Un caso de hipercalcemia hipocalciúrica de causa genética en niño prepúber / Genetic hypercalcemic hypocalciuria in a prepubertal boy

Un paciente de 12 años consultó por vómitos recurrentes asociados con cefaleas, con varios episodios durante 7 meses, y retraso ponderal secundario a esa sintomatología. Había recibido previamente un tratamiento con antibióticos e inhibidores de la bomba de protones, por diagnóstico de gastritis a Helicobacter pylori, después de biopsia gástrica realizada durante una videoendoscopía digestiva alta. Se desconoce su historia familiar porque es hijo adoptivo. Al examen físico el paciente estaba adelgazado, sin tumoración a nivel de cuello; presentaba genitales prepuberales. Como el paciente continuó con vómitos cíclicos recurrentes, siguieron exámenes complementarios donde se constató en 2 oportunidades hipercalcemia (13,2-13,6 mg/dl), acompañada de hipofosfatemia (2,7 mg/dl). Con un diagnóstico presuntivo de hiperparatiroidismo primario se realizaron dosajes de laboratorio: calcemia total e iónica elevada (12,1 y 5,6mg/dl respectivamente), fosfatemia baja (2,8 mg/dl), fosfatasa alcalina sérica normal (151 mU/ml), PTH sérica normal (47,1 pg/ml), 25(OH)vitamina D sérica adecuada (22 ng/ml). La ecografía de glándulas tiroides y paratiroides mostró una imagen redondeada hipoecoica, avascular, de 4 mm axial por 4 mm cefalocaudal, por 3 mm ánteroposterior en topografía paratiroidea derecha, planteándose la posibilidad de hipertrofia paratiroidea versus adenopatía. Se realizó estudio de paratiroides por imágenes: centellograma con 99mTc-MIBI y PET-CT con 18F-colina, pero no se constató captación anormal. Se realizaron nuevos estudios de laboratorio: en orina de 24 horas el calcio era de 19 mg, el cociente calcio/creatinina urinaria 0,03 mg/mg, la reabsorción tubular de fósforo normal (82%) y el cociente de las tasas de depuración de calcio y creatinina muy bajo (0,00046). El CTX sérico era bajo. El diagnóstico clínico fue de hipercalcemia hipocalciúrica; ante la falta de antecedentes familiares, se realizó un estudio de posibles mutaciones puntuales en el gen del receptor de calcio (CaSR), hallándose la presencia en heterocigosis de la mutación p.Arg185Gln (p.R185Q) en la posición 554 (c.554G>A) del exón 4 del gene CaSR. Esto implica el cambio de una arginina por glutamina en el codón 185 de la proteína, y confirma el origen genético de la hipercalcemia hipocalciúrica en nuestro paciente. La edad ósea era de 12 años, y se indicó un tratamiento con testosterona i.m. a bajas dosis para acelerar el desarrollo puberal; luego de 4 aplicaciones mensuales su talla se ha incrementado en 4 cm y su peso en 3 kg. Una aplicación subcutánea de denosumab (60 mg) no controló la hipercalcemia. Continuó por un año con hipoorexia y un episodio de vómitos por semana, pero actualmente tiene buen apetito y excelente tolerancia digestiva. Se le ha prescripto cinacalcet oral (AU)

A 12-year-old patient who consulted for recurrent vomiting associated with headaches, with several episodes for 7 months, and low body weight. The patient had previously received treatment with antibiotics and proton pump inhibitors, due to gastritis with Helicobacter pylori, after gastric biopsy performed during videoendoscopy. His family history is unknown because he is an adopted son. At physical examination the patient was thin, without neck tumor; he had prepubertal genitalia. As he patient continued with recurrent vomiting, he was admitted for further evaluation. Laboratory studies revealed hypercalcemia (13.2-13.6 mg/dl), accompanied by hypophosphatemia (2.7 mg/dl). With a presumptive diagnosis of primary hyperparathyroidism, complementary determinations were performed: total and high total and ionized serum calcium (12.1 and 5.6 mg/dl, respectively), normal serum alkaline phosphatase (151 mU/ml), and PTH (47.1 pg/ml), and normal serum 25(OH) vitamin D (32 ng/ml). The ultrasonography of thyroid and parathyroid glands showed a rounded hypoechoic, avascular image, 4 mm in diameter in the lower right parathyroid topography. A parathyroid imaging studies were performed: scintigraphy with 99mTc-MIBI and PET-CT with 18F-choline, but no abnormal uptake was observed. New laboratory studies were carried out: in 24-hour urine the calcium was 19 mg, the urinary calcium/creatinine ratio was 0.03 mg/mg, the tubular reabsorption of phosphorus was normal (82%) and the ratio of clearances rates of calcium and creatinine very low (0.00046). Serum CTX was low. The clinical diagnosis was hypocalciuric hypercalcemia; in the absence of a family history, a study of possible point mutations in the calcium receptor gene (CaSR) was carried out; there was a heterozygous mutation: p.Arg185Gln (p.R185Q) at position 554 (c.554G)>A) of exon 4 of the CaSR gene. This involves the exchange of an arginine for glutamine at codon 185 of the protein, and confirms the genetic origin of the hypocalciuric hypercalcemia in our patient. Bone age was 12 years, and a treatment with testosterone i.m. at low doses to accelerate pubertal development was started; after 4 monthly applications height has increased by 4 cm and weight by 3 kg. Loss of appetite and a weekly episode of postprandial vomiting continued during one yeas, but now his appetite is normal and vomiting has subsided. A subcutaneous application of denosumab (60 mg) did not control hypercalcemia. He has been prescribed oral cinacalcet (AU)

Distribution and localization of porcine calcium sensing receptor in different tissues of weaned piglets1.

Taste receptors including calcium sensing receptor (CaSR) are expressed in various animal tissues, and CaSR plays important roles in nutrient sensing and the physiology, growth, and development of animals. However, molecular distribution of porcine CaSR (pCaSR) in different tissues, especially along the longitudinal axis of the digestive tract in weaned piglets, is still unknown. In the present study, we investigated the distribution and localization of pCaSR in the different tissues including intestinal segments of weaned piglets. Six male pigs were anesthetized and euthanized. Different tissues such as intestinal segments were collected. The pCaSR mRNA abundance, protein abundance, and localization were measured by real-time PCR, Western blotting, and immunohistochemistry, respectively. The mRNA and protein of pCaSR were detected in the kidney, lung, liver, stomach, duodenum, jejunum, ileum, and colon. The pCaSR mRNA was much higher (five to 180 times) in the kidney when compared with other tissues (P < 0.05). The ileum had higher pCaSR mRNA and protein abundances than the stomach, duodenum, jejunum, and colon (P < 0.05). Immunohistochemical staining results indicated that the pCaSR protein was mostly located in the epithelia of the stomach, duodenum, jejunum, ileum, and colon. These results demonstrate that pCaSR is widely expressed in different tissues including intestinal segments in weaned piglets and the ileum has a higher expression level of pCaSR. Further research is needed to confirm the expression of CaSR in the different types of epithelial cells isolated from weaned piglets and characterize the functions of pCaSR, its potential ligands and cell signaling pathways related to CaSR activation in enteroendocrine cells and potentially in enterocytes.

Role of claudins in renal calcium handling.

Paracellular channels occurring in tight junctions play a major role in transepithelial ionic flows. This pathway includes a high number of proteins, such as claudins. Within renal epithelium, claudins result in an ionic selectivity in tight junctions. Ascending thick limb of loop of Henle (ATLH) is the most important segment for calcium reabsorption in renal tubules. Its cells create a water-proof barrier, actively transport sodium and chlorine through a transcellular pathway, and provide a paracellular pathway for selective calcium reabsorption. Several studies have led to a model of paracellular channel consisting of various claudins, particularly claudin-16 and 19. Claudin-16 mediates cationic paracellular permeability in ATLH, whereas claudin-19 increases cationic selectivity of claudin-16 by blocking anionic permeability. Recent studies have shown that claudin-14 promoting activity is only located in ATLH. When co-expressed with claudin-16, claudin-14 inhibits the permeability of claudin-16 and reduces paracellular permeability to calcium. Calcium reabsorption process in ATLH is closely regulated by calcium sensor receptor (CaSR), which monitors circulating Ca levels and adjusts renal excretion rate accordingly. Two microRNA, miR-9 and miR-374, are directly regulated by CaSR. Thus, miR-9 and miR-374 suppress mRNA translation for claudin-14 and induce claudin-14 decline.