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"Idiopathic" hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic
Insights
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and idiopathic hypercalciuria share a genetic kidney phosphate leak. The severity of this phosphate leak determines if individuals develop bone disease alongside hypercalciuria.
Area of Science:
- Nephrology
- Endocrinology
- Genetics
Background:
- Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare genetic disorder.
- Idiopathic hypercalciuria is a common cause of kidney stones and hypercalcemia.
Purpose of the Study:
- To investigate the genetic and biochemical basis of HHRH and idiopathic hypercalciuria in a Bedouin tribe.
- To determine the relationship between these two conditions.
Main Methods:
- Family-based genetic and biochemical analysis.
- Measurement of urinary calcium, serum phosphorus, and 1,25-dihydroxyvitamin D levels.
Main Results:
- Nine individuals with HHRH and 21 with idiopathic hypercalciuria were identified within 59 related subjects.
- Both groups exhibited a hereditary renal phosphate leak, leading to hypophosphatemia and elevated 1,25-dihydroxyvitamin D.
- Biochemical abnormalities were quantitatively milder in the idiopathic hypercalciuria group.
Conclusions:
- A shared hereditary renal phosphate leak underlies both HHRH and idiopathic hypercalciuria.
- The degree of hypophosphatemia dictates the clinical presentation, ranging from hypercalciuria alone to HHRH with bone disease.
Abstract:
Among 59 closely related members of one Bedouin tribe, we identified 9 who had the characteristic features of hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We found "idiopathic" hypercalciuria in 21 of the 50 asymptomatic members. The biochemical abnormalities observed in these 21 subjects were qualitatively similar to those in the 9 with HHRH, but were quantitatively milder. The urinary calcium concentration was 0.43 +/- 0.14 mg per milligram of creatinine (mean +/- SD) in the patients with HHRH, 0.34 +/- 0.07 in the subjects with idiopathic hypercalciuria, and 0.14 +/- 0.05 in normal subjects from the same tribe. Tubular reabsorption of phosphorus and serum phosphorus concentrations were 3.0 and 4.3 SD units below the age-related mean, respectively, in HHRH, and 1.1 SD units below the normal mean for both variables in idiopathic hypercalciuria. Mean serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D) were 303 pg per milliliter in HHRH and 145 pg per milliliter in idiopathic hypercalciuria (upper normal limit, 110). We conclude that the subjects with hypercalciuria and the patients with HHRH shared a hereditary renal phosphate leak that led to hypophosphatemia, elevated serum concentrations of 1,25-(OH)2D, increased intestinal calcium absorption, and hypercalciuria. The magnitude of the hypophosphatemia, which regulates 1,25-(OH)2D levels, appears to determine which subjects will have hypercalciuria alone and which will also have bone disease.