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Doctoral Thesis
DOI
Document
Author
Full name
Beatriz Marinho de Paula Mariani
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Fragoso, Maria Candida Barisson Villares (President)
Domenice, Sorahia
Kater, Cláudio Elias
Zerbini, Maria Claudia Nogueira
Title in Portuguese
Análise de variantes alélicas no gene Armadillo Repeat Containing 5 (ARMC5) em pacientes com incidentaloma da suprarrenal
Keywords in Portuguese
Achados incidentais
Gene ARMC5
Glândulas suprarrenais
Mutação
PMAH
Polimorfismo genético
Abstract in Portuguese
Análise de variantes alélicas no gene Armadillo Repeat Containing 5 (ARMC5) em pacientes com incidentaloma da suprarrenal identificamos 16 pacientes carreadores da mutação, a partir de dois irmãos inicialmente investigados. Aproximadamente 30% dos membros afetados desta genealogia, apresentavam somente uma suprarrenal acometida e a suprarrenal contra-lateral absolutamente normal ou discretamente espessada. Esta observação nos infere que a hiperplasia macronodular da PMAH pode ocorrer de forma assincrônica e dificultar aprincipio o seu diagnostico. A incidência de nódulos unilaterais identificados em exame de imagens na pratica clinica é muito elevada (1,4 - 2,9%, podendo chegar a 10% em pacientes com idade a cima de 70 anos) os denominados incidentalomas suprarrenais. Além disso, a grande maioria dos pacientes com nódulos suprarrenais apresentam alguma autonomia da secreção do cortisol. Considerando estes aspectos, nos propomos a investigar se os incidentalomas suprarrenais unilaterais com alguma autonomia da secreção do cortisol poderiam fazer parte do espectro de apresentação da PMAH. Nosso trabalho tem como foco analisar a frequência das variantes alélicas do ARMC5 em uma coorte multicêntrica de pacientes com nódulos suprarrenais incidentais e autonomia da secreção do cortisol. O esclarecimento da frequência da PMAH pode nos direcionar a uma melhor pratica clinica e cuidados com os pacientes
Title in English
Analysis of the allelic variants of the armadillo repeat containing 5 (ARMC5) gene in patients with adrenal incidentalomas
Keywords in English
Adrenal Glands
ARMC5 gene
Incidental Findings
Mutation
PMAH
Polymorphism genetic
Abstract in English
Primary macronodular adrenal hyperplasia (PMAH) was described in 1964 by Kirschner et al, and is considered a rare cause of endogenous ACTH-independent Cushing's syndrome (CS), usually associated with bilateral adrenal nodules. The clinical presentation of the patients is heterogeneous, ranging from subclinical to overt Cushing's syndrome, with all its characteristics. The cortisol secretion pattern, after the 1 mg dexamethasone overnight suppression test, identifies the intensity of cortisol secretion autonomy, ie, serum cortisol concentrations above 1.8 ug / dL and up to 5 ug / dL , characterize a possible autonomous cortisol secretion and above this value (5 ug / dL) an autonomous cortisol secretion. Patients are generally diagnosed with PMAH when undergoing ACTH-independent endogenous hypercortisolism investigation or, more frequently, during the investigation of bilateral adrenal incidentalomas and less likely in patients with metabolic syndrome associated with meningiomas of the central nervous system, since these are very prevalence in patients with PMAH. Bilateral adrenal involvement, along with the description in the literature of several PMAH-affected family relatives, has already indicated a genetic cause involved in the pathophysiology of this intriguing disease. In 2013, two studies, one Brazilian and one Franch, using distinct methodologies, identified germline mutations in ARMC5 as the major genetic cause of PMAH. The largest genealogy published so far was that of a Brazilian family, with 5 generations in which we identified 16 patients, carriers of the mutation, from two siblings initially investigated. Approximately 30% of the affected members of this genealogy had only one adrenal afected with the contralateral gland absolutely normal or discretely thickened. This observation infers us that the macronodular hyperplasia of PMAH can occur in an asynchronous way and make it difficult to diagnose it. The incidence of unilateral nodules identified in clinical imaging is very high (1.4-2.9%, and may reach 10% in patients over the age of 70), the so-called adrenal incidentalomas. In addition, the vast majority of patients with adrenal nodules have some autonomy in cortisol secretion. Considering these aspects, we propose to investigate whether unilateral adrenal incidentalomas, with some autonomy of cortisol secretion, could be part of the presentation spectrum of PMAH. Our work focuses on the frequency of allelic variants of ARMC5 in a multicentric cohort of patients with incidental adrenal nodules and autonomy of cortisol secretion. Clarifying the frequency of PMAH may lead to better clinical practice and patient care
 
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Publishing Date
2019-10-03
 
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