A 35-year-old man presents with episodic hypertension, diaphoresis, headache, and palpitations. 24-hour urinary metanephrines and normetanephrines are markedly elevated. CT abdomen shows a 4 cm right adrenal mass. He has a family history of renal cell carcinoma and cerebellar hemangioblastoma. Which syndromic cause is most likely, and which molecular pathway is constitutively activated in these tumors?

• A MEN 2A (RET proto-oncogene mutation); the RET-RAS-ERK pathway is activated; bilateral pheochromocytomas are common
• B NF1 (neurofibromatosis type 1, neurofibromin loss of function); NF1 is a RAS-GAP, and its loss causes constitutive RAS-MAPK activation; associated with peripheral neurofibromas and Lisch nodules
• C Von Hippel-Lindau syndrome (VHL tumor suppressor loss); loss of pVHL prevents ubiquitin-mediated proteasomal degradation of HIF-1α/HIF-2α, causing constitutive activation of hypoxia-inducible gene programs (VEGF, GLUT1, EPO) even under normoxia; pheochromocytoma in VHL is associated with bilateral/multifocal tumors and concurrent renal clear cell carcinoma and hemangioblastomas ✓
• D SDH subunit mutations (SDHA/B/C/D); SDH loss causes accumulation of succinate, an oncometabolite that inhibits alpha-KG-dependent dioxygenases, causing global hypermethylation and HIF activation; associated with paraganglioma-pheochromocytoma syndrome

Explanation

The clinical triad of pheochromocytoma + renal cell carcinoma + cerebellar hemangioblastoma is pathognomonic of Von Hippel-Lindau (VHL) syndrome. VHL gene (3p25) encodes the pVHL protein that serves as the recognition subunit of an E3 ubiquitin ligase complex targeting HIF-1α/HIF-2α for proteasomal degradation under normoxia. Loss of pVHL leads to constitutive HIF stabilization and activation of hypoxia-response elements, upregulating VEGF (angiogenesis), GLUT1 (aerobic glycolysis), EPO (erythrocytosis), and PDGF. VHL pheochromocytomas are non-secreting or normetanephrine-dominant, often bilateral, and associated with hypervascular histology reflecting VEGF overexpression.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.