Endocrine Abstracts

Pathogenic ARMC5 variants are the main genetic cause of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) explaining roughly 20% of index cases. These variants found both at germline and somatic level are mostly frameshift and nonsense leading to a loss of its function. ARMC5 acts then, as a tumor suppressor gene but little was initially known on its function. Using an RNAseq analysis on transient zebrafish models of Armc5 up- and d...

Introduction: Osilodrostat and Metyrapone are two CYP11B1 inhibitors used for the treatment of patients with Cushing syndrome. Despite their common suspected mechanism of action, the comparison of serum steroid profiles determined in HPLC-MS/MS in patients treated by either Osilodrostat or Metyrapone for an ACTH-dependent Cushing syndrome identified higher levels of 11-deoxycortisol and androgens in patients treated by Metyrapone than in those treated by Osilodrostat (F. B...

ACTH independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing’s syndrome. Both Phosphodiesterase 11A4 (PDE11A4) mutations and inactivating mutations of armadillo repeat containing 5(ARMC5) have been associated with familial AIMAH. A family with autosomal dominant AIMAH was studied trying to elucidate the involved genetic basis.Methods and results: Adrenal hypercortisolism with giant bilateral AH was diagnosed in three adult me...

Bilateral Adrenal Hyperplasias (BAH) are responsible for approximately 10% of ACTH-independent Cushing syndrome and are classified as either micronodular or macronodular. Whereas Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and isolated Micronodular Adrenal Disease (iMAD) are two types of micronodular hyperplasia, Primary Macronodular Adrenal Hyperplasia (PMAH) is a macronodular BAH. These tumors are classified differently based on clinical, histological and geneti...

Introduction: Bilateral macronodular adrenal disease (BMAD, former PBMAH) is a rare cause of Cushing’s syndrome. The few morphologic descriptions of BMAD mention multinodular hyperplastic adrenal glands composed of clear spongiocytic cells and fewer compact eosinophilic cells without any morphologic variation. The discovery of ARMC5 and KDM1A mutations argues for genetic heterogeneity. The aim of this work was to describe the morphological and immunohist...

Introduction: Bilateral macronodular adrenocortical disease (BMAD) is an adrenal cause of Cushing’s syndrome explained in a subset of patients by inactivation of the tumor suppressor genes ARMC5 or KDM1A. Genetic and transcriptomic studies cluster BMAD in 3 distinct molecular groups: one with ARMC5 inactivation, one with KDM1A inactivation and a third group with no known genetic cause. Although ARMC5 and KDM1A are invo...

The most frequent molecular alteration in adrenocortical tumors (ACT) is the activation of the Wnt/β-catenin pathway that is associated with poor prognosis in adrenocortical carcinoma. Activating β-catenin mutation (p.S31, p.S37, p.S45, T.41) inhibiting its proteosomal degradation by the canonical destruction complex is responsible for its abnormal activation in roughly 30% of ACT. However, the E3 ubiquitin protein ligase 1, SIAH1 is able to ubiquitinate β-caten...

ARMC5 is a tumor suppressor gene responsible for 20 to 40% of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) with a function that remains unclear. Based on pathway analysis from RNAseq results obtained on zebrafish models of transient Armc5 up- and down-regulation, we identified transcriptional alterations of several members of SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1) signaling in our models and hypothesized that ARM...

Introduction: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome. It is characterized by the development of supracentimetric nodules resulting in increased adrenal volume and weight. Its presentation is clinically, radiologically and biologically heterogeneous. Morphological descriptions of PBMAH are rare. Although the initial description highlights that multinodular hyperplastic adrenal glands are made of a majority...

Introduction: Bilateral macronodular adrenal disease (BMAD) is a genetically heterogeneous disease that can be caused by ARMC5 or KDM1A alterations. Indeed, a germline and somatic event leading to a bi-allelic inactivation of ARMC5 or KDM1A are responsible for 20 and 1% of BMAD cases, respectively. Genetic analysis identified three molecular groups: ARMC5, KDM1A and no genetic cause known to date. Although there is a high h...