Expanding the phenotype of multiple endocrine neoplasia type 5 (MEN5): Pituitary gigantism, myelolipoma and familial pheochromocytoma due to a germline pathogenic MAX variant

Purpose: Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome of endocrine and nonendocrine
tumors caused by germline pathogenic variants or genomic rearrangements of the MAX gene.
Although MAX variants are predominantly associated with pheochromocytoma-paraganglioma (PPGL)
risk, there are a growing number of associated tumors in other organs, including pituitary adenomas. We
characterized the clinical presentation of various tumors in an extensive new kindred with a novel germline
pathogenic variant of MAX.
Methods: Clinical, genetic, pathological, radiological and hormonal investigations to identify and
characterize disease status related to germline MAX gene sequence status.
Results: We identified a novel germline pathological variant in exon 4 of the MAX gene, c.228delG, which
was predicted to lead to a truncated protein (p.Asn78Thrfs*92). The propositus had developed pituitary
gigantism due to a mixed growth hormone-prolactin secreting pituitary macroadenoma, which was
controlled after two surgeries, medical therapy and radiotherapy. He subsequently developed bilateral and
recurrent pheochromocytomas and following his death an extra-adrenal myelolipoma was identified that
was negative for MAX immunohistochemistry. An extensive history of pheochromocytomas or
uncontrolled hypertension was present in the kindred and multiple affected and unaffected carriers of the
c.228delG MAX pathogenic variant were characterized.
Conclusion: We report the first case of pituitary gigantism in association with a pathogenic variant in the
MAX gene, and characterize myeloplipoma as a new disease-association in MEN5. Increased awareness of
MEN5 as a clinical entity and comprehensive screening of MAX pathogenic variant carriers can help to
identify rare disease associations beyond PPGL.