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.

(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.

Gene

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

Phenotype

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.

Images

 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.

Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is due to a defect in vitamin D 25-hydroxylation, and is caused by mutation in the CYP2R1 gene. The synthesis of bioactive vitamin D requires hydroxylation at the 1 α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively.

(OMIM phenotype number #600081)

Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is due to a defect in vitamin D 25-hydroxylation, and is caused by mutation in the CYP2R1 gene. The synthesis of bioactive vitamin D requires hydroxylation at the 1 α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1 α-hydroxylation in the kidney, and the CYP2R1 is the major enzyme for hydroxylation of vitamin D to 25-hydroxyvitamin D. See also VDDR1A.

Gene

CYP2R1 gene, 11p15.2 (OMIM gene/locus number #608713).

Phenotype

Hypotonia, muscle weakness, difficulty in walking, difficulty in standing, congenital rickets with fractures, bone pain, sparse bone trabeculae, thin bony cortex, delayed opacification of the epiphyses, widened, distorted epiphyses, frayed, irregular metaphyses, lower limb deformities, and bowing of the legs.

Main biochemical alterations

Low Ca, low Pi, high bone ALP, normal 1,25(OH)2D, decreased 25 OH D.

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.

(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.