Table 1.
| Gene | Gene type | Most common PPGL location | Biochemical phenotype | Related syndromes and other manifestations | Malignancy risk |
|---|---|---|---|---|---|
| Cluster 1 (pseudohypoxic signaling) | |||||
| SDHA | Germline | sPGL, HNPGL, PCC (very low penetrance) | NE; NE+DA; NS | PGL6 RCC; GIST; pituitary adenoma |
0-14% |
| SDHB | Germline | sPGL, HNPGL (intermediate penetrance) PCC (low penetrance) |
NE; NE+DA; NS | PGL4 RCC; GIST; pituitary adenoma; pulmonary condroma |
34-70% |
| SDHC | Germline | HNPGL, sPGL (intermediate penetrance) PCC (low penetrance) |
NS; NE +DA | PGL3 RCC; GIST; pituitary adenoma |
0-28% |
| SDHD | Germline | Multifocal HNPGL (high penetrance) sPGL (low penetrance) PCC (low penetrance |
NE; NE +DA; NS | PGL1 RCC; GIST; pituitary adenoma; pulmonary condroma |
<5% |
| SDHAF2 | Germline | Multifocal HNPGL (high penetrance) | NS | PGL2 | / |
| FH | Germline | PCC + sPGL | NE | Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) | / |
| MDH2 | Germline | sPGL | NE | Early-Onset Severe Encephalopathy (homozygous germline mutations) | / |
| VHL | Germline/somatic | PCC (high penetrance) usually bilateral (50%) sPGL (low penetrance) also multifocal HNPGL (very low penetrance) |
NE | VHL 2A: retinal and CNS hemangioblastomas, endolymphatic sac tumors, epididymal cystadenomas 2B: renal and pancreatic cell cysts and carcinomas, retinal and CNS hemangioblastomas, endolymphatic sac tumors, epididymal cystadenomas |
< 10% |
| EPAS-1 (HIF2A) | Postzygotic/somatic | Multifocal sPGL (high penetrance) PCC (high penetrance) |
NE | Pacak–Zhuang syndrome; Somatostatinoma; polycythemia; ocular lesions | 29% |
| IRP1 | Somatic | / | NE | / | / |
| DLST | Germline | sPGL (multiple) | NE | / | / |
| SLC25A11 | Germline | / | NE | / | Increased risk of metastatic disease |
| SUCLG2 | Germline | / | NE | / | / |
| Cluster 2 (kinase signaling) | |||||
| RET | Germline/somatic | PCC (high penetrance) usually bilateral (50-80%) sPGL (very low penentrance) HNPGL (very low penetrance) |
E | MEN2 2A: medullary thyroid carcinoma, hyperparatiroidism, cutaneous lichen amyloidosis 2B: medullary thyroid carcinoma, multiple mucocutaneous neuromas, marafanoid habitus, intestinal ganglioneuromas |
< 5% |
| NF1 | Germline/somatic | PCC (low penetrance) sPGL, HNPGL (very low penetrance) |
E and NE | Von Recklinghausen’s disease Café-au-lait spots, neurofibromas, Lisch nodules, Optic pathway/CNS gliomas, GIST |
< 10% |
| TMEM127 | Germline | PCC (intermediate penetrance) bilateral (33-39%) sPGL (low penetrance) HNPGL (very low penetrance) |
E | PGL5 RCC |
<5% |
| MAX | Germline/somatic | PCC (common bilateral) sPGL (very low penetrance) |
E and NE | PGL7 renal oncocytoma; pituitary adenoma |
7-25% |
| HRAS | Somatic | PCC PGL |
/ | / | / |
| MET | Germline/somatic | / | / | / | / |
| MERTK | Germline | / | / | / | / |
| DNMT3A | Germline | Multifocal HNPGL | / | / | / |
| Cluster 3 (Wnt signaling) | |||||
| CSDE1 | Somatic | PCC | E | / | Increased risk of recurrent and metastatic disease |
| UBTF-MAML3 | Fusion | PCC | E | / | Increased risk of recurrent and metastatic disease |
PPGL, pheochromocytoma-paraganglioma; SDHA, succinate dehydrogenase complex flavoprotein subunit A; sPGL, sympathetic paraganglioma; HNPGL, head and neck paraganglioma; PCC, pheochromocytoma; NE, norepinephrine; DA, dopamine; NS, non-secreting; RCC, renal cell carcinoma; GIST, gastrointestinal tumor; SDHB, succinate dehydrogenase complex flavoprotein subunit B; SDHC, succinate dehydrogenase complex flavoprotein subunit C; SDHD, succinate dehydrogenase complex flavoprotein subunit D; SDHAF2, Succinate dehydrogenase complex assembly factor 2; FH, fumarate hydratase; MDH2, malate dehydrogenase 2; VHL, von Hippel-Lindau; EPAS-1, Endothelial PAS domain protein 1; HIF2A, hypoxia-inducible factor 2 alpha; IRP1, Iron Regulator Protein 1; DLST, Dihydrolipoamide S-Succinyltransferase; SLC25A11, Solute Carrier Family 25 Member 11; SUCLG2, Succinyl Co-A Ligase G2; RET, rearranged during transfection; E, epinephrine; MEN2, multiple endocrine neoplasia type 2; NF1, neurofibromatosis type 1; CNS, central nervous system; TMEM127, transmembrane protein 127; MAX, Myelocytomatosis-associated factor X; HRAS, Harvey rat sarcoma viral gene homologue; MET, Mesenchymal to Epithelial Transition; MERTK, Tyrosine Kinase Protooncogene; DNMT3A, DNA methyltransferase 3 alpha; CSDE1, Cold shock domain containing E1; UBTF-MAML3, Upstream Binding Transcription Factor Mastermind-like Transcriptional Coactivator 3.