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1.
BMC Vet Res ; 15(1): 363, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651346

RESUMO

BACKGROUND: Glucocorticoids, among the most widely utilized drugs in veterinary medicine, are employed to treat a wide variety of diseases; however, their use often induces adverse events in dogs. The efficacy of glucocorticoids usually depends on dosage, although differences in sensitivity to glucocorticoids in individual animals have been reported. Glucocorticoids bind to the cytoplasmic glucocorticoid receptor (GR), which is expressed in almost all cells. These receptors are key factors in determining individual sensitivity to glucocorticoids. This study examined individual differences in glucocorticoid sensitivity in dogs, focusing on reactivity of the GR to prednisolone. RESULTS: We first molecularly cloned the GR gene from a healthy dog. We discovered a mutant GR in a dog suspected to have iatrogenic Cushing syndrome. The mutant GR had extra nucleotides between exons 6 and 7, resulting in a truncated form of GR that was 98 amino acids shorter than the wild-type dog GR. The truncated GR exhibited very low reactivity to prednisolone, irrespective of concentration. CONCLUSIONS: We have identified the truncated form of canine GR in a dog with iatrogenic Cushing syndrome. This truncated form showed the very less sensitivity to glucocorticoid in vitro, unfortunately, we could not elucidate its clinical significance. However, our data is a first report about the function of canine GR, and will facilitate the analysis of canine glucocorticoid sensitivity.


Assuntos
Síndrome de Cushing/veterinária , Doenças do Cão/induzido quimicamente , Doenças do Cão/genética , Receptores de Glucocorticoides/genética , Sequência de Aminoácidos , Animais , Células COS , Clonagem Molecular , Síndrome de Cushing/induzido quimicamente , Síndrome de Cushing/genética , Cães , Doença Iatrogênica/veterinária , Mutação , Prednisolona/farmacologia , Receptores de Glucocorticoides/efeitos dos fármacos
2.
J Steroid Biochem Mol Biol ; 191: 105316, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31014964

RESUMO

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS), which has been associated with ectopic G-protein coupled receptors (GPCRs) in the adrenal cortex. We recently studied a 51-year-old male with PBMAH who presented with severe CS and hyperestronemia, manifesting clinically with a Cushingoid appearance, gynecomastia, and telangiectasias. Analysis of adrenal tissues following bilateral adrenalectomy showed high expression of P450 aromatase (CYP19A1). The patient carried a germline non-sense pathogenic variant in ARMC5 (p.R173*), with two independent somatic pathogenic variants identified in the right (p.S571*) and left (p.Q235*) adrenal tissues, respectively. The expression of ARMC5 was drastically decreased in the hyperplastic regions when compared to either the adjacent non-hyperplastic regions and samples from PBMAH without pathogenic variants in ARMC5. We found expression of CYP19A1 in other cases of PBMAH, although there were no differences in aromatase expression between ARMC5-mutant and ARMC5-non-mutant cases. We conclude that in select cases, PBMAH can be associated with aromatase expression resulting in elevated estrogens, irrespective of sex. Additionally, CYP19A1 expression does not appear to depend on the ARMC5 variant status.


Assuntos
Aromatase/genética , Síndrome de Cushing/genética , Proteínas Supressoras de Tumor/genética , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Proteínas do Domínio Armadillo , Aromatase/análise , Síndrome de Cushing/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Proteínas Supressoras de Tumor/análise , Regulação para Cima
3.
J Clin Endocrinol Metab ; 104(5): 1792-1801, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30597087

RESUMO

CONTEXT: Genomic losses/gains are associated with cancer progression and prognosis. In pituitary adenomas, analyses of copy number variations (CNVs) have shown that a subset of adenomas have higher genomic variability. However, whether CNVs are associated with tumor aggressiveness and prognosis has not been determined. OBJECTIVE: We hypothesized that somatic CNVs of pituitary tumors may play a role in the progression and aggressiveness of pituitary corticotropinomas in children and adolescents. SAMPLES AND DESIGN: Paired germline and tumor DNA samples from 27 pediatric patients with Cushing disease (CD), were subjected to whole exome sequencing. Somatic CNVs were identified using the ExomeDepth tool. Clinical, histological, and biochemical data from the patients were collected and correlated with the results of the CNV analysis. RESULTS: Chromosomal instability, involving 23% to 59% of the tumor genome, was noted in 5 of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size, which was larger (median size 18 mm vs 5.5 mm, P = 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (P = 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability. CONCLUSIONS: A subgroup of corticotropinomas demonstrates chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that more genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD.


Assuntos
Adenoma Hipofisário Secretor de ACT/patologia , Biomarcadores/análise , Aberrações Cromossômicas , Síndrome de Cushing/patologia , Predisposição Genética para Doença , Adenoma Hipofisário Secretor de ACT/genética , Adolescente , Síndrome de Cushing/genética , Variações do Número de Cópias de DNA , Feminino , Seguimentos , Instabilidade Genômica , Humanos , Masculino , Prognóstico
4.
Endokrynol Pol ; 70(6): 489-495, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31909455

RESUMO

INTRODUCTION: Higher cortisol levels are associated with cardiovascular morbidity and mortality in the elderly, partially resulting from biologic effects of glucocorticoids (GCs) on endothelial cells observed in an experimental setting. These features are replicated in patients with endogenous GC excess (Cushing's syndrome) or with exogenous hypercortisolism due to excessive pharmacological application of GCs. Both groups present also an increased cardiovascular disease event rate. GCs may also adversely influence recovery after myocardial infarction. Recently it was proposed that microRNAs (miRNAs) - small noncoding RNAs functioning as antisense regulators of gene expression by targeting mRNA - may have a central role in regulating endothelial function through multiple mechanisms. Thus, the purpose of this study was to evaluate the effects of chronic GC excess on the expression of selected endothelium-controlling miRNAs expressed in nucleated cells circulating in peripheral blood (PBNCs) of patients with endogenous hypercortisolism either due to corticotrophin-independent or corticotrophin-dependent Cushing's syndrome (CS). MATERIAL AND METHODS: Peripheral blood nuclear cells were collected from 35 healthy subjects and 31 patients with endogenous hypercortisolism as a source of miRNAs. A self-validated individual quantitative RT-PCR study was then performed to evaluate the expression levels of selected miRNAs in PBNCs. Additionally, endothelin-1 (ET-1) expression in peripheral blood was assessed with respect to endothelial dysfunction using Western blotting. RESULTS: The ET-1 expression levels in CS were higher than in controls, confirming endothelial dysfunction in the CS group. Furthermore, miRNA analysis revealed a significantly decreased intracellular expression of selected endothelium-related miRNAs in patients with endogenous hypercortisolism, including miRNA-17-5p, miRNA-126-3p, and miRNA-126-5p, compared to controls. In contrast, two other angiogenic miRNAs, miRNA-150-5p and miRNA-223-3p, were significantly upregulated compared to controls. CONCLUSIONS: Cardiovascular events related to hypercortisolism remain a challenging problem in medical practice. This study has demonstrated that the chronic excess of GCs in endogenous CS might induce significant dysregulation of selected miRNAs involved in the control of endothelium biology. However, the lack of knowledge about specific miRNA expression postpones the full understanding of the biological roles of such miRNAs in hypercortisolism. Moreover, dysregulated miRNAs seem to be promising targets for further research, especially to search for potential therapies for several GC-induced cardiovascular complications.


Assuntos
Síndrome de Cushing/sangue , Regulação da Expressão Gênica , Glucocorticoides/sangue , MicroRNAs/genética , Síndrome de Cushing/genética , Síndrome de Cushing/metabolismo , Feminino , Humanos , Leucócitos/metabolismo , Masculino , MicroRNAs/sangue , Neovascularização Patológica
5.
Am J Case Rep ; 19: 1366-1369, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30442879

RESUMO

BACKGROUND Carney complex (CNC) is a genetic disorder that presents as an adrenocorticotropic hormone (ACTH)-independent variant of endogenous Cushing syndrome. It was first reported in 1985 and was described as a form of multiple endocrine hyperplasia associated with mutations of the c-AMP-dependent protein kinase (PRKAR1A) gene that causes bilateral adrenal hyperplasia. We report a case of an incidentally found CNC in a 35-year-old male, and this case report focuses on the diagnostic scheme as well as the surgical treatment of this rare challenging condition. CASE REPORT A-35-year-old male presented with pathological thoracic spine fracture. The patient exhibited obesity, facial flushing, red-purplish streaks on the abdominal wall, multiple pigmented nevi of the trunk, and hypertension. Family history was positive for cardiac myxoma. Laboratory investigation showed ACTH-independent Cushing syndrome. Abdominal magnetic resonance imaging and computed tomography scan showed bilateral adrenal hyperplasia. The ensuing Liddle test revealed the characteristic paradox increase of 24-hours urine cortisol for CNC. After a bilateral retroperitoneoscopic adrenalectomy, histologic examination confirmed the presence of bilateral primary pigmented nodular adrenocortical disease (PPNAD). Genetic testing revealed a unique mutation of the responsible PRKAR1A gene. CONCLUSIONS CNC presence was suspected due to the family history. Its characteristic pathologic manifestation called PPNAD, clinically presents as an ACTH-independent Cushing syndrome with paradoxical positive response of urinary glucocorticosteroid excretion after dexamethasone administration (Liddle's test). Bilateral retroperitoneoscopic adrenalectomy constitutes an acceptable surgical option for PPNAD.


Assuntos
Complexo de Carney/complicações , Síndrome de Cushing/complicações , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Fraturas Espontâneas/etiologia , Fraturas da Coluna Vertebral/etiologia , Adrenalectomia/métodos , Adulto , Complexo de Carney/diagnóstico , Complexo de Carney/genética , Meios de Contraste , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/genética , Fraturas Espontâneas/diagnóstico por imagem , Predisposição Genética para Doença , Humanos , Achados Incidentais , Imagem por Ressonância Magnética/métodos , Masculino , Mutação/genética , Prognóstico , Doenças Raras , Fraturas da Coluna Vertebral/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Resultado do Tratamento
6.
Endokrynol Pol ; 69(6): 675-681, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30259502

RESUMO

INTRODUCTION: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of ACTH-independent Cushing's syndrome (CS). Half of patients with PPNAD are sporadic cases and the other half familial. MATERIAL AND METHODS: We present two patients with PPNAD confirmed by genetic analysis. RESULTS: In both patients there were no abnormal findings on diagnostic imaging of both adrenals and heart. Patients underwent bilateral two-stage adrenalectomy. Histopathological examination confirmed PPNAD. Genetic testing showed the following mutations in the PRKAR1A gene coding for the regulatory subunit type 1A of the protein kinase A enzyme: c.125dupG (patient 1) and c.15dupT (patient 2). Both these defects lead to inactivation of the PRKAR1A protein and are consequently causative of PPNAD in these patients. CONCLUSIONS: The novel mutations presented in this article are considered to be pathogenic for PPNAD.


Assuntos
Síndrome de Cushing/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Mutação , Adolescente , Glândulas Suprarrenais/cirurgia , Adrenalectomia , Síndrome de Cushing/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Masculino
7.
Clin Cancer Res ; 24(17): 4126-4136, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30084836

RESUMO

Purpose: Pituitary adenomas are one of the most common benign neoplasms of the central nervous system. Although emerging evidence suggests roles for both genetic and epigenetic factors in tumorigenesis, the degree to which these factors contribute to disease remains poorly understood.Experimental Design: A multiplatform analysis was performed to identify the genomic and epigenomic underpinnings of disease among the three major subtypes of surgically resected pituitary adenomas in 48 patients: growth hormone (GH)-secreting (n = 17), adrenocorticotropic hormone (ACTH)-secreting (n = 13, including 3 silent-ACTH adenomas), and endocrine-inactive (n = 18). Whole-exome sequencing was used to profile the somatic mutational landscape, whole-transcriptome sequencing was used to identify disease-specific patterns of gene expression, and array-based DNA methylation profiling was used to examine genome-wide patterns of DNA methylation.Results: Recurrent single-nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy-number alterations (SCNA) were identified in all three pituitary adenoma subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GH-secreting adenomas being dominated by hypomethylated sites. Likewise, gene-expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene-expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMC gene in ACTH-secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1 among all three adenoma subtypes.Conclusions: Taken together, these data stress the contribution of epigenomic alterations to disease-specific etiology among adenoma subtypes and highlight potential targets for future immunotherapy-based treatments. This article reveals novel insights into the epigenomics underlying pituitary adenomas and highlights how differences in epigenomic states are related to important transcriptome alterations that define adenoma subtypes. Clin Cancer Res; 24(17); 4126-36. ©2018 AACR.


Assuntos
Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Epigenômica , Neoplasias Hipofisárias/genética , Acromegalia/genética , Acromegalia/patologia , Hormônio Adrenocorticotrópico/genética , Adulto , Idoso , Antígeno B7-H1/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Síndrome de Cushing/genética , Síndrome de Cushing/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Hormônio do Crescimento/genética , Humanos , Mutação INDEL/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/patologia , Regiões Promotoras Genéticas/genética , Receptores de Somatostatina/genética , Transcriptoma/genética , Sequenciamento Completo do Exoma
8.
Endocr J ; 65(11): 1139-1146, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158362

RESUMO

Glucocorticoid resistance syndrome (GRS) is a rare genetic disorder caused by inactivating mutations of the NR3C1 gene which encodes the glucocorticoid receptor. The phenotypic spectrum is broad but typically include symptoms of adrenal insufficiency, mineralocorticoid excess and hyperandrogenism. We report a new case associated with a novel NR3C1 mutation. A 55-year-old woman with lifelong history of low body weight, hyperandrogenism and anxiety was seen at the endocrine clinic after left adrenalectomy and salpingoophorectomy for lesions suspicious of ovarian cancer and adrenal metastasis. The tumors turned out to be a 3.5 cm benign ovarian serous adenofibroma and a 3.5 cm multinodular adrenal mass. She complained of worsened fatigue and inability to recover weight lost with surgery. Pre-operative serum and urinary cortisol were elevated, but she had no stigma of Cushing's syndrome. Plasma ACTH was elevated and a 1-mcg cosyntropin stimulation test was normal. Her fatigue persisted over ensuing years and ACTH-dependent hypercortisolemia remained stable. Low dose oral dexamethasone failed to suppress endogenous cortisol. A pituitary MRI was normal but revealed incidental brain aneurysms. Bone densitometry showed profound osteoporosis. On the bases of this contradictory clinical picture, glucocorticoid resistance syndrome (GRS) was suspected. Using next generation sequencing technology, a novel heterozygous pathogenic variant in the NR3C1 gene was detected. We speculate that vascular malformations and profound osteoporosis, findings associated to cortisol excess, reflect in our patient a variable tissue sensitivity to glucocorticoids. In conclusion, in patients with clinically unexpected ACTH-dependent hypercortisolemia, primary glucocorticoid resistance (GRS) should be considered.


Assuntos
Síndrome de Cushing/genética , Erros Inatos do Metabolismo/genética , Osteoporose/genética , Mutação Puntual , Receptores de Glucocorticoides/deficiência , Adenofibroma/genética , Adenofibroma/cirurgia , Adrenalectomia , Hormônio Adrenocorticotrópico/sangue , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Receptores de Glucocorticoides/genética , Síndrome
9.
Horm Res Paediatr ; 89(6): 423-433, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29909407

RESUMO

Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.


Assuntos
Doenças do Córtex Suprarrenal , Síndrome de Cushing , Adolescente , Doenças do Córtex Suprarrenal/diagnóstico , Doenças do Córtex Suprarrenal/genética , Doenças do Córtex Suprarrenal/patologia , Adulto , Criança , Pré-Escolar , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/genética , Síndrome de Cushing/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Clin Endocrinol (Oxf) ; 89(4): 437-443, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29927501

RESUMO

OBJECTIVE: Cushing disease (CD) is a rare entity caused by ACTH-secreting pituitary tumours, leading to prolonged hypercortisolism. Most cases are sporadic but can rarely occur in the context of familial predisposition, due to germline mutations in genes such as MEN1, leading to multiple endocrine neoplasia type 1, MEN1. We have reported previously that CD can be the first and only presenting manifestation of MEN1. In this report, we describe a cohort of paediatric patients who presented with CD as the first manifestation of MEN1. MATERIALS AND METHODS: A retrospective analysis of paediatric patients admitted to the National Institutes of Health (NIH) Clinical Center for evaluation of hypercortisolism, between 1997 and 2017. MEN1 was diagnosed on a clinical, familial and/or genetic basis. RESULTS: Of a total of 238 children with CD, six patients were subsequently diagnosed with MEN1, three males and three females with a mean age at diagnosis of CD at 13.4 ± 2.9 years. Five of the six patients had familial MEN1 and one patient was a sporadic case. Additional manifestations of MEN1 included primary hyperparathyroidism in three patients and hyperprolactinemia in two patients. DISCUSSION: This report describes a paediatric patient population with MEN1 in whom CD was the initial manifestation, confirming a previous observation that paediatric patients with MEN1 may present first with an ACTH-producing adenoma. Therefore, germline MEN1 mutations should be sought in paediatric CD and tested for when there is a suggestive family history and/or other manifestations.


Assuntos
Hipersecreção Hipofisária de ACTH/genética , Proteínas Proto-Oncogênicas/genética , Adolescente , Criança , Síndrome de Cushing/genética , Feminino , Humanos , Hiperparatireoidismo/genética , Hiperprolactinemia/genética , Masculino , Mutação/genética , Estudos Retrospectivos
11.
Endocrinol Metab Clin North Am ; 47(2): 275-297, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29754632

RESUMO

The knowledge on the molecular and genetic causes of Cushing's syndrome (CS) has greatly increased in the recent years. Somatic mutations leading to overactive 3',5'-cyclic adenosine monophosphate/protein kinase A and wingless-type MMTV integration site family/beta-catenin pathways are the main molecular mechanisms underlying adrenocortical tumorigenesis. Corticotropinomas are characterized by resistance to glucocorticoid negative feedback, impaired cell cycle control and overexpression of pathways sustaining ACTH secretion. Recognizing the genetic defects behind corticotroph and adrenocortical tumorigenesis proves crucial for tailoring the clinical management of CS patients and for designing strategies for genetic counseling and clinical screening to be applied in routine medical practice.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Síndrome de Cushing/genética , Neoplasias Hipofisárias/genética , Neoplasias das Glândulas Suprarrenais/complicações , Síndrome de Cushing/etiologia , Humanos , Neoplasias Hipofisárias/complicações
12.
Arch Endocrinol Metab ; 62(3): 376-382, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29791652

RESUMO

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.


Assuntos
Síndrome de Cushing/genética , Cardiopatias/genética , Lamina Tipo A/genética , Lipodistrofia/genética , Síndrome Metabólica/genética , Miosite/genética , Feminino , Humanos , Pessoa de Meia-Idade , Síndrome
13.
Ann Endocrinol (Paris) ; 79(3): 119-122, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29735160

RESUMO

In the setting of Cushing syndrome, genomic analyses can be performed either in tumors responsible for endogenous Cushing, or in patients exposed to glucocorticoid excess. Genomics of tumors identified several new genes - including ZNRF3 in adrenocortical carcinomas, PRKACA in cortisol-producing adrenal adenomas, ARMC5 in primary macronodular adrenal hyperplasia and USP8 in pituitary corticotroph adenomas. These genes shed new lights on the mechanisms responsible for these tumors. Integrated genomic studies of adrenal carcinomas identified distinct molecular classes, with remarkably different prognostic outcome. Beyond the mechanistic novelties, a new generation of prognostic markers emerges, with potentially important impact on patients care. For the future, genomic efforts should be pursued, focusing on poorly characterized tumors responsible for Cushing syndrome - including endocrine tumors secreting ACTH. In addition, epigenomics is emerging as an outstanding set of tools for characterizing tumors, unraveling unprecedented aspects of tumorigenesis. Applying these tools to endocrine tumors responsible for Cushing syndrome may also lead to important discoveries. Genomics of patients exposed to glucocorticoid excess is an emerging research field. Proof of principle studies have been performed, identifying molecular markers of glucocorticoid excess in blood. Research efforts should now concentrate on markers of mild glucocorticoid excesses - endogenous or exogenous -, owing to their high prevalence in general population. In addition, markers of individual susceptibility to each type of glucocorticoid complication are needed. It remains to be determined whether genomics can identify such markers.


Assuntos
Síndrome de Cushing/genética , Genômica/métodos , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Animais , Síndrome de Cushing/metabolismo , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/metabolismo
14.
Ann Endocrinol (Paris) ; 79(3): 98-106, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29685454

RESUMO

Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9ß) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients.


Assuntos
Glucocorticoides/metabolismo , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Receptores de Glucocorticoides/deficiência , Síndrome de Cushing/genética , Predisposição Genética para Doença , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Mutação , Sistema Hipófise-Suprarrenal/fisiologia , Polimorfismo Genético , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/genética
15.
Best Pract Res Clin Endocrinol Metab ; 32(2): 165-187, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29678284

RESUMO

The regulation of cortisol or aldosterone production when ACTH of pituitary origin or the renin-angiotensin systems are suppressed in primary adrenal Cushing's syndrome or in primary aldosteronism is exerted by diverse genetic and molecular mechanisms. In addition to recently identified mutations in various genes implicated in the cyclic AMP or ion channel pathways, steroidogenesis is not really autonomous as it is frequently regulated by the aberrant adrenocortical expression of diverse hormone receptors, particularly G-protein coupled hormone receptors (GPCR) which can substitute for the normal function of ACTH or angiotensin-II. In addition, paracrine or autocrine production of ligands for the aberrant GPCR such as ACTH or serotonin is found in some adrenal tumors or hyperplasias and participates in a complex regulatory loop causing steroid excess. Targeted therapies to block the aberrant ligands or their receptors could become useful in the future, particularly for patients with bilateral source of steroid excess.


Assuntos
Doenças das Glândulas Suprarrenais/genética , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/fisiologia , Doenças das Glândulas Suprarrenais/fisiopatologia , Neoplasias das Glândulas Suprarrenais/etiologia , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/fisiopatologia , Glândulas Suprarrenais/fisiopatologia , Hormônio Adrenocorticotrópico/metabolismo , Síndrome de Cushing/genética , Síndrome de Cushing/metabolismo , Síndrome de Cushing/fisiopatologia , Humanos , Hidrocortisona/metabolismo , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/fisiopatologia , Hiperplasia/genética , Hiperplasia/fisiopatologia , Mutação/fisiologia , Hipófise/patologia , Hipófise/fisiopatologia , Receptores Acoplados a Proteínas-G/metabolismo
16.
Ann Endocrinol (Paris) ; 79(3): 125-131, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29650225

RESUMO

Cushing syndrome (CS) in childhood results mostly from the exogenous administration of glucocorticoids; endogenous CS is a rare disease. The latter is the main reason pediatric patients with CS escape diagnosis for too long. Other barriers to optimal care of a pediatric patient with CS include improper following of the proper sequence of testing for diagnosing CS, which stems from lack of understanding of pathophysiology of the hypothalamic-pituitary-adrenal axis; lack of access to proper (i.e., experienced, state-of-the-art) surgical treatment; and unavailability of well-tolerated and effective medications to control hypercortisolemia. This report reviews the state-of-the-art in diagnosing CS and provides an update on the most recent discoveries in its genetics and treatment.


Assuntos
Síndrome de Cushing/diagnóstico , Síndrome de Cushing/terapia , Pediatria/tendências , Adolescente , Hormônio Adrenocorticotrópico , Criança , Síndrome de Cushing/epidemiologia , Síndrome de Cushing/genética , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Técnicas de Diagnóstico Molecular/normas , Pediatria/métodos , Guias de Prática Clínica como Assunto , Resultado do Tratamento
17.
BMC Med Genet ; 19(1): 49, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29587644

RESUMO

BACKGROUND: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS). BMAH is predominantly believed to be caused by two mutations, a germline and somatic one, respectively, as described in the two-hit hypothesis. In many familial cases of BMAH, mutations in armadillo repeat containing 5 (ARMC5), a putative tumor suppressor gene, are thought to induce the disorder. The objective of this study was to report a case in which the patient presented with BMAH induced by a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) alone rather than a two-hit mutation. CASE PRESENTATION: A 51-year-old woman was identified with masses in the bilateral adrenals. Serum cortisol levels were increased significantly both in the morning (08:00 AM) and late at night (24:00 AM), while plasma adrenocorticotropic hormone was normal. The patient underwent a left adrenalectomy and histopathology substantiated the BMAH diagnosis. WES of the germline DNA discovered a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) and in silico analysis predicted that the mutation significantly impaired protein function, resulting in inactivated ARMC5. Subsequently, WES of the tumor specimen identified 79 somatic single nucleotide polymorphisms (SNPs)/insertion-deletion (indel) mutations, including 32 missense/nonsense/splice/stop-loss mutations. None of these mutations were CS-related. CONCLUSIONS: A novel germline ARMC5 mutation (c. 517C > T, p. Arg173*) was identified that induced BMAH alone without a second mutation. ARMC5 sequencing may improve the identification of clinical forms of BMAH and allow earlier diagnosis of this disease.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Síndrome de Cushing/genética , Mutação em Linhagem Germinativa , Proteínas Supressoras de Tumor/genética , Hiperplasia Suprarrenal Congênita/diagnóstico por imagem , Hormônio Adrenocorticotrópico/sangue , Proteínas do Domínio Armadillo , Síndrome de Cushing/diagnóstico por imagem , Feminino , Heterozigoto , Humanos , Hidrocortisona/sangue , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único
18.
J Med Case Rep ; 12(1): 13, 2018 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-29343284

RESUMO

BACKGROUND: Primary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome characterized by the presence of bilateral secretory adrenal nodules. Recent studies have shown that primary bilateral macronodular adrenal hyperplasia is caused by combined germline and somatic mutations of the ARMC5 gene. Exophthalmos is an underappreciated sign of Cushing's syndrome. CASE PRESENTATION: A 52-year-old Chinese woman with progressively worsening bilateral proptosis presented to our hospital. Subsequently she was diagnosed as having primary bilateral macronodular adrenal hyperplasia and underwent bilateral laparoscopic adrenalectomy. Genomic deoxyribonucleic acid was isolated from lymphocytes as well as seven different adrenal nodules and the ARMC5 sequence was determined by Sanger sequencing. We identified one heterozygous ARMC5 germline mutation c.682C>T (p. Gln228*) and five heterozygous somatic mutations (c.310delG, c.347_357del11, c.267delC, c.283_289del7, and c.205-322del118) in five different adrenal nodules. All mutations are novel and were not found in any of the available online databases. To test whether the ARMC5 mutation induced messenger ribonucleic acid decay, real-time reverse transcriptase polymerase chain reaction was performed on patient and control adrenal tissue. We found that the adrenal cortex of our patient showed a low ARMC5 messenger ribonucleic acid expression compared with normal adrenal cortex, possibly as a result of nonsense-mediated messenger ribonucleic acid decay CONCLUSIONS: We demonstrated extensive genetic diversity of ARMC5 in a patient with primary bilateral macronodular adrenal hyperplasia that started with exophthalmos, which contributes to further understanding of the pathogenesis of this disease. Early recognition of atypical symptoms and screening for ARMC5 mutation in patients with primary bilateral macronodular adrenal hyperplasia has important clinical implications for the diagnosis and genetic counseling.


Assuntos
Síndrome de Cushing/genética , Mutação em Linhagem Germinativa , Proteínas Supressoras de Tumor/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/cirurgia , Proteínas do Domínio Armadillo , Síndrome de Cushing/diagnóstico , Exoftalmia/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Exame Físico , Tomografia Computadorizada por Raios X
19.
Endocr J ; 65(3): 269-279, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29279458

RESUMO

Primary macronodular adrenal hyperplasia (PMAH), also known in the past as bilateral macronodular adrenalhyperplasia or adrenocorticotropin (ACTH)-independent macronodular adrenal hyperplasia, is a rare type of Cushing's syndrome (CS) and is associated with bilateralenlargement of the adrenal glands. It accounts for <1% of all endogenous cases of CS. In order toidentify the pathogenic mutations in the causative gene of (AIMAH pedigrees, Whole-genome sequencing of three patients in family I was used to retrieve candidate causative genes. Meanwhile, the causative gene was identified by Sanger sequencing from the two pedigrees. Sequencing of ARMC5 exons of three patients was carried out to identify somatic mutations. Moreover, haploid clone of one tumor DNA sample was conducted. ARMC5 was the causative gene of two pedigrees confirmed by whole-genome sequencing (WGA) and Sanger sequencing. The variant sites of the two families were c.C943T (p.R315W) and c.C1960T (p.R654X), respectively. Autosomal dominant inheritance of AIMAH was confirmed by genotypes of one family member. Several somatic mutations were discovered in tumor DNA samples. In addition, haploid clone of tumor DNA was confirmed by germline mutation and somaticmutation, which suggested the pathogenic mechanism of "two-hit-model." ARMC5 was the causative gene of AIMAH pedigrees. This AIMAH in this study presented autosomal dominant inheritance, fitting to Mendelian inheritance law. However, the pathogenic mode of this disease showed as compound heterozygote.


Assuntos
Glândulas Suprarrenais/diagnóstico por imagem , Síndrome de Cushing/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Proteínas do Domínio Armadillo , Síndrome de Cushing/diagnóstico por imagem , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Tomografia Computadorizada por Raios X , Sequenciamento Completo do Genoma
20.
Endocr Rev ; 38(6): 516-537, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973103

RESUMO

Aldosterone and cortisol, the main mineralocorticoid and glucocorticoid hormones in humans, are produced in the adrenal cortex, which is composed of three concentric zones with specific functional characteristics. Adrenocortical adenomas (ACAs) can lead to the autonomous secretion of aldosterone responsible for primary aldosteronism, the most frequent form of secondary arterial hypertension. In the case of cortisol production, ACAs lead to overt or subclinical Cushing syndrome. Genetic analysis driven by next-generation sequencing technology has enabled the discovery, during the past 7 years, of the genetic causes of a large subset of ACAs. In particular, somatic mutations in genes regulating intracellular ionic homeostasis and membrane potential have been identified in aldosterone-producing adenomas. These mutations all promote increased intracellular calcium concentrations, with activation of calcium signaling, the main trigger for aldosterone production. In cortisol-producing adenomas, recurrent somatic mutations in PRKACA (coding for the cyclic adenosine monophosphate-dependent protein kinase catalytic subunit α) affect cyclic adenosine monophosphate-dependent protein kinase A signaling, leading to activation of cortisol biosynthesis. In addition to these specific pathways, the Wnt/ß-catenin pathway appears to play an important role in adrenal tumorigenesis, because ß-catenin mutations have been identified in both aldosterone- and cortisol-producing adenomas. This, together with different intermediate states of aldosterone and cortisol cosecretion, raises the possibility that the two conditions share a certain degree of genetic susceptibility. Alternatively, different hits might be responsible for the diseases, with one hit leading to adrenocortical cell proliferation and nodule formation and the second specifying the hormonal secretory pattern.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Síndrome de Cushing/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Predisposição Genética para Doença , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/patologia , Síndrome de Cushing/patologia , Humanos
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