Recurrent Cushing Syndrome From Metastatic Adrenocortical Carcinoma With Fumarate Hydratase Allelic Variant

Emily Silverman; Noor Addasi; Muaataz Azzawi; Ernesto Martinez Duarte; Dali Huang; Benjamin Swanson; Apar Kishor Ganti; Gwen Reiser; Abbey L Fingeret; Anupam Kotwal

doi:10.1016/j.aace.2022.09.003

Recurrent Cushing Syndrome From Metastatic Adrenocortical Carcinoma With Fumarate Hydratase Allelic Variant

AACE Clin Case Rep. 2022 Sep 17;8(6):259-263. doi: 10.1016/j.aace.2022.09.003. eCollection 2022 Nov-Dec.

Authors

Affiliations

¹ Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
² Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
³ Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska.
⁴ Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
⁵ Department of Internal Medicine, VA Nebraska Western Iowa Health Care System, Omaha, Nebraska.
⁶ Department of Genetic Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
⁷ Division of Surgical Oncology, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.

Abstract

Background: Adrenal Cushing syndrome (CS) is usually benign in etiology; however, although rarely, it can be due to adrenocortical carcinoma (ACC); in which case, diagnosis and management are quite complicated.

Case report: A 34-year-old woman presented with worsening confusion, weight gain, new-onset diabetes, and hypertension. Her history was significant for a 7.4-cm left adrenal mass and CS, which were treated with left adrenalectomy 2 years ago. She received hydrocortisone replacement therapy after the surgery, which was discontinued on admission when evaluation showed hypokalemia, hypercortisolemia, and undetectable adrenocorticotropic hormone. Subsequent testing included 1-mg and 8-mg dexamethasone suppression tests, which did not suppress cortisol; late-night salivary cortisol measurement, which yielded a very high salivary cortisol level; and 24-hour urinary cortisol measurement. The level of 11-deoxycortisol was elevated. A computed tomography scan revealed multiple hepatic lesions, which were fluorodeoxyglucose avid, and a biopsy confirmed metastatic ACC. She received treatment with mitotane, metyrapone (later changed to mifepristone), doxorubicin, cisplatin, and etoposide. Over 8 weeks, mitotane levels became therapeutic at 20 mcg/mL, the hepatic masses decreased in size, and she transitioned to adrenal insufficiency and improved glycemic control. Next-generation sequencing of liver biopsy and germline testing revealed a frameshift loss-of-function allelic variant in the FH gene that encodes the protein fumarate hydratase.

Discussion: We report a case of recurrent CS due to metastatic ACC in a patient with a previously resected adrenal adenoma and FH allelic variant.

Conclusion: Metastatic ACC presenting with severe CS presents a diagnostic and management challenge where combination therapy guided by a multidisciplinary team is essential. FH allelic variant may contribute to ACC progression.

Keywords: ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CS, Cushing syndrome; CT, computed tomography; HDDST, high-dose 8 mg dexamethasone suppression test; HLRCC, hereditary leiomyomatosis and renal cell cancer; LDDST, low-dose 1 mg dexamethasone suppression test; adrenal cancer; adrenal mass; hypercortisolism; metastases.

Publication types

Case Reports