Other types of vitamin D dependent Rickets

Vitamin D-dependent rickets (VDDR) refers to a group of rare hereditary disorders characterized by impaired metabolism or action of vitamin D, resulting in defective bone mineralization, growth retardation, and biochemical abnormalities. Unlike nutritional rickets, these conditions are caused by genetic defects affecting enzymes or receptors involved in the vitamin D pathway. Vitamin D is metabolized in the liver to ۲۵-hydroxyvitamin D [۲۵(OH)D] by ۲۵-hydroxylases, and subsequently in the kidney to its active form, ۱,۲۵-dihydroxyvitamin D [۱,۲۵(OH)۲D], by the mitochondrial enzyme lα-hydroxylase (CYP۲۷B۱). Active vitamin D binds to the vitamin D receptor (VDR) in target cells, regulating calcium and phosphate homeostasis. VDDR Type ۱A is caused by biallelic mutations in CYP۲۷B۱, leading to deficient lα-hydroxylase activity. Affected patients have low or undetectable ۱,۲۵(OH)۲D despite normal or elevated ۲۵(OH)D, with hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and radiographic rickets. Treatment with physiological doses of calcitriol corrects the abnormalities. VDDR Type ۱B results from mutations in CYP۲R۱, the major hepatic ۲۵-hydroxylase. This leads to markedly reduced ۲۵(OH)D levels and subsequently low ۱,۲۵(OH)۲D. High-dose cholecalciferol or calcifediol is effective. VDDR Type ۲A is caused by mutations in the VDR gene, leading to end-organ resistance to ۱,۲۵(OH)۲D. Despite elevated active vitamin D levels, target tissues fail to respond. Clinically, patients often present with severe rickets and alopecia, the latter resulting from defective VDR function in hair follicles. Management requires very high doses of calcitriol and calcium infusions to normalize mineral balance. VDDR Type ۲B presents similarly to type ۲A but is due to abnormal nuclear receptor coactivators affecting VDR-mediated gene transcription; the genetic basis is less well defined. VDDR Type ۳, recently described, is caused by gain-of-function mutations in CYP۳A۴, which enhance inactivation of both ۲۵(OH)D and ۱,۲۵(OH)۲D, leading to functional vitamin D deficiency. Treatment involves high-dose active vitamin D and careful monitoring. Early recognition of VDDR is crucial to prevent permanent skeletal deformities and optimize growth. Genetic testing confirms the diagnosis and enables targeted therapy. Lifelong treatment is often required, tailored to the specific molecular defect.