AUTHOR=Lian Bijun , Lu Jun , Fang Xudong , Zhang Yiming , Wang Wei , He Yi , Yu Hongyuan , Li Feiping , Wang Junwei , Chen Weiying , Qi Xiaoping 

TITLE=Genotype and clinical phenotype characteristics of MAX germline mutation–associated pheochromocytoma/paraganglioma syndrome

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1442691

DOI=10.3389/fendo.2024.1442691

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p>The aim of this study was to investigate the genotypic and clinical phenotypic characteristics of <italic>MAX</italic> germline mutation–associated pheochromocytoma (PCC) and paraganglioma (PGL).</p></sec><sec><title>Methods</title><p>We retrospectively analyzed the family investigation data and clinical genetic characteristics of six individuals from three independent families with PCC carrying <italic>MAX</italic> germline mutations from December 2005 to March 2024. A literature review was then conducted of the six carriers and another 103 carriers from the other 84 families with <italic>MAX</italic> germline mutations reported previously.</p></sec><sec><title>Results</title><p>There were 109 patients in 87 families with all five exons and 53 types of <italic>MAX</italic> germline mutations. p.R33* (c.97C&gt;T; 21.1%), p.R75* (c.223C&gt;T; 13.8%), and p.A67D (c.200C&gt;A; 7.3%), which accounted for 42.2% of mutations detected, were the most common mutations. Moreover, 101 (92.7%) patients developed PCCs, including 59 bilateral PCCs and 42 unilateral PCCs, and 19 (18.8%) patients showed metastasis. The mean age at diagnosis was 32.8 ± 12.6 (13-80) years. The male-to-female ratio was 1.3:1. In 11 (10.9%) patients, the PCC was accompanied by chest or abdominal PGL, and one other patient had sole head and neck PGL. Nine (8.3%) patients also had functional pituitary adenomas, 11 (10.9%) developed other neuroendocrine tumors (NETs), and 7 (6.4%) presented with concomitant non-NET. Meanwhile, <italic>MAX</italic>-p.Q82Tfs*89 and p.E158A mutations are reported for the first time in this study.</p></sec><sec><title>Conclusion</title><p><italic>MAX</italic> germline mutations may cause new types of multiple endocrine neoplasia. A comprehensive baseline assessment of neural crest cell–derived diseases is recommended for all individuals with <italic>MAX</italic> germline mutations. The risk of bilateral and metastatic PCCs should also be considered.</p></sec>