Activating mutations of the calcium-sensing receptor: Management of hypocalcemia

Activating mutations of the calcium-sensing receptor (CaR) can cause isolat ed hypoparathyroidism. Treatment of hypocalcemia in these patients remains to be optimized, because the use of 1-hydroxylated vitamin D3 derivatives c an cause hypercalciuria and nephrocalcinosis. We identified activating CaR mutations in 8 (42%) of 19 unrelated probands with isolated hypoparathyroidism: The severity of hypocalcemic symptoms at diagnosis was independent of age, mutation type, or mode of inheritance but was related to the degree of hypocalcemia; serum Ca was 1.97 +/- 0.08, 1.8 2 +/- 0.14, and 1.54 +/- 0.22 mmol/liter, respectively, in asymptomatic (n = 7), mildly symptomatic (n = 8), and severely symptomatic patients (n = 6) . Hypocalcemia segregated with the CaR mutation, but no phenotype-genotype relationships were identified. Fourteen patients received regular 1-hydroxy lated vitamin D3 treatment (mean duration, 7.2 +/- 4.9 yr). Nine had hyperc alciuric episodes, which were associated with nephrocalcinosis in eight cas es. Serum Ca during treatment predicted hypercalciuria and nephrocalcinosis poorly, because either or both of the latter could develop in hypocalcemic patients. Thus, mutational analysis of the CaR gene should be considered early in the work-up of isolated hypoparathyroidism. Treatment options should be weighe d carefully in patients with serum Ca below 1.95 mmol/liter. The risk of ne phrocalcinosis during treatment can be minimized by carefully monitoring ur inary Ca excretion.