A Case of Neonatal Severe Hyperparathyroidism: Challenges in Management

Neonatal severe hyperparathyroidism is a rare disorder arising from inherited defects in the calcium sensing receptor (CaSR) that presents early in life with severe hypercalcemia, failure to thrive, and developmental retardation. The authors describe an infant with neonatal severe hyperparathyroidism due to homozygous CaSR gene mutation presenting with recurrent episodes of severe hypercalcemia, growth retardation, and developmental delay. Medical management served as an efective bridge therapy to surgery. Total parathyroidectomy with right hemithyroidectomy was performed at 7 mo of age and resulted in successful cure and normalization of growth and developmental milestones. Timely medical and surgical management can help prevent mortality and morbidity in the form of neurodevelopmental sequelae. Life-long monitoring and treatment is mandatory for the resultant hypoparathyroidism.

Clinical characteristics and genetic analysis of familial hypocalciuric hypercalcemia type 1 / 中华内分泌代谢杂志

A case of familial hypocalciuric hypercalcemia type 1 (FHH1) was reported detailing the course of diagnosis and treatment. The main clinical manifestations of the patient were recurrent pancreatitis with moderate hypercalcemia and low urinary calcium. The C→T heterozygous missense mutation at nucleotide 2 393 with conversion of codon Pro798 to Leu (p.P155L) in CaSR gene was identified. Serum calcium and parathyroid hormone levels of the patient were decreased significantly after treatment with cinacalcet.

Cultivation and characterization of primary human parathyroid cells from patients with severe secondary hyperparathyroidism / 南方医科大学学报

OBJECTIVE@#To establish an cell model of hyperparathyroidism by isolation, in vitro culture, and identification of parathyroid cells from patients with secondary hyperparathyroidism (SHPT).@*METHODS@#The parathyroid gland tissues obtained from 10 patients with SHPT were dissociated by collagenase digestion for primary culture of the parathyroid cells. Morphological changes and growth characteristics of the cells were assessed by microscopic imaging and cell counting. The mRNA and protein expression levels of parathyroid hormone (PTH), calcium-sensing receptor (CaSR), and glial cells missing 2 (GCM2) in the primary and passaged cells were determined by immunofluorescence, qRT-PCR, and Western blotting.@*RESULTS@#Primary cultures of parathyroid cells were successfully obtained. The cells exhibited a high expression of PTH shown by immunofluorescence assay and had a population doubling time of approximately 71.61 h. PTH secretion in the second-passage (P2) cells was significantly lower than that in the primary (P0) and first-passage (P1) cells (P < 0.001). Despite a significant downregulation of CaSR mRNA (P=0.017) and protein (P=0.006) in P1 cells as compared with P0 cells, no significant differences were found in mRNA and protein expressions of PTH or GCM2 between the two cell generations.@*CONCLUSION@#Primary cultures of parathyroid cells isolated from SHPT patients by collagenase digestion show similar biological properties to the cells in vivo.

VEGF121 como Mediador de Efeitos Cardioprotetores Pós-Hipóxia via CaSR e via da Protease Dependente de Mitocôndria / VEGF121 Mediates Post-Hypoxia Cardioprotective Effects Via CaSR and Mitochondria-Dependent Protease Pathway

Resumo Fundamento: A doença cardiovascular é a principal causa de morte em todo o mundo. A apoptose mediada por hipóxia em cardiomiócitos é uma das principais causas de distúrbios cardiovasculares. O tratamento com a proteína do fator de crescimento endotelial vascular (VEGF, do inglês vascular endothelial growth factor) foi testado, mas as dificuldades operacionais limitaram seu uso. Entretanto, com os avanços da terapia gênica, aumentou o interesse na terapia gênica baseada no VEGF em doenças cardiovasculares. No entanto, o mecanismo preciso pelo qual a reposição de VEGF resgata os danos pós-hipóxia em cardiomiócitos não é conhecido. Objetivos: Investigar o efeito da expressão de VEGF121 pós-hipóxia utilizando cardiomiócitos de ratos neonatos. Métodos: Cardiomiócitos isolados de ratos neonatos foram utilizados para estabelecer um modelo in vitro de lesão cardíaca induzida por hipóxia. O efeito da superexpressão de VEGF, isolado ou em conjunto com inibidores de moléculas pequenas que têm como alvo os canais de cálcio, receptores sensíveis ao cálcio (CaSR, do inglês calcium-sensitive receptors) e calpaína, no crescimento e proliferação celular em lesão de cardiomiócitos induzidos por hipóxia, foram determinados com ensaio de MTT, coloração TUNEL, coloração com Anexina V/PI, lactato desidrogenase e atividade da caspase. Para análise estatística, um valor de p<0,05 foi considerado significativo. Resultados: Verificou-se que o efeito do VEGF121 foi mediado por CaSR e calpaína, mas não foi dependente dos canais de cálcio. Conclusões: Nossos resultados, mesmo em um ambiente in vitro, estabelecem as bases para uma validação futura e testes pré-clínicos da terapia gênica baseada em VEGF em doenças cardiovasculares.

Abstract Background: Cardiovascular disease is the major cause of death worldwide. Hypoxia-mediated apoptosis in cardiomyocytes is a major cause of cardiovascular disorders. Treatment with vascular endothelial growth factor (VEGF) protein has been tested but operational difficulties have limited its use. However, with the advancements of gene therapy, interest has risen in VEGF-based gene therapy in cardiovascular disorders. However, the precise mechanism by which VEGF replenishment rescues post-hypoxia damage in cardiomyocytes is not known. Objectives: To investigate the effect of post-hypoxia VEGF121 expression using neonatal rat cardiomyocytes. Methods: Cardiomyocytes isolated from neonatal rats were used to establish an in vitro model of hypoxia-induced cardiac injury. The effect of VEGF overexpression, alone or in combination with small-molecule inhibitors targeting calcium channel, calcium sensitive receptors (CaSR), and calpain on cell growth and proliferation on hypoxia-induced cardiomyocyte injury were determined using an MTT assay, TUNEL staining, Annexin V/PI staining, lactate dehydrogenase and caspase activity. For statistical analysis, a value of P<0.05 was considered to be significant. Results: The effect of VEGF121 was found to be mediated by CaSR and calpain but was not dependent on calcium channels. Conclusions: Our findings, even though using an in vitro setting, lay the foundation for future validation and pre-clinical testing of VEGF-based gene therapy in cardiovascular diseases.

Role of calcium sensing receptors in proliferation and migration of renal artery smooth muscle cells under insulin resistance / 中国药理学通报

To investigate the role and mechanism of calcium-sensing receptor (CaSR) in the proliferation and migration of renal artery smooth muscle cells (RASMCs) under insulin resistance. Methods RAMSCs in the logarithmic growth stage were randomly divided into control, pure model, model + GdCl

Role of Gq-PLC-IP3 signal transduction pathway in calcium-sensing receptor-mediated proliferation of A549 cells / 解剖学报

Objective: To explore the signal transduction pathway of calcium-sensing receptor (CaSR) mediating hypoxia-induced proliferation of A549 cells of human non-small cell lung cancer. Methods: The A549 cells were randomly divided into several groups which conclude control group, hypoxia group (H), hypoxia + CaSR agonist group (H + Gd), hypoxia + CaSR inhibitor group (H + NPS) and phospholipase C(PLC) pathway inhibitor group (H + Gd +U73122). Expression of CaSR and proliferating cell nuclear antigen (PCNA) in A549 cells under different treatments was analyzed by Western blotting. The changes of intracellular calcium ion concentration were detected by confocal laser scanning microscope. The effects of cell proliferation cycle and proliferation index were gauged by flow cytometry under different drugs. HE staining was used to observe the changes of cell number with different drugs. Results: The expression levels of CaSR and PCNA in A549 cells increased by hypoxia. Meanwhile, cell proliferation index and cell number were also upregulated. GdCl3(CaSR agonist) could amplify the effect of hypoxia, and NPS2390 (CaSR inhibitor) could reduce the effect of hypoxia. All effects mentioned above could be inhibited by U73122 (PLC pathway inhibitor). Conclusion: Hypoxia-induced CaSR can mediate the proliferation of A549 cells through Gq-PLC-IP, signal transduction pathway.

Influences of Xinnaoning capsules on aorta calcium sensing receptor of rats with myocardial infarction and endothelial protection mechanisms based on the theory of phlegm and blood stasis / 中国医师杂志

Objective To observe the impacts of Xinnaoning capsules on the aortic intimal structure,serum levels of diponectin (APN) and calcium sensing receptor (CaSR) expression in rats with myocardial infarction,and explore the endothelial protection mechanisms of Xinnaoning.Methods 15 male Sprague Dawley (SD) rats in sham operation group were randomly selected from 60 rats,the rest 45 rats were fed with high fat diet for 6 weeks and received coronary artery ligation operation.The successful modeling rats were randomly divided into model group,western medicine group and traditional Chinese medicine (TCM) group,and fed with high fat diet for 8 weeks.The sham operation group fed with normal diet.The western medicine group and TCM group received atorvastatin and Xinnaoning capsules,respectively;the sham operation group and model group received same amount of distilled water.After treatment of 4 weeks,the aortic intimal structure was observed by hematoxylin-eosin (HE);the serum levels of triacylglycerol (TG),total cholesterol (TC),low density lipoprotein (LDL) and high density lipoprotein (HDL) were measured by microplate test;serum levels of APN and CaSR expression were determined by enzyme linked immunosorbent assay (ELISA) and Western blot,respectively.Results Compared with sham operation group,aortic intimal structure derangement and plaque formation in intima in model group,and serum levels of TG,TC,LDL and CaSR expression were increased;HDL and APN were decreased (P ＜ 0.05).Compared with model group,the endarterium was more smooth in the western medicine group and TCM group,serum levels of TG,TC,LDL and CaSR expression were decreased;HDL and APN were increased (P ＜0.05).And there were no significant differences between western medicine group and TCM group (P ＞0.05).Conclusions Xinnaoning capsules are effective for myocardial infarction.

Role of PI3K/Akt pathway in hypoxic-activated calcium sensing receptor mediated A549 cell metastasis / 中国药理学通报

Aim: To explore the role of PI3K/Akt signaling pathway in A549 and A549/DDP cells metastasis mediated by hypoxic-activated calcium sensing receptor (CaSR). Methods: The A549 and A549/DDP cells in the logarithmic growth stage were randomly divided into control, hypoxia, hypoxia + GdCl3 (CaSR agonist), hypoxia + NPS2143 (CaSR inhibitor) and hypoxia + LY294002 (PI3K inhibitor) + GdCl3 group. The protein levels of CaSR, MMP-2 and p-Akt were analyzed by Western blot in A549 and A549/DDP cells under different treatment conditions. The effects of different treatment factors on the ability of cell migration and invasion were measured by wound scratch assay and transwell migration assay. The effects of different treatment factors on the secretion of matrix metalloproteinase-2 (MMP-2) protein by A549 and A549/DDP cells was analyzed by ELISA. Results: Compared with control group, hypoxia increased the protein expression of CaSR, enhanced cell migration ability, increased MMP-2 protein expression in cells and culture medium, and promoted Akt protein phosphorylation in A549 and A549/DDP cells. NPS2143 reduced the effect of hypoxia, GdCl3 amplified the effect of hypoxia, and LY294002 inhibited effect of hypoxia and GdCl3. Conclusions: Hypoxic-activated CaSR promotes A549 cell metastasis, and its mechanism may involve PI3K/Akt pathway.

Influences of Xinnaoning capsules on aorta calcium sensing receptor of rats with myocardial infarction and endothelial protection mechanisms based on the theory of phlegm and blood stasis / 中国医师杂志

Objective@#To observe the impacts of Xinnaoning capsules on the aortic intimal structure, serum levels of diponectin (APN) and calcium sensing receptor (CaSR) expression in rats with myocardial infarction, and explore the endothelial protection mechanisms of Xinnaoning.@*Methods@#15 male Sprague Dawley (SD) rats in sham operation group were randomly selected from 60 rats, the rest 45 rats were fed with high fat diet for 6 weeks and received coronary artery ligation operation. The successful modeling rats were randomly divided into model group, western medicine group and traditional Chinese medicine(TCM) group, and fed with high fat diet for 8 weeks. The sham operation group fed with normal diet. The western medicine group and TCM group received atorvastatin and Xinnaoning capsules, respectively; the sham operation group and model group received same amount of distilled water. After treatment of 4 weeks, the aortic intimal structure was observed by hematoxylin-eosin (HE); the serum levels of triacylglycerol (TG), total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) were measured by microplate test; serum levels of APN and CaSR expression were determined by enzyme linked immunosorbent assay (ELISA) and Western blot, respectively.@*Results@#Compared with sham operation group, aortic intimal structure derangement and plaque formation in intima in model group, and serum levels of TG, TC, LDL and CaSR expression were increased; HDL and APN were decreased (P<0.05). Compared with model group, the endarterium was more smooth in the western medicine group and TCM group, serum levels of TG, TC, LDL and CaSR expression were decreased; HDL and APN were increased (P<0.05). And there were no significant differences between western medicine group and TCM group (P>0.05).@*Conclusions@#Xinnaoning capsules are effective for myocardial infarction.

Role of calcium-sensing receptor, Galectin-3, Cyclin D1, and Ki-67 immunohistochemistry to favor in the diagnosis of parathyroid carcinoma

Background: As histopathological findings of parathyroid carcinoma are not certain, the diagnosis of tumors with degenerative changes may be difficult. In these cases, immunohistochemical markers are beneficial. We aimed to research the acceptability of calcium-sensing receptor (CaSR), Galactin-3, Cyclin D1, and Ki-67 as helpful markers in parathyroid tumors in cases which are difficult to diagnose. Materials and Methods: Those cases who had been diagnosed with atypical parathyroid adenoma and parathyroid carcinoma between 2010 and 2015 were reevaluated. ?mmunohistochemical markers were applied to this cases. Results: About 21 cases were parathyroid adenoma, 14 were atypical adenoma, and 10 cases were parathyroid carcinoma. According to the immunohistochemical results, global loss of CaSR staining was seen in 50% (5/10) of the patients with carcinoma while there was no loss of staining in those with parathyroid adenoma (P = 0,001). Global loss of CaSR staining was found in only one out of 14 cases with atypical adenoma. The expression of Galactin-3 was found to be positive in 40% (4/10) of carcinoma cases, 71.4% (10/14) of those with atypical adenoma, and 14.3% (3/21) of those with adenoma (P = 0,002). Cyclin D1 expression was determined to be positive in 70% (7/10) of patients with carcinoma, 71.4% (10/14) of atypical adenoma cases, and 23.8% (5/21) of those with adenoma. The Ki-67 proliferation index was seen to be above 5% in 50% (5/10) of carcinoma cases and 35,7% (5/14) of those with atypical adenoma. Conclusion: In these studies, it has been emphasized that the global loss of CaSR staining was used as a negative marker in the diagnosis of carcinoma. In this study, we have also confirmed that the global loss of CaSR staining is a useful marker to determine potential increased malignancy.

Protective effect of calcium-sensing receptor inhibitor Calhex231 on traumatic hemorrhagic shock rats / 中华创伤杂志

Objective To observe the protective effects of calcium-sensing receptor (CaSR) inhibitor Calhex231 on traumatic hemorrhagic shock rats. Methods 144 SD rats were divided into six groups by random number table method: normal group, shock group, lactated Ringer's solution (LR) group, LR + Calhex231 0.1 mg/kg group, LR + Calhex231 1 mg/kg group, and LR + Calhex231 5 mg/kg group, with 16 rats in each group for survival observation and 8 rats for hemodynamics test. 64 SD rats were divided into four groups: normal group, shock group, lactated Ringer's solution (LR) group, LR + Calhex231 1 mg/kg group, with 8 rats in each group for detecting organ blood flow and superior mesenteric artery vascular reactivity and the other 8 rats for mesenteric artery vascular reactivity. After the establishment of traumatic hemorrhagic shock model, the shock group did not receive resuscitation, and the LR group was resuscitated with LR equal to two times of the blood loss volume. The three LR + Calhex231 groups with different dosages were firstly given LR of equal volume to that of blood loss, and then the Calhex231 was dissolved into LR (equal to the blood loss volume) to resuscitate. The wound was ligated and sutured immediately after resuscitation. The effect of Calhex231 on animal's 24-hour survival since the beginning of resuscitation was observed. The hemodynamics including the mean arterial blood pressure (MAP), left intraventricular systolic pressure (LVSP), maximal rising, and declining rate of left intraventricular pressure (±dp/dtmax) were observed before shock, at the end of shock, 1 hour after resuscitation, and 2 hours after resuscitation. The effects of Calhex231 on vital organ blood flow and vascular reactivity were observed 2 hours after resuscitation. Results All the shock rats died within 9 hours after the shock model was established. The survival outcomes of LR group rats were slightly improved compared with the shock group rats(P ＜0.05). The survival time and 24 hour survival rate of LR + Calhex231 1 mg/kg group and LR + Calhex231 5 mg/kg group rats were significantly increased compared with the shock group rats (P ＜0.05). The hemodynamic indexes of LR + Calhex231 groups were higher than those of the LR group. The best effect was observed in LR + Calhex231 1 mg/kg group rats (P ＜ 0.01). The MAP, LVSP and ± dp/dtmax were restored to normal level (64.9％, 82.4％, 89.8％, and 77.8％, respectively). Meanwhile, the blood flow in liver and kidney of LR + Calhex231 1 mg/kg group rats were increased from 57.2％ and 41％ to 108.7％ and 95.1％, respectively. The vascular reactivity including superior mesenteric artery and mesenteric artery of LR + Calhex231 1 mg/kg group rats were also increased (P ＜0.01). Conclusions In rats with hemorrhagic shock, the calcium sensitive receptor inhibitor Calhex231 can improve the vascular reactivity, the hemodynamics, and the blood flow of important organs. It plays a role in protecting the cardiovascular function and reducing the mortality after traumatic hemorrhagic shock.

Calcium-sensing receptor-mediated L-tryptophan-induced secretion of cholecystokinin and glucose-dependent insulinotropic peptide in swine duodenum

This study aimed to elucidate the effect of tryptophan (Trp) on gut hormone secretion as well as the roles of the calcium-sensing receptor (CaSR) and its downstream signaling pathway in gut hormone secretion by assessing swine duodenal perfusion in vitro. Swine duodenum was perfused with Krebs-Henseleit buffer as a basal solution. Various concentrations (0, 10, and 20 mM) of Trp were applied to investigate its effect on gut hormone secretion. A CaSR antagonist was used to detect the involvement of CaSR and its signal molecules. The 20 mM Trp concentration promoted the secretion of cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP), elevated the mRNA level of CaSR, and upregulated the protein levels of CaSR, protein kinase C (PKC), and inositol trisphosphate receptor (IP3R). However, NPS 2143, an inhibitor of CaSR, attenuated the CCK and GIP release, reduced the mRNA level of CaSR, and decreased the protein levels of CaSR, PKC, and IP3R with 20 mM Trp perfusion. The results indicate that CCK and GIP secretion can be induced by Trp in swine duodenum in vitro, and the effect is mediated by CaSR and its downstream signal molecules PKC and IP3R.

Effect of calcium-sensitive receptor on intracellular Ca2+ concentration in pulmonary arterial smooth muscle cells of hypoxia-induced persistent pulmonary hypertension in mice / 中国新生儿科杂志

Objective To study the changes of intracellular calcium ion concentration in pulmonary artery smooth muscle cells (PASMCs) of hypoxic-induced persistent pulmonary hypertension (PPH) induced by calcium-sensitive receptor (CaSR) in a newborn mouse model.Method Ninety-six newbom C57BL/6 mice were randomly divided into control group,PPH group,PPH + agonist group and PPH + inhibitor group,with 24 mice in each group.The PPH model was induced by 12％ oxygen for 14 days.In the beginning,intraperitoneal injection of CaSR agonist (GdCl3) and CaSR inhibitor (NPS2390) were performed to mice in PPH + agonist group and PPH + inhibitor group respectively daily.After 14 days of modeling,pulmonary artery smooth muscle cells (PASMCs) of all four groups were cultured in vitro.Changes of Ca2+ fluorescence intensity in PASMCs of the four groups were detected by laser confocal microscope continuously.Result The ratio of pulmonary small vascular wall thickness to the vascular diameter and right ventricle/left ventricular thickness in PPH group were greater than those in the control group [(21.1％ ±1.8％) vs.(27.0％ ±0.9％),(0.62 ±0.22) vs.(0.83±0.45)],the differences were statistically significant (P ＜ 0.05),which imply that PPH mouse model was constructed successfully.The average Ca2+ fluorescence intensity in PASMCs of control group,PPH group,PPH + agonist group and PPH+ antagonist group were 122.5 ± 3.0,2 058.8 ±46.3,2 286.6 ±51.4 and 1 134.8 ± 8.5,respectively.The average Ca2+ fluorescence intensity in PASMCs of the PPH group,PPH + agonist group and PPH + antagonist group was higher than that of the control group respectively,the average Ca2+ fluorescence intensity in PASMCs of PPH group was higher than that of PPH + antagonist group,the differences were statistically significant (P ＜ 0.05).Whereas the difference of average Ca2 + fluorescence intensity in PASMCs of PPH group and PPH + agonist group was of no statistical significance (P ＞ 0.05).Conclusion CaSR may be involved in the occurrence and development of hypoxic-induced PPH in neonatal mice by affecting the intracellular Ca2+ concentration in pulmonary artery smooth muscle cells.

One pedigree analysis of a familial hypocalciuric hypercalcemia caused by a new heterozygous mutation in calcium-sensing receptor gene / 中华内分泌代谢杂志

Medical history and physical examinations were performed to assess the clinical manifestations and growth of one patient with familial hypocalciuric hypercalcemia(FHH). Clinical data, including histories of his parents and 3 maternal relatives were collected. Serum parathyroid hormone(PTH), calcium, phosphorus, 24-hour urinary calcium, and 24-hour urinary calcium to creatinine ratio(UCCR)were measured or calculated. Meanwhile, after peripheral blood samples were collected and genomic DNA was extracted, the whole exome sequencing to detect gene mutations of the proband was performed. Further family screenings were also performed by Sanger sequencing to assess the relationship between genotype and phenotype. The results showed that the proband with motor developmental delays had severe hypercalcemia(4.20 mmol/L), while his mother without clinical symptoms had a higher blood calcium within the normal range(2.57 mmol/L). However, their urinary calcium levels were both low(UCCR< 0.01). The C→T heterozygous missense mutation was found by exome sequencing at nucleotide 1243 within exon 4 of calcium sensing receptor(CaSR)gene in the proband, which caused a substitution of Arginine to Tryptophan(R415W). Sanger sequencing confirmed the same mutation in his mother. There was no mutation in other family members. (Chin J Endocrinol Metab, 2018, 34: 583-586)

Expression of CaSR in neurons and cardiomyocytes incubated with magnesium-free extracellular fluid and its relationship with the MAPK pathway / 医学研究生学报

Objective At present, studies on the calcium sensing receptor (CaSR) in the pathogenesis of epilepsy are carried out in animal models in vivo and in single cells cultured in vitro. This study was to investigate the expression of CaSR and its relationship with the MAPK pathway in the rat model of epilepsy.Methods The neurons and cardiomyocytes of 3-day-old Wistar rats were cultured for 10 days and randomly divided into groups A (control), B (magnesium-free), C (magnesium free+spermine), D (magnesium free+calhex231), and E (magnesium free+spermine+calhex231). The model of epilepsy was made by abnormal discharge of the neurons induced by coculturing magnesium-free extracellular fluid with cardiomyocytes. The morphological changes of the cells were observed by HE staining and transmission electron microscopy, their survival rate detected by MTT, and the expressions of the CaSR, Bcl-2, P-ERK, P-JNK and P-P38 proteins in the cocultured cells determined by Western blot.Results Compared with the cells in group B, those in group C were swollen and broken with nuclear fragmentation, those in group D showed a relative integrity, and those in group E were also swollen and broken but improved in comparison with those in group C. The survival rates of the cells were (61.08±15.44)%, (82.80±14.37)% and (82.04±17.37)% in groups C, D and E, respectively, all significantly lower than in A (\[100.00±0.00\]%, P<0.01) and B (\[88.88±9.85\]%, P<0.01). The expression of CaSR was markedly higher in group B than in A (\[0.73±0.19\] vs \[0.45±0.12\], P<0.01) but lower than in C (1.32±0.15) and E (1.19±0.12) (P<0.01). The expression levels of Bcl-2 and P-ERK were remarkably lower in group B than in A but higher than in C (P<0.01), and those of P-JNK and P-P38 significantly higher in group B than in A and lower than in C and E (P<0.05).Conclusion Magnesium-free extracellular fluid can damage neurons and cardiomyocytes, increase the expression of CaSR, participate in the MAPK signaling pathway, and mediate the apoptosis of neurons and cardiomyocytes, while CaSR inhibitors can relieve the CaSR agonist-induced damage to the cells.

De novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism

Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.

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)

Triangle relationship of PTH, intracellular calcium and CaSR in myocardial damage / 中国病理生理杂志

Parathyroid hormone ( PTH) is an important hormone secreted by parathyroid cells , and regulates the metabolism of calcium and phosphorus in the body .In recent years , the toxic effect of PTH on myocardium has been re-ported.Calcium-sensing receptor (CaSR), a member of G protein-coupled receptor family, can feel the subtle change of extracellular calcium concentration and regulate intracellular calcium concentration through multifarious ways in order to control the secretion of PTH .The expression of CaSR is observed in parathyroid cells , renal tubular epithelial cells , myo-cardial cells, etc.Intracellular calcium, as a second messenger, participates in various cell functions , such as excitation-contraction coupling , fertilization and so on .The injury of myocardial cells is intimately linked with high concentrations of PTH and intracellular calcium , and high expression of CaSR .

Calcium-sensing receptor diseases and their molecular pathogenesis / 中华内分泌代谢杂志

[Summary] Extracellular calcium is essential for the regulation of a variety of biological processes. Calcium-sensing receptor (CaSR) plays a central role in maintaining Ca2+ homeostasis, while G-protein α-11 (Gα11 ) subunit and adaptor-related protein complex 2 sigma (AP2σ) are also involved in CaSR signaling transduction. Loss- or gain-of-function mutations of these encoding genes cause different types of familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH). Calcimimetic and calcilytic drugs are useful in treating these FHH and ADH disorders. The current paper is a Chinese translation of a review entitled as “Disorder of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis” published in 《 Journal of Molecular Endocrinology》(2016,57:R127-R142) with the permission from the author and the journal.

Calcemic response to burns differs between adults and children: A review of the literature

OBJECTIVES: The calcemic and parathyroid hormone (PTH) responses to severe burn injury appear to differ between children and adults. In our limited studies children exhibited hypocalcemic hypoparathyroidism consistent with up-regulation of the parathyroid calcium-sensing receptor (CaSR) while adults did not, suggesting a developmental cutoff in cytokine-mediated up-regulation of the CaSR. This difference may be clinically important as published studies indicate that extracellular calcium (Ca) may stimulate the inflammatory response. The aim of this study was to examine the existing literature on burns to see if the differences between pediatric and adult calcemic and PTH responses to burn supported our findings providing stronger evidence to support this developmental difference. METHODS: We reviewed the National Library of Medicine database using the terms burns, PTH and ionized calcium and found 9 articles from 8 different medical centers; one was eliminated due to mixing of adults and children. RESULTS: There were 245 burn patients reported from the literature, 178 pediatric and 67 adults. The data are mostly consistent with our reported findings. Of the 10 pediatric patients with severe burns that we studied, mean ionized Ca concentration was below the lower limit of normal of 1.10 mM. The 67 adult burn patients reported in the literature had a mean blood ionized Ca concentration that was within the adult normal range or was lower than normal but with secondary hyperparathyroidism. Moreover, serum PTH concentrations were uniformly low in the 178 children in the burn literature but normal or mildly elevated in the 67 adults. CONCLUSIONS: These results support the hypothesis that the difference between pediatric and adult victims is consistent with an age-related CaSR response to cytokine stimulation and may be consistent with a lower level of inflammation in children. Ionized Ca and PTH might serve as possible therapeutic targets to lower the inflammatory response in burn victims.