Expressions of Cushing’s syndrome in multiple endocrine neoplasia type 1

Abstract

Cushing’s syndrome (CS) resulting from endogenous hypercortisolism can be sporadic or can occur in the context of familial disease because of pituitary or extra-pituitary neuroendocrine tumors. Multiple endocrine neoplasia type 1 (MEN1) is unique among familial endocrine tumor syndromes because hypercortisolism in this context can result from pituitary, adrenal, or thymic neuroendocrine tumors and can therefore reflect either ACTH-dependent or ACTH-independent pathophysiologies. The prominent expressions of MEN1 include primary hyperparathyroidism, tumors of the anterior pituitary, gastroenteropancreatic neuroendocrine tumors, and bronchial carcinoid tumors along with several common non-endocrine manifestations such as cutaneous angiofibromas and leiomyomas. Pituitary tumors are present in about 40% of MEN1 patients, and up to 10% of such tumors secrete ACTH that can result in Cushing’s disease. Adrenocortical neoplasms occur frequently in MEN1. Although such adrenal tumors are mostly clinically silent, this category can include benign or malignant tumors causing hypercortisolism and CS. Ectopic tumoral ACTH secretion has also been observed in MEN1, almost exclusively originating from thymic neuroendocrine tumors. The range of clinical presentations, etiologies, and diagnostic challenges of CS in MEN1 are reviewed herein with an emphasis on the medical literature since 1997, when the MEN1 gene was identified.

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance

“…In addition to pancreatic NET-related ACTH ectopic secretion (causing Cushing’s syndrome) [ 121 , 167 ], tumor-related high calcium levels are caused by PTHrP (parathyroid hormone-related peptide) overproduction that suppresses PTH levels during negative feedback via serum calcium (in patients with intact parathyroid glands) [ 168 , 169 ]. PTHrP encoded by the PTHLH gene represents the molecular signature of various tissues, including the pancreas [ 170 ].…”

Follow-up study of a Colombian family with a novel MEN1 variant and rare ACTH-producing pancreatic neuroendocrine carcinoma

“…These ndings align with the presentations in the index case and patient II-4. Notably, the index case's second pancreatic tumor, causing ectopic ACTH secretion syndrome (EAS), is a novel nding in MEN1, as such carcinomas are typically associated with thymic NETs [13][14][15][16][17]. This is the rst report of a family exhibiting an ACTH-producing pancreatic NEC, marking a distinctive nding within the landscape of MEN1 phenotypic expression.…”

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

“…TNETs can be functioning, leading to Cushing’s syndrome due to hypersecretion of Adrenocorticotropic Hormone (ACTH). The 5-year survival of the TNET patients is approximately 62.5% and the 10-year survival is 31.3% [ 87 , 88 ].…”