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

Abstract

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.

Effect of the Calcimimetic R-568 [3-(2-Chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on Correcting Inactivating Mutations in the Human Calcium-Sensing Receptor

“…For instance, we found that R-568 was able to potentiate orthosteric agonist potency and maximal agonist response of F809L, R185Q, F180C, P39A, Y218C, and L13P mutant hCaSRs that have been described in the literature (Aida et al, 1995;Heath et al, 1996;Bai et al, 1997;Chikatsu et al, 1999;Cetani et al, 2003;Miyashiro et al, 2004;Timmers et al, 2006;Zajickova et al, 2007). It is interesting to note that the L13P mutation occurs in the 19 amino acid signal peptides of the hCaSR.…”

“…Treatments of these illnesses involve counteracting the effects of elevated levels of PTH (Miyashiro et al, 2004). Recently, cinacalcet was to the receptor).…”

Is calcium signaling relevant for long bone growth?

“…The urgent nature of the surgery is important for neuropsychological development, as even a delay of 4 months was shown to be associated with neuropsychological developmental delay, social functioning limits, mental disability, and cerebral calcifications [5,9,21]. Our patient, surgically treated at the age of 30 days, led, in adulthood, a normal social life, although the performance at school was not optimal, complaining an irritable mood with poor concentration.…”

“…Classical NSHPT is caused by homozygous inactivating mutations of the calcium sensing receptor (CaSR) gene [4], with only few cases described so far who were heterozygous for a de novo mutation, all of them with a milder disease phenotype than in classical NSPHT [3,5,6]. About 84 cases of NSHPT have been described since 1964 to the present [1,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Other NSHPT adults successfully treated into adulthood have been reported [14,15], mostly lacking an uninterrupted clinical, radiologic, and laboratory follow-up.…”

Estudo do gene do receptor sensor do cálcio (CASR) em pacientes com distúrbios do metabolismo do cálcio

“…Pacientes portadores de HPTNG apresentam hiperplasia de todas as paratireoides e sintomas que incluem: hipotonia, desnutrição, grave desmineralização óssea e distúrbios respiratórios associados a fraturas de costelas (33). O quadro pode ser dramático, de evolução rápida, e até mesmo fatal caso a paratireoidectomia total não seja realizada nas primeiras semanas de vida; entretanto, é importante destacar que alguns relatos descrevem uma forma de HPTNG onde a hipercalcemia não era tão elevada e/ou transitória (34). Crianças com HPTNG apresentam mutações inativadoras no CASR em homozigose ou em heterozigose composta.…”