Rare disorders of vitamin D metabolism

Vitamin D metabolism is a complex process involving synthesis, activation, transport, receptor-mediated action, and degradation. Rare genetic disorders affecting specific steps of metabolism can lead to severe clinical consequences. Defects in vitamin D activation include CYP27B1 mutations in vitamin D-dependent rickets type 1A (VDDR1A), which impair renal 1α-hydroxylation of 25-hydroxyvitamin D (25(OH)D) to its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D). Similarly, CYP2R1 mutations in VDDR1B disrupt 25-hydroxylation in the liver. Disorders affecting vitamin D receptor function, such as hereditary vitamin D-resistant rickets (HVDRR) due to VDR mutations, lead to endorgan resistance despite elevated 1,25(OH)2D levels. Impaired degradation, as seen in idiopathic infantile hypercalcemia (IIH) caused by CYP24A1 mutations, results in hypercalcemia and nephrocalcinosis due to reduced breakdown of active vitamin D. Such conditions can lead to severe bone abnormalities, calcium dysregulation, and organ dysfunction. Early diagnosis through genetic and biochemical testing is critical, as treatment varies depending on the underlying defect. Management strategies include high-dose vitamin D, calcitriol, or alternative therapies like calcium infusions in resistant cases. Understanding these rare disorders provides insight into vitamin D physiology and highlights the need for precise genetic and biochemical diagnosis to guide tailored treatments.