Endocrine Abstracts

Introduction and rationale: Cushing’s syndrome (CS) is a rare disease with hypercortisolism caused either by ACTH excess from a pituitary or non-pituitary tumor or by an ACTH-independent primary adrenal overproduction of cortisol. It is associated with significant comorbidities potentially lethal: hypertension, diabetes, coagulopathy, cardiovascular disease, infections, and osteoporotic fractures. It is usually managed by surgery and/or medical treatment with steroidogene...

Recent studies have reported a high prevalence of USP8 mutations in corticotroph adenomas causing Cushing’s disease. Nelson’s syndrome is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory Cushing’s disease that is caused by the development of an ACTH-secreting tumor in the pituitary gland. Whether USP8 alterations are also present in Nelson’s tumors has not been studied in detail so far....

Genetic alterations affecting the PKA/cAMP pathway are commonly found in cortisol-producing adrenocortical adenomas (ACAs), while activating mutations in the gene coding for β-catenin (CTNNB1) have been reported in both adenomas and carcinomas. However, the molecular pathogenesis of most ACAs is still unclear. Aim of the study was a comprehensive genetic characterization of sporadic ACAs and the identification of novel molecular markers involved in adrenal tumori...

We have recently reported that somatic mutations in the ubiquitin-specific protease 8 (USP8) are present in corticotropinomas of patients with Cushing’s disease and that these mutations reduced the interaction with 14-3-3. Mutant USP8 exhibited higher deubiquitination activity and potentiated EGFR-induced POMC expression (Reincke et al., Nat Genet 2014). To further study the prevalence of these mutations, we have analyzed 134 ACTH-producing corticotropin...

Background and Methods: Corticotropin-independent Cushing’s syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol producing adrenal adenomas is not well understood. Therefore, exome sequencing was performed in 10 cortisol-producing adenomas and recurrent mutations in candidate genes were evaluated in additional 171 patients with adrenocortical tumors. In addition, genome-wide copy number analysis was performed in 35 pati...

Metyrapone treatment in endogenous Cushing’s syndrome. Results from a prospective multicenter, open-label, phase III/IV study: PROMPTBackground: Metyrapone is a steroidogenesis inhibitor approved in Europe for the treatment of endogenous Cushing’s syndrome (CS) based on observational retrospective studies published over more than 50 years. We present data from the first prospective study designed to confirm metyrapone efficacy and good tolera...

Introduction: Cushing’s disease (CD) is caused by pituitary tumors hypersecreting adrenocorticotropin (ACTH). Until now somatic mutations in the 14-3-3 binding domain of Ubiquitin Specific Peptidase 8 gene (USP8) were the only recurring, driver mutations and were described in about 40% of the 446 CD samples that have been analysed wordwide. We wanted to assess if other driver mutations might be the pathogenetic cause of CD in those tumors without USP8 mu...

Background: Patients with active Cushing’s syndrome (CS) have increased mortality.Aims: Evaluate cause of death in a large cohort of CS patients, and establish factors associated with increased mortality.Methods: We analysed 1514 patients included in the European Registry on Cushing’s syndrome (ERCUSYN): 1022 (68%) had pituitary-dependent CS (PIT-CS), 379 (25%) adrenal-dependent CS (ADR-CS), 71 (5%) had an ectopic source ...

BackgroundRetrospective studies led to European approval of the steroidogenesis inhibitor Metyrapone for the treatment of endogenous Cushing’s syndrome (CS). We prospectively showed good efficacy and safety of Metyrapone after 12 weeks (Wk12) treatment in the phase III/IV PROMPT study and now report results of an extension study (EXT) sponsored by HRA Pharma Rare Diseases.DesignThis was a single arm, ope...

Introduction: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare disease responsible for variable levels of cortisol excess. Constitutional pathogenic variants of the tumor suppressor gene ARMC5 are its most frequent molecular cause (20% of index cases). Recently, KDM1A has been identified as the causing gene for PBMAH associated with food-dependent Cushing’s syndrome (FDCS), consecutive to the illegitimate expression of the GIP recepto...