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 - März, Juliane A1 - Kurlbaum, Max A1 - Roche-Lancaster, Oisin A1 - Deutschbein, Timo A1 - Peitzsch, Mirko A1 - Prehn, Cornelia A1 - Weismann, Dirk A1 - Robledo, Mercedes A1 - Adamski, Jerzy A1 - Fassnacht, Martin A1 - Kunz, Meik A1 - Kroiss, Matthias T1 - Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors JF - Frontiers in Endocrinology N2 - Context Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet. Objective Evaluation of quantitative metabolomics as a diagnostic tool for PPGL. Design Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study. Patients Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded. Results Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines. By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling. Conclusions The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability. KW - adrenal KW - pheochromocytoma KW - paraganglioma KW - targeted metabolomics KW - mass spectronomy KW - catecholamines KW - machine learning KW - feature selection Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245710 SN - 1664-2392 VL - 12 ER -