Hypophosphatemic rickets is a hereditary disease involving genetic disorders of excessive renal phosphate loss. It is characterized by a phosphate imbalance in the body. Phosphate plays a critical role in the formation and growth of bones in childhood and helps maintain bone strength in adults, mainly controlled in large part of the kidneys. The kidneys normally excrete excess phosphate in urine, and they reabsorb this mineral into the bloodstream when more is needed. However, people who suffer hereditary hypophosphatemic rickets, the kidneys cannot reabsorb phosphate effectively resulting insufficient phosphate is available in the bloodstream for bone development because the phosphate is excreted from the body in urine tremendously. Therefore, there are two main reasons of this disease to be inherited, the mutations in the PHEX genes caused by X-linked hypophosphatemia (XLH) and the effect of low phosphate reabsorption on bone metabolism.
The genes associated with hereditary hypophosphatemic rickets are involved in maintaining the proper balance of phosphate in the body. Many of these genes, including the PHEX gene, directly or indirectly regulate a protein called fibroblast growth factor 23 which produced from the FGF-23 gene. This protein normally inhibits the kidneys’ ability to reabsorb phosphate into the bloodstream. Gene mutations increase the production or reduce the breakdown of fibroblast growth factor 23 causing the overactivity of the protein. As a result, it reduces phosphate reabsorption by the kidneys, leading to hypophosphatemia and the related features of hereditary hypophosphatemic rickets.
Besides, low phosphate level gives huge impact on the ability of a person to establish normal ossification. This is predominantly due to the level of phosphate wasting at the proximal tubule. As additional factor in the pathogenesis of the phosphaturia, an abnormal phosphate reabsorption in response to calcitriol shows that the sodium-phosphate cotransporter is incapable of proper function and is intrinsically defective. Hence, poor levels of inorganic phosphate impair the function of mature osteoblasts because formation of mature bone involves the precipitation of hydroxyapatite crystals. All attempts have failed though treatment with oral phosphate supplements should cure the defect. This failure could be due to the enhanced mineralization-inhibiting presence of the ASARM peptide secondary to the mutated PHEX gene in bone.