Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets

Abstract

Heterogeneous loss of function mutations in the vitamin D receptor (VDR) interfere with vitamin D signaling and cause hereditary vitamin D-resistant rickets (HVDRR). HVDRR is characterized by hypocalcemia, secondary hyperparathyroidism and severe early-onset rickets in infancy and is often associated with consanguinity. Affected children may also exhibit alopecia of the scalp and total body. The children usually fail to respond to treatment with calcitriol; in fact, their endogenous levels are often very elevated. Successful treatment requires reversal of hypocalcemia and secondary hyperparathyroidism and is usually accomplished by administration of high doses of calcium given either intravenously or sometimes orally to bypass the intestinal defect in VDR signaling.

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

“…But these babies appear normal at birth (apart from alopecia in VDDR-II) and have normal calcium levels (66,180,312,408,538,621,662,665). In both conditions the child is fated to develop hypocalcemia, hypophosphatemia, and rickets.…”

“…Mortality can also occur in infancy or childhood due to the severity of the hypocalcemia (36,374). Pseudofractures and fractures can occur in both conditions, but bowing of the long bones and metaphyseal widening are much more common (36,66,180,230,258,312,408,538,621,662,665,727).…”

1,25-Dihydroxyvitamin D3 Controls a Cohort of Vitamin D Receptor Target Genes in the Proximal Intestine That Is Enriched for Calcium-regulating Components

“…As the elaboration of these hormones is modulated directly by the calcium content in the blood, the activities of 1,25(OH) 2 D 3 in the intestine, kidney, and bone as well as other target tissues are linked directly to the levels of calcium and phosphate that are present in the extracellular compartment. Interestingly, although the vast majority of these fundamental principles of calcium homeostasis has been defined through studies in animal models as well as in humans over several decades (5,6), the phenotypes of a number of genetically modified murine models are currently providing important new insights. These models include strains which contain crippling genomic mutations in either the Cyp27b1 (7,8) or the Vdr genes (9 -12) that closely replicate the molecular defects observed and characterized in humans.…”

Vitamin D – what is normal according to latest research and how should we deal with it?

“…There is no apparent early excess risk of cancers nor autoimmune conditions or hypertension in these patients. 11 Due to rarity, the numbers of patients studied is small so no firm conclusions can be drawn from the human disease state. …”