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Dominant hypophosphatemia with nephrolithiasis or osteoporosis
A rare, genetic renal tubular disease characterized by phosphate loss in the proximal tubule, leading to hypercalciuria and recurrent urolithiasis and/or osteoporosis.
ORPHA:244305Classification level: Disorder
More than 10 cases have been identified to date.
Disease onset is in adulthood with presentation of nephrolithiasis, renal phosphate wasting and skeletal abnormalities variably including osteopenia, osteoporosis and increased susceptibility to fractures. Cases of spinal deformity have also been described.
Heterozygous mutations have been identified in two genes SCL34A1 (5q35), and SLC9A3R1 (17q25.1). SCL34A1 encodes the main sodium-phosphate cotransporter, sodium-dependent phosphate transport protein 2A (NPT2a), located in the apical membrane of renal proximal tubular cells. SLC9A3R1 encodes the Na(+)/H(+) exchange regulatory cofactor (NHERF1), a cytoplasmic protein essential for recruitment of transporter or signaling proteins to the plasma membrane which stabilize NaPi-IIa, the parathyroid hormone (PTH) receptor 1, and phospholipase C at the brush border membrane and creates a platform for PTH signaling to NaPi-IIa . SLC9A3R1 mutations decreases NPT2a expression directly or indirectly via an increase in PTH-responsive downregulation of NaPi-IIa. The decreased serum phosphate levels stimulate 1,25-dihydroxy-Vitamin D synthesis leading to absorptive hypercalciuria, which together with elevated urinary phosphate levels can trigger the formation of calcium-phosphate crystals favoring the development of renal calcifications.
Diagnosis is usually based on clinical features, plasma and urine electrolytes showing hypophosphatemia, hyperphosphaturia, hypercalciuria and increased serum 1,25-dihydroxy-Vitamin D in response to phosphate deprivation. A definitive diagnosis can be achieved by genetic testing.
The differential diagnosis includes other forms of inherited hypophosphatemia such as X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria.
The pattern of inheritance is autosomal dominant. There is a 50% risk of the disease occurring in a sibling or being transmitted to the offspring of affected individuals.
Management and treatment
Supportive treatment is with phosphate and low‐ dose vitamin D supplementation.
There is no information available on outcomes.