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Severe Hypercalcemia in a 9-Year-Old Brazilian Girl Due to a Novel Inactivating Mutation of the Calcium-Sensing Receptor

Laboratório de Endocrinologia Molecular (K.M., I.K., O.M.H.), Disciplina de Endocrinologia, Escola Paulista de Medicina–Universidade Federal de São Paulo 04039-032; and Unidade de Endocrinologia Pediátrica do Instituto da Criança–Faculdade de Medicina da Universidade de São Paulo (T.D.M., H.C.d.M.F., D.D., N.S.), 05403-900 São Paulo, Brazil

Address all correspondence and requests for reprints to: Omar M. Hauache, Laboratorio de Endocrinologia Molecular, Disciplina de Endocrinologia, Escola Paulista de Medicina–Universidade Federal de São Paulo, Rua Pedro de Toledo, 781, 12° andar, 04039-032 São Paulo–SP, Brazil. E-mail: omar.hauache{at}fleury.com.br.

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 (L13P) 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.

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