Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

Abstract

CONTEXT:

Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors.

OBJECTIVE:

To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors.

METHODS:

Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants.

RESULTS:

Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (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, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified.

CONCLUSION:

Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

• Authors: Amanda J Seabrook, Jessica E Harris, Sofia B Velosa, Edward Kim, Aideen M McInerney-Leo, Trisha Dwight, Jason I Hockings, Nicholas G Hockings, Judy Kirk, Paul J Leo, Amanda J Love, Catherine Luxford, Mhairi Marshall, Ozgur Mete, David J Pennisi, Matthew A Brown, Anthony J Gill, Gregory I Hockings, Roderick J Clifton-Bligh, Emma L Duncan
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 106 Issue 4 Pg. 1163-1182 (03 25 2021) ISSN: 1945-7197 [Electronic] United States
• PMID: 33367756 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• MAX protein, human

Topics

• Adolescent
• Adrenal Gland Neoplasms (diagnosis, genetics)
• Adult
• Aged
• Australia
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics)
• Child, Preschool
• Family
• Female
• Germ-Line Mutation
• Humans
• Infant
• Male
• Middle Aged
• Multiple Endocrine Neoplasia (classification, diagnosis, genetics)
• Neoplasms, Multiple Primary (diagnosis, genetics)
• Neuroendocrine Tumors (diagnosis, genetics)
• Pedigree
• Pheochromocytoma (diagnosis, genetics)
• Young Adult