Analysis of the allelic variants of the armadillo repeat containing 5 (ARMC5) gene in patients with adrenal incidentalomas

Author(s)

Beatriz Marinho de Paula Mariani

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2019-07-05

Examining board members

Maria Candida Barisson Villares Fragoso; Cláudio Elias Kater; Maria Claudia Nogueira Zerbini

• Advisor: Maria Candida Barisson Villares Fragoso

Abstract

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 (AU)

• FAPESP's process: 15/06146-2 - The frequency of ARMC5 Mutation in incidental nodules in the adrenal gland associated with subclinical hypercortisolism
• Grantee: Beatriz Marinho de Paula Mariani
• Support Opportunities: Scholarships in Brazil - Doctorate