RESUMEN
BACKGROUND: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy. CASE PRESENTATION: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings. CONCLUSION: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.
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Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Aldosterona , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico , Hidrocortisona , Mutación , Complicaciones Neoplásicas del Embarazo , Humanos , Femenino , Embarazo , Adulto , Hidrocortisona/metabolismo , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/patología , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/cirugía , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Complicaciones Neoplásicas del Embarazo/genética , Complicaciones Neoplásicas del Embarazo/patología , Hiperaldosteronismo/genética , Hiperaldosteronismo/patología , Hiperaldosteronismo/cirugía , Síndrome de Cushing/genética , Síndrome de Cushing/patología , Adenoma/genética , Adenoma/patología , Adenoma/metabolismoRESUMEN
A man in his 20s was referred by his general practitioner because of the finding of adrenocorticotropic hormone (ACTH)-dependent hypercortisolaemia, discovered as part of investigation of fatigue and alopecia. The man had no other clinical findings suggestive of Cushing syndrome. Further investigation revealed intact diurnal rhythm in cortisol production, normal bone density and excluded assay interference. Further investigation revealed the man's sibling had been labelled as having Cushing syndrome because of similar biochemical abnormalities. A diagnosis of familial primary generalised glucocorticoid resistance syndrome was made. Testing for mutations in the NR3C1 gene is awaited.
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Enfermedades de las Glándulas Suprarrenales , Síndrome de Cushing , Humanos , Hormona Adrenocorticotrópica , Síndrome de Cushing/complicaciones , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/genética , Hidrocortisona , Mutación , Masculino , AdultoRESUMEN
INTRODUCTION/OBJECTIVES: Mutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. METHODS, RESULTS AND CONCLUSIONS: We present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.
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Hiperplasia Suprarrenal Congénita , Síndrome de Cushing , Neoplasias , Humanos , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/genética , Síndrome de Cushing/genética , Mutación de Línea Germinal , Hidrocortisona , Hiperplasia , Proteínas Supresoras de Tumor/genéticaRESUMEN
Endogenous Cushing's syndrome (CS) is a rare condition due to prolonged exposure to elevated circulating cortisol levels that features its typical phenotype characterised by moon face, proximal myopathy, easy bruising, hirsutism in females and a centripetal distribution of body fat. Given the direct and indirect effects of hypercortisolism, CS is a severe disease burdened by increased cardio-metabolic morbidity and mortality in which visceral adiposity plays a leading role. Although not commonly found in clinical setting, endogenous CS is definitely underestimated leading to delayed diagnosis with consequent increased rate of complications and reduced likelihood of their reversal after disease control. Most of all, CS is a unique model for systemic impairment induced by exogenous glucocorticoid therapy that is commonly prescribed for a number of chronic conditions in a relevant proportion of the worldwide population. In this review we aim to summarise on one side, the mechanisms behind visceral adiposity and lipid metabolism impairment in CS during active disease and after remission and on the other explore the potential role of cortisol in promoting adipose tissue accumulation.
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Síndrome de Cushing , Hidrocortisona , Femenino , Humanos , Hidrocortisona/metabolismo , Síndrome de Cushing/complicaciones , Síndrome de Cushing/genética , Síndrome de Cushing/metabolismo , Tejido Adiposo/metabolismo , Metabolismo de los Lípidos , CorazónRESUMEN
Adrenal Cushing's syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing's driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAcW196G is unexpectedly distinct from other described Cushing's variants, exhibiting retained association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of tryptophan-196 with glycine creates a 653-cubic angstrom cleft between the catalytic core of PKAcW196G and type II regulatory subunits (RII), but only a 395-cubic angstrom cleft with RI. Endocrine measurements show that overexpression of RIα or redistribution of PKAcW196G via AKAP recruitment counteracts stress hormone overproduction. We conclude that a W196G mutation in the kinase catalytic core skews R subunit selectivity and biases AKAP association to drive Cushing's syndrome.
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Síndrome de Cushing , Humanos , Síndrome de Cushing/genética , Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Anclaje a la Quinasa A/metabolismo , Transducción de Señal , Dominio Catalítico , SesgoRESUMEN
OBJECTIVE: Cushing's syndrome is characterized by high morbidity and mortality with high interindividual variability. Easily measurable biomarkers, in addition to the hormone assays currently used for diagnosis, could reflect the individual biological impact of glucocorticoids. The aim of this study is to identify such biomarkers through the analysis of whole blood transcriptome. DESIGN: Whole blood transcriptome was evaluated in 57 samples from patients with overt Cushing's syndrome, mild Cushing's syndrome, eucortisolism, and adrenal insufficiency. Samples were randomly split into a training cohort to set up a Cushing's transcriptomic signature and a validation cohort to assess this signature. METHODS: Total RNA was obtained from whole blood samples and sequenced on a NovaSeq 6000 System (Illumina). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore the transcriptome profile. Ridge regression was used to build a Cushing's transcriptome predictor. RESULTS: The transcriptomic profile discriminated samples with overt Cushing's syndrome. Genes mostly associated with overt Cushing's syndrome were enriched in pathways related to immunity, particularly neutrophil activation. A prediction model of 1500 genes built on the training cohort demonstrated its discriminating value in the validation cohort (accuracy .82) and remained significant in a multivariate model including the neutrophil proportion (P = .002). Expression of FKBP5, a single gene both overexpressed in Cushing's syndrome and implied in the glucocorticoid receptor signaling, could also predict Cushing's syndrome (accuracy .76). CONCLUSIONS: Whole blood transcriptome reflects the circulating levels of glucocorticoids. FKBP5 expression could be a nonhormonal marker of Cushing's syndrome.
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Síndrome de Cushing , Transcriptoma , Humanos , Síndrome de Cushing/sangre , Síndrome de Cushing/genética , Síndrome de Cushing/diagnóstico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Perfilación de la Expresión Génica , Estudios de Cohortes , Biomarcadores/sangre , Anciano , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/sangreRESUMEN
Cushing's syndrome is due to overproduction of cortisol, leading to abnormal and prolonged exposure to cortisol. The most common etiology is Cushing disease, while adrenal causes are rarer. Knowledge of the genetics of Cushing's syndrome, and particularly the adrenal causes, has improved considerably over the last 10 years, thanks in particular to technical advances in high-throughput sequencing. The present study, by a group of experts from the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology, reviewed the literature on germline genetic alterations leading to a predisposition to develop Cushing's syndrome. The review led to a consensus statement on genetic screening for Cushing disease and adrenal Cushing's syndrome.
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Consenso , Síndrome de Cushing , Endocrinología , Niño , Humanos , Síndrome de Cushing/genética , Síndrome de Cushing/diagnóstico , Endocrinología/normas , Endocrinología/métodos , Endocrinología/tendencias , Francia , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Mutación de Línea Germinal , Sociedades Médicas/normasRESUMEN
In Cushing syndrome (CS), prolonged exposure to high cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders. The present article reviews the evidence on epigenetic changes induced by (long-term) glucocorticoid exposure. Key aspects of some glucocorticoid-target genes and their implications in the context of CS are described. Lastly, the effects of epigenetic drugs influencing glucocorticoid effects are discussed for their ability to be potentially used as adjunctive therapy in CS.
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Síndrome de Cushing , Epigénesis Genética , Glucocorticoides , Humanos , Síndrome de Cushing/genética , Síndrome de Cushing/tratamiento farmacológico , Epigénesis Genética/efectos de los fármacos , Glucocorticoides/uso terapéutico , MicroARNs/genética , AnimalesRESUMEN
Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD. Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023416988.
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Enfermedades de la Corteza Suprarrenal , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico , Mutación , Humanos , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Enfermedades de la Corteza Suprarrenal/genética , Enfermedades de la Corteza Suprarrenal/patología , Femenino , Adulto , Masculino , Síndrome de Cushing/genética , Síndrome de Cushing/cirugía , Síndrome de Cushing/diagnóstico , Complejo de Carney/genética , Complejo de Carney/diagnóstico , Adulto Joven , Osteoporosis/genéticaRESUMEN
Introduction: Patients with Cushing's syndrome (CS) in remission show sustained fatigue, myopathy, and an increased prevalence of sarcopenia. The mechanisms that determine these persistent muscle problems are not well known. We aimed to identify circulating microRNAs (miRNAs) with differential expression that could be potential biomarkers for the diagnosis and/or prognosis in CS. Patients and methods: Thirty-six women in sustained remission for 13 ± 7 years (mean ± SD) from CS, with a median age (IQ range) of 51 (45.2-60) years and mean ± SD BMI of 27 ± 4 Kg/m2, and 36 matched healthy controls were investigated. In 7 patients sarcopenia was present according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Small RNA libraries were generated and indexed using a modified Illumina TruSeq small RNA-sequencing protocol. MiRNAs were identified in plasma using bioinformatic analysis, and validation was carried out using RT-qPCR. For the validation, Taqman probes were performed on QuantStudio 5 equipment (Applied Biosystems). Results: In a first discovery group using RNA-sequencing, plasma samples of 18 CS patients and 18 healthy subjects were investigated; circulating miR-28-5p, miR-495-3p and miR-654-5p were upregulated in CS patients as compared with controls (p<0.05). In a validation study of the 3 upregulated miRNAs in 36 patients and 26 controls, no differences were observed by RT-qPCR; however, the expression of circulating miR-28-5p was upregulated in CS patients with sarcopenia as compared with those without (AUC for fold-change in the ROC analysis, 0.798; p=0.0156). The optimized cut-off value for miR-28-5p to identify CS patients with sarcopenia was 3.80, which yielded a sensitivity of 86% and a specificity of 69%. Conclusion: MiR-28-5p, a muscle-specific microRNA involved in myotube proliferation and differentiation in vivo, may serve as an independent non-invasive biomarker for identifying CS patients at high-risk of sarcopenia despite biochemical remission.
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Biomarcadores , Síndrome de Cushing , MicroARNs , Sarcopenia , Humanos , Sarcopenia/sangre , Sarcopenia/genética , Femenino , Persona de Mediana Edad , Proyectos Piloto , Síndrome de Cushing/sangre , Síndrome de Cushing/genética , Síndrome de Cushing/diagnóstico , MicroARNs/sangre , MicroARNs/genética , Biomarcadores/sangre , MicroARN Circulante/sangre , MicroARN Circulante/genética , Estudios de Casos y Controles , Pronóstico , Inducción de RemisiónRESUMEN
Background: Some observational studies and clinical experiments suggest a close association between gut microbiota and metabolic diseases. However, the causal effects of gut microbiota on adrenal diseases, including Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism, remain unclear. Methods: This study conducted a two-sample Mendelian randomization analysis using summary statistics data of gut microbiota from a large-scale genome-wide association study conducted by the MiBioGen Consortium. Summary statistics data for the three adrenal diseases were obtained from the FinnGen study. The study employed Inverse variance weighting, MR-Egger, and MR-PRESSO methods to assess the causal relationship between gut microbiota and these three adrenal diseases. Additionally, a reverse Mendelian randomization analysis was performed for bacteria found to have a causal relationship with these three adrenal diseases in the forward Mendelian randomization analysis. Cochran's Q statistic was used to test for heterogeneity of instrumental variables. Results: The IVW test results demonstrate that class Deltaproteobacteria, Family Desulfovibrionaceae, and Order Desulfovibrionales exhibit protective effects against adrenocortical insufficiency. Conversely, Family Porphyromonadaceae, Genus Lachnoclostridium, and Order MollicutesRF9 are associated with an increased risk of adrenocortical insufficiency. Additionally, Family Acidaminococcaceae confers a certain level of protection against Cushing syndrome. In contrast, Class Methanobacteria, Family Lactobacillaceae, Family Methanobacteriaceae, Genus. Lactobacillus and Order Methanobacteriales are protective against Hyperaldosteronism. Conversely, Genus Parasutterella, Genus Peptococcus, and Genus Veillonella are identified as risk factors for Hyperaldosteronism. Conclusions: This two-sample Mendelian randomization analysis revealed a causal relationship between microbial taxa such as Deltaproteobacteria and Desulfovibrionaceae and Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism. These findings offer new avenues for comprehending the development of adrenal diseases mediated by gut microbiota.
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Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Microbioma Gastrointestinal/genética , Enfermedades de las Glándulas Suprarrenales/microbiología , Enfermedades de las Glándulas Suprarrenales/genética , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Hiperaldosteronismo/genética , Hiperaldosteronismo/microbiología , Síndrome de Cushing/microbiología , Síndrome de Cushing/genética , Insuficiencia Suprarrenal/microbiologíaRESUMEN
Background: We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets. Methodology: Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1). Results: Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes - FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively. Outcome: This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.
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Síndrome de Cushing , Humanos , Adrenalectomía/métodos , Síndrome de Cushing/genética , Síndrome de Cushing/cirugía , Síndrome de Cushing/tratamiento farmacológico , Hidrocortisona/metabolismo , Hiperplasia , PPAR gamma/genéticaRESUMEN
SUMMARY Carney complex (CNC) is a rare syndrome of multiple endocrine and non-endocrine tumors. In this paper we present a 23-year-old Iranian woman with CNC who harbored a novel mutation (c.642dupT) in PRKAR1A gene. This patient presented with pituitary macroadenoma, acromegaly, recurrent atrial myxoma, Cushing's syndrome secondary to primary pigmented nodular adrenocortical disease and pigmented schwanoma of the skin. PRKAR1A gene was PCR amplified using genomic DNA and analyzed for sequence variants which revealed the novel mutation resulting in substitution of amino acid cysteine instead of the naturally occurring valine in the peptide chain and a premature stop codon at position 18 (V215CfsX18). This change leads to development of tumors in different organs due to lack of tumor suppressive activity secondary to failure of synthesis of the related protein.
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Humanos , Femenino , Adulto , Adulto Joven , Acromegalia/genética , Síndrome de Cushing/genética , Complejo de Carney/genética , Mixoma/cirugía , Mixoma/genética , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Irán , MutaciónRESUMEN
Summary Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.
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Humanos , Femenino , Persona de Mediana Edad , Síndrome de Cushing/genética , Síndrome Metabólico/genética , Lamina Tipo A/genética , Cardiopatías/genética , Lipodistrofia/genética , Miositis/genética , SíndromeRESUMEN
Os corticotrofinomas representam aproximadamente 80 por cento dos casos de síndrome de Cushing de origem endógena em adultos. Na última década, foram feitos avanços consideráveis na compreensäo do desenvolvimento da hipófise anterior, na patogênese dos tumores hipofisários e nos fatores envolvidos na progressäo tumoral. A aplicaçäo do conceito geral de tumorigênese é adequada aos tumores corticotróficos, sendo este um processo que envolve várias etapas, resultantes da interaçäo de eventos iniciadores e subseqüentemente de fatores promotores, sendo portanto multifatorial. De modo geral, oncogenes e genes de supressäo tumoral freqüentemente relacionados a outros tipos de tumores näo parecem contribuir neste processo, embora alteraçäo na expressäo de alguns destes genes, como p53, plb e PTTG, possa estar relacionada a um comportamento fenotípico mais agressivo. A investigaçäo das vias regulatórias específicas dos corticotrofos, principalmente a estrutura e a expressäo dos genes dos receptores do CRH, AVP e GR também näo evidenciou a presença de mutações. Entretanto, é possível que alterações em regiões promotoras ou em co-fatores que regulam estes genes possam estar presentes. Estudos futuros sobres os mecanismos de regulaçäo da célula corticotrófica normal e tumoral deveräo contribuir na definiçäo de marcadores prognósticos e no desenvolvimento de novas modalidades de tratamento.
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Humanos , Neoplasias Hipofisarias , Síndrome de Cushing/genética , Hormona Adrenocorticotrópica , Apoptosis , Citocinas , Genes Reguladores , Sustancias de Crecimiento , Metilación , Mutación , OncogenesRESUMEN
Dos hermanas (14 y 18 años) estudiadas por hipercortisolismo en nuestro servicio en el último año presentaron datos analíticos y bioquímicos de síndrome de Cushing independiente del ACTH, aun cuando los estudios de localización realizados no pudieron poner de manifiesto un agrandamiento uni o bilateral de las glándulas adrenales. En sus antecedentes figuraba una tía materna con hallazgos "similares". La clínica de hipercortisolismo sólo fue evidente en la mayor de las hermanas, mientras que la hiperfunción adrenal fue demostrada tras un estudio de secreción espontánea en 24 h en la más pequeña. Fueron remitidas a cirugía siendo practicada en ambas una adrenalectomía bilateral. El estudio anatomopatológico reveló la presencia de múltiples nódulos entre 1 y 3 mm, de coloración oscura y atrofia perinodular confirmando la existencia de displasia micronodular pigmentaria. No se objetivaron datos de presencia de síndrome de Carney en ellas. Presentamos la clínica, los hallazgos analíticos e histológicos de nuestras pacientes afectadas de esta inusual enfermedad y una revisión de la bibliografía científica (AU)
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Adolescente , Femenino , Humanos , Síndrome de Cushing/genética , Hiperplasia Suprarrenal Congénita/genética , Hiperfunción de las Glándulas Suprarrenales/genética , Hormona de Crecimiento HumanaRESUMEN
A lot of evidence supports the existence of a monoclonal origin for pituitary tumors, and several genetic alterations have already been confirmed as necessary or sufficient for unrestrained cellular growth and pituitary function. The p53 gene, a known tumor-suppressor gene (TSG), encodes a protein that exerts antiproliferative effects such as cell-growth arrest and apoptosis in response to several types of stimuli. In fact, several human cancers are believed to be caused by p53 mutations. In the case of pituitary tumors, p53 protein accumulation has been described in ACTH-secreting pituitary adenomas. Since increased amounts of the p53 protein are often related to mutations of its gene, we decided to explore the existence of p53 mutations in the tumor tissues of 9 patients bearing non-invasive corticotropinomas, excised by the transphenoidal route. We screened mutations in exons 5 to 8 of the p53 gene by the PCR-SSCP analysis. We were not able to find any mutation in the exons investigated. Our results are in close accordance with those obtained previously for other types of pituitary tumors.
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Humanos , Adenoma/genética , Síndrome de Cushing/genética , Genes p53/genética , Genes Supresores de Tumor , Mutación , Electroforesis en Gel de Poliacrilamida , Exones/genética , Marcadores Genéticos , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
A lot of evidence supports the existence of a monoclonal origin for pituitary tumors, and several genetic alterations have already been confirmed as necessary or sufficient for unrestrained cellular growth and pituitary function. The p53 gene, a known tumor-suppressor gene (TSG), encodes a protein that exerts antiproliferative effects such as cell-growth arrest and apoptosis in response to several types of stimuli. In fact, several human cancers are believed to be caused by p53 mutations. In the case of pituitary tumors, p53 protein accumulation has been described in ACTH-secreting pituitary adenomas. Since increased amounts of the p53 protein are often related to mutations of its gene, we decided to explore the existence of p53 mutations in the tumor tissues of 9 patients bearing non-invasive corticotropinomas, excised by the transphenoidal route. We screened mutations in exons 5 to 8 of the p53 gene by the PCR-SSCP analysis. We were not able to find any mutation in the exons investigated. Our results are in close accordance with those obtained previously for other types of pituitary tumors. (AU)