Comparison of hypocalcemic hypercalciuria between patients with idiopathichypoparathyroidism and those with gain-of-function mutations in the calcium-sensing receptor: Is it possible to differentiate the two disorders?

Gain-of-function mutations in the calcium ion-sensing receptor (CaR) cause hypocalcemia with low PTH levels. It is stated that patients with activatin g CaR mutations generally show milder degree of hypocalcemia before treatme nt and more profound hypercalciuria during treatment than those with idiopa thic hypoparathyroidism (IHP). To test this validity we analyzed the data o f serum and urinary calcium collected from 85 patients with IHP and 15 with activating CaR mutations. The mean (+/-SEM) serum calcium concentration be fore treatment was significantly higher (P < 0.001) in patients with activa ting CaR mutations (1.76 +/- 0.05 mmol/L; n = 15) than in those with IHP (1 .41 +/- 0.03; n = 58), but there was a substantial overlap in the range of hypocalcemia between the two groups (1.25-2.05 vs. 0.90-1.95). The mean uri nary calcium/creatinine ratio (Ca/Cr) in patients with activating CaR mutat ions before treatment (0.362 +/- 0.045 mmol/mmol; n = 9) was almost equal t o that in normocalcemic controls (0.331 +/- 0.022; n = 56) and markedly hig her (P < 0.001) than in patients with IHP (0.093 +/- 0.008; n = 57). The ov erlap of pretreatment urinary Ca/Cr between the 2 disorders was relatively small; subnormal urinary Ca/Cr was observed in only 1 of 9 patients with Ca R mutations and in the majority (49 of 57) of patients with IHP. In contras t to pretreatment findings, the degree of hypercalciuria during treatment w as not different between the 2 disorders. The data points of urinary Ca/Cr plotted as a function of the serum calcium concentration were not separable between patients with CaR mutations (n = 8) and those with IHP (n = 40). C omparison of urinary Ca/Cr between 2 patients with a CaR mutation and 7 wit h IHP over a wide range of serum calcium concentrations measured during 4-8 yr of treatment also indicated that the 2 disorders mere inseparable. Thes e results suggested that inappropriately normal urinary Ca/Cr in patients w ith untreated hypocalcemia, mostly of mild degree, might be a better bioche mical clue than the development of severe hypercalciuria during treatment t o suspect gain-of-function mutations in the CaR.