Abstract

Background/aims: Two unrelated patients found to have hereditary vitamin D resistant rickets (HVDRR) were admitted to our hospital.

Methods: This article describes the diagnosis, management and molecular basis for their disease.

Results: Both patients had severe growth and motor developmental retardation, rickets with chest deformities and pulmonary abnormalities, but no alopecia. Both had hypocalcemia, secondary hyperparathyroidism and susceptibility to pulmonary infections. In both cases, good response with normalization of abnormal biochemistries and healing of rickets was achieved with IV calcium infusion. Subsequently, improvement was maintained with oral calcium. Both children harbored the same unique missense mutation in the vitamin D receptor (VDR) gene that substituted arginine with histidine at amino acid 274 (R274H) in the VDR ligand-binding domain (LBD). R274 is a contact point for the 1α-hydroxyl group of 1,25(OH)₂D₃, the active ligand for the VDR. Functional analyses of the R274H mutation revealed a 100-fold decrease in activity compared to wild-type VDR.

Conclusion: We describe a novel missense mutation at R274H in the VDR gene that resulted in the HVDRR syndrome in two unrelated children. Vigorous treatment using IV calcium to normalize their hypocalcemia achieved dramatic improvement in these complex and severely ill patients.