Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?
Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and non-endocrine tumors.To report two families with germline MAX variants, pheochromocytomas (PC) and multiple other tumors.Clinical, genetic, immunohistochemical, and functional studies.University Hospitals in Australia.Two families with germline MAX variants.Usual clinical care.Phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants.Family A has multiple individuals with PC (including bilateral and metastatic disease) and two children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive GHRH staining. Another individual with previously resected PCs has pituitary enlargement and elevated IGF-1. A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss-of-heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss-of-function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multi-gland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified.Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as non-endocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.