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

• Published in: The journal of clinical endocrinology and metabolism 2001-11, Vol.86 (11), p.5313-5323
• Main Authors: LIENHARDT, Anne, MEI BAI, LAGARDE, Jean-Pierre, RIGAUD, Michel, ZAIXIANG ZHANG, YOUGFENG JIANG, KOTTLER, Marie-Laure, BROWN, Edward M, GARABEDIAN, Michèle
• Format: Article
• Language: English
• Subjects: Aging - physiology; Amino Acid Substitution; Biological and medical sciences; Calcium - metabolism; Cholecalciferol - administration & dosage; Cholecalciferol - adverse effects; Cholecalciferol - therapeutic use; DNA Mutational Analysis; Endocrinopathies; Female; Humans; Hypocalcemia - diagnosis; Hypocalcemia - drug therapy; Hypocalcemia - genetics; Hypoparathyroidism - complications; Hypoparathyroidism - genetics; Male; Medical sciences; Middle Aged; Nephrocalcinosis - chemically induced; Nephrocalcinosis - prevention & control; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Parathyroid Hormone - blood; Parathyroid Hormone - genetics; Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases); Pedigree; Receptors, Calcium-Sensing; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.86.11.5313

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.