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Activating Mutations of the Calcium-Sensing Receptor: Management of Hypocalcemia

Service de Pédiatrie (A.L.), Centre Hospitalier Universitaire, 87042 Limoges, France; Endocrine-Hypertension Division, Department of Medicine (M.B., Z.Z., Y.J., E.M.B.), Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115; Service de Biochimie Médicale, AP-HP (J.-P.L.), Hôpital Pitié-Salpétrière, 75013 Paris, France; Service de Biochimie (M.R.), Faculté de Médecine, 87025 Limoges, France; Département de Génétique et de Reproduction (M.-L.K.), Centre Hospitalier Universitaire, 14031 Caen, France; and Unité Centre de la Recherche Scientifique, Unité Propre de Recherche 1524 (M.G.), Hôpital Saint Vincent de Paul, 75014 Paris, France

Address all correspondence and requests for reprints to: Dr. Anne Lienhardt, Département de Pédiatrie Médicale, Center Hospitalier Universitaire Dupuytren, 2 avenue Martin Luther King, 87042 Limoges Cedex, France. E-mail: anne.lienhardt{at}unilim.fr

Abstract

Activating mutations of the calcium-sensing receptor (CaR) can cause isolated hypoparathyroidism. Treatment of hypocalcemia in these patients remains to be optimized, because the use of 1-hydroxylated vitamin D3 derivatives can 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, 1.82 ± 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-hydroxylated vitamin D3 treatment (mean duration, 7.2 ± 4.9 yr). Nine had hypercalciuric episodes, which were associated with nephrocalcinosis in eight cases. 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 weighed carefully in patients with serum Ca below 1.95 mmol/liter. The risk of nephrocalcinosis during treatment can be minimized by carefully monitoring urinary Ca excretion.

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