Alternative titles; symbols
SNOMEDCT: 67049004; ORPHA: 289157; DO: 0080886;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q14.1 | Vitamin D-dependent rickets, type I | 264700 | Autosomal recessive | 3 | CYP27B1 | 609506 |
A number sign (#) is used with this entry because hereditary selective deficiency of the active form of vitamin D (1,25-dihydroxyvitamin D3), also known as vitamin D-dependent rickets type 1A (VDDR1A), is caused by mutation in the gene encoding 25-hydroxyvitamin D3-1-alpha-hydroxylase (CYP27B1; 609506) on chromosome 12q13.
Vitamin D3 (cholecalciferol), synthesized in the epidermis in response to UV radiation, and dietary vitamin D2 (ergocalciferol, synthesized in plants) are devoid of any biologic activity. Vitamin D hormonal activity is due primarily to the hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the actions of which are mediated by the vitamin D receptor (VDR; 601769) (Koren, 2006; Liberman and Marx, 2001).
In the liver, vitamin D 25-hydroxylase (CYP2R1; 608713) catalyzes the initial hydroxylation of vitamin D at carbon 25; in the kidney, 1-alpha-hydroxylase (CYP27B1; 609506) catalyzes the hydroxylation and metabolic activation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3. The active metabolite 1,25(OH)2D3 binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis and cellular differentiation and proliferation (Takeyama et al., 1997).
Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (Liberman and Marx, 2001).
Genetic Heterogeneity of Vitamin D-Dependent Rickets
Vitamin D-dependent rickets type 1A (VDDR1A) is due to an enzymatic defect in synthesis of the active form of vitamin D caused by mutation in the CYP27B1 gene. VDDR1B (600081) is a form of rickets due to mutation in the gene encoding a vitamin D 25-hydroxylase (CYP2R1; 608713), another enzyme necessary for the synthesis of active vitamin D. Vitamin D-dependent rickets type 2A (VDDR2A; 277440) is caused by end-organ unresponsiveness of active vitamin D due to mutation in the gene encoding the vitamin D receptor (VDR; 601769). VDDR2B (600785) is an unusual form of end-organ unresponsiveness to active vitamin D due to an abnormal protein (see HNRNPC, 164020) that interferes with the function of the VDR. VDDR3 (619073) is a dominant form of VDDR caused by accelerated inactivation of vitamin D metabolites due to mutation in the CYP3A4 gene (124010).
Other Forms of Hypophosphatemic Rickets
For a discussion of other forms of hypophosphatemic rickets, see ADHR (193100).
Kitanaka et al. (1998) reported 4 unrelated Japanese patients with vitamin D-dependent rickets confirmed by genetic analysis. All presented by age 2 years with inability to walk, bone deformities, or seizures. One showed poor growth as an infant. Laboratory studies showed hypocalcemia, markedly decreased serum 1,25-dihydroxyvitamin D3, normal serum 25-hydroxyvitamin D3, aminoaciduria, hyperparathyroidism, and absence of 1-alpha-hydroxylase activity. Effective treatment required large doses of vitamin D2 and physiologic doses of 1-alpha-hydroxyvitamin D3.
Vitamin D-dependent rickets type 1A is an autosomal recessive disorder. Prader et al. (1961) originally suggested dominant inheritance, but later changed his view when he identified an affected family with healthy first-cousin parents who had normal plasma levels of calcium and phosphorus (cited by Dent et al., 1968). Dent et al. (1968) described a severely affected patient and made brief mention of 2 other patients known to them, both with normal parents who were related as first cousins.
Scriver (1970) supported autosomal recessive inheritance and suggested that the condition may be more frequent than previously realized.
Hamilton et al. (1970) demonstrated defective intestinal absorption of calcium in patients with VDDR1A. Reitz and Weinstein (1973) found elevated peripheral parathyroid hormone concentrations in all subjects with vitamin D-dependent rickets.
Fraser et al. (1973) concluded that the basic defect in VDDR1A was an inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by enzyme 25-hydroxyvitamin D-1-hydroxylase. Prader et al. (1976) stated that patients with VDDR1A had a specific response to 1-alpha-hydroxyvitamin D3, but not to 25-hydroxyvitamin D3, suggesting a specific deficiency of renal 1-alpha-hydroxylase.
Delvin et al. (1981) reported successful treatment of vitamin D-dependent rickets with calcitriol supplementation.
Kitanaka et al. (1998) reported that physiologic doses of 1,25(OH)2D3 administered on a daily basis was efficient replacement therapy.
By linkage analysis of 5 French Canadian families with vitamin D-dependent rickets type 1A, Labuda et al. (1989) found linkage to markers on chromosome 12. Labuda et al. (1989, 1990, 1992) narrowed the assignment to 12q14 by finding flanking DNA markers. One of the flanking markers was COL2A1 (120140) and the other was a 3-marker haplotype: D12S14, D12S17, and D12S6. Linkage disequilibrium between VDDR1A and the 3-marker haplotype supported the notion of founder effect in the French Canadian population studied.
Sinnett et al. (1990) described a new approach based on PCR amplification with Alu-specific primers to reveal multiple-loci DNA markers, which they called alumorphs. Using the alumorph technique to study genomic DNA samples from 2 families with a history of VDDR1A, Zietkiewicz et al. (1992) found linkage to several markers on 12q known to be tightly linked to the locus for PDDR I. Furthermore, the polymorphic band, denoted 30A, specifically hybridized to DNA digests from hybrid cell lines carrying a human chromosome 12.
In 4 unrelated Japanese patients with VDDR1A, Kitanaka et al. (1998) identified 4 different homozygous mutations in the CYP27B1 gene (609506.0001-609506.0004). Two of the patients were born of consanguineous parents.
Bouchard et al. (1985) reported that vitamin D-dependent rickets is unusually frequent in French Canadians in the Saguenay region of Quebec, where the estimated gene frequency is 0.02.
De Braekeleer (1991) estimated the prevalence at birth to be 1 in 2,358, giving a carrier rate of 1 in 26 in the Saguenay-Lac-Saint-Jean region of Quebec province.
Fraser and Salter (1958) and Scriver (1970) suggested the term 'vitamin D-dependent rickets' to describe this disorder. It has also been referred to as 'pseudovitamin D-deficiency rickets' (Prader et al., 1961). Other suggested terms include '1-alpha-hydroxylase deficiency' (Wang et al., 1998) and 'selective 1-alpha, 25-hydroxyvitamin D3 deficiency' (Liberman and Marx, 2001).
Winkler et al. (1986) reported absence of renal 25-hydroxyvitamin D-1-hydroxylase activity in a pig strain with vitamin D-dependent rickets.
Bouchard, G., Laberge, C., Scriver, C. R. La tyrosinemie hereditaire et le rachitisme vitamino-dependant au Saguenay. Un. Med. Canada 114: 633-636, 1985. [PubMed: 4060342]
De Braekeleer, M. Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada). Hum. Hered. 41: 141-146, 1991. [PubMed: 1937486] [Full Text: https://doi.org/10.1159/000153992]
Deluca, H. F. Vitamin D. New Eng. J. Med. 281: 1103-1104, 1969. [PubMed: 4309963] [Full Text: https://doi.org/10.1056/NEJM196911132812006]
Delvin, E. E., Glorieux, F. H., Marie, P. J., Pettifor, J. M. Vitamin D dependency: replacement therapy with calcitriol. J. Pediat. 99: 26-34, 1981. [PubMed: 6265615] [Full Text: https://doi.org/10.1016/s0022-3476(81)80952-3]
Dent, C. E., Friedman, M., Watson, L. Hereditary pseudo-vitamin D deficiency rickets ('pseudo-mangelrachitis'). J. Bone Joint Surg. Br. 50: 708-719, 1968. [PubMed: 5706877]
Fraser, D., Kooh, S. W., Kind, H. P., Holick, M. F., Tanaka, Y., DeLuca, H. F. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1-alpha, 25-dihydroxyvitamin D. New Eng. J. Med. 289: 817-822, 1973. [PubMed: 4357855] [Full Text: https://doi.org/10.1056/NEJM197310182891601]
Fraser, D., Salter, R. B. The diagnosis and management of the various types of rickets. Pediat. Clin. N. Am. 5: 417-441, 1958.
Hamilton, R., Harrison, J., Fraser, D., Raddle, I., Morecki, R., Paunier, L. The small intestine in vitamin D dependent rickets. Pediatrics 45: 364-373, 1970. [PubMed: 5442911]
Holick, M. F., Uskokovic, M., Henley, J. W., MacLaughlin, J., Holick, S. A., Potts, J. T., Jr. The photoproduction of 1-alpha, 25-dihydroxyvitamin D3 in skin: an approach to the therapy of vitamin-D-resistant syndromes. New Eng. J. Med. 303: 349-354, 1980. [PubMed: 6248779] [Full Text: https://doi.org/10.1056/NEJM198008143030701]
Kitanaka, S., Takeyama, K., Murayama, A., Sato, T., Okumura, K., Nogami, M., Hasegawa, Y., Niimi, H., Yanagisawa, J., Tanaka, T., Kato, S. Inactivating mutations in the 25-hydroxyvitamin D3-1-alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. New Eng. J. Med. 338: 653-661, 1998. [PubMed: 9486994] [Full Text: https://doi.org/10.1056/NEJM199803053381004]
Koren, R. Vitamin D receptor defects: the story of hereditary resistance to vitamin D. Pediat. Endocr. Rev. Suppl. 3: 470-475, 2006.
Labuda, M., Fujiwara, T. M., Ross, M. V., Morgan, K., Garcia-Heras, J., Ledbetter, D. H., Hughes, M. R., Glorieux, F. H. Two hereditary defects related to vitamin D metabolism map to the same region of human chromosome 12q13-14. J. Bone Miner. Res. 7: 1447-1453, 1992. [PubMed: 1336301] [Full Text: https://doi.org/10.1002/jbmr.5650071212]
Labuda, M., Morgan, K., Glorieux, F. H. Autosomal recessive, vitamin D dependency type I (VDD1) mapped to chromosome 12q by linkage analysis. (Abstract) Cytogenet. Cell Genet. 51: 1027-1028, 1989.
Labuda, M., Morgan, K., Glorieux, F. H. Regional assignment of vitamin D dependent rickets type I to chromosome 12q14. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A147 only, 1989.
Labuda, M., Morgan, K., Glorieux, F. H. Mapping autosomal recessive vitamin D dependency type I to chromosome 12q14 by linkage analysis. Am. J. Hum. Genet. 47: 28-36, 1990. [PubMed: 1971995]
Labuda, M., Ross, M. V., Fujiwara, T. M., Morgan, K., Ledbetter, D., Hughes, M. R., Glorieux, F. H. Two hereditary defects related to vitamin D metabolism map to the same region of human chromosome 12q. (Abstract) Cytogenet. Cell Genet. 58: 1978 only, 1991.
Liberman, U. A., Marx, S. J. Vitamin D and other calciferols. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 4223-4240.
Matsuda, I., Sugai, M., Ohsawa, T. Laboratory findings in a child with pseudo-vitamin D deficiency rickets. Helv. Paediat. Acta 24: 329-336, 1969. [PubMed: 5800164]
Prader, A., Illig, R., Heierli, E. Eine besondere Form der primaeren Vitamin-D-resistenten Rachitis mit Hypocalcaemie und autosomal-dominantem Erbgang: die hereditaere Pseudo-Mangelrachitis. Helv. Paediat. Acta 16: 452-468, 1961. [PubMed: 14488440]
Prader, A., Kind, H. P., DeLuca, H. F. Pseudovitamin D deficiency (vitamin D dependency). In: Bickel, H.; Stern, J. (eds.): Inborn Errors of Calcium and Bone Metabolism. Baltimore: University Park Press (pub.) 1976. Pp. 115-123.
Reitz, R. E., Weinstein, R. L. Parathyroid hormone secretion in familial vitamin-D-resistant rickets. New Eng. J. Med. 289: 941-945, 1973. [PubMed: 4355232] [Full Text: https://doi.org/10.1056/NEJM197311012891804]
Scriver, C. R., Reade, T. M., DeLuca, H. F., Hamstra, A. J. Serum 1, 25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. New Eng. J. Med. 299: 976-979, 1978. [PubMed: 308618] [Full Text: https://doi.org/10.1056/NEJM197811022991803]
Scriver, C. R. Vitamin D dependency. (Editorial) Pediatrics 45: 361-363, 1970. [PubMed: 5445543]
Sinnett, D., Deragon, J.-M., Simard, L. R., Labuda, D. Alumorphs--human DNA polymorphisms detected by polymerase chain reaction using Alu-specific primers. Genomics 7: 331-334, 1990. [PubMed: 1973138] [Full Text: https://doi.org/10.1016/0888-7543(90)90166-r]
Takeyama, K., Kitanaka, S., Sato, T., Kobori, M., Yanagisawa, J., Kato, S. 25-hydroxyvitamin D3 1-alpha-hydroxylase and vitamin D synthesis. Science 277: 1827-1830, 1997. [PubMed: 9295274] [Full Text: https://doi.org/10.1126/science.277.5333.1827]
Wang, J. T., Lin, C.-J., Burridge, S. M., Fu, G. K., Labuda, M., Portale, A. A., Miller, W. L. Genetics of vitamin D 1-alpha-hydroxylase deficiency in 17 families. Am. J. Hum. Genet. 63: 1694-1702, 1998. [PubMed: 9837822] [Full Text: https://doi.org/10.1086/302156]
Winkler, I., Schreiner, F., Harmeyer, J. Absence of renal 25-hydroxycholecalciferol-1-hydroxylase activity in a pig strain with vitamin D-dependent rickets. Calcif. Tissue Int. 38: 87-94, 1986. [PubMed: 3082499] [Full Text: https://doi.org/10.1007/BF02556835]
Zietkiewicz, E., Labuda, M., Sinnett, D., Glorieux, F. H., Labuda, D. Linkage mapping by simultaneous screening of multiple polymorphic loci using Alu oligonucleotide-directed PCR. Proc. Nat. Acad. Sci. 89: 8448-8451, 1992. [PubMed: 1528850] [Full Text: https://doi.org/10.1073/pnas.89.18.8448]