Genetic Causes of Pheochromocytoma
Approximately 30% of pheochromocytomas and paragangliomas (PPGLs) are caused by germline mutations and should be considered hereditary, with several specific genes implicated in their development. 1
Major Hereditary Syndromes Associated with Pheochromocytoma
Classical Syndromes
- Multiple Endocrine Neoplasia Type 2 (MEN2): Caused by mutations in the RET proto-oncogene, accounting for 5-30% of hereditary pheochromocytomas with 50% penetrance 1
- Von Hippel-Lindau (VHL) syndrome: Caused by mutations in the VHL gene, representing approximately 13% of hereditary cases with 10-30% penetrance 1
- Neurofibromatosis Type 1 (NF1): Caused by mutations in the NF1 gene, accounting for about 3% of hereditary cases with 1-6% penetrance 1
Succinate Dehydrogenase (SDHx)-Related Syndromes
- PGL1: Caused by mutations in SDHD gene (11q23.1), representing 7-10% of hereditary cases with 86% penetrance when paternally inherited (subject to maternal imprinting) 1
- PGL2: Caused by mutations in SDHAF2 gene (11q12.2), accounting for approximately 1% of cases with 100% penetrance when paternally inherited 1
- PGL3: Caused by mutations in SDHC gene (1q23.3), representing about 2% of hereditary cases 1
- PGL4: Caused by mutations in SDHB gene (1p36.13), accounting for 8-10% of hereditary cases with 30% penetrance and highest risk of malignancy 1
- PGL5: Caused by mutations in SDHA gene (5p15.33), representing approximately 1% of hereditary cases 1
Recently Discovered Susceptibility Genes
- TMEM127: Located on chromosome 2q11.2, accounting for 1-2% of hereditary cases with 32% penetrance 1
- MAX: Located on chromosome 14q23.3, representing about 1% of hereditary cases 1
- FH: Associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), accounting for <1% of cases 1
- MEN1: Associated with Multiple Endocrine Neoplasia Type 1, representing <1% of cases 1
Rare Genetic Causes
- BAP1: Associated with tumor predisposition syndrome 1
- EGLN1/PHD2: Associated with familial erythrocytosis type 3 1
- EGLN2/PHD1: Rare cause with limited reported cases 1
- EPAS1/HIF2A: Associated with familial erythrocytosis type 4 1
- KIF1B: Rare cause with limited reported cases 1
- KMT2D: Rare cause with limited reported cases 1
- MDH2: Rare cause with limited reported cases 1
Inheritance Patterns
- Most hereditary PPGLs show autosomal dominant inheritance, often with reduced penetrance 1
- Important exception: SDHD and SDHAF2 mutations exhibit maternal imprinting with silencing of the maternal allele, meaning only mutations inherited from the father will cause disease 1
Clinical Implications of Genetic Status
- SDHB mutation carriers have the highest risk of malignancy and metastatic disease, significantly affecting survival rates 1
- The 5-year survival rate with metastasized PPGL is only 50-60%, highlighting the importance of early identification 1
- Patients with hereditary syndromes often develop tumors at younger ages and are more likely to have bilateral, multifocal, or extra-adrenal disease 2
Recommendations for Genetic Testing
- The American College of Medical Genetics recommends genetic testing consideration for any individual with a personal history of or a first-degree relative with a paraganglioma or pheochromocytoma 1
- Testing is particularly important for patients with:
Clinical Pitfalls and Caveats
- Failure to identify a hereditary syndrome can lead to missed opportunities for early detection of other syndrome-associated tumors 2
- The frequency of germline mutations in apparently sporadic cases is higher than previously thought, approaching 20% 3
- Genetic testing algorithms should prioritize testing based on clinical presentation, tumor location, and biochemical profile 4
- Maternal imprinting in SDHD and SDHAF2 means that family history may appear negative if the mutation was inherited from the mother 1