Germline mutations in young-onset sporadic pituitary macroadenomas: a multigene panel analysis

Objective Mutations in several genes have been associated with familial forms of pituitary adenomas. Sporadic pituitary adenomas (i.e. with no family history or coexistent endocrine tumours) are also occasionally found to result from germline mutations in these genes, especially in young patients with larger tumours. The aim of this study was to determine the frequency of germline mutations in patients with young-onset sporadic pituitary macroadenomas. Methods A cohort of 225 Portuguese patients with sporadic pituitary macroadenomas diagnosed before the age of 40 years was studied by whole exome sequencing (WES) followed by the analysis of a virtual panel of 29 genes that have been associated with predisposition to pituitary adenomas. Results Pathogenic and likely pathogenic variants were identified in 16 (7.1%) of patients. The affected genes were AIP (n=4), PMS2 (n=4), MEN1 (n=2), VHL (n=2), CDH23 (n=1), MSH2 (n=1), SDHB (n=1), and TP53 (n=1). In patients diagnosed under the ages of 30 and 18 years, the frequency of mutations increased to 9.0% and 12.0%, respectively. Conclusion This is so far the largest multigene analysis of patients with young-onset sporadic pituitary macroadenomas. We confirmed the AIP as the most frequently involved gene, but also uncovered rarer genetic causes of pituitary adenomas, including the first independent confirmation of a role of the CDH23 gene. The results may contribute to a better understanding of the genetic landscape of these tumours and help to decide which genes to include in the genetic screening of patients with young-onset pituitary macroadenomas.