Abstract
OBJECTIVE: We aimed to summarize the tumor spectrum and clinical features of multiple endocrine neoplasia type 5 (MEN5) caused by heterozygous inactivating germline MYC-associated factor X (MAX) mutations. METHODS: Articles were retrieved from PubMed and EMBASE from inception to June 2025 using search terms related to "MAX gene" and "MEN5". Additional cases were identified from a targeted Google Scholar search and supporting references of MAX variants reported in the ClinVar database. Eligible articles included those reporting patient-level data on individuals with germline MAX mutations. Data from all reported patients were extracted to generate a dataset containing phenotype information for descriptive analysis. RESULTS: Of 621 records screened, 45 studies comprising 127 patients with germline MAX mutations met the eligibility criteria. The median age at first tumor diagnosis was 29 years (23.0 - 39.0) and 37.0% were women. The most frequent tumors were pheochromocytoma (PCC, N = 112), pituitary adenoma (N = 11), and paraganglioma (N = 10), with median ages at diagnosis of 31.0, 33.0, and 43.0 years, respectively. Evidence implicating MAX loss in tumorigenesis included paraganglioma, pituitary adenoma, ganglioneuroma, neuroblastoma, pancreatic neuroendocrine tumor, renal oncocytoma, myelolipoma, and liver sarcoma. The causal association between primary hyperparathyroidism and MAX loss remains uncertain. Among PCCs, 38.3% were unilateral, 27.6% were metastatic, and most were norepinephrine-secreting. CONCLUSION: Our systematic review characterized the tumor spectrum and clinical features of MEN5. While these findings outline the emerging clinical phenotype, further studies are needed to define the epidemiology, penetrance and genotype-phenotype associations of this newly recognized entity.