Familial
forms
revisited.
X-linked
autosomal Donald
of vitamin
Fraser2
Charles
vitamin
perspectives
Darwin perceived natural selection as the driving force for the origin of species. He had identified a force; but without knowledge of genes, he was unable to understand the vehicle upon which the force was acting. Mendel proposed the vehicle and formulated the laws of segregation and assortment of genes, the units of heredity. Neither scholar knew of the other’s contribution (2). The rediscovery of Mendelian genetics and its flowering at the beginning of the 20th century (3) was not lost on Sir Archibald Garrod who removed Nature’s rare “sports” from the vague realm of the “familial diathesis” and developed the elegant concept of monogenic “inborn errors of metabolism” (4). It was then but a short step for Garrod to postulate a genetic basis for all human biochemical individuality. He The American
Journal
of Clinical
and
D dependency1
R. Scriver3
Through inheritance, the biochemical mdividuality of man (1) is expressed in many forms, some advantageous, some harmful, while many appear neutral. In this paper, we will discuss two examples of extreme biochemical individuality that are disadvantageous. One (familial hypophosphatemia) is an aberration of phosphorus transport; the other (vitamin D dependency) is a disorder of vitamin D metabolism that affects calcium metabolism. Both conditions have been termed “vitamin D resistant”; they cause rickets or osteomalacia, skeletal deformity, dwarfism, and discomfort. They are inherited; one is x-linked, the other autosomal recessive. In both cases, the pressure exerted against the afflicted subjects in the day-to-day world by “natural selection” can be relaxed by treatment, the rationale for which is based on detailed knowledge of these inborn errors o mineral metabolism. Historical
rickets
hypophosphatemia
recessive and
D-resistant
Nutrition
29: NOVEMBER
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proposed that modification of the human environment might relax selection against harmful genes. But Garrod was far ahead of his times; few contemporaries heard his messages (5) and nearly half a century was to elapse before “biochemical individuality” was reformulated by Williams (I) to become a cornerstone to our understanding of health and disease in man. Rickets was reported as a clinical entity by English physicians in the mid-l7th century (see Park (6) and Hunter (7)). By the mid-l9th century, the near-epidemic nature of rachitic bone disease among children under the blackened skies of industrial cities in Europe was widely recognized (8). Eminent physicians, for example, Theobald of 18thcentury England (9) and West of 19th-century London (10), wrote on the causes of rickets and offered elaborate prescriptions for its cure. Meanwhile, the simple and effective use of cod liver oil, while known and documented at the time (annotated in Ref. 1 1), was largely ignored throughout the latter half of the 19th-century. It was the 20th-century discovery of an accessory food substance (12), eventually identified as vitamin D and subsequently produced for therapeutic use (12a), 1 The Medical Research Council of Canada. the Quebec Medical Research Council, and the Quebec Network of Genetic Medicine supported, in part, the investigations from our own laboratories. 2 Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada, and The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. The deBelle Laboratory for Biochemical Genetics, McGill University-Montreal Children’s Hospital Research Institute, Departments of Pediatrics and Biology, McGill University, Montreal. Quebec, Canada. ‘Address reprint requests to: Dr. Charles R. Scriver, The McGill-University Montreal Children’s Hospital Research Institute, 2300 Tupper Street, Montreal, Quebec H3H 1P3, Canada.
1976, pp. 1315- 1329. Printed
in U.S.A.
1315
1316
that dramatically changed rickets in the world. Yet uncertain of the nature causing rickets, ended his with a phrase reminiscent found in a modern Whole
FRASER
AND
the prevalence of Park in 1923, still of “substance X” classic review (6) of what might be Earth Catalogue:
Rickets is indeed a price paid by man for his abandonment of a life out-of-doors and a natural diet for life in houses and a diet of denaturated food stuffs: it is a sign of the operation of the immutable law of nature that nothing out of accord with her shall flourish.
Park did not know about the hereditary forms of rickets at the time; and it was only toward the end of his long life, as a student of rickets, that the relationship between vitamin D and the metabolism of calcium and phosphorus began to be clarified at the cellular level. For as long as environmentally caused rachitic or osteomalaciac bone disease rem ained widespread, inherited conditions that would be refractory to vitamin D therapy were unlikely to gain much attention. When, however, the flood of deficiency rickets receded, following public health measures taken to cure or prevent the occurrence of the disease, the monadnocks of “vitamin-Drefractory rickets” could be seen to protrude from the flood-plain of metabolic bone disease. It was then that Albright et al. (13) would publish the first carefully documented report on “vitamin D resistant rickets.” Soon thereafter attention was drawn to the role played by renal tubular loss of phosphate in the pathogenesis of “refractory,” hypophosphatemic rickets (14). Subsequent systematic approaches to the classification of vitamin D refractory rickets and osteomalacia (15, 16) have brought increasing order to this difficult area of clinical medicine. Two decades after the report by Albright and colleagues had appeared, Fraser and Salter (17) were able to list 13 conditions in the category of hereditary “refractory” rickets or osteomalacia for which a variety of pathogenetic mechanisms was apparent. However, patients with such diseases are rarely “resistant” to vitamin D. Rather they are “refractory,” i.e., their disease does not respond to what is considered the amount of vitamin D that will prevent nutritional rickets. (An average daily intake of 40 IU (1.0 g)
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SCR
IVER
of
crystalline vitamin D2 (ergocalciferol) or (cholecalciferol) will prevent rickets in normal growing children. The average requirement has been set at 10 times this dose, or 400 IU to cover the needs of all normal subjects. A precise requirement for vitamin D in adult life has not been established, but there can be little doubt that adults in the total absence of sunlight, require exogenous vitamin D.) Some will exhibit the appropriate physiological response to pharmacological doses of vitamin D; others will respond to replacement of phosphate in combination with an augmented vitamin D intake. Because the subject of “refractory” rickets still remains rather refractory to classification, and as a means of focussing attention on the primary aberrant process, the terms “calciopenic” and “phosphopenic” rickets (Table 1) were proposed recently (18) to interpret the rationale for preference of one mode of treatment over another. Calciopenia suggests that the primary disturbance is in calcium availability and that the disease may, therefore, respond to vitamin D therapy; phosphopenia suggests a primary abnormality in available phosphate, where vitamin D would only be an adjunct to a primary emphasis on phosphate replacement. D3
Calciopenic rickets
and phosphopenic
Calciopenic
rickets
mechanisms
of
Rickets or osteomalacia will occur when the long-term availability of calcium is sufficiently impaired to cause calciopenia as the initial event. Simple dietary restriction of calcium must be extreme to achieve rickets by this mechanism in the experimental animal. In man, such extremes of dietary restriction have almost never been observed; the iatrogenic case reported by Maltz et al. (19) appears to be a rare human example of diet-induced calciopenia with rickets. Barring a primary abnormality of the absorbing epithelium (e.g., celiac disease or sprue) which may impair absorption of calcium and other nutrients, the integrity of calcium transport depends on access to the biologically active forms of vitamin D. In the past decade it has been shown that vitamin D as cholecalciferol, (D3) or ergocalciferol, (D2)
FAMILIAL TABLE Causes
I of rickets
“refractory”
FORMS
to vitamin
OF
VITAMIN
D-RESISTANT
Da
Calciopenic
Phosphopenic
causes
deprivation
Calcium
Transport
Defective absorption: bile salt depletion (effect on vitamin D absorption) Sprue, celiac disease, etc. (effect on calcium and vitamin D absorption)
X-linked
1) Defective synthesis of 25-OH-D:
Secondary forms parathyroidism
-Hepatoceblular -Drug-induced somal
2)
disease: increase
Defective
synthesis
-Hereditary dency’ “Refractory
to
physiological
Tubulopathies
involving phosphate solutes (15, 16): includes the Fanconi syndrome (36) and
Whereas also plays
other
(secondary to hyperwith calciopenia)
of micro-
of la,25-(OH)2D; (cortex)
vitamin D depen(pseudodeficiency rickets) doses
doses in text.
of
D (prohormone), can be responsive D metabolites (25-OH-D or la-OH-vitamin
vitamin
of vitamin
must be hydroxylated first in liver, to form 25-hydroxyvitamin D (25-OH-D) and then in kidney to form la, 25-dihydroxyvitamin D (la, 25-(OH)2D), (see also this symposium). The latter product is a sterol, possessing hormone-like activity with respect to calcium metabolism in the intestine and bone. The formation of a trihydroxyvitamin D metabolite Ia-24, 25-(OH)3D2 has also been described in rat kidney; this substance acts specifically on intestine to stimulate calcium transport. The formation, regulation, and function of vitamin D hormone has been a very active field of research in recent years (20-27). The specific control of transepithehal movement of calcium by vitamin D and other calciotropic agents has also been the subject of some interesting observations and speculations (28). It follows that a hereditary impairment in the biosynthesis of vitamin D hormone, should it ever occur, would be likely to cause calciopenic rickets. We believe that autosomal-recessive, vitamin D dependency is a prototype of calciopenic, hereditary refractory rickets (Table 2). Phosphopenic
Hypophosphatemia’
oxidation
-Renal parenchymal disease;
vitamin D or “physiological” types discussed in detail
causes
Phosphate deprivation (in antacid therapy with magnesium-aluminum hydroxides)
Nutritional
Metabolic
1317
RICKETS
rickets there is evidence that vitamin a role in the intestinal absorption
D of
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to pharmacological D analogues).
doses of 1Proto-
phosphate (29), and that phosphate anion participates in the negative feedback regulation of the biosynthesis of la,25-(OH)2D3 (29), the weight of evidence indicates that hypophosphatemia, secondary to vitamin D depletion, is the result of renal tubular rejection of phosphate in the presence of the elevated serum parathyroid hormone activity which characterizes vitamin D deficiency (18, 30). The primary mechanisms of membrane transport of phosphate in gut and kidney are still not well described beyond the fact that an anion carrier is involved; a carrier has been most intensively studied in erythrocyte membranes (31-33). Since renal tubular reabsorption of inorganic phosphate exhibits a maximum transport rate (34), one of the transepithelial transport events must be limiting. This could either be a membranebound anion carrier, or a subsequent intracellular step (35). It therefore follows that a mutation that affects the reabsorptive process could lead to phosphopenia. Tubular reabsorption of filtered phosphate is critical to the maintenance of the endogenous phosphate poo1 (34). We believe that familial (x-linked) hypophosphatemia is a prototype of phosphopenic refractory rickets.
FRASER
1318 TABLE 2 Comparative
phenotypes
of familial
AND
hypophosphatemia
SCR
IVER
and vitamin
D dependency
Familial
Vitamin dependency
hypophosphatemia Type
Presumed
Age Mode
X-ray
Phosphopenie
of rickets
defect
Calciopenic
Transepithelial of phosphate
at onset of findings
Immediately
of presentation
findings
Biochemical findings Serum calcium (total: ionized) Serum inorganic phosphate Serum 25-OH-D#{176} Serum alkaline phosphatase (bone fraction) Serum iPTH Urine phosphate’ Urine amino acids
transport anion postnatal
Early
infancy
Hypophosphatemia: rickets (3 6 mos): dwarfism with particular shortening of lower segment. Males uniformly affected; females variably affected
Hypocalcemia, irritability. Seizures, bulging fontanelle; rickets; secondary hyperparathyroidism: enamel hypoplasia (in teeth formed
Mild to severe rickets: shafts widened with undermineralization coarse trabeculation. No signs of hyperparathyroidism usually
Resembles later stages of vitamin D deficiency. Signs of hyperparathyroidism usually evident in late-diagnosed patients
postnatally). Males and females equally affected
Ii. N
N
N (or sl.I)”
II
TI N X-linked ‘Patients phosphate
Autosomal
on diet providing low Ca:inorganic excretion is abnormally increased
In the same vein, but with different pathogenetic mechanisms involved, it is evident that the various causes of tubular wasting of phosphate ( 15, 16), which include complex tubulopathies resulting in pure and variant forms of the Fanconi syndrome (35, 36), can produce phosphopenia with associated bone disease. Secondary
Deficient 25-hydroxyvitamin D- Ia-hydroxylase activity
N
Inheritance In the untreated state. iPTH. Urine inorganic concentration.
D
phosphopenia
While there is evidence for independent, primary mechanisms ofcalciopenia and phosphopenia, it is also apparent that the calciopenic state can cause “secondary” hypophosphatemia through the mechanism of hyperparathyroidism and probably also through calcium-mediated primary cellular events
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recessive
phosphate ratio (
10’
-1
0
1
2
3
4 Time,
5
6
7
8
9
10
11
weeks
FIG. 3. The serum calcium response in calciopenic autosomal recessive vitamin D dependency (ARVDD) treated with vitamin D2, 25-OHD3 and la,25-(OH)2D3 or la-OHD3. The vitamin D requirement for restoration of serum calcium to normal is expressed as equivalents of vitamin D2 (40,000 units vitamin D2 = 1000 g: and 2 g la,25-(OH)2D3 corresponds to --400 units D and assuming that 10 zg vitamin D = 3 zg 25-OHD3 = I jig la,25(OH)2D3 in biological potency). The figure reveals the expected normal response to Ia-OH metabolites and increased requirements for 25-OHD3 and vitamin D2 (the latter dose was 10 times higher in the initial trial than the eventual attenuated
requirement response
for this patient). to pharmacologic
The data also indicate the rapid response doses of precursor forms of vitamin D.
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to hormone
replacement
and
the
1324
FRASER
AND
and D3 (in the order of 1,000 to 3,000 tg per day, or 100 to 300 times the normal requirement) are required to maintain biochemical and radiological healing in ARVDD probands (89, 93). The maintenance requirement for 25-OH-D3, is also elevated (200 to 1,000 /.Lg per day) (88, 95-97). By contrast only a minute dose of la-25-(OH)2D3 (1 to 8 ,ug per day) is required to correct hypocalcemia, augment intestinal calcium absorption, establish positive calcium balance, and initiate radiological healing in vitamin D dependency (88, 94, 95). Estimates of the therapeutic dose requirements for the various forms of vitamin D indicate a requirement ratio of about 1700:700:1, for vitamin D2, 25-OH-D3 and la,25-(OH)2D3, respectively; the normal requirement ratio is believed to be about 10:3:1. If one assumes that vitamin D and 25-OH-D3 can function in ARVDD only through the production of la-25(OH)2D3 by means ofa mutant 25-hydroxy vitamin D-la hydroxylase that retains some activity, then the ratio of the therapeutic requirements of vitamin D: 25-OH-D3:la,25-(OH)2D3 can be taken as an indirect measure of the efficiency of vitamin D conversion to its active metabolite in ARVDD. Conversion of vitamm D to 25-OH-D appears to be relatively efficient in vitamin D dependency rickets, the 3: 1 dosage requirement ratio for vitamin D:25-OH-D3 being similar to that described in the rat (98). However, the meaning of the high requirement for 25-OH-D3 relative to la,25-(OH)2D3 (700:1 in ARVDD) requires a knowledge of the relative efficacies of these two metabolites in man under circumstances where biosynthesis of vitamin D hormone is not impaired. Observations in vitamin D deficiency can serve in this capacity. Balsan and colleagues (88) and Fraser and Kooh (unpublished data) have shown that the therapeutic dose requirement for la,25-(OH)2D3 (or crystalline la-OH-D3) is about 50 ng per kilogram per day to bring about healing in vitamin D deficiency; the requirement for 25OH-D3 is only about three times higher (Fraser and Kooh, unpublished data). Although the requirement for 1aOH vitamin D analogues in ARVDD may be slightly increased above “normal” (to 80 to 100 ng per kg (94), or even somewhat higher (88)) for
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SCRIVER
reasons that are still unclear, nonetheless they are close to the physiological range, whereas those for 25-OH-D3 as mentioned above, are 200 to 300 times higher than normal. The above mentioned evidence indicates that ARVDD is an inborn error ofvitamin D hormone biosynthesis, affecting the conversion of 25-OH-D to la,25-(OH)2D. The defect is presumed to be an attenuation of 25-hydroxy-vitamin D- 1-hydroxylase activity in the kidney. Treatment with la-OH-D analogues presumably bypasses the enzymatic defect and supplies the deficient, active metabolite of vitamin D. Confirmation of the hypothesis awaits study of mitochondrial 1-hydroxylase in proband kidneys at which time evaluation of the kinetics of the mutant enzyme may also provide an explanation for the therapeutic response to pharmacological doses of vitamin D or 25-OH-D. Because of the complex pathway of vitamin D metabolism it seems likely then that ARVDD is but the first of many possible inborn errors affecting it, and we can expect to find the customary genetic heterogeneity involving the different enzymes (and gene loci) in the vitamin D dependency syndrome in the future.
Treatment
of ARVDD
With the demonstration that biochemical and radiographic healing can be initiated with minute doses of la,25-(OH)2D3 or laOH-D3, the possibility exists of using these active agents in therapy. The more rapid onset, and the shorter duration of action could theoretically be of advantage over vitamm D in the clinical setting (Fig. 3). However, until la-25-(OH)2D3 and la-OH-D3 become readily available for clinical use, and until there has been sufficient experience with dosage and use of these drugs, vitamin D remains the agent of choice. Several high-potency vitamin D preparations are available. All those in North America contain vitamin D2; preparations of vitamin D3 are available in Europe. As far as we know at present there is no reason to prefer one form over the other for therapeutic purposes in man. Products with the vitamin in
FAMILIAL
FORMS
OF
VITAMIN
liquid form (usually 2,500 g per ml) have major advantages over capsules. In contrast to the inflexibility of treatment with capsules, liquid preparations permit the physician to prescribe the specific dose of vitamin D required by the patient. The most practical means to measure and administer the dose is with a turberculin syringe from which the vitamin D is instilled directly into the mouth of the patient. ARVDD can also be treated with 25-OH-D3 on a long-term basis (99; Fraser and Kooh, unpublished data). The dosage requirement to maintain normal plasma calcium and phosphorus levels and normal bone architecture is in excess of 150 to 200 zg per day. Although 25-OH-D3 is a satisfactory therapeutic agent, it is no less likely to cause hypercalcemia than is vitamin D, nor does the hypercalcemia disappear more rapidly when the agent is withheld. Despite the smaller dosage of 25-OH-D3 needed to control the rachitic disease, the drug offers no substantial advantages over vitamin D. Patients with vitamin D dependency rickets will also respond to treatment with dihydrotachysterol (DHT), but the dose required is large. The theoretical possibility that the configuration of the rotated A-ring of the DHT molecule would provide an antirachitic agent ofa potency approaching that of la,25(OH)2D3 has not been borne out, as daily doses of 500 to 1,000 .Lg appear to be needed in ARVDD. Although it is clear from published reports (100) that DHT is a satisfactory agent for treatment of ARVDD, we do not believe the agent has any special advantages over vitamin D.
Inheritance
of ARVDD
and recurrence
risks
The inheritance of ARVDD is almost certainly autosomal recessive (91, 92). Heterozygotes show no biochemical or clinical manifestations by currently available tests (91). At present, we do not know whether the serum concentration of la,25-(OH)2D is very low in homozygotes and intermediate in heterozygotes. A radioimmune assay (101) is now available and should help provide quantitative answers. In addition, enzyme studies would provide data on the relative enzyme
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D-RESISTANT
RICKETS
1325
activities in homozygous and heterozygous subjects. The recurrence risk for the disease is 25% at each birth for siblings of homozygous probands. Diagnosis can be made within a few weeks after birth on the basis of serum calcium and iPTH levels and treatment can be started, accordingly, to prevent florid phenotypic manifestations.
Retrospective
comment
Albright and colleagues (13) were among the first to delineate “rickets resistant to vitamin D therapy.” Although no family data were mentioned, the case report indicates that the 16-year-old male patient probably had x-linked hypophosphatemia. The authors found histological evidence for hyperparathyroidism in their patient. They also showed that his urinary excretion of phosphorus fell by about 25%, without a concomitant rise in serum phosphorus, when he was treated with massive doses of vitamin D2. Healing of rickets was observed under these conditions. The title of their paper, and the towering reputation of the authors each played their part in influencing the subsequent analysis of phosphopenic rickets. The finding of hyperparathyroidism in the patient was an important diversion. In retrospect it is of interest that the calcium:phosphorus intake ratio in the patient was about 0.75. When phosphate absorption is defective, calcium absorption is likely to be compromised and could thus initiate parathyroid hyperactivity. It is of interest that very few of the many hundred known XLH probands have apparently experienced hyperparathyroidism worthy of documentation in the literature (102). When it occurs, it is often during a period of augmented phosphorus intake relative to calcium. Calcium infusion studies at first seemed to support the Albright hypothesis. Later work (45) in patients known to maintain a normal or near normal serum iPTH concentration (54) indicated that calcium was exerting its effect on phosphate reabsorption independent of any major effect of PTH on phosphate reabsorption by the tubule. At present, we are inclined to believe that calcium modifies phosphate transport in XLH through its
FRASER
1326
AND
intracellular effects in tubular epithelium. Confirmation of this speculation must await further studies and evidence. Meanwhile, in response to the phosphopenia hypothesis, it has been found that XLH patients respond well to phosphate replacement. The same has been found in our own experience in tubulopathies (15, 16) which also cause primary phosphopenia. The role of vitamin D in the treatment regimen for all tubular forms of phosphopenic rickets is essentially to offset the hypocalcemia induced by high phosphate intake. The above mentioned studies served to make clear, upon the discovery of ARVDD (17, 89), that the latter trait was very different from XLH. ARVDD is in fact a calciopenic form of “refractory rickets” and it fits the Albright hypothesis far better than XLH. Recognition of an elevated serum iPTH concentration in ARVDD (91) provides the essential link in the hypothesis. Research on vitamin D, and the chemical synthesis of pure crystalline analogues bearing the la-hydroxyl group (81, 82), coincided with the studies of ARVDD to provide an important opportunity for replacement of the suspected missing metabolite and to assign the putative enzyme defect in ARVDD to an abnormality of the la-OH hydroxylase activity in homozygotes. The clinical studies in two “classical” forms of phosphopenic and calciopenic vitamin-D refractory rickets show us that appropriate modification of the environment will allow the affected person to escape the otherwise predictable expression of his genotype. These studies illustrate as well as any why research on disease must continue. All citizens are not “equal” biologically and the handicap of biochemical individuality can be great in the absence of corrective knowledge.
El We
are grateful to our many
Arnaud, Hector DeLuca, Kooh, and Terry Reade tions to the work with involved.
colleagues
SCRIVER 3. 4.
5.
6. 7.
Lancet
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phosphaturic
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cytoplasmic
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renal
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GLORIEUX,
cine
Int.
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R.
FANCONI,
AND
Nature
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E. R. YENDT. D-refractory
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Aspects
B. Anion permeability of the red blood Naturwissenschaften 57: 172, 1970. CABANTCHIK, Z. I., AND ROTHSTEIN, A. Membrane to anion
junction
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Frame,
DEUTICKE,
related
B., AND
of
metabolism in X-linked
SCRIVER,
proteins
ROSE,
of phosphate
cell. 32.
A.
BINSWANGER,
BAERLOCHER
phosphatemia:
Hor-
Talmage, M. Owen and of the 5th Parathyroid ConExcerpta Medica, ICS 346,
U.
A. PRADER. serum parathyroid hormone concentrations in vitamin D deficiency rickets of infancy: effects of intravenous calcium and vitamin D. Horm. Metabol. Res. 5: 381, 1973. BORLE, A. B. Calcium metabolism at the cellular lesel. Federation Proc. 32: 1944, 1973. BAKER, P. F. Transport and metabolism of calcium ions in nerve. Prog. Biophys. Mol. Biol. 24: 179,
cium
1975,
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K.
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CASTILLO. and
J. A.,
FISCHER, ILLIG,
41.
1327
RICKETS
ARNAUD, Serum
phatemia. 55.
C., parathyroid
F.
GL0RIEUx hormone
AND
C.
in X-linked
R.
SCRIVER.
hypophos-
Science 173: 845, 1971. J. E., E. C. CABANA, H. A. REPETTO, J. M. CANTERBURY AND E. REISS. Serum parathyroid LEWY,
FRASER
1328 hormone
in hypophosphatemic J. Pediat. 81: 294,
rickets.
56.
FANCONI, Serum
J.
A.,
A.
parathyroid
vitamin
AND
D-resistant
FISChER
ANI)
hormone
A.
PRADER.
concentrations
in
vitamin D resistant rickets. 29: 187, 1974. TALWALKAR, Y. B., J. E. MUSGRAVE, N. R. M. BUIST, R. A. CAMPBELL AND J. R. CAMPBELL. Vitamin D-resistant rickets and parathyroid adenomas. Am. J. Diseases Children 128: 704, 1974. LORENTZ, W. B., JR. The effect ofcyclic AMP and dibutyryl cyclic AMP on the permeability characteristics ofthe renal tubule. J. Clin. Invest. 53: 1250,
57.
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59.
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WONG, WILSON.
T.
S.,
Energy
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system of Escherichia 65: 63, 1970. 60.
R.
coupling
KASHKET in
Co/i.
the Proc.
AND
lactose NatI.
T.
H. 74.
transport Acad.
Sci.
P., AND C. R. SCRIVER. The isolation properties of a fl-alanine permeaseless mutant of Pseudomonas fluorescens. Biochim. Biophys. Acta 219: 428, 1970. GLORIEUX, F. H., C. R. SCRIVER, E. M. EICHER, J. L. SOUTHARD AND R. TRAVERS. X-linked hypophosphatemia in Hvp/Y mouse (Abst.) Pediat. Res. 8: 389, 1974. CARTIER, P., J. P. LEROUX, S. BALSAN AND P. HECHTSIAN,
and
61.
62.
ROYER.
Etude
de
Ia glycolyse
66.
D. Treatment of Rickets in Current Therapy. Edited by H. F. Conn. Philadelphia: W. B. Saunders Co., 1972, p. 407. HARRISON, J. E., W. E. CUMMING, V. FORNASIER, D. FRASER, S. W. KooH AND K. G. MCNEILL. Increased bone mineral content in young adults with familial hypophosphatemic vitamin D refracrickets.
PARFITT, refractory
Clin. 68.
76.
77.
78.
79.
80.
FRASER,
tory 67.
75.
et de Ia perm#{233}abilit#{233}
des #{233}rythrocytes aux ions orthophosphates dans Ic rachitisme vitamino-r#{233}sistant hypophosphat#{233}mique h#{233}r#{233}ditaire. Clin. Chim. Acta 29: 261, 1970. 63. GLORIEUX, F. H., C. R. SCRIVER, T. M. READE, H. GOLDMAN AXE) A. ROSEBOROUGH. Use of phos. phate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. New EngI. J. Med. 287: 481, 1972. 64. WILLIASIS, T. F., AND R. W. WINTERS. Familial (hereditary) vitamin D-resistant rickets with hypophosphatemia. In: The Metabolic Basis of Inherited Disease, 3rd ed. edited by J. B. Stanbury, J. B. Wyngaarden and D. S. Fredrickson. 1972, p. 1465. 65.
A.
Metabolism, 25: 33, M. Hypophosphatemic
rickets
N.
and
osteomalacia.
81.
1976. vitamin Orthopedic.
IVER calcification vitamin
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hypophosphataemic Helv.
SCR
D 82.
Am. 3: 653, 1972. G., W. A. COCHRANE,
NIGRIN, D. JANNIGAN AND A ERNST. Results of calcium infusion renal biopsy studies in refractory rickets. Am. J. Diseases Children 104: 478, 1962. (Abst.). 69. PAUNIER, L., S. W. Kooti, P. E. CONEN, A. A. M. GIBSON ANI) D. FRASER. Renal function and histology after long-term vitamin D therapy of vitamin D refractory rickets. J. Pediat. 73: 833, 1968. 70. LILLY, C. A., C. B. PEIRCE AND R. L. GRANT. The effects of phosphates on the bones of rachitic rats. J. Nutr. 9: 25, 1935. 71. FRASER, D., N. T. JACO, E. R. YENDT,J. D. MUNN AND E. LIN. The induction of in vitro and in vivo
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83.
84.
large doses of vitamin D. Am. J. Diseases Children 93: 84, 1957. (Abstr.). FRASER, D., D. W. GEIGER, J. D. MUNN, P. E. SLATER, R. JOHN AND E. LIN. Calcification studies in clinical vitamin D deficiency and in hypophosphatemic vitamin D refractory rickets: the induction of calcium deposition in rachitic cartilage without the administration of vitamin D. Am. J. Diseases Children 96: 460, 1958. (Abstr.). STEENDIJK, R. The effect of a continuous intravenous infusion of inorganic phosphate on the rachitic lesions in cystinosis. Arch. Disease Childhood 36: 321, 1961. SCRIVER, C. R., R. B. G0LDBL00SI AND C. C. Ro’i. Hypophosphatemic rickets with renal hyperglycinuria, renal glucosuria and glycylprolinuria. A syndrome with evidence for renal tubular secretion of phosphorus. Pediatrics 34: 357, 1964. WEST, C. D., J. C. BLANTON, F. N. SILVERMAN AND N. H. HOLLAND. Use of phosphate salts as an adjunct to vitamin D in the treatment of hypophosphatemic vitamin D refractory rickets. J. Pediat. 64: 469, 1964. FRAME, B., R. W. SMITH, JR., J. L. FLEMING AND G. MANSON. Oral phosphates in vitamin D-refractory rickets and osteomalacia. Am. J. Diseases Children 106: 147, 1963. STICKI.ER, G. B., A. B. HAYLES AND J. W. ROSEVEAR. Familial hypophosphatemic vitamin Dresistant rickets. Am. J. Diseases Children I 10: 664, 1965. CLOW, C., T. READE AND C. R. SCRIVER. Management of hereditary metabolic disease. The role of Allied Health Personnel. New EngI. J. Med. 284: 1292, 1971. STAMP, T. C. B. The hypocalcemic effect of intravenous phosphate administration. Clin. Sci. 40: 55, 1971. REISS, E., AND J. M. CANTERBURY. The effects of phosphate on parathyroid hormone secretion. In: Calcium-Regulating Hormones, edited by R. V. Talmage, M. Owen and J. A. Parsons. Proc. of the 5th Parathyroid Conference. Amsterdam: Excerpta Medica ICS 346, 1975, p. 66. HOLICK, M. F., E. J. SEMMLER, H. K. SCHNOES AND H. F. DELUCA. I a-hydroxy derivative of vitamin D3: a highly potent analogue of I a-25dihydroxyvitamin D3. Science 180: 190, 1973. PETER LAM, H-Y., H. K. SCHNOES AND H. F. DELUCA. la-hydroxyvitamin D2: a potent synthetic analogue of vitamin D2. Science 186: 1038, 1974. HARRISON, H. E., H. C. HARRISON, F. LIFSHITZ AND A. D. JOHNSON. Growth disturbance in hereditary hypophosphatemia. Am. J. Diseases Children 112: 290, 1966. MCENERY, P. T., F. N. SILVERMAN AND C. D. WEST. Acceleration of growth with combined vitamm
D-phosphate
resistant
85.
in bones of children suffering from D-resistant rickets without recourse to
GLORIEUX, AND
therapy
J. Pediat. F. H., C. R.
of
H.
F. DELUCA. Inadequate
rickets. 1,25-dihydroxycholecalciferol.
hypophosphatemic
80: 763,
rickets.
SCRIVER,
X-linked
1972. M. F.
HOLICK
hypophosphataemic
therapeutic Lancet
response to 2: 287, 1973.
FAMILIAL 86.
E.
VITAMIN
Actions
of
patients
and therapeutic effects in nutritional rickdifferent types of vitamin D resistance. Pediat. Res. 9: 586, 1975. 88. DENT, C. E., AND T. C. B. STAMP. Hypophosphataemic osteomalacia presenting in adults. Q. J. Med. 40: 303, 1971. 89. PRADER, VON A., R. ILLIG AND E. HEIERLI. Eine
95.
biologic ets and
besondere tenten
Form Rachitis
der mit
primaren
Vitamin-D
Hypocalc#{228}mie
und
Acidic tration
I phosphate in x-linked
(Joulie’s) solution hvpophosphatemia
for
oral
97.
adminis.
Ingredients: Dibasic sodium phosphate (Na2HPO4. 7 H2O, reagent grade), 102 g: Phosphoric acid (NF 85%), 58.8 g: distilled water to 1000 ml. Dissolve the phosphate salt in approximately 750 ml warm water, to which has been added the phosphoric acid. Make the solution up to I liter distilled H20. Store at room temperature. The concentration of phosphorus in this phosphate solution is 3.04 g per 100 ml; the pH is 4.3. Treatment protocol. Phosphate supplements are given
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98.
99.
RICKETS F.
DELUCA.
1329 Response
to
crystalline
Ia-
hydroxyvitamin D3 in vitamin D dependency. Pediatric Res. 9: 593, 1975. FRASER, D., S. W. KOOH, H. P. KIND, M. F. HOLICK, Y. TANAKA AND H. F. DELUCA. Pathogenesis of hereditary vitamin D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxy-vitamin D to la,25-dihydroxyvitamin D. New EngI. J. Med. 289: 817, 1973. BALSAN, S., AND M. GARABEDIAN, 25-Hydroxycholecalciferol. A comparative study in deficiency rickets and different types of resistant rickets. J. Clin. Invest. SI: 749, 1972. BALSAN, S., M. GAJtABEDIAN AND L. LEBOUADEC. Le
autosomal-
Erbgang: die heredit#{228}re Pseudo-ManHelvet. Paediat. Acta 16: 452, 1961. 90. SCRIVER, C. R. Vitamin D dependency. Pediatrics 45: 361, 1970. 91. ARNAUD, C., R. MAIJER, T. READE, C. R. SCRIVER AND D. T. WHELAN. Vitamin D dependency: An inherited postnatal syndrome with secondary hyperparathyroidism. Pediatrics 46: 871, 1970. 92. FANCONI, A., AND A. PRADER. Die heredit#{228}re Pseudomangel rachitis. Helvet. Paediat. Acta 24: 423, 1969. 93. HAMILTON, J. R., J. HARRISON, D. FRASER, I. RADDE, R. MORECKI AND L. PAUNIER. The small intestine in vitamin D dependent rickets. Pediatrics 45: 364, 1970. 94. READE, T. M., C. R. SCRIVER, F. H. GLORIEUX, B. NOGRADY, E. DELVIN, R. POIRIER, M. F. HOLICK
Appendix
96.
resis-
dominanten gelrachitis.
H.
AND
1,25-dihydroxycholecalciferol
with hypophosphatemic, vitamin Dresistant rickets. New EngI. J. Med. 289: 495, 1973. BALSAN, S., M. GARABEDIAN, R. SORGNIARD, M. F. HOLICK AND H. F. DELUCA. 1,25-dihydroxyvitamin D3 and la-hydroxyvitamin D3 in children: in
D-RESISTANT
BETHUNE,
NORMAN.
87.
OF
A. S., J. W. COBURN, K. KUROKAWA, H. E. HARRISON AND A. W.
BRICKMAN,
J.
FORMS
rachitisme
vitam
mo-resistant
pseudocarentiel
hypocalc#{233}mique. Arch. Franc. P#{233}d. 29: 287, 1972. TANAKA, Y., H. FRANK AND H. F. DELUCA. Biological activity of 1,25-dihydroxy vitamin D3 in the rat. Endocrinology 92: 417, 1973. BALSAN, S. 25-Hydroxycholecalciferol: Effects in idiopathic
vitamin
D-resistant
rickets.
4: 45, 1970. (Suppl.). ROSEN, J. F., AND L. FINBERG.
CaIc.
Tiss.
Res.
100.
ent
101.
102.
rickets:
Actions
of
Vitamin
parathyroid
D-dependhormone
and
25-hydroxycholecalciferol. Pediat. Res. 6:552, 1972. BRUMBAUGH, P. F., D. H. MAUSSLER, R. BRESSLER AND M. R. HAUSSLER. Radioreceptor assay for la,25-dihydroxyvitamin D3. Science 183: 1089, 1974. THOMAS, W. C., JR., AND R. M. FRY. Parathyroid adenomas in chronic rickets. Am. J. Mcd. 49: 404, 1970.
five
times
the
response
daily. of
Depending
and
skeleton,
and
his his
upon
serum tolerance
the
child’s
inorganic of
body
phosphate the
solution,
weight, level treat-
should provide I to 5 g of phosphorus per day. begin treatment in the 1-year-old child, we administer 5 ml t.i.d. on the 1st day: 10 ml t.i.d. on the 2nd day; 10 ml q.i.d. on the 3rd day; 10 ml q.4.h. five times a day on the 4th day, and thereafter. This dose provides 1.5 g of supplemental phosphorus daily. Older children may require 20 ml (or more) every 4 hr five times daily. The solution is given with meals when possible: when taken between meals and at bedtime, it is followed by a drink of the patient’s choice (100 to 150 ml). ment
To
forms
revisited.
X-linked
autosomal Donald
of vitamin
Fraser2
Charles
vitamin
perspectives
Darwin perceived natural selection as the driving force for the origin of species. He had identified a force; but without knowledge of genes, he was unable to understand the vehicle upon which the force was acting. Mendel proposed the vehicle and formulated the laws of segregation and assortment of genes, the units of heredity. Neither scholar knew of the other’s contribution (2). The rediscovery of Mendelian genetics and its flowering at the beginning of the 20th century (3) was not lost on Sir Archibald Garrod who removed Nature’s rare “sports” from the vague realm of the “familial diathesis” and developed the elegant concept of monogenic “inborn errors of metabolism” (4). It was then but a short step for Garrod to postulate a genetic basis for all human biochemical individuality. He The American
Journal
of Clinical
and
D dependency1
R. Scriver3
Through inheritance, the biochemical mdividuality of man (1) is expressed in many forms, some advantageous, some harmful, while many appear neutral. In this paper, we will discuss two examples of extreme biochemical individuality that are disadvantageous. One (familial hypophosphatemia) is an aberration of phosphorus transport; the other (vitamin D dependency) is a disorder of vitamin D metabolism that affects calcium metabolism. Both conditions have been termed “vitamin D resistant”; they cause rickets or osteomalacia, skeletal deformity, dwarfism, and discomfort. They are inherited; one is x-linked, the other autosomal recessive. In both cases, the pressure exerted against the afflicted subjects in the day-to-day world by “natural selection” can be relaxed by treatment, the rationale for which is based on detailed knowledge of these inborn errors o mineral metabolism. Historical
rickets
hypophosphatemia
recessive and
D-resistant
Nutrition
29: NOVEMBER
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proposed that modification of the human environment might relax selection against harmful genes. But Garrod was far ahead of his times; few contemporaries heard his messages (5) and nearly half a century was to elapse before “biochemical individuality” was reformulated by Williams (I) to become a cornerstone to our understanding of health and disease in man. Rickets was reported as a clinical entity by English physicians in the mid-l7th century (see Park (6) and Hunter (7)). By the mid-l9th century, the near-epidemic nature of rachitic bone disease among children under the blackened skies of industrial cities in Europe was widely recognized (8). Eminent physicians, for example, Theobald of 18thcentury England (9) and West of 19th-century London (10), wrote on the causes of rickets and offered elaborate prescriptions for its cure. Meanwhile, the simple and effective use of cod liver oil, while known and documented at the time (annotated in Ref. 1 1), was largely ignored throughout the latter half of the 19th-century. It was the 20th-century discovery of an accessory food substance (12), eventually identified as vitamin D and subsequently produced for therapeutic use (12a), 1 The Medical Research Council of Canada. the Quebec Medical Research Council, and the Quebec Network of Genetic Medicine supported, in part, the investigations from our own laboratories. 2 Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada, and The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. The deBelle Laboratory for Biochemical Genetics, McGill University-Montreal Children’s Hospital Research Institute, Departments of Pediatrics and Biology, McGill University, Montreal. Quebec, Canada. ‘Address reprint requests to: Dr. Charles R. Scriver, The McGill-University Montreal Children’s Hospital Research Institute, 2300 Tupper Street, Montreal, Quebec H3H 1P3, Canada.
1976, pp. 1315- 1329. Printed
in U.S.A.
1315
1316
that dramatically changed rickets in the world. Yet uncertain of the nature causing rickets, ended his with a phrase reminiscent found in a modern Whole
FRASER
AND
the prevalence of Park in 1923, still of “substance X” classic review (6) of what might be Earth Catalogue:
Rickets is indeed a price paid by man for his abandonment of a life out-of-doors and a natural diet for life in houses and a diet of denaturated food stuffs: it is a sign of the operation of the immutable law of nature that nothing out of accord with her shall flourish.
Park did not know about the hereditary forms of rickets at the time; and it was only toward the end of his long life, as a student of rickets, that the relationship between vitamin D and the metabolism of calcium and phosphorus began to be clarified at the cellular level. For as long as environmentally caused rachitic or osteomalaciac bone disease rem ained widespread, inherited conditions that would be refractory to vitamin D therapy were unlikely to gain much attention. When, however, the flood of deficiency rickets receded, following public health measures taken to cure or prevent the occurrence of the disease, the monadnocks of “vitamin-Drefractory rickets” could be seen to protrude from the flood-plain of metabolic bone disease. It was then that Albright et al. (13) would publish the first carefully documented report on “vitamin D resistant rickets.” Soon thereafter attention was drawn to the role played by renal tubular loss of phosphate in the pathogenesis of “refractory,” hypophosphatemic rickets (14). Subsequent systematic approaches to the classification of vitamin D refractory rickets and osteomalacia (15, 16) have brought increasing order to this difficult area of clinical medicine. Two decades after the report by Albright and colleagues had appeared, Fraser and Salter (17) were able to list 13 conditions in the category of hereditary “refractory” rickets or osteomalacia for which a variety of pathogenetic mechanisms was apparent. However, patients with such diseases are rarely “resistant” to vitamin D. Rather they are “refractory,” i.e., their disease does not respond to what is considered the amount of vitamin D that will prevent nutritional rickets. (An average daily intake of 40 IU (1.0 g)
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SCR
IVER
of
crystalline vitamin D2 (ergocalciferol) or (cholecalciferol) will prevent rickets in normal growing children. The average requirement has been set at 10 times this dose, or 400 IU to cover the needs of all normal subjects. A precise requirement for vitamin D in adult life has not been established, but there can be little doubt that adults in the total absence of sunlight, require exogenous vitamin D.) Some will exhibit the appropriate physiological response to pharmacological doses of vitamin D; others will respond to replacement of phosphate in combination with an augmented vitamin D intake. Because the subject of “refractory” rickets still remains rather refractory to classification, and as a means of focussing attention on the primary aberrant process, the terms “calciopenic” and “phosphopenic” rickets (Table 1) were proposed recently (18) to interpret the rationale for preference of one mode of treatment over another. Calciopenia suggests that the primary disturbance is in calcium availability and that the disease may, therefore, respond to vitamin D therapy; phosphopenia suggests a primary abnormality in available phosphate, where vitamin D would only be an adjunct to a primary emphasis on phosphate replacement. D3
Calciopenic rickets
and phosphopenic
Calciopenic
rickets
mechanisms
of
Rickets or osteomalacia will occur when the long-term availability of calcium is sufficiently impaired to cause calciopenia as the initial event. Simple dietary restriction of calcium must be extreme to achieve rickets by this mechanism in the experimental animal. In man, such extremes of dietary restriction have almost never been observed; the iatrogenic case reported by Maltz et al. (19) appears to be a rare human example of diet-induced calciopenia with rickets. Barring a primary abnormality of the absorbing epithelium (e.g., celiac disease or sprue) which may impair absorption of calcium and other nutrients, the integrity of calcium transport depends on access to the biologically active forms of vitamin D. In the past decade it has been shown that vitamin D as cholecalciferol, (D3) or ergocalciferol, (D2)
FAMILIAL TABLE Causes
I of rickets
“refractory”
FORMS
to vitamin
OF
VITAMIN
D-RESISTANT
Da
Calciopenic
Phosphopenic
causes
deprivation
Calcium
Transport
Defective absorption: bile salt depletion (effect on vitamin D absorption) Sprue, celiac disease, etc. (effect on calcium and vitamin D absorption)
X-linked
1) Defective synthesis of 25-OH-D:
Secondary forms parathyroidism
-Hepatoceblular -Drug-induced somal
2)
disease: increase
Defective
synthesis
-Hereditary dency’ “Refractory
to
physiological
Tubulopathies
involving phosphate solutes (15, 16): includes the Fanconi syndrome (36) and
Whereas also plays
other
(secondary to hyperwith calciopenia)
of micro-
of la,25-(OH)2D; (cortex)
vitamin D depen(pseudodeficiency rickets) doses
doses in text.
of
D (prohormone), can be responsive D metabolites (25-OH-D or la-OH-vitamin
vitamin
of vitamin
must be hydroxylated first in liver, to form 25-hydroxyvitamin D (25-OH-D) and then in kidney to form la, 25-dihydroxyvitamin D (la, 25-(OH)2D), (see also this symposium). The latter product is a sterol, possessing hormone-like activity with respect to calcium metabolism in the intestine and bone. The formation of a trihydroxyvitamin D metabolite Ia-24, 25-(OH)3D2 has also been described in rat kidney; this substance acts specifically on intestine to stimulate calcium transport. The formation, regulation, and function of vitamin D hormone has been a very active field of research in recent years (20-27). The specific control of transepithehal movement of calcium by vitamin D and other calciotropic agents has also been the subject of some interesting observations and speculations (28). It follows that a hereditary impairment in the biosynthesis of vitamin D hormone, should it ever occur, would be likely to cause calciopenic rickets. We believe that autosomal-recessive, vitamin D dependency is a prototype of calciopenic, hereditary refractory rickets (Table 2). Phosphopenic
Hypophosphatemia’
oxidation
-Renal parenchymal disease;
vitamin D or “physiological” types discussed in detail
causes
Phosphate deprivation (in antacid therapy with magnesium-aluminum hydroxides)
Nutritional
Metabolic
1317
RICKETS
rickets there is evidence that vitamin a role in the intestinal absorption
D of
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to pharmacological D analogues).
doses of 1Proto-
phosphate (29), and that phosphate anion participates in the negative feedback regulation of the biosynthesis of la,25-(OH)2D3 (29), the weight of evidence indicates that hypophosphatemia, secondary to vitamin D depletion, is the result of renal tubular rejection of phosphate in the presence of the elevated serum parathyroid hormone activity which characterizes vitamin D deficiency (18, 30). The primary mechanisms of membrane transport of phosphate in gut and kidney are still not well described beyond the fact that an anion carrier is involved; a carrier has been most intensively studied in erythrocyte membranes (31-33). Since renal tubular reabsorption of inorganic phosphate exhibits a maximum transport rate (34), one of the transepithelial transport events must be limiting. This could either be a membranebound anion carrier, or a subsequent intracellular step (35). It therefore follows that a mutation that affects the reabsorptive process could lead to phosphopenia. Tubular reabsorption of filtered phosphate is critical to the maintenance of the endogenous phosphate poo1 (34). We believe that familial (x-linked) hypophosphatemia is a prototype of phosphopenic refractory rickets.
FRASER
1318 TABLE 2 Comparative
phenotypes
of familial
AND
hypophosphatemia
SCR
IVER
and vitamin
D dependency
Familial
Vitamin dependency
hypophosphatemia Type
Presumed
Age Mode
X-ray
Phosphopenie
of rickets
defect
Calciopenic
Transepithelial of phosphate
at onset of findings
Immediately
of presentation
findings
Biochemical findings Serum calcium (total: ionized) Serum inorganic phosphate Serum 25-OH-D#{176} Serum alkaline phosphatase (bone fraction) Serum iPTH Urine phosphate’ Urine amino acids
transport anion postnatal
Early
infancy
Hypophosphatemia: rickets (3 6 mos): dwarfism with particular shortening of lower segment. Males uniformly affected; females variably affected
Hypocalcemia, irritability. Seizures, bulging fontanelle; rickets; secondary hyperparathyroidism: enamel hypoplasia (in teeth formed
Mild to severe rickets: shafts widened with undermineralization coarse trabeculation. No signs of hyperparathyroidism usually
Resembles later stages of vitamin D deficiency. Signs of hyperparathyroidism usually evident in late-diagnosed patients
postnatally). Males and females equally affected
Ii. N
N
N (or sl.I)”
II
TI N X-linked ‘Patients phosphate
Autosomal
on diet providing low Ca:inorganic excretion is abnormally increased
In the same vein, but with different pathogenetic mechanisms involved, it is evident that the various causes of tubular wasting of phosphate ( 15, 16), which include complex tubulopathies resulting in pure and variant forms of the Fanconi syndrome (35, 36), can produce phosphopenia with associated bone disease. Secondary
Deficient 25-hydroxyvitamin D- Ia-hydroxylase activity
N
Inheritance In the untreated state. iPTH. Urine inorganic concentration.
D
phosphopenia
While there is evidence for independent, primary mechanisms ofcalciopenia and phosphopenia, it is also apparent that the calciopenic state can cause “secondary” hypophosphatemia through the mechanism of hyperparathyroidism and probably also through calcium-mediated primary cellular events
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recessive
phosphate ratio (
10’
-1
0
1
2
3
4 Time,
5
6
7
8
9
10
11
weeks
FIG. 3. The serum calcium response in calciopenic autosomal recessive vitamin D dependency (ARVDD) treated with vitamin D2, 25-OHD3 and la,25-(OH)2D3 or la-OHD3. The vitamin D requirement for restoration of serum calcium to normal is expressed as equivalents of vitamin D2 (40,000 units vitamin D2 = 1000 g: and 2 g la,25-(OH)2D3 corresponds to --400 units D and assuming that 10 zg vitamin D = 3 zg 25-OHD3 = I jig la,25(OH)2D3 in biological potency). The figure reveals the expected normal response to Ia-OH metabolites and increased requirements for 25-OHD3 and vitamin D2 (the latter dose was 10 times higher in the initial trial than the eventual attenuated
requirement response
for this patient). to pharmacologic
The data also indicate the rapid response doses of precursor forms of vitamin D.
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to hormone
replacement
and
the
1324
FRASER
AND
and D3 (in the order of 1,000 to 3,000 tg per day, or 100 to 300 times the normal requirement) are required to maintain biochemical and radiological healing in ARVDD probands (89, 93). The maintenance requirement for 25-OH-D3, is also elevated (200 to 1,000 /.Lg per day) (88, 95-97). By contrast only a minute dose of la-25-(OH)2D3 (1 to 8 ,ug per day) is required to correct hypocalcemia, augment intestinal calcium absorption, establish positive calcium balance, and initiate radiological healing in vitamin D dependency (88, 94, 95). Estimates of the therapeutic dose requirements for the various forms of vitamin D indicate a requirement ratio of about 1700:700:1, for vitamin D2, 25-OH-D3 and la,25-(OH)2D3, respectively; the normal requirement ratio is believed to be about 10:3:1. If one assumes that vitamin D and 25-OH-D3 can function in ARVDD only through the production of la-25(OH)2D3 by means ofa mutant 25-hydroxy vitamin D-la hydroxylase that retains some activity, then the ratio of the therapeutic requirements of vitamin D: 25-OH-D3:la,25-(OH)2D3 can be taken as an indirect measure of the efficiency of vitamin D conversion to its active metabolite in ARVDD. Conversion of vitamm D to 25-OH-D appears to be relatively efficient in vitamin D dependency rickets, the 3: 1 dosage requirement ratio for vitamin D:25-OH-D3 being similar to that described in the rat (98). However, the meaning of the high requirement for 25-OH-D3 relative to la,25-(OH)2D3 (700:1 in ARVDD) requires a knowledge of the relative efficacies of these two metabolites in man under circumstances where biosynthesis of vitamin D hormone is not impaired. Observations in vitamin D deficiency can serve in this capacity. Balsan and colleagues (88) and Fraser and Kooh (unpublished data) have shown that the therapeutic dose requirement for la,25-(OH)2D3 (or crystalline la-OH-D3) is about 50 ng per kilogram per day to bring about healing in vitamin D deficiency; the requirement for 25OH-D3 is only about three times higher (Fraser and Kooh, unpublished data). Although the requirement for 1aOH vitamin D analogues in ARVDD may be slightly increased above “normal” (to 80 to 100 ng per kg (94), or even somewhat higher (88)) for
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SCRIVER
reasons that are still unclear, nonetheless they are close to the physiological range, whereas those for 25-OH-D3 as mentioned above, are 200 to 300 times higher than normal. The above mentioned evidence indicates that ARVDD is an inborn error ofvitamin D hormone biosynthesis, affecting the conversion of 25-OH-D to la,25-(OH)2D. The defect is presumed to be an attenuation of 25-hydroxy-vitamin D- 1-hydroxylase activity in the kidney. Treatment with la-OH-D analogues presumably bypasses the enzymatic defect and supplies the deficient, active metabolite of vitamin D. Confirmation of the hypothesis awaits study of mitochondrial 1-hydroxylase in proband kidneys at which time evaluation of the kinetics of the mutant enzyme may also provide an explanation for the therapeutic response to pharmacological doses of vitamin D or 25-OH-D. Because of the complex pathway of vitamin D metabolism it seems likely then that ARVDD is but the first of many possible inborn errors affecting it, and we can expect to find the customary genetic heterogeneity involving the different enzymes (and gene loci) in the vitamin D dependency syndrome in the future.
Treatment
of ARVDD
With the demonstration that biochemical and radiographic healing can be initiated with minute doses of la,25-(OH)2D3 or laOH-D3, the possibility exists of using these active agents in therapy. The more rapid onset, and the shorter duration of action could theoretically be of advantage over vitamm D in the clinical setting (Fig. 3). However, until la-25-(OH)2D3 and la-OH-D3 become readily available for clinical use, and until there has been sufficient experience with dosage and use of these drugs, vitamin D remains the agent of choice. Several high-potency vitamin D preparations are available. All those in North America contain vitamin D2; preparations of vitamin D3 are available in Europe. As far as we know at present there is no reason to prefer one form over the other for therapeutic purposes in man. Products with the vitamin in
FAMILIAL
FORMS
OF
VITAMIN
liquid form (usually 2,500 g per ml) have major advantages over capsules. In contrast to the inflexibility of treatment with capsules, liquid preparations permit the physician to prescribe the specific dose of vitamin D required by the patient. The most practical means to measure and administer the dose is with a turberculin syringe from which the vitamin D is instilled directly into the mouth of the patient. ARVDD can also be treated with 25-OH-D3 on a long-term basis (99; Fraser and Kooh, unpublished data). The dosage requirement to maintain normal plasma calcium and phosphorus levels and normal bone architecture is in excess of 150 to 200 zg per day. Although 25-OH-D3 is a satisfactory therapeutic agent, it is no less likely to cause hypercalcemia than is vitamin D, nor does the hypercalcemia disappear more rapidly when the agent is withheld. Despite the smaller dosage of 25-OH-D3 needed to control the rachitic disease, the drug offers no substantial advantages over vitamin D. Patients with vitamin D dependency rickets will also respond to treatment with dihydrotachysterol (DHT), but the dose required is large. The theoretical possibility that the configuration of the rotated A-ring of the DHT molecule would provide an antirachitic agent ofa potency approaching that of la,25(OH)2D3 has not been borne out, as daily doses of 500 to 1,000 .Lg appear to be needed in ARVDD. Although it is clear from published reports (100) that DHT is a satisfactory agent for treatment of ARVDD, we do not believe the agent has any special advantages over vitamin D.
Inheritance
of ARVDD
and recurrence
risks
The inheritance of ARVDD is almost certainly autosomal recessive (91, 92). Heterozygotes show no biochemical or clinical manifestations by currently available tests (91). At present, we do not know whether the serum concentration of la,25-(OH)2D is very low in homozygotes and intermediate in heterozygotes. A radioimmune assay (101) is now available and should help provide quantitative answers. In addition, enzyme studies would provide data on the relative enzyme
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D-RESISTANT
RICKETS
1325
activities in homozygous and heterozygous subjects. The recurrence risk for the disease is 25% at each birth for siblings of homozygous probands. Diagnosis can be made within a few weeks after birth on the basis of serum calcium and iPTH levels and treatment can be started, accordingly, to prevent florid phenotypic manifestations.
Retrospective
comment
Albright and colleagues (13) were among the first to delineate “rickets resistant to vitamin D therapy.” Although no family data were mentioned, the case report indicates that the 16-year-old male patient probably had x-linked hypophosphatemia. The authors found histological evidence for hyperparathyroidism in their patient. They also showed that his urinary excretion of phosphorus fell by about 25%, without a concomitant rise in serum phosphorus, when he was treated with massive doses of vitamin D2. Healing of rickets was observed under these conditions. The title of their paper, and the towering reputation of the authors each played their part in influencing the subsequent analysis of phosphopenic rickets. The finding of hyperparathyroidism in the patient was an important diversion. In retrospect it is of interest that the calcium:phosphorus intake ratio in the patient was about 0.75. When phosphate absorption is defective, calcium absorption is likely to be compromised and could thus initiate parathyroid hyperactivity. It is of interest that very few of the many hundred known XLH probands have apparently experienced hyperparathyroidism worthy of documentation in the literature (102). When it occurs, it is often during a period of augmented phosphorus intake relative to calcium. Calcium infusion studies at first seemed to support the Albright hypothesis. Later work (45) in patients known to maintain a normal or near normal serum iPTH concentration (54) indicated that calcium was exerting its effect on phosphate reabsorption independent of any major effect of PTH on phosphate reabsorption by the tubule. At present, we are inclined to believe that calcium modifies phosphate transport in XLH through its
FRASER
1326
AND
intracellular effects in tubular epithelium. Confirmation of this speculation must await further studies and evidence. Meanwhile, in response to the phosphopenia hypothesis, it has been found that XLH patients respond well to phosphate replacement. The same has been found in our own experience in tubulopathies (15, 16) which also cause primary phosphopenia. The role of vitamin D in the treatment regimen for all tubular forms of phosphopenic rickets is essentially to offset the hypocalcemia induced by high phosphate intake. The above mentioned studies served to make clear, upon the discovery of ARVDD (17, 89), that the latter trait was very different from XLH. ARVDD is in fact a calciopenic form of “refractory rickets” and it fits the Albright hypothesis far better than XLH. Recognition of an elevated serum iPTH concentration in ARVDD (91) provides the essential link in the hypothesis. Research on vitamin D, and the chemical synthesis of pure crystalline analogues bearing the la-hydroxyl group (81, 82), coincided with the studies of ARVDD to provide an important opportunity for replacement of the suspected missing metabolite and to assign the putative enzyme defect in ARVDD to an abnormality of the la-OH hydroxylase activity in homozygotes. The clinical studies in two “classical” forms of phosphopenic and calciopenic vitamin-D refractory rickets show us that appropriate modification of the environment will allow the affected person to escape the otherwise predictable expression of his genotype. These studies illustrate as well as any why research on disease must continue. All citizens are not “equal” biologically and the handicap of biochemical individuality can be great in the absence of corrective knowledge.
El We
are grateful to our many
Arnaud, Hector DeLuca, Kooh, and Terry Reade tions to the work with involved.
colleagues
SCRIVER 3. 4.
5.
6. 7.
Lancet
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Metabolism, 25: 33, M. Hypophosphatemic
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N.
and
osteomalacia.
81.
1976. vitamin Orthopedic.
IVER calcification vitamin
1972.
hypophosphataemic Helv.
SCR
D 82.
Am. 3: 653, 1972. G., W. A. COCHRANE,
NIGRIN, D. JANNIGAN AND A ERNST. Results of calcium infusion renal biopsy studies in refractory rickets. Am. J. Diseases Children 104: 478, 1962. (Abst.). 69. PAUNIER, L., S. W. Kooti, P. E. CONEN, A. A. M. GIBSON ANI) D. FRASER. Renal function and histology after long-term vitamin D therapy of vitamin D refractory rickets. J. Pediat. 73: 833, 1968. 70. LILLY, C. A., C. B. PEIRCE AND R. L. GRANT. The effects of phosphates on the bones of rachitic rats. J. Nutr. 9: 25, 1935. 71. FRASER, D., N. T. JACO, E. R. YENDT,J. D. MUNN AND E. LIN. The induction of in vitro and in vivo
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large doses of vitamin D. Am. J. Diseases Children 93: 84, 1957. (Abstr.). FRASER, D., D. W. GEIGER, J. D. MUNN, P. E. SLATER, R. JOHN AND E. LIN. Calcification studies in clinical vitamin D deficiency and in hypophosphatemic vitamin D refractory rickets: the induction of calcium deposition in rachitic cartilage without the administration of vitamin D. Am. J. Diseases Children 96: 460, 1958. (Abstr.). STEENDIJK, R. The effect of a continuous intravenous infusion of inorganic phosphate on the rachitic lesions in cystinosis. Arch. Disease Childhood 36: 321, 1961. SCRIVER, C. R., R. B. G0LDBL00SI AND C. C. Ro’i. Hypophosphatemic rickets with renal hyperglycinuria, renal glucosuria and glycylprolinuria. A syndrome with evidence for renal tubular secretion of phosphorus. Pediatrics 34: 357, 1964. WEST, C. D., J. C. BLANTON, F. N. SILVERMAN AND N. H. HOLLAND. Use of phosphate salts as an adjunct to vitamin D in the treatment of hypophosphatemic vitamin D refractory rickets. J. Pediat. 64: 469, 1964. FRAME, B., R. W. SMITH, JR., J. L. FLEMING AND G. MANSON. Oral phosphates in vitamin D-refractory rickets and osteomalacia. Am. J. Diseases Children 106: 147, 1963. STICKI.ER, G. B., A. B. HAYLES AND J. W. ROSEVEAR. Familial hypophosphatemic vitamin Dresistant rickets. Am. J. Diseases Children I 10: 664, 1965. CLOW, C., T. READE AND C. R. SCRIVER. Management of hereditary metabolic disease. The role of Allied Health Personnel. New EngI. J. Med. 284: 1292, 1971. STAMP, T. C. B. The hypocalcemic effect of intravenous phosphate administration. Clin. Sci. 40: 55, 1971. REISS, E., AND J. M. CANTERBURY. The effects of phosphate on parathyroid hormone secretion. In: Calcium-Regulating Hormones, edited by R. V. Talmage, M. Owen and J. A. Parsons. Proc. of the 5th Parathyroid Conference. Amsterdam: Excerpta Medica ICS 346, 1975, p. 66. HOLICK, M. F., E. J. SEMMLER, H. K. SCHNOES AND H. F. DELUCA. I a-hydroxy derivative of vitamin D3: a highly potent analogue of I a-25dihydroxyvitamin D3. Science 180: 190, 1973. PETER LAM, H-Y., H. K. SCHNOES AND H. F. DELUCA. la-hydroxyvitamin D2: a potent synthetic analogue of vitamin D2. Science 186: 1038, 1974. HARRISON, H. E., H. C. HARRISON, F. LIFSHITZ AND A. D. JOHNSON. Growth disturbance in hereditary hypophosphatemia. Am. J. Diseases Children 112: 290, 1966. MCENERY, P. T., F. N. SILVERMAN AND C. D. WEST. Acceleration of growth with combined vitamm
D-phosphate
resistant
85.
in bones of children suffering from D-resistant rickets without recourse to
GLORIEUX, AND
therapy
J. Pediat. F. H., C. R.
of
H.
F. DELUCA. Inadequate
rickets. 1,25-dihydroxycholecalciferol.
hypophosphatemic
80: 763,
rickets.
SCRIVER,
X-linked
1972. M. F.
HOLICK
hypophosphataemic
therapeutic Lancet
response to 2: 287, 1973.
FAMILIAL 86.
E.
VITAMIN
Actions
of
patients
and therapeutic effects in nutritional rickdifferent types of vitamin D resistance. Pediat. Res. 9: 586, 1975. 88. DENT, C. E., AND T. C. B. STAMP. Hypophosphataemic osteomalacia presenting in adults. Q. J. Med. 40: 303, 1971. 89. PRADER, VON A., R. ILLIG AND E. HEIERLI. Eine
95.
biologic ets and
besondere tenten
Form Rachitis
der mit
primaren
Vitamin-D
Hypocalc#{228}mie
und
Acidic tration
I phosphate in x-linked
(Joulie’s) solution hvpophosphatemia
for
oral
97.
adminis.
Ingredients: Dibasic sodium phosphate (Na2HPO4. 7 H2O, reagent grade), 102 g: Phosphoric acid (NF 85%), 58.8 g: distilled water to 1000 ml. Dissolve the phosphate salt in approximately 750 ml warm water, to which has been added the phosphoric acid. Make the solution up to I liter distilled H20. Store at room temperature. The concentration of phosphorus in this phosphate solution is 3.04 g per 100 ml; the pH is 4.3. Treatment protocol. Phosphate supplements are given
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98.
99.
RICKETS F.
DELUCA.
1329 Response
to
crystalline
Ia-
hydroxyvitamin D3 in vitamin D dependency. Pediatric Res. 9: 593, 1975. FRASER, D., S. W. KOOH, H. P. KIND, M. F. HOLICK, Y. TANAKA AND H. F. DELUCA. Pathogenesis of hereditary vitamin D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxy-vitamin D to la,25-dihydroxyvitamin D. New EngI. J. Med. 289: 817, 1973. BALSAN, S., AND M. GARABEDIAN, 25-Hydroxycholecalciferol. A comparative study in deficiency rickets and different types of resistant rickets. J. Clin. Invest. SI: 749, 1972. BALSAN, S., M. GAJtABEDIAN AND L. LEBOUADEC. Le
autosomal-
Erbgang: die heredit#{228}re Pseudo-ManHelvet. Paediat. Acta 16: 452, 1961. 90. SCRIVER, C. R. Vitamin D dependency. Pediatrics 45: 361, 1970. 91. ARNAUD, C., R. MAIJER, T. READE, C. R. SCRIVER AND D. T. WHELAN. Vitamin D dependency: An inherited postnatal syndrome with secondary hyperparathyroidism. Pediatrics 46: 871, 1970. 92. FANCONI, A., AND A. PRADER. Die heredit#{228}re Pseudomangel rachitis. Helvet. Paediat. Acta 24: 423, 1969. 93. HAMILTON, J. R., J. HARRISON, D. FRASER, I. RADDE, R. MORECKI AND L. PAUNIER. The small intestine in vitamin D dependent rickets. Pediatrics 45: 364, 1970. 94. READE, T. M., C. R. SCRIVER, F. H. GLORIEUX, B. NOGRADY, E. DELVIN, R. POIRIER, M. F. HOLICK
Appendix
96.
resis-
dominanten gelrachitis.
H.
AND
1,25-dihydroxycholecalciferol
with hypophosphatemic, vitamin Dresistant rickets. New EngI. J. Med. 289: 495, 1973. BALSAN, S., M. GARABEDIAN, R. SORGNIARD, M. F. HOLICK AND H. F. DELUCA. 1,25-dihydroxyvitamin D3 and la-hydroxyvitamin D3 in children: in
D-RESISTANT
BETHUNE,
NORMAN.
87.
OF
A. S., J. W. COBURN, K. KUROKAWA, H. E. HARRISON AND A. W.
BRICKMAN,
J.
FORMS
rachitisme
vitam
mo-resistant
pseudocarentiel
hypocalc#{233}mique. Arch. Franc. P#{233}d. 29: 287, 1972. TANAKA, Y., H. FRANK AND H. F. DELUCA. Biological activity of 1,25-dihydroxy vitamin D3 in the rat. Endocrinology 92: 417, 1973. BALSAN, S. 25-Hydroxycholecalciferol: Effects in idiopathic
vitamin
D-resistant
rickets.
4: 45, 1970. (Suppl.). ROSEN, J. F., AND L. FINBERG.
CaIc.
Tiss.
Res.
100.
ent
101.
102.
rickets:
Actions
of
Vitamin
parathyroid
D-dependhormone
and
25-hydroxycholecalciferol. Pediat. Res. 6:552, 1972. BRUMBAUGH, P. F., D. H. MAUSSLER, R. BRESSLER AND M. R. HAUSSLER. Radioreceptor assay for la,25-dihydroxyvitamin D3. Science 183: 1089, 1974. THOMAS, W. C., JR., AND R. M. FRY. Parathyroid adenomas in chronic rickets. Am. J. Mcd. 49: 404, 1970.
five
times
the
response
daily. of
Depending
and
skeleton,
and
his his
upon
serum tolerance
the
child’s
inorganic of
body
phosphate the
solution,
weight, level treat-
should provide I to 5 g of phosphorus per day. begin treatment in the 1-year-old child, we administer 5 ml t.i.d. on the 1st day: 10 ml t.i.d. on the 2nd day; 10 ml q.i.d. on the 3rd day; 10 ml q.4.h. five times a day on the 4th day, and thereafter. This dose provides 1.5 g of supplemental phosphorus daily. Older children may require 20 ml (or more) every 4 hr five times daily. The solution is given with meals when possible: when taken between meals and at bedtime, it is followed by a drink of the patient’s choice (100 to 150 ml). ment
To
