitamin D or of 25-OH vitamin D, or both, so that the negative feedback through serum Ca ++ concentration and parathyroid hormone output for regulation of the concentration of 1,25-di OH vitamin D is not the controlling factor. On the basis of our current knowledge the various forms of rickets which we encounter can be divided into two main groups: (1) those in which there is some interference in the metabolic cycle of vitamin D leading to a diminished concentration of the active compound, 1,25di OH vitamin D, and (2) those due to an abnormality of the target cells responsible f o r calcium and phosphate homeostasis so that normal concentrations of these ions cannot be maintained. The only target cell abnormalities thus far demonstrated are of the renal tubule cell mechanism for retrieval of phosphate from glomerular filtrate. This defect of tubular reabsorption results in renal hypophosphatemia. In the first group lack of the active vitamin D compound causes impaired calcium absorption from the intestine, hypocalcemia, and attempted compensation by secondary hyperparathyroidism which, however, may not be adequate to correct the hypocalcemia2 In the second group hypocalcemia and secondary hyperparathyroidism are not present and the rickets is predominantly a phosphate deficiency phenomenon. The various clinical entities of these two groups are listed in Table I. RICKETS DUE TO DEFICIENCY OF ACTIVE VITAMIN D METABOLITE If we examine the first group in which there are blocks or abnormal diversions of the metabolic cycle of vitamin D, the first is, of course, the lack of ultraviolet exposure of the skin of infants. Since neither human nor unfortified cow's milk contains adequate amounts of vitamin D to provide for the infant's requirements, this was the basis for the widespread occurrence of infantile rickets in the industrial cities of northern Europe and the United States prior to the discovery of vitamin D. This block was overcome by the irradiation of ergosterol in the laboratory

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Table I. Classification of various forms of rickets and osteomalacia Deficiency of active vitamin D metabolite

Vitamin D deficiency Absence of sunshine Dietary lack Vitamin D malabsorption Liver disease Anticonvutsant drugs Renal disease Vitamin D dependency (1-OHase abnormality)

Target cell abnormality

Fanconi syndrome Cystinosis Tyrosinosis Other causes Renal tubular acidosis Genetic primary hypophosphatemia Hypophosphatemia with "nonendocrine tumors"

and its addition to the diets of infants and children, particularly in the form of vitamin D enriched cow's milk. There are currently waves of food faddism among which is strict vegetarianism that prohibits all food of animal origin except human milk. Infants and children so fed may develop vitamin D deficiency and some cases of rickets under these circumstances have been seen. Except for this small group of infants at risk, however, nutritional vitamin D-deficiency rickets has been essentially eliminated by the fortification of cow's milk and the special infant feeding preparations with irradiated ergosterol. Malabsorption of vitamin D provided in this form can occur, however, in steatorrhea, and rickets may result unless large doses of vitamin D are given. A more common block, however, occurs at the 25-hydroxylation stage in the liver. Hepatocellular injury resulting from "neonatal hepatitis" may apparently be sufficient to reduce the efficiency of this reaction as indicated by the occurrence of hypocalcemia and rickets in such patients.' The common occurrence of vitamin D deficiency in infants with biliary atresia may be the result both of malabsorption of vitamin D due to lack of bile salts in the intestinal lumen as well as a deficiency of 25-hydroxylation secondary to destruction of liver parenchyma associated with bile duct obstruction. A reduced availability of the liver metabolite, 25-OH vitamin D, may also be responsible for the occasional case of rickets in children receiving chronic anticonvulsant treatment, particularly those treated with combined diphenylhydantoin and phenobarbital or primidone? The deficiency of the liver metabolite in this instance is thought to be due to an increased rate of liver microsomal metabolism of 25-hydroxyvitamin D to more polar inactive metabolites/; thus diverting the 25-OH vitamin D from the main cycle to a side track through which inactive metabolites are excreted in the bile. The net result would be a deficiency of the final active metabolite 1,25 di-OH

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Harrison and Harrison

The Journal of Pediatrics December 1975

VITAMIND CYCLE Cholesterol Intestinal ~ 7-dehydrocholesterol-,

Mueosa\

U- V radiation

Skin

transport %

Increased of calcium and BonePh~

I

25-OHation Liver

\

1-OHation

Iff-" ~ 1

Solubilization of bone mineralcooperative action with PTH ~

~ Cholecalciferol

1~,Z5-diOHCC ~ [ j ~

Kidney

25-OHCC Polar inactive metabolites

Renal Tubule Increased TRP Fig. 1. Cycle of metabolism of vitamin D leading to formation of active physiologicprinciple: 1,25-Dihydroxyvitamin D. vitamin D. Although the increased risk of hypocalcemia, hypophosphatemia, rickets, and osteomaiacia in patients receiving anticonvulsant drugs is real, only an occasional case is found among the many thousands of children and adults receiving anticonvulsant therapy. This is probably explained by the fact that vitamin D intake in diet and that produced by exposure to sunshine is ordinarily sufficiently greater than the minimal requirement; the diversion of part of the 25-OH vitamin D formed out of the main metabolic cycle is not sufficient to reduce the final concentration of 1,25-di OH vitamin D to deficiency levels. It has been estimated that the extra cholecalciferol requirement of children receiving anticonvulsants is of the order of an additional 3,000 units of vitamin D per week. 7 Children with severe motor difficulties either in institutions or at home who ,nay get very little exposure to sunshine are particularly dependent on increased oral intake of vitamin D and most of the cases of rickets related to anticonvulsant therapy have been found in such children. One of the most interesting varieties of rickets which occurs despite ordinarily adequate intake of vitamin D and exposure to sunshine is variously termed pseudovitamin D-deficiency rickets, vitamin D-dependent rickets, or simply increased requirement for vitamin D. This may be a heterogenous group of entities. There is a genetically determined variety which is transmitted as an autosomal recessive and which manifests itself in the first years of life? There are ~ilso sporadic cases in which obvious bone disease develops slowly and may not be recognized until late in the first decade of life or even early adult life. These patients show the biochemical manifestations of vitamin D deficiency, ie, hypocalcemia, hypophosphatemia, increased alkaline phosphatase activity, and generalized aminoaciduria. The last is presumably contributed

to by secondary hyperparathyroidismY The roentgenographic findings in early life are those of rickets; in the more chronic case appearing in later childhood or adolescence the bony lesions of hyperparathyroidism may predominate. The biochemical and roentgenographic adnormalities are restored to normal by large doses of vitamin D but recur if vitamin D intake is reduced to usual amounts. For this reason the term vitamin D-dependent rickets has been suggested, but this seems inexact since vitamin D-deficiency rickets is also vitamin D dependent. Increased requirement for vitamin D best describes the situation. When the first metabolite of vitamin D, 25-OH cholecalciferol, was discovered, a possible explanation for "increased requirement for vitamin D" was quickly put forth, namely, that there was an inborn error of metabolism with a block in the metabolism of vitamin D in the liver. Unfortunately, administration of25-OH cholecalciferol to several such patients did not support this hypothesis, since physiologic amounts of this compound did not effect a return to normal. More recently it has been proposed that the deficiency is at a subsequent step, 1hydroxylation in the kidney: an abnormality of the enzyme system requires a much higher Concentration of 25-OH vitamin D to obtain a physiologic concentration of 1,25-di OH vitamin D than in the normal subject? ~ Whether this be true of all varieties of increased requirement for vitamin D remains to be seen. We have studied a patient with the sporadic form with onset in later childhood with severe skeletal changes of secondary hyperparathyroidism (Fig. 2); this child showed healing when treated with 25-OH vitamin D but only at doses of 40 ~gm/day, at least four- to fivefold the physiologic requirement. This would be compatible with the concept that the active vitamin D metabolite is produced only at concen-

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Rickets then and now

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Fig.'2. Roentgenographic findings in boy age 15 with increased requirement for vitamin D and skeletal changes of secondary hyperparathyroidism due to lack of active vitamin D hormone despite ordinary vitamin D dosage. A, Pretreatment. B, Following treatment with 25-hydroxyvitamin D. trations of the substrate, 25-OH vitamin D, considerably higher than normal. The most common block in the availability of the active metabolite, 1,25-di OH vitamin D, results from inadequate functioning renal tissue, since 1-hydroxylation of 25-OH vitamin probably occurs only in the kidney. The lack of the active vitamin D metabolite, owing to kidney insufficiency, causes malabsorption of calcium; this is one of the factors responsible for the parathyroid hyperplasia and marked increase of circulating parathyroid hormone characteristic of severe kidney disease. The other important factor is the increased concentration of phosphate in extracellular fluid, which results from the great reduction of glomerular filtration rate and is not overcome by the increased parathyroid hormone output. The bone disease of renal insufficiency is histologically and roentgenographically predominantly that of hyperparathyroidism. The skeletal disorder of vitamin D-deficiency states on the other hand is rickets and osteomalacia, ie, failure of mineralization of bone and cartilage matrix osteoid because of the hypophosphatemia. Although these patieffts also have secondary hyperparathyroidism, the increased parathyroid hormone is relatively ineffective on bone cell metabolism in the vitamin D deficient state; thus the hypophosphatemia is the dominant factor. The skeletal lesions of secondary hyperparathyroidism can

appear within the first two years of life in infants with congenital hypoplasia of the kidneys or obstructive uropathy with hydronephrosis. Fig. 3 shows the roentgenographic findings in one such patient. These lesions are reversible, even in the face of continued renal insufficiency, by suitable therapy for the secondary hyperparathyroidism as shown in Fig. 4. With our current understanding of the problem, this lesion should be prevented by early therapy directed at reduction of serum phosphate concentration by sequestration of phosphate in the gut, and administration of a substitute for 1,25-di OH vitamin D to maintain calcium absorption. At the present time dihydrotachysterol can be used as such a substitute but synthetic 1-ahydroxyvitamin D may be available in the future as a more potent steroid for this purpose. Dihydrotachysterol is a stable derivative of tachysterol which like ergocalciferol, vitamin D2, is a product of the ultraviolet irradiation of ergosterol. Tachysterol differs from vitamin D in the geometric orientation of the A ring. The A ring of tachysterol is a mirror inaage of that of vitamin D so that the OH group on the 3 carbon of tachysteroI is in the 1 carbon position of vitamin D. Thus tachysterol has some of the properties of a 1-hydroxylated vitamin D and is not dependent upon kidney metabolism for its activity. '~ Dihydrotachysterol is, therefore, more potent than vitamin D in patients with severe renal insufficiency, and

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The Journal of Pediatrics December 1975

Fig, 3. Roentgenographic changes of secondary hyperparathyroidism in child with renal hypoplasia. Age, 18 months; before treatment. its action is more consistent and controllable. As mentioned above, synthetic 1-aOH cholecalciferol should eventually be available, and it already has been shown to be potent at low dosage in increasing intestinal absorption of calcium in subjects with renal disease. 1~ RICKETS DUE TO TARGET ABNORMALITY

CELL

As stated in the introduction the only target cell abnormality which causes rickets is that of the renal tubule. In this instance the rickets arises from the hypophosphatemia resulting from deficiency of net tubular reabsorption of phosphate. The inorganic phosphate concentrations in extracellular fluid are maintained in a normal range by a balance between glomerular filtration

Fig. 4. Complete healing of secondary hyperparathyroidism following treatment with calcium lactate and dihydrotachysterol in doses which maintained normal concentrations of Ca and P in serum. rate and tubular reabsorption of phosphate. This normal range differs with age and is much higher in the infant and growing child than in the adult, because of a higher rate of tubular reabsorption of phosphate in the former group in relation to the volume of glomerular filtrate formed. There are a variety of disorders of tubular function, genetic and acquired, in which there is a deficiency of net retrieval of phosphate by the tubule with consequent hypophosphatemia of renal origin. The Fanconi syndrome describes the manifestations of disturbed function of the proximal tubule: renal glycosu-

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ria, renal aminoaciduria, and renal hypophosphatemia. Aside from the well-known causes of this syndrome such as cystinosis, tyrosinosis, heavy metal poisoning (particularly cadmium and lead), glycogenosis, multiple myeloma, and toxic organic compounds such as degraded tetracycline, there are so-called idiopathic cases without known cause. It is now recognized that vitamin D deficiency and the associated secondary hyperparathyroidism cause generalized renal aminoaciduria as well as renal hypophosphatemia. In a few instances renal glycosuria has also been detected in patients with rickets not responsive to ordinary amounts of vitamin D so that secondary hyperparathyroidism due to some block in vitamin D metabolism may be a pathogenetic factor in some patients with the Fanconi syndromeY ~ This may account for the reduction or disappearance of r e n a l glycosuria and aminoaciduria as well as correction of renal hypophosphatemia in occasional patients with the idiopathic Fanconi syndrome following treatment with large doses of vitamin D? 4 Since 25-OH vitamin D and 1,25-di OH vitamin D have an action on the renal tubule and, in patients with normal parathyroid function, increase tubular reabsorption of phosphate, large doses of vitamin D, 25,000 to 50,000 units per day, may increase serum phosphate levels in patients with the Fanconi syndrome due to cystinosis even though there is no specific failure of vitamin D metabolism. Another type of target cell abnormality is seen in renal tubular acidosis of the distal type in which there is inadequacy of the tubule mechanism for developing a H + ion gradient between tubular contents and cell. These patients also usually have a vasopressin-resistant polyuria, indicating another abnormality of distal tubular function. Even though the primary functional lesion is in the distal tubule there may .be an associated marked impairment of renal tubular reabsorption of phosphate and hypophosphatemia in the untreated state of chronic bicarbonate deficit. If the bicarbonate deficit is corrected by sodium bicarbonate or a bicarbonate precursor such as sodium lactate or sodium citrate, the serum concentration of phosphate returns to normal values. This type of renal hypophosphatemia is readily correctable, and there is no need for increased intake of vitamin D once the bicarbonate deficit is corrected. The mechanism of the renal hypophosphatemia secondary to bicarbonate deficit is unknown. Albright had postulated that these patients had secondary hyperparathyroidism due to excessive losses of calcium in urine. However, patients with idiopathic hypercalciuria with as great or greater losses of calcium in urine do not have hypophosphatemia of this degree and do not develop rickets and osteomalacia. It seems more likely that a deficiency of bicarbonate in the glomerular

Rickets then and now

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filtrate in some way alters tubular reabsorption of phosphate and this fits with studies of experimental acidosis. 1~ The most frequently encountered target cell abnormality is primary hypophosphatemia. Many of these cases are familial and the most common mode of genetic transmission is as an X-linked dominant so that the disorder is frequently termed X-linked genetic hypophosphatemia. There are other modes of transmission, however, which include both autosomal dominant and recessive and which cannot be distinguished phenotypically from the X-linked dominant variety. There are also sporadic cases which may represent spontaneous mutants who will start new kindreds of genetic hypophosphatemia. Despite strenuous efforts to demonstrate an abnormality of vitamin D metabolism in these patients, none has been found. Early suggestions of a defect in 25-hydroxylation were not confirmed and the hypophosphatemia is not corrected by large doses of 25-OH vitamin D. Also, 1,25-di OH vitamin D does not increase renal tubular reabsorption of phosphate in such subjects even though increased intestinal absorption of calcium in response to this steroid can be demonstrated. TM The accepted current theory is a defect at the renal tubule level involving the system for net transport of phosphate from tubular lumen to peritubular fluid. 17 One possible explanation is excessive back leak of phosphate into the lumen. The growth retardation of children with primary hypophosphatemia also seems to be secondary to the deficiency of inorganic phosphate, t8 The newer information has consequences for the treatment of these patients. The older approach of using progressively larger doses of vitamin D in an effort to correct the hypophosphatemia has no theoretical basis and such treatment bears with it the risk of hypervitaminosis D and renal injury. The serum phosphate concentration may be elevated by large doses of vitamin D, but this is usually associated with a reduced glomerular filtration ratel The use of the various vitamin D metabolites has not been of specific value. The current therapeutic approach is to load these patients with inorganic phosphate by giving as much phosphate as can be tolerated in frequent doses throughout the day. Although fasting serum phosphate levels remain 10w, there is an increase after each phosphate feeding so that the average concentration of serum phosphate throughout the day is higher and can be sufficient to maintain bone mineralization and stimulate growth. Such high phosphate loads can interfere with calcium absorption and cause secondary, hyperparathyroidism unless calcium absorption is maintained by vitamin D intake beyond the physiologic requirement. There is, therefore, a role for high vitamin D intake in this

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Harrison and Harrison

disease, but only in the amount required to m a i n t a i n good calcium absorption. Dihydrotachysterol, rather than vitamin D, can also be used for this purpose. 19It promotes calcium absorption from the intestine and is possibly safer to use than vitamin D because its effects are less cumulative and the dose can be adjusted more easily. Whether i,itamin D or dihydrotachysterol is prescribed, it is mandatory that serum calcium and preferably also urinary concentrations of calcium be monitored frequently to obviate the possible nephrotoxic effects of hypercalcemia and hypercalcuria. Another group of patients with severe hypophosphatemic tickets and osteomalacia are those with "nonendocrine" tumors which apparently secrete a phosphaturic factor. Although rare there may be more such cases than has been recognized, and some cases of sporadic primary hypophosphatemia might fall into this group when the tumor is in a location not accessible to diagnosis. The tumors which have been described are either small superficial masses which histologically are of vascular and fibrous tissue origin ~176or nonossifying tumors of bone which appear as lucent lesions on roentgenogramsY 1 They are usually solitary. The striking feature is the marked increase of renal tubular reabsorption of phosphate, which results within a relatively few hours after excision of the tumor; this suggests the removal of the source of a factor which inhibits renal tubular reabsorption of phosphate.~, o~ This factor is not parathyroid hormone but there is nothing else known about its composition. It is important to recognize such cases because of the rapid recovery following removal of the tumor. It would be important to try to determine the presence in extracts of the tumor or in plasma or urine o f a phosphaturic agent so that a method of assay might be developed which could be a diagnostic tool in the recognition of such patients. W e cannot say with certainty that patients with genetic Xlinked hypophosphatemia might not have impaired renal tubular reabsorption of phosphate due to the formation of such a phosphatutic compound in the absence of an obvious connective tissue tumor.

SUMMARY Major advances in our knowledge of vitamin D metabolism and function in the past two decades have enabled us to present a classification of disorders of bone mineralization resulting from lack of the active vitamin D metabolite, 1,25 di OH vitamin D. There are also forms of rickets and osteomalacia which cannot be attributed to such abnormalities of vitamin D metabolism and are essentially due to factors which impair renal tubular reabsorption of phosphate leading to primary hypophosphatemia. The possibility that Some of these m a y be

The Journal of Pediatrics December 1975

caused by the circulation of a phosphaturic factor should stimulate further studies in the mechanisms of renal tubular transport of phosphate so that we might have a better understanding and perhaps better treatment of the primary hypophosphatemic forms of rickets and osteomalacia.

REFERENCES 1. DeLuca HF: Vitamin D: The vitamin and the hormone, Fed Proc 33:2211, 1974. 2. Larkins RG, MacAuley SJ and Maclntyre I: Feedback control of vitamin D metabolism by a nuclear action of 1,25-dihydroxycholecalciferol on the kidney, Nature 252:412, 1974. 3. Harrison HE, and Harrison HC: The interaction of vitamin D and parathyroid hormone on calcium, phosphorus and magnesium homeostasis, Metabolism 13:952, 1964. 4. Harrison HE: Barnett HL, and Einhorn AH, editors: Calcium metabolism in pediatrics, ed 15, New York, 1972, Appleton-Century-Crofts, Inc, p 201. 5. Dent CE, Richens A, Rowe DJF, and Stamp TCB: Osteomalacia with long-term anti-convulsant therapy in epilepsy, Br Med J 4:69, 1970. 6. Hahn TJ, Hendlin BA, Scharp CR, and Haddad JG: Effect of chronic anticonvulsant therapy on serum 25-hydrc~xycholecalciferol levels in adults, N Engl J Med 287:900, 1972. 7. Silver J, Davies TJ, Kupersmitt E, Orme M, Petrie A, and Vajda I: Prevalence and treatment of vitamin D deficiency in children on anticonvulsant drugs, Arch Dis Child 49:344, 1974. 8. Stoop JW, Schraagen MJC, and Tidden HAWM: Pseudo vitamin D deficiency rickets, Acta Paediatr Scand 56:607, 1967. 9. Fraser D, Kooh SW, and Scriver CR: Hyperparathyroidism as the cause of hyperaminoaciduria and phosphaturia in human vitamin D deficiency, Pediatr Res 1:425, 1967. 10. Fraser D, Kooh SW; Kind HP, Holick MF, Tanaka Y, and DeLuca HF: Pathogenesis of hereditary vitamin D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D, New Engl J Med 289:817, 1973. 11. Harrison HE, and Harrison HC: Dihydrotachysterol. A calcium active steroid not dependent upon kidney metabolism, J Clin Invest 51:1919, 1972. 12. Chalmers TM, Davies MW, Hunter JO, Davie MW, Szaz KF, Pelc B, and Kodicek E: 1-Alpha hydroxycholecalciferol as a substitute for the kidney hormone 1,25-dihydroxycholecalciferol in chronic renal failure, Lancet 2:696, 1973. 13. Chesney RW, and Harrison HE: Fanconi syndrome following bowel surgery and hepatitis reversed by 25hydroxycholecalciferol J PEDIATR86:857, 1975. 14. Salassa RM, Power MH, Ulrich JA, and Hayles AB: Observations on the metabolic effects of vitamin D in Fanconi syndrome, Staff Meetings Mayo Clinic 29:214, 1954. 15. Harrison HE, and Harrison HC: The effect of acidosis upon the renal tubular reabsorption of phosphate, Am J Physiol 134:781, 1941. 16. Brickman AS, Coburn JW, Kurokawa K, Bethnne JE;

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Harrison HE, and Norman AW: Actions of 1,25-dihydroxy vitamin D in patients with hypophosphatemic vitamin D resistant rickets, N Engl J Med 289:495, 1973. 17. Glorieux F, and Scriver CR: Loss of a parathyroid hormone-sensitive component of phosphate transport in Xlinked hypophosphatemia, Science 175:997, 1972. 18. Harrison HE, Harrison HC, Lifshitz F, and Johnson ADi Observations on the growth disturbance of hereditary hypophosphatemia, Am J Dis Child 112"290, 1966. 19. Harrison HE, Lifshitz F, and Blizzard RM: Comparison between crystalline dihydrotachysterol and calciferol in

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patients requiring pharmacologic vitamin D therapy, N Engl J Med 27:894, 1967. 20. Salassa RM, Jowsey J, and Arnaud CD: Hypophosphatemic osteomalacia associated with "non endocrine" tumors, N Engl J Med 283:65, 1972. 21. Pollack JA, Schuller AL, and Crawford JD: Rickets and myopathy cured by removal of a non-ossifying fibroma of bone, Pediatrics 52:364, 1973. 22. Harrison HE: Oncogenous rickets. Possible elaboration by a tumor of a humoral substance inhibiting tubular reabsorption of phosphate, Pediatrics 52:432,. 1973.

Rickets then and now.

Since the introduction of irradiated ergosterol into our food supply, nutritional vitamin D-deficiency rickets has become an uncommon disease. However...
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