TY  - JOUR
A1  - Detomas, Mario
A1  - Altieri, Barbara
A1  - Schlötelburg, Wiebke
A1  - Appenzeller, Silke
A1  - Schlaffer, Sven
A1  - Coras, Roland
A1  - Schirbel, Andreas
A1  - Wild, Vanessa
A1  - Kroiss, Matthias
A1  - Sbiera, Silviu
A1  - Fassnacht, Martin
A1  - Deutschbein, Timo
T1  - Case Report: Consecutive Adrenal Cushing’s Syndrome and Cushing’s Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations
JF  - Frontiers in Endocrinology
N2  - The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.
KW  - Cushing’s syndrome
KW  - Cushing’s disease
KW  - hypercortisolism
KW  - glucocorticoid excess
KW  - USP8
KW  - CTNNB1
KW  - NR3C1
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244596
SN  - 1664-2392
VL  - 12
ER  - 
TY  - JOUR
A1  - Sbiera, Silviu
A1  - Kunz, Meik
A1  - Weigand, Isabel
A1  - Deutschbein, Timo
A1  - Dandekar, Thomas
A1  - Fassnacht, Martin
T1  - The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight
JF  - Cancers
N2  - Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.
KW  - Cushing’s disease
KW  - pathogenesis
KW  - somatic mutations
KW  - deubiquitinases
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193194
SN  - 2072-6694
VL  - 11
IS  - 11
ER  -