Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 581
Filtrar
1.
Adv Exp Med Biol ; 1164: 161-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576548

RESUMO

PTHrP was first discovered as the most common mediator of malignancy-associated hypercalcemia. Subsequently, the discovery of its ubiquitous expression in normal tissues unraveled its role as a physiological autocrine/paracrine regulator. The significance of PTHrP in cancer is not confined to malignancy-associated hypercalcemia, and sufficient evidence now also supports its role in skeletal metastasis through its modulation of bone turnover. Furthermore, our own studies have recently shown the critical role of PTHrP in breast cancer initiation, growth, and metastasis. More recently, we have provided new evidence that overexpression of PTHrP is associated with higher incidence of brain metastasis and decreased overall survival in triple-negative breast cancer patients. Further mechanistic studies in human and mouse model are necessary to fully understand the role of PTHrP in tumor progression and metastasis.


Assuntos
Neoplasias Ósseas , Hipercalcemia , Proteína Relacionada ao Hormônio Paratireóideo , Animais , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/fisiopatologia , Neoplasias da Mama , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Hipercalcemia/etiologia , Hipercalcemia/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo
2.
Pancreatology ; 19(6): 801-804, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31391146

RESUMO

Familial hypocalciuric hypercalcemia is an autosomal dominant genetic disorder characterized by hypercalcemia associated with inappropriate hypocalciuria and normal parathyroid hormone levels. Acute recurrent pancreatitis (ARP) is rare in children. Predisposing factors include hypercalcemia and mutations in the serine protease inhibitor Kazal-type 1 (SPINK1) gene. The disease carries a heavy morbidity and preventive treatment options are scant. Here, we report a child with a novel genetic/metabolic form of ARP associated with compound heterozygous SPINK1/AP2S1 (adaptor protein-2 σ1-subunit) mutations, recurrence of which was completely abrogated for 6 years by cinacalcet treatment.


Assuntos
Complexo 2 de Proteínas Adaptadoras/genética , Subunidades sigma do Complexo de Proteínas Adaptadoras/genética , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Cinacalcete/uso terapêutico , Pancreatite/genética , Pancreatite/prevenção & controle , Inibidor da Tripsina Pancreática de Kazal/genética , Doença Aguda , Adolescente , Feminino , Humanos , Hipercalcemia/complicações , Hipercalcemia/congênito , Hipercalcemia/genética , Mutação/genética , Recidiva
3.
Rev. med. Rosario ; 85(2): 77-80, mayo-ago. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1053282

RESUMO

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)


Assuntos
Humanos , Masculino , Criança , Receptores de Detecção de Cálcio/genética , Cinacalcete/uso terapêutico , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Doenças Genéticas Inatas
4.
Fetal Pediatr Pathol ; 38(1): 44-56, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30633617

RESUMO

BACKGROUND: Biallelic pathogenic variants in CYP24A1 can cause idiopathic infantile hypercalcemia (HCINF). METHODS: We report 2 additional molecular abnormalities in 2 Chinese children with CHINF1. RESULTS: Biallelic variants in CYP24A1 were found in two patients. Patient One was compound heterozygous for c.449 + 1G > T and c.1426_1427delCT. Patient Two was compound heterozygous for c.1310C > A and c.1426_1427delCT. The c.1310C > A and c.449 + 1G > T were two different novel CYP24A1 variants. Multiple computational tools predicted that both impact protein function. A total of 36 variants have been previously reported in patients with HCINF1, of which 27 were classified as pathogenic or likely pathogenic and nine as uncertain clinical significance. CONCLUSION: Genetic tests are helpful in order to counsel the susceptible individuals to avoid vitamin D and take preventive measures in order to avoid complications.


Assuntos
Hipercalcemia/genética , Doenças do Recém-Nascido/genética , Erros Inatos do Metabolismo/genética , Vitamina D3 24-Hidroxilase/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Variação Genética , Humanos , Lactente , Masculino , Linhagem
5.
Front Horm Res ; 51: 52-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30641521

RESUMO

Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are genetically determined variants of primary hyperparathyroidism. FHH usually has a benign course, and patients do not require treatment, whereas NSHPT is a severe disorder often requiring early parathyroidectomy for young patients to survive. Recent discoveries in the genetic basis and new findings in therapeutic approaches have led to a great interest in these rare diseases.


Assuntos
Hipercalcemia/congênito , Hiperparatireoidismo Primário , Doenças do Recém-Nascido , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Hipercalcemia/terapia , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/terapia , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/terapia
6.
Front Horm Res ; 51: 77-90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30641526

RESUMO

Primary hyperparathyroidism is among the most common causes of hypercalcemia. However, ingestion of medication, including hydrochlorathiazide, lithium, and foscarnet, excessive vitamin A ingestion, endocrinopathies such as hyperthyroidism, adrenal insufficiency, and acromegaly, abnormal nutrient intake such as parenteral nutrition in preterm infants and milk-alkali syndrome, and prolonged immobilization have all been associated with hypercalcemia. The most common cause of nonparathyroid hypercalcemia is neoplasia. Hypercalcemia is generally due to the secretion of parathyroid hormone (PTH)-related peptide (PTHrP) by a wide variety of nonmetastatic solid tumors, including squamous cell tumors but also hematologic tumors. PTHrP, although encoded by a distinct gene, shares amino acid sequence homology with PTH in the amino-terminal domain, which allows it to cross-react at a common G protein receptor, the type 1 PTH/PTHrP receptor (PTHR1), resulting in similar skeletal effects and effects on calcium and phosphorus metabolism. Increased PTHrP action with hypercalcemia may be seen in the benign disease Jansen's metaphyseal chondrodysplasia due to a gain-of-function mutation in PTHR1. Another humoral factor, 1,25-dihyroxyvitamin D [1,25(OH)2D] may be produced by lymphomas, but also by benign granulomatous disorders and may also cause hypercalcemia when its metabolism is genetically impaired. Vitamin D intoxication may cause hypercalcemia due to overproduction of the metabolite, 25 hydroxyvitamin D, apparently in the absence of conversion to 1,25(OH)2D. Malignancies metastatic to bone or arising in bone (such as multiple myeloma) may produce a variety of growth factors and cytokines, in addition to PTHrP, which can contribute to tumor growth as well as osteolysis and hypercalcemia.


Assuntos
Doenças do Sistema Endócrino/complicações , Hipercalcemia/etiologia , Neoplasias/complicações , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Humanos , Hipercalcemia/genética , Hipercalcemia/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/genética
7.
Horm Res Paediatr ; 91(4): 278-284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30227399

RESUMO

BACKGROUND: Under physiological conditions, proximal tubular phosphate reabsorption via NaPi-IIa (and NaPi-IIc) ensures the maintenance of phosphate homeostasis. Impairment of NaPi-IIa, encoded by SLC34A1, is associated with various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi's syndrome with chronic kidney disease, and idiopathic infantile hypercalcemia and nephrocalcinosis. METHODS: A patient was referred to our hospital due to hyponatremia, hyperkalemia, and hypophosphatemia, as well as persistent hypercalcemia after fluid therapy and sodium replacement. At admission to our hospital, potassium and sodium values were normal. After initiation of phosphorus therapy, hypokalemia and metabolic alkalosis were observed. Renal sonography showed bilateral medullary nephrocalcinosis. Analyses of the SLC34A1 gene were performed due to hypercalcemia and hypophosphatemia. RESULTS: Gene analyses identified a novel homozygous c.682T>C (p.W228R) (p.Trp228Arg) mutation. There are no previous reports of patients with SLC34A1 gene mutations presenting with hypokalemia and metabolic alkalosis. CONCLUSION: Herein, we present a case of infantile hypercalcemia 2 with a very different phenotype from that of previously described patients. Our findings provide further evidence for the wide range of phenotypic heterogeneity associated with NaPi-IIa impairment.


Assuntos
Homozigoto , Hipercalcemia/genética , Mutação de Sentido Incorreto , Nefrocalcinose/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Substituição de Aminoácidos , Feminino , Humanos , Hipercalcemia/sangue , Hipercalcemia/diagnóstico por imagem , Hipercalcemia/tratamento farmacológico , Lactente , Nefrocalcinose/sangue , Nefrocalcinose/diagnóstico por imagem , Nefrocalcinose/tratamento farmacológico
8.
Joint Bone Spine ; 86(4): 459-466, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30300686

RESUMO

A genetic disorder should be suspected in patients with hypercalcemia, notably those who are young; have family members with hypercalcemia; or have had a tumor of the endocrine pancreas, thyroid, pituitary, adrenal gland, or jaw bone. All forms of hypercalcemia should be interpreted according to the serum level of parathyroid hormone (PTH). Genetic forms are thus classified as related or unrelated to a parathyroid gland disorder. When the PTH level is elevated or is not depressed despite the hypercalcemia, findings that suggest family history of hypercalcemia due to a genetic cause include syndromic manifestations in the patient or family members, parathyroid cancer (either suspected before surgery or confirmed during parathyroidectomy), multiple or recurrent parathyroid tumors, a family history of primary hyperparathyroidism, and the onset of primary hyperthyroidism before 50 years of age. In patients with moderate hypercalcemia, a normal PTH level, and relative hypocalciuria, the first hypothesis is a mutation in the calcium-sensing receptor gene, which is often difficult to distinguish from primary hyperparathyroidism, particularly when there is no known family history of hyperparathyroidism, as is often the case. A low PTH level suggests non-parathyroid hypercalcemia due to a genetic defect in patients with no evidence of other conditions associated with hypercalcemia and low PTH levels and in those whose calcitriol levels are elevated or normal (instead of depressed as expected when PTH is elevated). Patients with hypercalciuria but no evidence of conditions such as granulomatous diseases should be evaluated for increased vitamin D sensitivity due to a CYP 4A1 mutation. Other very rare causes include hypophosphatasia due to ALPL mutations, which is characterized by a low alkaline phosphatase level; and renal phosphate wasting due to an NPT2A mutation, in which serum phosphate levels are low. A thorough analysis of the clinical and laboratory data can point toward a genetic disorder in patients with hypercalcemia. The diagnosis is then confirmed by obtaining genetic tests tailored to the clinical and laboratory test abnormalities. The current development of diagnostic genetic testing is shedding new light on the phenotypes, thereby improving their management.


Assuntos
Citocromo P-450 CYP4A/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Hipercalcemia/genética , Hormônio Paratireóideo/sangue , Receptores de Detecção de Cálcio/genética , Feminino , Testes Genéticos , Humanos , Hipercalcemia/sangue , Hipercalcemia/diagnóstico , Hipercalcemia/epidemiologia , Hiperparatireoidismo/complicações , Hiperparatireoidismo/diagnóstico , Incidência , Masculino , Mutação , Prognóstico , Medição de Risco
9.
Fam Cancer ; 18(2): 161-163, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30284660

RESUMO

One of a pair of monozygous twins was diagnosed and died of small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) at the age of 30 years. Her sister remained unaffected and was very concerned about her risk for developing SCCOHT. By performing comprehensive molecular analysis using whole exome sequencing (WES) approach, we showed that the deceased twin's tumour has bi-allelic somatic genetic defects (a pathogenic frameshift deletion in SMARCA4 and LOH on chr19p). Results of WES of constitutional DNA from her unaffected sister were confirmatory. Based on our findings, we concluded that the living twin is not at risk for SCCOHT and does not need to consider preventive oophorectomy.


Assuntos
Carcinoma de Células Pequenas/diagnóstico , Doenças em Gêmeos/diagnóstico , Hipercalcemia/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adulto , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , DNA Helicases/genética , Análise Mutacional de DNA , Doenças em Gêmeos/genética , Doenças em Gêmeos/patologia , Evolução Fatal , Feminino , Humanos , Hipercalcemia/genética , Hipercalcemia/patologia , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/patologia , Fatores de Transcrição/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma
10.
Eur J Med Genet ; 62(11): 103577, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30423445

RESUMO

Loss-of-function mutations in CYP24A1 (MIM 126065 20q13.2), the gene encoding the 24-hydroxylase responsible for 25-OH-D and 1,25-(OH)2D degradation, are identified in about 20% of patients presenting Idiopathic Infantile Hypercalcemia (IIH) (MIM 143880). Common features of this autosomal recessive condition included hypercalcemia with hypercalciuria, suppressed PTH and a high 25-OH-D3:24,25-(OH)2D3 ratio. Medical care mainly relies on sun protection and life-long contraindication of vitamin D to avoid complications such as early nephrocalcinosis and renal failure. Molecular diagnosis therefore keeps a crucial place in the diagnosis of IIH, and genetic counseling should be systematically recommended to prevent vitamin D administration in affected siblings. In this report is described the molecular characterization of a CYP24A1 deletion identified in two unrelated families. This highlights the potential role of CYP24A1 copy number variations (CNV) in IIH. Considering the presence of CNV affecting CYP24A1 in public databases, CNV analysis should be systematically added to the sequencing studies in IIH. Targeted Massively Parallel Sequencing (MPS) study coupled with a CNV detection tool called CovCop is a powerful method to detect genic rearrangement and improve genetic analysis.


Assuntos
Hipercalcemia/diagnóstico , Hipercalcemia/genética , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Patologia Molecular , Vitamina D3 24-Hidroxilase/genética , Adolescente , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/patologia , Lactente , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/patologia , Mutação com Perda de Função/genética , Masculino , Erros Inatos do Metabolismo/tratamento farmacológico , Erros Inatos do Metabolismo/patologia , Nefrocalcinose/tratamento farmacológico , Nefrocalcinose/genética , Nefrocalcinose/prevenção & controle , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/genética , Insuficiência Renal/prevenção & controle , Deleção de Sequência/genética , Vitamina D/uso terapêutico
11.
Eur J Endocrinol ; 180(1): 59-70, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30407919

RESUMO

Objective Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described. Methods The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing. Results Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median: 11.3 mg/dL) but normal or abnormally high parathyroid hormone (PTH) levels (median: 52 pg/mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from eight families. These patients had a median serum calcium level of 7.4 mg/dL and hypoparathyroidism (median: PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium: 10.6 mg/dL; median PTH: 65 pg/mL) with no other alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, p.Lys119Ile, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351Ile, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.Ile816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup). Conclusions Patients with CASR mutations may not fit the classic clinical pictures of hypercalcemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are important for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorders in 82 patients in the study cohort.


Assuntos
Hipercalcemia/genética , Hipercalciúria/genética , Hipocalcemia/genética , Mutação , Polimorfismo Genético , Receptores de Detecção de Cálcio/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Extratos Vegetais
12.
Arch. argent. pediatr ; 116(6): 757-761, dic. 2018. ilus, tab
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-973692

RESUMO

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.


Assuntos
Humanos , Masculino , Criança , Receptores de Detecção de Cálcio/genética , Hipercalcemia/congênito , Hipercalcemia/etiologia , Éxons , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Mutação
13.
Nat Rev Endocrinol ; 15(1): 33-51, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30443043

RESUMO

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and ß-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.


Assuntos
Calcimiméticos/uso terapêutico , Hipercalcemia/congênito , Hipercalciúria/genética , Hipocalcemia/genética , Hipoparatireoidismo/congênito , Nefrolitíase/genética , Receptores de Detecção de Cálcio/genética , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença/epidemiologia , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/genética , Hipercalcemia/fisiopatologia , Hipercalciúria/tratamento farmacológico , Hipercalciúria/fisiopatologia , Hipocalcemia/tratamento farmacológico , Hipocalcemia/fisiopatologia , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/genética , Hipoparatireoidismo/fisiopatologia , Incidência , Masculino , Mutação/genética , Nefrolitíase/tratamento farmacológico , Nefrolitíase/fisiopatologia , Prognóstico , Receptores de Detecção de Cálcio/efeitos dos fármacos , Medição de Risco , Resultado do Tratamento
14.
Best Pract Res Clin Endocrinol Metab ; 32(5): 609-619, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30449544

RESUMO

Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit α11, or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-h urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH.


Assuntos
Hipercalcemia/congênito , Complexo 2 de Proteínas Adaptadoras/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Humanos , Hipercalcemia/complicações , Hipercalcemia/diagnóstico , Hipercalcemia/epidemiologia , Hipercalcemia/genética , Hipercalcemia/terapia , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/epidemiologia , Hiperparatireoidismo Primário/terapia , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/genética , Nefropatias/terapia , Mutação , Receptores de Detecção de Cálcio/genética
15.
Best Pract Res Clin Endocrinol Metab ; 32(6): 891-908, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30477753

RESUMO

Parathyroid tumors represent an elusive endocrine neoplasia, which lead to primary hyperparathyroidism, pHPT, a common endocrine calcium disorder characterized by hypercalcemia and normal-high parathormone secretion. Parathyroid tumours are benign adenomas or multiple glands hyperplasia in the vast majority (>99% of cases), while malignant neoplasms are rare (less than 1%). Despite pHPT is a common disorder, our knowledge about the genetic predisposition and molecular pathophysiology is limited to the familial syndromic forms of parathyroid tumour, that, however, represent not more than the 10% of all the cases; instead, the pathophysiology of sporadic forms remains an open field, although data about epigenetic mechanisms or private genes have been supposed. Here we present an overview of more recent acquisitions about the genetic causes along with their molecular mechanisms of benign, but also, malignant parathyroid tumours either in sporadic and familial presentation.


Assuntos
Adenoma/genética , Neoplasias das Paratireoides/genética , Adenoma/patologia , Epigênese Genética , Predisposição Genética para Doença , Humanos , Hipercalcemia/genética , Hiperparatireoidismo Primário/genética , Neoplasias das Paratireoides/patologia
16.
Arch Argent Pediatr ; 116(6): e757-e761, 2018 12 01.
Artigo em Espanhol | MEDLINE | ID: mdl-30457731

RESUMO

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.


Assuntos
Hipercalcemia/congênito , Hipercalcemia/etiologia , Receptores de Detecção de Cálcio/genética , Criança , Éxons , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Masculino , Mutação
17.
Medicine (Baltimore) ; 97(40): e12090, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290590

RESUMO

RATIONALE: Malakoplakia is a rare disease characterized by the presence of nongranulomatous macrophage infiltration. In most cases, it affects the urinary tract. Malakoplakia can cause acute kidney injury when it is localized in the kidneys. PATIENT CONCERNS: Here, we report the case of a 65-year-old female patient with renal malakoplakia responsible for hypercalcemia. During her initial assessment, she was also diagnosed 25-OH vitamin D insufficiency, for which she was prescribed oral cholecalciferol. Three months later, she developed severe hypercalcemia with normal 25-OH vitamin D and parathyroid hormone levels and high 1,25-dihydroxyvitamin D levels. DIAGNOSES: After a superimposed granulomatous disease was excluded, malakoplakia cells were suspected to be responsible for the abnormal 25-hydroxyvitamin D3 1-alpha-hydroxylase activity, which was confirmed by immunohistochemistry. INTERVENTIONS: Cholecalciferol was stopped, the patient was rehydrated with intravenous physiological saline, and prednisone was initiated to decrease the enzyme activity. OUTCOMES: Six months later, she displayed normal serum calcium, 25-OH vitamin D and 1,25-dihydroxyvitamin D levels. LESSONS: This case illustrates that malakoplakia may exhibit ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase activity and cause severe hypercalcemia upon vitamin D supplementation. Therefore, such supplementation should not be given in malakoplakia patients without an actual deficiency and requires careful monitoring of serum calcium.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Hipercalcemia/genética , Nefropatias/complicações , Malacoplasia/complicações , Deficiência de Vitamina D/terapia , Idoso , Cálcio/sangue , Colecalciferol/efeitos adversos , Suplementos Nutricionais , Expressão Ectópica do Gene , Feminino , Humanos , Nefropatias/sangue , Nefropatias/genética , Malacoplasia/sangue , Malacoplasia/genética , Hormônio Paratireóideo/sangue , Deficiência de Vitamina D/complicações , Vitaminas/efeitos adversos
18.
J Clin Invest ; 128(12): 5222-5234, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30179220

RESUMO

The mechanisms that drive T cell aging are not understood. We report that children and adult telomerase mutation carriers with short telomere length (TL) develop a T cell immunodeficiency that can manifest in the absence of bone marrow failure and causes life-threatening opportunistic infections. Mutation carriers shared T cell-aging phenotypes seen in adults 5 decades older, including depleted naive T cells, increased apoptosis, and restricted T cell repertoire. T cell receptor excision circles (TRECs) were also undetectable or low, suggesting that newborn screening may identify individuals with germline telomere maintenance defects. Telomerase-null mice with short TL showed defects throughout T cell development, including increased apoptosis of stimulated thymocytes, their intrathymic precursors, in addition to depleted hematopoietic reserves. When we examined the transcriptional programs of T cells from telomerase mutation carriers, we found they diverged from older adults with normal TL. Short telomere T cells upregulated DNA damage and intrinsic apoptosis pathways, while older adult T cells upregulated extrinsic apoptosis pathways and programmed cell death 1 (PD-1) expression. T cells from mice with short TL also showed an active DNA-damage response, in contrast with old WT mice, despite their shared propensity to apoptosis. Our data suggest there are TL-dependent and TL-independent mechanisms that differentially contribute to distinct molecular programs of T cell apoptosis with aging.


Assuntos
Apoptose/imunologia , Transtornos do Crescimento , Hipercalcemia , Síndromes de Imunodeficiência , Doenças Metabólicas , Mutação , Nefrocalcinose , Telomerase , Homeostase do Telômero/imunologia , Adulto , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/patologia , Animais , Apoptose/genética , Dano ao DNA/imunologia , Feminino , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Transtornos do Crescimento/imunologia , Transtornos do Crescimento/patologia , Humanos , Hipercalcemia/complicações , Hipercalcemia/genética , Hipercalcemia/imunologia , Hipercalcemia/patologia , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/genética , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/genética , Doenças Metabólicas/imunologia , Doenças Metabólicas/patologia , Camundongos , Camundongos Knockout , Nefrocalcinose/complicações , Nefrocalcinose/genética , Nefrocalcinose/imunologia , Nefrocalcinose/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Telomerase/genética , Telomerase/imunologia
19.
Am J Physiol Renal Physiol ; 315(5): F1271-F1282, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30110571

RESUMO

To better understand the role of the inward-rectifying K channel Kir4.1 (KCNJ10) in the distal nephron, we initially studied a global Kir4.1 knockout mouse (gKO), which demonstrated the hypokalemia and hypomagnesemia seen in SeSAME/EAST syndrome and was associated with reduced Na/Cl cotransporter (NCC) expression. Lethality by ~3 wk, however, limits the usefulness of this model, so we developed a kidney-specific Kir4.1 "knockdown" mouse (ksKD) using a cadherin 16 promoter and Cre-loxP methodology. These mice appeared normal and survived to adulthood. Kir4.1 protein expression was decreased ~50% vs. wild-type (WT) mice by immunoblotting, and immunofluorescence showed moderately reduced Kir4.1 staining in distal convoluted tubule that was minimal or absent in connecting tubule and cortical collecting duct. Under control conditions, the ksKD mice showed metabolic alkalosis and relative hypercalcemia but were normokalemic and mildly hypermagnesemic despite decreased NCC expression. In addition, the mice had a severe urinary concentrating defect associated with hypernatremia, enlarged kidneys with tubulocystic dilations, and reduced aquaporin-3 expression. On a K/Mg-free diet for 1 wk, however, ksKD mice showed marked hypokalemia (serum K: 1.5 ± 0.1 vs. 3.0 ± 0.1 mEq/l for WT), which was associated with renal K wasting (transtubular K gradient: 11.4 ± 0.8 vs. 1.6 ± 0.4 in WT). Phosphorylated-NCC expression increased in WT but not ksKD mice on the K/Mg-free diet, suggesting that loss of NCC adaptation underlies the hypokalemia. In conclusion, even modest reduction in Kir4.1 expression results in impaired K conservation, which appears to be mediated by reduced expression of activated NCC.


Assuntos
Néfrons/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/deficiência , Potássio na Dieta/sangue , Reabsorção Renal , Alcalose/sangue , Alcalose/genética , Alcalose/fisiopatologia , Animais , Aquaporina 3/metabolismo , Técnicas de Silenciamento de Genes , Genótipo , Hipercalcemia/sangue , Hipercalcemia/genética , Hipercalcemia/fisiopatologia , Hiperpotassemia/sangue , Hiperpotassemia/genética , Hiperpotassemia/fisiopatologia , Hipernatremia/sangue , Hipernatremia/genética , Hipernatremia/fisiopatologia , Capacidade de Concentração Renal , Camundongos Endogâmicos C57BL , Camundongos Knockout , Néfrons/fisiopatologia , Fenótipo , Fosforilação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo
20.
J Biol Chem ; 293(39): 15055-15069, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30082316

RESUMO

Antibody-mediated blockade of cluster of differentiation 47 (CD47)-thrombospondin-1 (TSP-1) interactions blocks osteoclast formation in vitro and attenuates parathyroid hormone (PTH)-induced hypercalcemia in vivo in mice. Hypercalcemia in this model reflects increased bone resorption. TSP-1 has two cell-associated binding partners, CD47 and CD36. The roles of these two molecules in mediating the effects of TSP1 in osteoclasts are unclear. Osteoclast formation was attenuated but not absent when preosteoclasts isolated from CD47-/- mice were cocultured with WT osteoblasts. Suppressing CD36 in osteoclast progenitors also attenuated osteoclast formation. The hypercalcemic response to a PTH infusion was blunted in CD47-/-/CD36-/- (double knockout (DKO)) female mice but not CD47-/- mice or CD36-/- animals, supporting a role for both CD47 and CD36 in mediating this effect. Consistent with this, DKO osteoclasts had impaired resorptive activity when analyzed in vitro Inhibition of nitric oxide (NO) signaling is known to promote osteoclastogenesis, and TSP-1 suppresses NO production and signaling. An anti-TSP-1 antibody increased NO production in osteoclasts, and the inhibitory effect of anti-TSP-1 on osteoclastogenesis was completely rescued by l-nitroarginine methyl ester (l-NAME), a competitive NO synthase inhibitor. Supportive of an important role for CD36 in mediating the pro-osteoclastogenic effects of TSP-1, engaging CD36 with a synthetic agonist, p907, suppressed NO production in anti-TSP-1-treated cultures, allowing osteoclast maturation to occur. These results establish that CD36 and CD47 both participate in mediating the actions of TSP-1 in osteoclasts and establish a physiologically relevant cross-talk in bone tissue between these two molecules.


Assuntos
Antígenos CD36/genética , Antígeno CD47/genética , Óxido Nítrico/biossíntese , Trombospondina 1/genética , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Antígenos CD36/química , Antígeno CD47/química , Feminino , Hipercalcemia/genética , Hipercalcemia/patologia , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/química , Osteoclastos/química , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/genética , Hormônio Paratireóideo/química , Hormônio Paratireóideo/genética , Detecção de Sinal Psicológico , Transdução de Sinais/efeitos dos fármacos , Trombospondina 1/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA