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 non-endocrine tumors. Objective To report two families with germline MAX variants, pheochromocytomas (PC) and multiple other tumors. Design Clinical, genetic, immunohistochemical, and functional studies. Setting University Hospitals in Australia Participants Two families with germline MAX variants. Interventions Usual clinical care. Main Outcome measures 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 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. Conclusions 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.

Familial Acromegaly and Bilateral Asynchronous Pheochromocytomas in a Female Patient With a MAX Mutation: A Case Report

“…One further case was described by Kobza et al in 2018 (8). In 2020, Seabrook et al described two families with MAX mutations which were remarkable not only for the presence of PA and PCC/PGL (metastatic in some cases), but also for the presence of many other tumors (paravertebral ganglioneuroma, abdominal neuroblastoma, multiple parathyroid adenomas, chondrosarcoma, multifocal pulmonary adenocarcinomas), suggesting MAX as a novel multiple endocrine neoplasia gene (9).…”

“…The clinical features of patients with a combination of PA and PCC due to mutations in the MAX gene described in the literature (5)(6)(7)(8)(9) are summarized in Table 1. As can be seen from the table, the disease can occur in both men and women, and it presents with both macro-or microPA.…”

“…In one family, there was a patient with acromegaly, but it was not clear whether it was due to a PA or a growth hormone-releasing hormone-secreting PGL and another patient with pituitary enlargement with intermittently mildly elevated serum IGF-1 and normal GH suppression and no clinical features of acromegaly. In the other family, there was a patient with a microprolactinoma (not requiring dopamine agonist therapy) (9).…”

“…A wide range of other tumors has been described in patients with MAX mutations: breast cancer, renal oncocytoma, squamous cell carcinoma of the tongue, renal carcinoma (5), ganglioneuroblastoma, ganglioneuroma, chondrosarcoma, lung adenocarcinoma, parathyroid adenomas (9,13). In patients with a combination of PA and PCC and MAX mutations (Table 1), a follicular variant of papillary thyroid cancer was described in case 2 (7), and in the son of case 1 (7) with the same confirmed mutation-deletion of exon 3-a neuroendocrine tumor of the pancreas was detected in the absence of other manifestations (14), as well as a rib chondrosarcoma and multiple parathyroid tumors in a case described by Seabrook et al (9); thus it can be assumed that for MAX mutation carriers, life-long surveillance in order to detect early various tumors may be necessary.…”

“…In 2011, it was shown that Myc-associated factor X (MAX) gene mutations predispose to the development of hereditary PCC/PGL (4). Since 2012, several cases of co-occurrence of PA and PCC/PGL due to MAX mutations have been reported (5)(6)(7)(8)(9).…”