Vitamin D-dependent rickets type 2A (VDDR2A)

(OMIM phenotype number #277440)

Vitamin D-dependent rickets type 2A (VDDR2A) is an autosomal recessive disorder caused by mutation in the gene encoding the vitamin D receptor (VDR). Signalling via this receptor regulates gene expression in 1,25 OHvitamin D3-responsive cells. It is characterized by hypocalcemia, due to reduced intestinal absorption of calcium, with secondary hyperparathyroidism and hypophosphataemia. Hypocalcemia and hypophosphataemia impair normal bone mineralization leading to childhood rickets. Other clinical manifestations include muscle weakness and convulsions caused by hypocalcaemia, and in many cases alopecia.

Therapeutic management consists in daily administration of high doses of calcitriol and calcium.

Gene

VDR gene, 12q13.11 (OMIM gene/locus number *601769).

Phenotype

Growth retardation, muscle weakness, convulsion for hypocalcemia, bone pain at the lower extremities that delays their development of walking, dental caries or hypoplasia of the teeth, scalp and total alopecia, mild deafness, congenital rickets with fracture and pseudofractures, sparse bone trabeculae, thin bony cortex, delayed opacification of the epiphyses, widened, distorted epiphyses, frayed, irregular metaphyses, lower limb deformities, bowing of the legs, curvatures of the femur, tibia, fibula, enlargement of the wrists, enlargement of the ankles, and subperiosteal erosions due to secondary hyperparathyroidism.

Main biochemical alterations:

High 1,25(OH)2D normal 25 OH D, markedly high PTH, low Ca and Pi, and markedly high bone ALP.

References

  1. Arita K, Nanda A, Wessagowit V, et al. A novel mutation in the VDR gene in hereditary vitamin D-resistant rickets. Br J Dermatol. 2008 Jan;158(1):168-71.
  2. Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A. 1988 May;85(10):3294-8.
  3. Koren R. Vitamin D receptor defects: the story of hereditary resistance to vitamin D. Pediatr Endocrinol Rev. 2006 Aug;3 Suppl 3:470-5.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org