Hereditary hypophosphatemic rickets with hypercalciuria

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare genetic disorder of phosphate metabolism characterized by renal phosphate wasting, hypophosphatemia (low blood phosphate levels), and rickets or osteomalacia. Unlike other forms of hypophosphatemic rickets, HHRH is distinguished by an appropriately elevated level of 1,25-dihydroxyvitamin D (calcitriol) in response to hypophosphatemia, which leads to increased intestinal calcium absorption and consequent hypercalciuria (excessive calcium in the urine). The disease is also known as hypophosphatemic rickets with hypercalciuria or phosphate transport defect. HHRH primarily affects the skeletal system and kidneys. Key clinical features include short stature, lower limb deformities (bowing of the legs), bone pain, muscle weakness, and radiographic evidence of rickets in children or osteomalacia in adults. The chronic hypercalciuria can predispose affected individuals to nephrolithiasis (kidney stones) and nephrocalcinosis (calcium deposits in the kidneys). The disease is caused by loss-of-function mutations in the SLC34A3 gene (also known as NPC2T or NPT2c), which encodes the sodium-phosphate cotransporter NPT2c in the renal proximal tubule, impairing phosphate reabsorption from the urine. Treatment of HHRH centers on oral phosphate supplementation, which is typically sufficient to correct the biochemical and skeletal abnormalities. Importantly, unlike X-linked hypophosphatemic rickets, active vitamin D analogs (such as calcitriol) are generally not required and may even be harmful, as endogenous calcitriol levels are already elevated. Phosphate supplementation alone usually improves growth, corrects bone deformities, and normalizes biochemical parameters. Long-term monitoring of renal function and urinary calcium excretion is recommended to detect and manage potential complications such as nephrocalcinosis.

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