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

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Germline MAX variants have been associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors, and other neoplasms.
• This study investigates two families with germline MAX variants presenting with PPGL and diverse other tumors.

Observation:

• Family A exhibited multiple individuals with PPGL, including metastatic disease, and children with neuroendocrine tumors (ganglioneuroma, neuroblastoma).
• One family member had acromegaly, and another presented with pituitary enlargement and elevated IGF-1 post-PPGL resection.
• Family B's proband had metastatic PPGL, a prolactin-producing pituitary tumor, parathyroid adenomas, chondrosarcoma, and pulmonary adenocarcinomas.

Findings:

• A loss-of-function germline MAX variant (p.Ala67Asp) was identified in Family A, with loss of heterozygosity in tumors and absent MAX staining.
• A truncating germline MAX variant (p.Glu8*) was identified in Family B.
• In vitro studies confirmed the p.Ala67Asp variant as loss of function.

Implications:

• Germline MAX mutations are associated with a spectrum of tumors including PPGL, ganglioneuromas, neuroblastomas, pituitary tumors, parathyroid adenomas, chondrosarcoma, and lung adenocarcinoma.
• These findings suggest MAX is a novel multiple endocrine neoplasia (MEN) gene.
• This expands the understanding of genetic predispositions to endocrine and nonendocrine tumors.