Non-nutritional rickets: Approach, precision medicine, and outcomes

Figure 2 Regulation of calcium and phosphate homeostasis and disorders associated with rickets. Schematic representation of calcium (Ca) and phosphate homeostasis regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D [1,25(OH)₂D], and fibroblast growth factor 23 (FGF-23). In Ca regulation (upper panel), PTH increases bone resorption, renal Ca²⁺ reabsorption via transient receptor potential vanilloid 5, and 1,25(OH)₂D synthesis, while 1,25(OH)₂D enhances intestinal absorption via transient receptor potential vanilloid 6. In phosphate regulation (lower panel), FGF-23 and PTH reduce renal phosphate reabsorption by downregulating sodium-phosphate cotransporters NaPi-IIa (solute carrier family 34 member 1) and NaPi-IIc (solute carrier family 34 member 3), while 1,25(OH)₂D increases intestinal phosphate absorption. Disorders shown include vitamin D-dependent rickets (vitamin D dependent rickets type 1A: Cytochrome P450 family 27 subfamily B member 1; vitamin D dependent rickets type 1B: Cytochrome P450 family 2 subfamily R member 1; vitamin D dependent rickets type 2: Vitamin D receptor), X-linked hypophosphatemia (X-linked hypophosphatemic rickets; phosphate regulating endopeptidase homolog X-linked), autosomal dominant hypophosphatemic rickets (autosomal dominant hypophosphatemic rickets; FGF-23), autosomal recessive hypophosphatemic rickets (autosomal recessive hypophosphatemic rickets; dentin matrix protein 1, ectonucleotide pyrophosphatase/phosphodiesterase 1), fibrous dysplasia/McCune-Albright syndrome (fibrous dysplasia/McCune-Albright syndrome), and hereditary hypophosphatemic rickets with hypercalciuria (hereditary hypophosphatemic rickets with hypercalciuria; solute carrier family 34 member 3). PTH: Parathyroid hormone; Ca: Calcium; 1,25(OH)₂D: 1,25-dihydroxyvitamin D; TRPV5: Transient receptor potential vanilloid 5; CaSR: Calcium-sensing receptor; FGF-23: Fibroblast growth factor 23; VDDR: Vitamin D dependent rickets; VDDR2: Vitamin D dependent rickets type 2; TRPV6: Transient receptor potential vanilloid 6; 1,25(OH)₂D₃:1,25-dihydroxyvitamin D₃; VDDR1A: Vitamin D dependent rickets type 1A; VDDR1B: Vitamin D dependent rickets type 1B; VDDR3: Vitamin D dependent rickets type 3; Pi: Phosphate; XLH: X-linked hypophosphatemic ricket; ARHR: Autosomal recessive hypophosphatemic ricket; FD: Fibrous dysplasia; MAS: McCune-Albright syndrome; IIH: Idiopathic hypercalciuria; ADHR: Autosomal dominant hypophosphatemic ricket.