MIM Entry: 264700
#264700 VITAMIN D HYDROXYLATION-DEFICIENT RICKETS, TYPE 1A; VDDR1A
;;VITAMIN D-DEPENDENT RICKETS, TYPE 1A;;
1@-ALPHA, 25-HYDROXYVITAMIN D3 DEFICIENCY, SELECTIVE;;
VITAMIN D DEPENDENCY, TYPE 1; VDD1;;
PSEUDOVITAMIN D-DEFICIENCY RICKETS, TYPE IA; PDDR1A;;
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
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
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
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
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
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:
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:
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:
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:
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:
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:
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:
Failure to thrive;
HEAD AND NECK:
Delayed tooth eruption;
[Ribs, sternum, clavicles, and scapulae];
Enlargement of the costochondral junction;
'Bulging' of the costochondral junction;
Deformed rib cage
Protuberant abdomen due to muscle weakness
Sparse bone trabeculae;
Thin bony cortex;
Widened cranial sutures;
Posterior flattening of the skull;
Delayed opacification of the epiphyses;
Widened, distorted 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, SOFT TISSUE:
[Central nervous system];
Delayed motor development;
Seizures due to hypocalcemia;
Increased serum parathyroid hormone (PTH);
Increased serum alkaline phosphatase;
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
John F. Jackson: 6/15/1995
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
Victor A. McKusick: 6/4/1986