CASE REPORT published: 20 August 2021 doi: 10.3389/fendo.2021.731579 Case Report: Consecutive Adrenal Cushing’s Syndrome and Cushing’s Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations Mario Detomas 1*, Barbara Altieri 1, Wiebke Schlötelburg 2,3, Silke Appenzeller 4, Sven Schlaffer 5, Roland Coras 6, Andreas Schirbel 3, Vanessa Wild 7, Matthias Kroiss 1,8, Silviu Sbiera 1, Martin Fassnacht 1 and Timo Deutschbein 1,9 1 Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, Würzburg, Germany, 2 Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, University of Würzburg, Würzburg, Germany, 3 Department of Nuclear Medicine, University Hospital Würzburg, University of Edited by: Würzburg, Würzburg, Germany, 4 Core Unit Bioinformatics, Comprehensive Cancer Center Mainfranken, University Hospital Dragana Nikitovic, of Würzburg, University of Würzburg, Würzburg, Germany, 5 Department of Neurosurgery, University Hospital Erlangen, University of Crete, Greece Erlangen, Germany, 6 Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany, 7 Institute of Reviewed by: Pathology, University of Würzburg, Würzburg, Germany, 8 Department of Internal Medicine IV, University Hospital Munich, Marcio Machado, Ludwig-Maximilians-Universität München, Munich, Germany, 9 Medicover Oldenburg MVZ, Oldenburg, Germany University of São Paulo, Brazil Anna Aulinas, Hospital de la Santa Creu i Sant Pau, The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single Spain individuals is extremely rare. We here present the case of a female patient who was *Correspondence: successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s Mario Detomas [email protected] 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 Specialty section: confirmation of a cortisol-producing adrenocortical adenoma, biochemical This article was submitted to hypercortisolism and clinical symptoms significantly improved. However, starting from Cancer Endocrinology, a section of the journal 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent Frontiers in Endocrinology biochemical and radiological workup suggested the presence of ACTH-dependent CS Received: 27 June 2021 along with a pituitary microadenoma. The patient underwent successful transsphenoidal Accepted: 29 July 2021 fi Published: 20 August 2021 adenomectomy, and both postoperative adrenal insuf ciency and histopathological Citation: workup confirmed the diagnosis of CD. Exome sequencing excluded a causative Detomas M, Altieri B, Schlötelburg W, germline mutation but showed somatic mutations of the b-catenin protein gene Appenzeller S, Schlaffer S, Coras R, (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specificpeptidase8 Schirbel A, Wild V, Kroiss M, Sbiera S, Fassnacht M and Deutschbein T (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In (2021) Case Report: Consecutive conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS Adrenal Cushing’s Syndrome and Cushing’s Disease in a Patient may develop in a single individual even without evidence for a common With Somatic CTNNB1, USP8, and genetic background. NR3C1 Mutations. Front. Endocrinol. 12:731579. Keywords: Cushing’ssyndrome,Cushing’s disease, hypercortisolism, glucocorticoid excess, USP8, doi: 10.3389/fendo.2021.731579 CTNNB1, NR3C1 Frontiers in Endocrinology | www.frontiersin.org 1 August 2021 | Volume 12 | Article 731579 Detomas et al. Case Report: Patient With Two Cushing Subtypes INTRODUCTION micronodular or macronodular hyperplasia (5–9). A sequence of CD and PPNAD was also described in presence of Carney Endogenous Cushing´s syndrome (CS) is a rare disorder with an complex, a genetic syndrome characterized by the loss of incidence of 0.2–5.0 per million people per year (1, 2). The function of the gene encoding for the regulatory subunit type predominant subtype (accounting for about 80%) is 1a of protein kinase A (PRKAR1A)(10). Moreover, another adrenocorticotropic hormone (ACTH)-dependent CS. The vast group reported the case of a patient with Cushing's disease majority of this subtype is due to an ACTH-secreting pituitary followed by ectopic Cushing's syndrome more than 30 years adenoma [so called Cushing´s disease (CD)], whereas ectopic later (8). To our knowledge, however, we here describe the first ACTH-secretion (e.g. through pulmonary carcinoids) is much case report on a single patient with a cortisol-producing less common. In contrast, ACTH-independent CS can mainly be adrenocortical adenoma and subsequent CD. attributed to cortisol-producing adrenal adenomas. Adrenocortical carcinomas, uni-/bilateral adrenal hyperplasia, and primary pigmented nodular adrenocortical disease CASE DESCRIPTION (PPNAD) may account for some of these cases as well (3, 4). Coexistence of different subtypes of endogenous CS in single In March 2014, a 49-year old female underwent an abdominal individuals is even rarer but has been described in few reports. magnetic resonance imaging (MRI) because of recurrent abdominal These cases were usually observed in the context of prolonged pain and irregular hypermenorrhea. This revealed the presence of a ACTH stimulation on the adrenal glands, resulting in left-sided adrenal lesion of 4.5 x 4.2 cm (Figure 1A). Due to the A BCD FIGURE 1 | Abdominal magnetic resonance imaging performed in March 2014 and histological analysis of the adrenal adenoma. (A) Contrast-enhanced coronal T1- weighted MRI showing a 4.5 x 4.2 cm adenoma of the left adrenal gland (white arrow). (B–D) Histological investigation of the adrenal adenoma with hematoxylin and eosin staining: (B) Solitary, well circumscribed intra-adrenal mass confined to the gland; (C) Nested/fasciculated growth pattern of uniform tumor cells; (D) Tumor cells showing lipid-rich foamy cytoplasm with small uniform nuclei. Absent mitosis or necrosis. (H.E. 6.5x, 10.0x, 40.0x). Frontiers in Endocrinology | www.frontiersin.org 2 August 2021 | Volume 12 | Article 731579 Detomas et al. Case Report: Patient With Two Cushing Subtypes persistence of menstrual cycle irregularities and the development of In February 2015, the patient underwent successful hirsutism, the general practitioner finally suspected a cortisol- laparoscopic left-sided adrenalectomy. Postoperatively, morning producing adrenal tumor and the patient was, therefore, referred serum cortisol was < 5 µg/dl and glucocorticoid replacement to our outpatient clinic. therapy was initiated. The histopathological analysis revealed a Atthetimeofherfirst examination at our outpatient clinic well-circumscribed tumor, with foamy lipid-rich cytoplasm, a Ki- (January 2015), the patient reported muscle-weakness, asthenia, and 67 <1%, and no signs of malignancy (Weiss score: 1) (13). The hirsutism. She suffered from arterial hypertension and was treated analysis was compatible with a cortisol-producing adrenocortical with a triple anti-hypertensive therapy. Other comorbidities and adenoma. Slides from the histological investigations are medical therapies were not reported. Both parents had arterial exemplarily shown in Figures 1B–D. hypertension, and the familial history was positive for breast Between February and May 2015, anti-hypertensive therapy cancer (mother). The physical examination revealed classical signs could already be reduced to only one drug, and subsequent blood of CS such as centripetal obesity (body mass index: 45.2 kg/m2), pressure levels were normal. Hydrocortisone was stopped in May striae rubrae, hirsuitism, facial plethora, skin atrophy, and multiple 2015, taking into account a normalized adrenal function hematomas. Her glycated hemoglobin was slightly elevated (HbA1c measured by an ACTH stimulation test and no clinical 6.4%). The routine laboratory (including electrolytes) was evidence for an ongoing glucocorticoid withdrawal syndrome. unremarkable. The endocrine workup was conducted according In August 2015, the patient reported a weight loss of 5 kg and an to published guidelines (12), involved commercially available improvement of her general condition. The 1 mg dexamethasone analytical procedures (i.e., theImmulite2000XpifromSiemens suppression test (DST) and the late-night salivary cortisol (LNSC) for the analysis of ACTH and serum cortisol, a manual results were remarkably lower than preoperatively, but not luminescence immunoassay from IBL for the analysis of salivary normalized (Figure 2). In contrast, 24-hour urinary free cortisol cortisol, and a manual radioimmunoassay from Immuntech for the (UFC) was within the reference range and the ACTH was no longer analysis of urinary free cortisol) and indicated presence of ACTH- suppressed. The patient was subsequently followed up for three years independent CS (as shown in Table 1). Of note, basal ACTH was on an annual basis. The course of the four most relevant endocrine repeatedly <10 ng/l (reference range 0-46 ng/l). Furthermore, there parameters (i.e., ACTH, 1 mg DST, LNSC, and 24-hour UFC) during was no evidence for primary hyperaldosteronism or a our observation is provided in Figure 2.Twoyearsafter catecholamine excess. adrenalectomy, the antihypertensive therapy was discontinued and the patient did not take any medication at all. Additionally, the HbA1c was clearly improved