The germline landscape of pituitary adenomas: established and emerging predisposition genes

Pituitary adenomas are increasingly recognized to have a germline genetic component in a subset of patients, particularly those with young-onset disease, familial clustering or syndromic features. The spectrum of germline variants implicated in pituitary tumorigenesis has broadened considerably, with evidence of both established predisposition genes and a growing number of emerging candidate genes. Established germline predisposition genes-namely, MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHx, and MAX-remain central to our understanding of familial pituitary adenoma predisposition and have defined roles in specific clinical contexts which influence adenoma phenotype, age at presentation, surveillance strategies, and family screening. Beyond this, a set of less prevalent variants in other genes-for example, CABLES1, CDH23, PAM, CHEK2, and the mismatch repair genes-are emerging as potential contributors, although the pathogenicity and clinical relevance of these genes remain to be fully established. Identifying causative germline variants in people with pituitary adenomas offers the opportunity of personalized care via gene-specific surveillance strategies, prognostication, cascade testing, and reproductive planning to the potential benefit of the individual as well as their families. In this review, we provide a clinically orientated overview of the established and emerging genes implicated in the germline predisposition to pituitary adenomas. We also present a contemporary clinical approach to germline genetic testing in patients with pituitary adenomas.