Database: OMIM
Entry: 264700
LinkDB: 264700
MIM Entry: 264700
  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.
  - Other Forms of Hypophosphatemic Rickets
  For a discussion of other forms of hypophosphatemic rickets, see ADHR
  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
  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 St. 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
See Also:
  Deluca  (1969); Holick et al. (1980); Labuda et al. (1991); Matsuda
  et al. (1969); Scriver et al. (1978)
  1. Bouchard, G.; Laberge, C.; Scriver, C. R.: La tyrosinemie hereditaire
  et le rachitisme vitamino-dependant au Saguenay. Un. Med. Canada 114:
  633-636, 1985.
  2. De Braekeleer, M.: Hereditary disorders in Saguenay-Lac-St-Jean
  (Quebec, Canada). Hum. Hered. 41: 141-146, 1991.
  3. Deluca, H. F.: Vitamin D. New Eng. J. Med. 281: 1103-1104, 1969.
  4. 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.
  5. Dent, C. E.; Friedman, M.; Watson, L.: Hereditary pseudo-vitamin
  D deficiency rickets ('pseudo-mangelrachitis'). J. Bone Joint Surg.
  Br. 50: 708-719, 1968.
  6. 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.
  7. Fraser, D.; Salter, R. B.: The diagnosis and management of the
  various types of rickets. Pediat. Clin. N. Am. 5: 417-441, 1958.
  8. 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.
  9. 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.
  10. 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.
  11. Koren, R.: Vitamin D receptor defects: the story of hereditary
  resistance to vitamin D. Pediat. Endocr. Rev. Suppl. 3: 470-475,
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.  New
  York: McGraw-Hill  (8th ed.): 2001. Pp. 4223-4240.
  18. Matsuda, I.; Sugai, M.; Ohsawa, T.: Laboratory findings in a
  child with pseudo-vitamin D deficiency rickets. Helv. Paediat. Acta 24:
  329-336, 1969.
  19. 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.
  20. Prader, A.; Kind, H. P.; DeLuca, H. F.: Pseudovitamin D deficiency
  (vitamin D dependency).In: Bickel, H.; Stern, J.: Inborn Errors of
  Calcium and Bone Metabolism.  Baltimore: University Park Press (pub.)
  1976. Pp. 115-123.
  21. Reitz, R. E.; Weinstein, R. L.: Parathyroid hormone secretion
  in familial vitamin-D-resistant rickets. New Eng. J. Med. 289: 941-945,
  22. Scriver, C. R.: Vitamin D dependency. (Editorial) Pediatrics 45:
  361-363, 1970.
  23. 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,
  24. 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.
  25. 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.
  26. 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.
  27. Winkler, I.; Schreiner, F.; Harmeyer, J.: Absence of renal 25-hydroxycholeca  lciferol-1-hydroxylase
  activity in a pig strain with vitamin D-dependent rickets. Calcif.
  Tissue Int. 38: 87-94, 1986.
  28. 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.
Clinical Synopsis:
     Autosomal recessive
     Failure to thrive;
     Poor growth;
     Growth retardation
     Frontal bossing;
     Delayed tooth eruption;
     Enamel hypoplasia
     [Ribs, sternum, clavicles, and scapulae];
     Enlargement of the costochondral junction;
     'Bulging' of the costochondral junction;
     Deformed rib cage
     [External features];
     Protuberant abdomen due to muscle weakness
     Increased fractures;
     Bone pain;
     Sparse bone trabeculae;
     Thin bony cortex;
     Widened cranial sutures;
     Posterior flattening of the skull;
     Delayed opacification of the epiphyses;
     Widened, distorted epiphyses;
     'Bulging' epiphyses;
     Frayed, irregular metaphyses;
     Curvatures of the femur, tibia, fibula;
     Lower limb deformities;
     Bowing of the legs;
     Enlargement of the wrists;
     Enlargement of the ankles;
     Subperiosteal erosions due to secondary hyperparathyroidism
     Muscle weakness;
     Difficulty walking;
     Difficulty standing
     [Central nervous system];
     Delayed motor development;
     Seizures due to hypocalcemia;
     [Behavioral/psychiatric manifestations];
     Secondary hyperparathyroidism
     Increased serum parathyroid hormone (PTH);
     Increased serum alkaline phosphatase;
     Generalized aminoaciduria;
     Markedly decreased or absent serum 1,25-dihydroxyvitamin D3;
     Normal serum 25-hydroxyvitamin D3
     Clinical onset within first 2 years of life;
     Can be treated with physiologic levels of 1,25-dihydroxyvitamin D3
     or 1-alpha-hydroxyvitamin D3;
     Increased frequency among French-Canadians from the Charlevoix-Saguenay-Lac
     Saint Jean area of Quebec (carrier rate 1 in 26)
     Caused by mutations in the 25-hydroxyvitamin D3-1-alpha-hydroxylase
     gene (CYP27B1, 609506.0001).
  Cassandra L. Kniffin - revised: 9/12/2005
Creation Date: 
  John F. Jackson: 6/15/1995
Edit Dates: 
  ckniffin: 09/26/2005
  ckniffin: 9/15/2005
  joanna: 9/12/2005
  ckniffin: 9/12/2005
  ckniffin: 8/15/2005
  Marla J. F. O'Neill - updated: 3/29/2010
  Marla J. F. O'Neill - updated: 3/22/2010
  Cassandra L. Kniffin - reorganized: 8/23/2005
  Cassandra L. Kniffin - updated: 8/15/2005
  John A. Phillips, III - updated: 1/21/2003
  John A. Phillips, III - updated: 7/23/2001
  John A. Phillips, III - updated: 2/9/2001
  John A. Phillips, III - updated: 10/2/2000
  Victor A. McKusick - updated: 2/25/2000
  Victor A. McKusick - updated: 12/21/1998
  Victor A. McKusick - updated: 3/30/1998
  John A. Phillips, III - updated: 3/18/1998
  Victor A. McKusick - updated: 3/5/1998
  Victor A. McKusick - updated: 3/2/1998
  Victor A. McKusick - updated: 9/18/1997
Creation Date: 
  Victor A. McKusick: 6/4/1986
Edit Dates: 
  terry: 01/13/2011
  carol: 3/29/2010
  carol: 3/22/2010
  carol: 8/23/2005
  ckniffin: 8/15/2005
  carol: 7/22/2004
  carol: 7/21/2004
  carol: 3/17/2004
  tkritzer: 11/14/2003
  alopez: 3/14/2003
  alopez: 1/21/2003
  alopez: 7/23/2001
  alopez: 7/16/2001
  mcapotos: 7/6/2001
  alopez: 2/22/2001
  terry: 2/9/2001
  mgross: 10/12/2000
  terry: 10/2/2000
  mgross: 3/15/2000
  terry: 2/25/2000
  carol: 12/28/1998
  terry: 12/21/1998
  carol: 7/9/1998
  terry: 7/7/1998
  carol: 6/19/1998
  alopez: 3/30/1998
  terry: 3/25/1998
  psherman: 3/20/1998
  psherman: 3/19/1998
  psherman: 3/18/1998
  dholmes: 3/10/1998
  alopez: 3/6/1998
  terry: 3/5/1998
  alopez: 3/2/1998
  terry: 3/2/1998
  terry: 2/27/1998
  mark: 9/18/1997
  terry: 9/16/1997
  davew: 8/19/1994
  mimadm: 3/12/1994
  warfield: 3/10/1994
  carol: 10/1/1992
  carol: 3/31/1992
  supermim: 3/17/1992
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