Germline genetic variants in young-onset sporadic pituitary macroadenomas: A multigene panel analysis

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. 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. Pathogenic and likely pathogenic variants were identified in 16 (7.1 %) of patients. The affected genes were <i>AIP</i> (n = 4), <i>PMS2</i> (n = 4), <i>MEN1</i> (n = 2), <i>VHL</i> (n = 2), <i>CDH23</i> (n = 1), <i>MSH2</i> (n = 1), <i>SDHB</i> (n = 1), and <i>TP53</i> (n = 1). In patients diagnosed under the ages of 30 and 18 years, the frequency of pathogenic and likely pathogenic variants increased to 9.0 % and 12.0 %, respectively. This is so far the largest multigene analysis of patients with young-onset sporadic pituitary macroadenomas. We confirmed the <i>AIP</i> as the most frequently involved gene, but also uncovered rarer genetic causes of pituitary adenomas. 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.