What causes acquired and congenital rickets?
Rickets results from impaired skeletal mineralization during childhood. Acquired rickets has the same etiologies as osteomalacia in adults. Additionally, there are three main inherited disorders resulting in congenital rickets:
- 1. Hypophosphatemic rickets: X-linked hypophosphatemic rickets results from inherited loss of function mutations in the PHEX gene, leading to increased bone expression of fibroblast growth factor 23 (FGF 23) due to decreased FGF 23 proteolysis. Autosomal dominant hypophosphatemic rickets results from activating mutations in the gene that encodes FGF 23, resulting in increased FGF 23 levels. FGF 23, the body’s main phosphaturic factor, lowers serum phosphate by forming a ternary complex with the FGF 23 receptor and the Klotho protein to enhance renal phosphate loss through renal sodium-phosphate transporters. FGF 23 also reduces intestinal phosphate absorption by lowering serum 1,25 (OH) 2 vitamin D levels through inhibition of renal 1-alpha-hydroxylase and stimulation of renal 24 hydroxylase. This disorder was previously termed “Vitamin D-Dependent Rickets Type 1” because some patients partially respond to high-dose vitamin D therapy.
- 2. Congenital 1-alpha-hydroxylase deficiency: inactivating mutations of 1-alpha hydroxylase cause lifelong impairment of conversion of 25-OH vitamin D into 1,25 (OH) 2 vitamin D, resulting in chronic intestinal calcium and phosphate malabsorption. This disorder was previously termed “Vitamin D-Dependent Rickets Type 2” because some patients partially respond to high-dose vitamin D therapy.
- 3. Congenital vitamin D resistance: genetic mutations resulting in defective or absent vitamin D receptors cause impaired vitamin D action leading to chronic intestinal calcium and phosphate malabsorption. This disorder was previously termed “Vitamin D-Resistant Rickets” because high-dose vitamin D therapy is not beneficial.
