Hereditary disorders of vitamin-D metabolism and its receptor.

PURPOSE

Hereditary disorders of vitamin D metabolism are rare diseases. This review summarizes the current knowledge in this field and highlights the complicated metabolism of vitamin D.

METHODS

PubMed and Google Scholar databases were searched in English. The keywords rickets, VDDR, vitamin D, metabolism, hypercalcemia, CYP2R1, CYP3A4, CYP24A1, and receptor were used and original and review articles were retrieved.

RESULTS

Vitamin D is produced in the skin following the action of ultraviolet light on 7-dehydrocholesterol or is taken up by food. The active form of the hormone 1,25(OH)D is produced after two-step hydroxylations. The first hydroxylation takes place in the liver, in which 25(OH)D is produced by the enzyme CYP2R1. The second hydroxylation occurs in the kidneys where 1,25(OH)D is produced by CYP27B1. Mutations in the genes encoding these enzymes can lead to vitamin D-dependent rickets type 1B (VDDR1B) and VDDR1A, respectively. CYP24A1 is the main catabolic enzyme of vitamin D. Loss-of-function mutations of the CYP24A1 gene can lead to idiopathic infantile hypercalcemia (IIH). Moreover, loss-of-function mutations of the vitamin D receptor (VDR) gene can cause VDDR2. Recently, gain-of-function mutations of the CYP3A4 gene have been found to be responsible for a distinct form of rickets, VDDR 3, characterized by accelerated clearance of 1,25(OH)D.

CONCLUSIONS

Based on the evidence in the current literature, this article thoroughly reviews the metabolism of vitamin D, clinical symptoms, imaging findings, and available treatments for the different types of hereditary disorders related to vitamin D metabolism and action.

© 2025. The Author(s), under exclusive licence to Hellenic Endocrine Society.