A Case of Cushing's Disease and a RET Pathogenic Variant: Exploring Possible Rare Associations

Abstract

Cushing disease (CD), a rare endocrine disorder characterized by a pituitary adenoma that secretes excess adrenocorticotropic hormone (ACTH), leads to overproduction of cortisol by the adrenal glands and, depending on severity and duration, manifests with a broad spectrum of clinical signs and symptoms, ranging from classical features to more common conditions seen in the general population. Discovery of molecular and pathogenic mechanisms related to the development of CD tumors has increased in recent years, almost two-thirds of the somatic variants cases have been linked to the USP8 gene, while very rare germline variants in MEN1 and AIP genes have been associated with pituitary adenomas. Variants affecting the RET proto-oncogene, which encodes a receptor tyrosine kinase involved in cell growth and differentiation, are implicated in the development of medullary thyroid carcinoma (MTC) and its hereditary form, multiple endocrine neoplasia type 2 (MEN2). This genetic syndrome is also associated with extra-thyroidal manifestations, such as pheochromocytoma, hyperparathyroidism, Hirschsprung's disease, mucosal neuromas, or cutaneous lichen amyloidosis. In both hereditary and sporadic forms of MTC, genetic testing is essential for promoting preventive strategies for first-degree relatives and facilitating early diagnosis. We report a case of a 35-year-old male with a history of hypertension, bilateral carotid artery aneurysms, and intracranial fusiform dolichoectasia, with clinical manifestations suggestive of Cushing syndrome. Laboratory investigation confirmed ACTH-dependent hypercortisolism. However, magnetic resonance imaging did not reveal any pituitary tumor. A bilateral inferior petrosal sinus sampling confirmed the diagnosis of CD. The patient underwent successful transsphenoidal endoscopic surgery to remove the corticotropinoma, resulting in significant biochemical and clinical improvement. Due to the patient history of multiple vascular abnormalities and the suspicion of a possible genetic connective tissue disorder, comprehensive genetic testing with whole exome sequencing was performed, identifying a heterozygous pathogenic variant in RET (c.2410G>T p.{Val804Leu}). This variant has been previously associated with MEN2 manifestations and described as having a moderate risk for aggressive MTC and a low risk for pheochromocytoma and hyperparathyroidism. Genetic testing of available first-degree relatives for the RET variant was negative. To our knowledge, this is the third reported case of Cushing disease in a patient with a RET variant. This rare association can be due to coincidence, but we cannot exclude the possibility that the two conditions could share a common pathogenic mechanism. Although further research is needed to firmly establish a possible association, this case also highlights the necessity of exploring genetic backgrounds when patients present with clinical manifestations not readily explained by a single endocrine disorder. Investigating potential genetic associations is crucial since a positive genetic test allows for the testing of relatives, genetic counseling, and proper surveillance of individuals at risk.

Keywords: case report; cushing disease; endocrine familial disorders; men2; pathogenetics; ret gene variant.

Figure 1. Patient photos on the first physical examination demonstrating a moon face and marked facial plethora.

Figure 2. The patient before surgery (A) and a few months after surgery (B) demonstrating a recovery of facial features and loss of weight.

Figure 3. Pedigree of the investigated family regarding RET variant status.