Loss of heterozygosity and absence of MAX immunostaining in a prolactinoma associated with multiple endocrine neoplasia type 5 (MEN5)

Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome caused by germline pathogenic variants involving the MYC Associated Factor X (MAX) gene. Affected individuals typically have pheochromocytomas, often bilateral, at a relatively early age. In MAX pheochromocytoma cohorts, pituitary adenomas are rarely reported. The role of MAX as a tumor suppressor gene in the pituitary gland has not been directly proven to date.The propositus came from a pheochromocytoma kindred with a germline pathogenic MAX variant c.97C > T (p.R33*). In his late 30’s he developed asynchronous bilateral pheochromocytomas and underwent bilateral adrenalectomy. At age 46, he developed hyperprolactinemia (45.1 µg/L; 3x ULN) and increased IGF-1 (460 ng/mL; 1.9x ULN). Total testosterone was low (1.5 ng/mL) as was LH (1.2 IU/L). Pituitary MRI showed a microadenoma (6 mm), which was resected and his prolactin, IGF1, and testosterone levels normalized. A pituitary adenoma was confirmed on pathology, which showed positivity for prolactin only and a Ki67 of 2%. MAX staining was lost in the pituitary adenoma cells. Tumoral DNA analysis (120X read depth) showed that at the MAX locus the pathogenic variant c.97C > T constituted > 90% of the reads indicating that tumoral loss of heterozygosity (LOH) was present.Loss of MAX staining and the identification of tumor LOH at the MAX locus confirms pituitary adenomas as a component tumor in the emerging MEN5 syndrome due to germline pathogenic MAX variants.