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.

Diethyl citrate inhibits vascular calcification in chronic kidney disease by CaSR/autophagy signaling axis / 西安交通大学学报(医学版)

Objective: To investigate the effects of calcium sensitive receptor (CaSR)/autophagy signaling axis on the inhibition of vascular calcification in chronic kidney disease (CKD) by diethyl citrate (Et2Cit). Methods: Rats and vascular smooth muscle cells (VSMCs) were divided into 5 groups: normal control group, model group, low-dose Et2Cit group, high-dose Et2Cit group and high-dose Et2Cit+NPS-2143 (CaSR inhibitor) group. After the intervention, the content of aorta calcium in each group was detected. Alizarin red staining was used to detect calcification in each cell group. mRNA expressions of calcification-related proteins, CaSR and autophagy-related proteins in the aorta of each group were detected by qRT-PCR. The expressions of the above proteins in each group were detected by Western blotting. Results: Compared with the control group, the calcification in model group was significantly increased, and Et2Cit intervention could reduce the calcification in a dose-dependent manner (P<0.05). Compared with high-dose Et2Cit group, high-dose Et2Cit+NPS-2143 group had significantly higher calcium content (P<0.05). Compared with those in the control group, the expressions of smooth muscle 22α (SM22α), CaSR and Beclin1 were decreased (P<0.05), while the expressions of runt related transcription factor 2 (RUNX2) and P62 were increased (P<0.05). Et2Cit intervention could reverse the above changes (P<0.05). Compared with the high-dose Et2Cit group, the high-dose Et2Cit + NPS-2143 group had significantly lower SM22α, CaSR and Beclin1, and significantly higher RUNX2 and P62 levels (P<0.05). Results: Et2Cit inhibits CKD vascular calcification partly via the CaSR and CaSR/autophagy signal axis.

Hipercalcemia hipocalciúrica familiar: Descripción de un caso / Familial hypocalciuric hypercalcemia: A case report

La presencia de hipercalcemia mantenida obliga a realizar pruebas complementarias para determinar su origen. Es benigna y, generalmente, no requiere tratamiento. La secuenciación del gen CaSR confirma el diagnóstico y evita tratamientos innecesarios. Se presenta a un niño de 12 años, asintomático, con hipercalcemia persistente entre 11,4 y 12,2 mg/dl. El padre y dos hermanos tenían hipercalcemia asintomática. El análisis de laboratorio mostró valores de magnesio, fósforo y vitamina D normales y de hormona paratiroidea llamativamente normal para el valor de la hipercalcemia. Indice de calcio/creatinina urinario: 0,11 mg/mg; y calciuria de 24 h: 1,8 mg/kg/día. Ecografía abdominal, paratiroides, radiografías de huesos largos y densitometría ósea, normales. El estudio genético mostró mutación en exón 6 (c.1651A>G) del gen CaSR (en heterocigosis), confirmada en el padre y los hermanos.

The finding of persistent hypercalcemia suggests doing other medical tests to find the cause. Familial hypocalciuric hypercalcemia is usually benign and it requires no treatment. It is important to do CASR gene sequencing to avoid unnecessary treatments. We report a 12-year-old child, asymptomatic, with calcemia between 11.4 and 12.2 mg/dl. His father and two brothers presented asymptomatic hypercalcemia. The blood test with magnesium, phosphorus, 25(OH)Vit D was normal, remarkable normal parathyroid hormone for the level of hypercalcemia. Urinary calcium/creatinine ratio was 0,11 mg/dl and 24-hour urinary calcium was 1,8 mg/kg per day. Abdominal and parathyroid ecography, long bone radiographs and densitometry were normal. Genetic study showed a mutation, c.1651A>G, in exon 6 of the calciumsensing receptor gene, confirmed in father and brothers, too.

Expressions of CaSR and Claudin-14 and the formation of nanobacterial renal stone: A dynamic study / 医学研究生学报

Objective Nanobacteria are one of the factors for urinary calculi and its exact pathogenic mechanism is not yet clear.The aim of this study was to investigate the role of the CaSR -Claudin-14 regulatory channel in the formation of calculi . Methods Sixty Wistar male rats were equally randomized into a normal control group and nanobacterial group , the former injected via the tail vein with 1.2 mL of 0.9％ sodium chloride solution while the latter with 1.2 mL of nanobacterial suspension , both for once.Three of the rats in each group were sacrificed every week in the first 10 weeks after injection.Histopathological examination was performed every week to evaluate the stone formation in the kidneys of the rats , and the expressions of the CaSR and Claudin -14 proteins were determined by immunohistochemistry. Results From the 1st to the 10th week after injection, crystal particles were observed in the rat kidneys of the nanobacterial group, but not in the normal controls (52.4％ vs 0％, P<0.01).The expressions of CaSR and Claudin -14 showed no statistically significant differences between the nanobacterial and control groups in the first 3 weeks (P>0.05) but both gradually in-creased in the former group from the 4th to the 10th week as compared with the latter, mainly in membrane of the renal tubular epithelial cells. Conclusion The increased activity of the CaSR -Claudin-14 regulatory channel may play an important role in the formation of nanobacterial renal stone .

Regulation of Ca2+ Signaling in Pulmonary Hypertension

Understanding the cellular and molecular mechanisms involved in the development and progression of pulmonary hypertension (PH) remains imperative if we are to successfully improve the quality of life and life span of patients with the disease. A whole plethora of mechanisms are associated with the development and progression of PH. Such complexity makes it difficult to isolate one particular pathway to target clinically. Changes in intracellular free calcium concentration, the most common intracellular second messenger, can have significant impact in defining the pathogenic mechanisms leading to its development and persistence. Signaling pathways leading to the elevation of [Ca2+]cyt contribute to pulmonary vasoconstriction, excessive proliferation of smooth muscle cells and ultimately pulmonary vascular remodeling. This current review serves to summarize the some of the most recent advances in the regulation of calcium during pulmonary hypertension.

Genetic and Clinical Characteristics of Korean Patients with Isolated Hypoparathyroidism: From the Korean Hypopara Registry Study

Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.

Hiperparatiroidismo primario: presentación de un caso y revisión de la literatura / Primary hyperparathyroidism: clinical case and literature review

Hypercalcemia is infrequent in pediatrics, causes include mutations of calcium sensing receptor (CaSRs), PT adenoma or hyperplasia, D or A hypervitaminosis, inborn errors of metabolism, parenteral nutrition, and others. Objective: To report a case of severe hypercalcemia in a adolescent due to primary hyperparathyroidism. Case: Fourteen years old adolescent girl with 2 weeks of weight loss, polyuria, malaise and emotional lability. Laboratory reveals hypercalcemia (16.6 mg/dl), hypophosphemia (2.2 mg/dl) and elevated PTH (450 pg/ml). Management of severe hypercalcemia at ICU was done. PT Scintigraphy study reveals increased uptake in the lower pole of right thyroid lobe. Right inferior parathyroidectomy was performed and biopsy revealed right lower parathyroid hyperplasia. Discusion: Primary hyperparathyroidism (HPT) is an uncommon condition in children. The main causes are parathyroid adenomas or hyperplasia, frequently one or two PT glands involved. HPT must be suspected in symptomatic hypercalcemia, nephrourinary symptoms in scholars and adolescents (polyuria and nephrolithiasis) and in newborn with pathologic fractures and costal rosary. The pathogenesis includes mutations in CaSRs, cyclin D1/PRAD 1 and MEN 1 genes.

La hipercalcemia es infrecuente en pediatría, existen diferentes causas que incluyen mutaciones del receptor sensible al calcio (CaSRs), adenoma o hiperplasia de PT, hipervitaminosis D o A, errores congénitos del metabolismo, nutrición parenteral total, etc. Objetivo: Comunicar un caso de hipercalcemia severa en una adolescente causado por un hiperparatiroidismo primario. Caso: Escolar de 14 años con cuadro de 2 semanas de baja de peso, poliuria, compromiso del estado general y labilidad emocional. Los exámenes revelaron hipercalcemia (16 mg/dl), hipofosfemia (2,2 mg/dl) y PTH elevada (450 pg/ml). Se hospitalizó para manejo de hipercalcemia severa, con diagnósticos de Hiperparatiroidismo primario. Se completó estudio con cintigrama de PT, encontrando hipercaptación en polo inferior de lóbulo tiroideo derecho. Se realizó una paratiroidectomia inferior derecha y la biopsia reveló hiperplasia de paratiroides inferior derecha. Discusión: El hiperparatiroidismo primario es una condición infrecuente en niños. Las principales causas son adenomas o hiperplasia de paratiroides, frecuentemente con 1 o dos glándulas PT comprometidas. Debe sospecharse en casos de hipercalcemia sintomática, escolares o adolescentes con síntomas nefrourinarios (poliuria importante y nefrolitiasis) y frente a un recién nacido grave, con fracturas patológicas o rosario costal. La etiopatogenia incluye mutaciones del gen CaSRs, Ciclin D1/PRAD 1 y el MEN 1.

The relationship between calcium sensing receptor gene (CA) polymorphism, bone mineral density and bone responsiveness to hormone replacement therapy in postmenopausal Korean women / 대한산부인과학회잡지

OBJECTIVE: To evaluate the relationship between the calcium sensing receptor (Casr) gene cytosine adenine (CA) polymorphism, bone mineral density (BMD) and bone responsiveness to hormone replacement therapy (HRT). METHODS: Casr (CA) polymorphism was analyzed by polyacrylamide-urea gel electrophoretic patterns, genescan and direct DNA sequencing in 502 postmenopausal Korean women. Among these women, 352 women received sequential HRT for 1 year. Serum bone alkaline phosphatase, CrossLaps, osteocalcin, calcitonin, and parathyroid hormone levels were measured by immunoassay and Serum calcium and phosphorus levels by atomic absorptiometry. BMD at the lumbar spine and proximal femur was determined by dual energy X-ray absorptiometry before and after HRT of 1 year. RESULTS: Nine Casr alleles were observed with product sizes ranging between 176-196 bp, and their distribution was as follows: 188 bp 26.2%, 194 bp 19.8%, 186 bp 18.2%, 190 bp 15.5%. 192 bp 14.3% etc. BMD at the Ward's triangle was significantly lower in women carrying at least one copy of 216 bp Casr (CA) allele than in women who did not this allele, but no significant differences in annual percentage changes of BMD were noted among Casr (CA) genotypes. There were no significant differences in after HRT levels of biochemical bone markers and their 6 month percentage changes after HRT among Casr (CA) genotypes. The Casr (CA) genotypes were not distributed differently between HRT-responders and HRT-nonresponders (women who lose more than 3% of bone mass per year) or between women with normal BMD and women with low bone mass. CONCLUSION: The Casr (CA) polymorphism is not associated with bone responsiveness to HRT but BMD of Ward's triangle in Korean women.