Genotype and clinical phenotype characteristics of MAX germline mutation-associated pheochromocytoma/paraganglioma syndrome

Front Endocrinol (Lausanne). 2024 Aug 30:15:1442691. doi: 10.3389/fendo.2024.1442691. eCollection 2024.

Abstract

Objective: The aim of this study was to investigate the genotypic and clinical phenotypic characteristics of MAX germline mutation-associated pheochromocytoma (PCC) and paraganglioma (PGL).

Methods: We retrospectively analyzed the family investigation data and clinical genetic characteristics of six individuals from three independent families with PCC carrying MAX 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 MAX germline mutations reported previously.

Results: There were 109 patients in 87 families with all five exons and 53 types of MAX germline mutations. p.R33* (c.97C>T; 21.1%), p.R75* (c.223C>T; 13.8%), and p.A67D (c.200C>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, MAX-p.Q82Tfs*89 and p.E158A mutations are reported for the first time in this study.

Conclusion: MAX 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 MAX germline mutations. The risk of bilateral and metastatic PCCs should also be considered.

Keywords: MAX gene; genealogy; multiple endocrine neoplasia; paraganglioma; pheochromocytoma.

MeSH terms

  • Adolescent
  • Adrenal Gland Neoplasms* / genetics
  • Adrenal Gland Neoplasms* / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genotype*
  • Germ-Line Mutation*
  • Humans
  • Male
  • Middle Aged
  • Paraganglioma* / genetics
  • Paraganglioma* / pathology
  • Pedigree
  • Phenotype*
  • Pheochromocytoma* / genetics
  • Pheochromocytoma* / pathology
  • Retrospective Studies
  • Young Adult

Substances

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

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. National Natural Science Foundation of China (81472861), the Key Project of Zhejiang Province Science and Technology Plan (2014C03048-1), and Hangzhou Municipal Commission of Health and Family Planning Science and Technology Program (B20210355), Medical and Health Science and Technology Project of Zhejiang Province (2023KY1343, 2024KY1830); Taizhou Social Development Science and Technology Planning Project (23ywb56, 23ywb156).