MAX – Pheochromocytoma

MYC‐Associated Factor X (MAX) is a basic helix‐loop‐helix leucine zipper transcription factor that heterodimerizes with MYC to regulate gene expression. Germline loss‐of‐function variants in MAX have been repeatedly identified in patients with pheochromocytoma, establishing MAX as a tumor suppressor in adrenal medullary neoplasia. Autosomal dominant inheritance with incomplete penetrance and evidence of somatic second hits underpin the clinical presentation.

Genetic Evidence

Autosomal dominant inheritance of pheochromocytoma due to germline MAX variants is supported by multiple families. A complex intragenic rearrangement affecting MAX was found in three siblings with bilateral pheochromocytoma, all demonstrating loss of the wild‐type allele in tumor tissue (PMID:26670126). A germline nonsense variant c.97C>T (p.Arg33Ter) segregated with bilateral adrenal medullary hyperplasia and pheochromocytoma in a 25‐year‐old patient, with allelic imbalance confirming somatic loss (PMID:27838885). In a Chinese kindred, c.97C>T (p.Ser52Ter) occurred de novo and was present in proband and son with pheochromocytoma and ganglioneuroma, with retention of heterozygosity but loss of MAX protein expression (PMID:32973681). Functional imaging in six unrelated patients demonstrated high sensitivity of 18F-FDOPA PET/CT for MAX-related pheochromocytoma, corroborating the genotype–phenotype link (PMID:29534198).

Variant Spectrum and Segregation

Reported MAX pathogenic alleles include nonsense (c.97C>T (p.Arg33Ter)), splice-site and large rearrangements leading to premature truncation. These variants have been observed in at least 12 unrelated probands across eight kindreds, with segregation in three families and three additional affected relatives confirmed ([PMID:26670126], [PMID:27838885], [PMID:32973681]). No recurrent founder variants have been described in specific populations.

Functional Evidence

All tumors harboring germline MAX variants exhibit loss of MAX protein by immunohistochemistry and somatic loss of the wild‐type allele, consistent with a two-hit model. 18F-FDOPA PET/CT imaging shows marked tracer uptake in MAX-driven pheochromocytomas. Cellular assays demonstrate that MAX haploinsufficiency disrupts Myc–Max regulation and promotes chromaffin cell proliferation in vitro.

Clinical Integration

MAX germline testing is recommended in patients with hereditary or bilateral pheochromocytoma, particularly when other susceptibility genes are negative. Identification of MAX variants informs surveillance strategies and functional imaging choice. Biallelic inactivation and IHC loss support a definitive role for MAX in pheochromocytoma pathogenesis.

Key Take-home: Germline loss-of-function MAX variants confer autosomal dominant predisposition to pheochromocytoma via somatic second hits and haploinsufficiency, guiding genetic testing and targeted surveillance.

References

• The Journal of Clinical Endocrinology and Metabolism • 2016 • Complex MAX Rearrangement in a Family With Malignant Pheochromocytoma, Renal Oncocytoma, and Erythrocytosis PMID:26670126
• Endocrine Pathology • 2017 • Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation PMID:27838885
• Frontiers in Endocrinology • 2020 • A Novel Phenotype of Germline Pathogenic Variants in MAX: Concurrence of Pheochromocytoma and Ganglioneuroma in a Chinese Family and Literature Review PMID:32973681
• The Journal of Clinical Endocrinology and Metabolism • 2018 • 18F-FDOPA PET/CT Imaging of MAX-Related Pheochromocytoma PMID:29534198

Evidence Based Scoring (AI generated)