Endocrine Abstracts

Corticotropinomas represent only a small fraction of all the cases of pituitary adenomas, yet they have the potential for great morbidity and mortality. Presenting clinically as Cushing’s disease (CD), corticotropinomas are characterized at the molecular level by resistance to glucocorticoid negative feedback, dysregulation of proteins controlling cell cycle progression, and overexpression of pathways that sustain overactive ACTH production and secretion. Until recently, little was known about the genetic defects underlying most of the cases of CD, and the discovery of somatic gain-of-function USP8 mutations as the most common genetic abnormality in corticotropinomas has represented a breakthrough in the field. Nevertheless, germline causes of CD remain greatly unknown. The vast majority of the patients present sporadically, but CD is part of a growing number of syndromes of isolated pituitary adenoma or multiple endocrine and non-endocrine neoplasia. Although rare, familial forms of CD should be overrepresented among young-onset cases, therefore, pediatric patients represent an excellent opportunity for gene discovery. This talk will review the most recent findings in genetic causes of CD, placed in the context of a large cohort of more than 200 pediatric patients studied at a single center during the last 20 years. The frequency of multiple genetic causes of CD in such setting will be presented, while exploring currently ongoing research projects and discussing new avenues for further investigation. Understanding the genetic defects driving corticotroph tumorigenesis should lead to unraveling novel therapeutic targets. This will hopefully be translated into more efficient strategies for the medical treatment of patients with CD.