Hipercalcemia hipocalciurica familiar en una paciente con mutación del receptor de calcio: forma atípica de presentación y tratamiento con cinacalcet / Familial hypocalciuric hypercalcemia in a patient with calcium-sensing receptor mutation: atypical clinical presentation and treatment with cinacalcet

El hiperparatiroidismo familiar y la hipercalcemia hipocalciúrica familiar (HHF) constituyen un subgrupo heterogéneo de trastornos con herencia mendeliana, que representan en conjunto el 5% de las causas de hipercalcemia PTH dependiente. La HHF se asocia con mutaciones del gen del receptor sensor de calcio (CaSR). Esta entidad se manifiesta, en la mayoría de los casos, con la presentación asintomática y familiar de hipercalcemia e hipocalciuria y valores elevados o normales de hormona paratiroidea (PTH). Los avances en la biología molecular han contribuido al diagnóstico, evaluación del fenotipo de cada entidad y elección del tratamiento. Se describe el caso de una paciente con hipercalcemia estudiada a partir de una tumoración de cuello asociada con una glándula paratiroides quística. Luego de un exhaustivo proceso diagnóstico se halló en el estudio genético una mutación inactivante en el gen CaSR. Teniendo en cuenta la presencia de la relación clearance calcio/clearance creatinina <0,01 y la falta de respuesta al tratamiento quirúrgico, se consideró la entidad de HHF con forma de presentación atípica. La paciente, sin tratamiento, presentaba un progresivo incremento de la calcemia luego de la cirugía de las glándulas paratiroides, que no se controló con el uso de bifosfonatos y evolucionó con episodios de mareos y desmayos frecuentes sin causa neurológica o cardiovascular detectada. Por lo tanto, se inició el tratamiento con cinacalcet, con el cual se obtuvo una buena respuesta terapéutica: descenso de la calcemia y mejoría de la sintomatología luego de un año de su comienzo. El cinacalcet es una herramienta terapéutica de importancia en estos raros casos de HHF. (AU)

Familial hyperparathyroidism including familial hypocalciuric hypercalcemia (FHH) is an heterogeneous subgroup of disorders with Mendelian inheritance, that account for 5% of PTH dependent hypercalcemia. FHH is associated with mutations of the calcium receptor (CaSR) gene. This entity is manifested by hypercalcemia with hypocalciuria and high or normal levels of parathyroid hormone (PTH) generally asymptomatic and with familial presentation. Advances in molecular biology have contributed to the diagnosis, evaluation of the phenotype of each entity and the choice of treatment. We describe a patient with hypercalcemia diagnosed following the finding of a neck tumor associated with cystic parathyroids. After an exhaustive diagnostic process, an inactivating mutation in the CaSR gene was found. Considering the presence of a ratio clearance calcium / clearance creatinine <0.01 and the lack of response to surgical treatment, HHF entity with atypical presentation was considered. The patient exhibited progressive increase in serum calcium following parathyroid surgery, which was not controlled with the use of bisphosphonates and evolved into episodes of frequent dizziness and fainting, without neurological or cardiovascular causes. Treatment with cinacalcet was initiated, with a good therapeutic response. The use of cinacalcet is a useful therapeutic tool in these rare cases of FHH. (AU)

Role of calcium-sensing receptor in bone biology.

Bone turnover helps accomplish long-term correction of the extracellular calcium (Ca2+ o) homeostasis by the actions of osteoblasts and osteoclasts. These processes are highly regulated by the actions of hormones, most prominently parathyroid hormone (PTH), the release of which is a function of the Ca2+ o, and is regulated by the action of the Ca2+ -sensing receptor (CaR) in the parathyroid gland. Various mutations of the CaR gene give rise to gain or loss of functions leading respectively to hypo- or hypercalcaemic conditions. CaR could conceivably be a target for local changes in the Ca2+ o in the bone microenvironment thereby acting as a 'growth factor' in various cells residing in the bone marrow. This review discusses about the roles of the CaR in bone. In osteoblasts, CaR promotes its proliferation, differentiation and mineralization. In osteoclasts, CaR mediates high Ca2+ o-stimulated osteoclast differentiation as well as osteoclast apoptosis. CaR regulates localization of haematopoietic stem cells from the foetal liver to endosteal niche, the socalled homing. Although the CaR plays a key role in the defense against hypercalcaemia, its function can be aberrant in humoral hypercalcaemia of malignancy in which CaR activation stimulates secretion of parathyroid hormone-related peptide (PTHrP) secretion. Increased levels of PTHrP cause a vicious hypercalcaemic state resulting from its increased bone-resorptive and positive renal calcium reabsorbing effects give rise to hypercalcaemia. CaR mediates a variety of functions of Ca2+ o in the bone microenvironment under both normal and pathological conditions.