Severe hypercalcemia in a 9-year-old Brazilian girl due to a novel inactivating mutation of the calcium-sensing receptor.

[familial hypocalciuric hypercalcemia]

Familial hypocalciuric hypercalcemia (FHH ) and neonatal severe hyperparathyroidism (NSHPT ) are consequent to inactivating mutations of the calcium-sensing receptor (CaR ) gene . FHH is usually associated with heterozygous inactivating mutations of the CaR gene , whereas NSHPT is usually due to homozygous inactivation of the CaR gene . FHH is generally asymptomatic and is characterized by mild to moderate lifelong hypercalcemia , relative hypocalciuria , and normal intact PTH , whereas individuals with NSHPT frequently show life-threatening hypercalcemia . In this study , we report a novel inactivating mutation of the CaR gene , identified in a 9 -yr -old Brazilian girl who was found to be severely hypercalcemic during investigation of a 6 -month history of headaches and vomits . Direct sequencing of the CaR gene from this patient showed a novel homozygous mutation (L 13 P ) in exon 2 . Functional characterization by intracellular calcium measurement by fluorometry showed that the mutant receptor had a dose-response curve shifted to the right relative to that of wild type . The proband 's consanguineous parents , who had mild asymptomatic hypercalcemia , showed the same mutation in the heterozygous form . The mutation described in this study is the inactivating missense mutation present at the most N-terminal end among the known CaR missense mutations . This study reinforces the fact that patients with homozygous inactivation of the CaR gene may present with severe hypercalcemia in different phases of life .