Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A)

(OMIM phenotype number #264700)

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, resulting in 1α-hydroxylase enzyme deficiency. Two forms of vitamin D exist: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Both forms of vitamin D need two-step hydroxylation to become biologically active. The first step occurs in the liver where vitamin D is hydroxylated to 25-hydroxyvitamin D 25(OH)D by several hepatic enzymes having 25-hydroxylase activity, and CYP2R1 is the major enzyme. The second step of hydroxylation occurs mainly in the kidney, where 25(OH)D is hydroxylated by the mitochondrial 25-OHvitamin D-1α-hydroxylase to the biologically active hormone 1,25-(OH)2D. The 1,25-(OH)2D plays a central role in calcium homeostasis, bone metabolism, and on cell proliferation and differentiation of a variety of tissues. Alteration of vitamin D metabolism causes defects in the growth plate and bone demineralization, resulting rickets in children and osteomalacia in adults. Clinical manifestations of VDDR1A include: hypotonia, growth retardation, muscle weakness, hypocalcaemic seizures in early infancy and rickets. Until now, over 60 mutations have been described in different ethnic groups. Certain mutations are more frequent in certain ethnic groups. Radiographic findings include: widening of the distal physis, fraying and widening of the metaphysis, and angular deformities of the arm and leg bones.

Treatment: Consists of administration of large doses of vitamin D and physiologic doses of calcitriol. The potential complications of therapy are: nephrocalcinosis, hypercalciuria, and hypercalcemia. Therefore, regular checks monitoring of physical and biochemical examination, and renal ultrasound are required.


CYP27B1 gene, 12q14.1 (OMIM gene/locus number *609506).


Growth retardation, muscle weakness, irritability, congenital rickets with enlarged costochondral junctions of the ribs, pectus carinatum, metaphyseal flaring of the wrists or ankles, genus varus, frontal bossing enlarges sutures and fontanels or craniotabes, and long bone deformities.

Main biochemical alterations

Low Ca, low Pi, high bone ALP, low 1,25(OH)2D, normal 25 OH D, slightly high PTH, and generalized aminoaciduria.


a b

 Fig. X-ray images showing generalized osteopenia with altered texture (a,b). Humeral metaphysis shows frying with more pronounced lucency (a), and ulnar/radial metaphysis shows frying and cupping of their outline (b) - (white arrows). The cortices are indistinct with coarse fuzzy trabecuale (a & b). Fracture of right clavicle (a), and proximal shaft of the ulna (b) - (black arrows).

Reproduced from BMC Res Notes. 2014 Nov 5;7:783 under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.



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