VHL disease

**Genetics/Pathophysiology** - Autosomal dominant; VHL tumor suppressor gene on chromosome 3p (3p25-26). Follows Knudson two-hit hypothesis: inherited germline mutation in one allele plus somatic loss of the second allele. - Normal pVHL is part of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor 1-alpha (HIF-1α) for proteasomal degradation when oxygen is present. - Loss of pVHL function causes constitutive HIF-1α stabilization (a "pseudo-hypoxic" state). This increases transcription of VEGF, PDGF, EPO, and TGF-α, which drives angiogenesis, tumor growth, and erythrocytosis. - Sporadic clear cell RCC also frequently has somatic VHL (3p) inactivation.

**Clinical features** - Hemangioblastomas: retina (retinal angiomas, often the earliest manifestation), cerebellum (headache, ataxia, obstructive hydrocephalus), brainstem, and spinal cord. - Clear cell renal cell carcinoma: often bilateral and multifocal, and the leading cause of death. Also renal cysts. - Pheochromocytoma: episodic hypertension, headache, palpitations, and diaphoresis. Can be bilateral. - Pancreatic cysts and pancreatic neuroendocrine tumors. - Endolymphatic sac tumors, which cause hearing loss, tinnitus, and vertigo. - Epididymal cystadenomas in men and broad ligament cystadenomas in women. - Secondary polycythemia can occur from EPO production by cerebellar hemangioblastomas or renal tumors.

**Subtypes** - Type 1: low pheochromocytoma risk (hemangioblastoma and RCC are present). - Type 2: high pheochromocytoma risk. 2A has a low RCC risk, 2B has a high RCC risk, and 2C has isolated pheochromocytoma only.

**Diagnosis/Management** - Diagnosis is by genetic testing (VHL germline mutation) and by clinical criteria. Screen first-degree relatives. - Surveillance starts in childhood: annual ophthalmologic exam, plasma or urine metanephrines, MRI of brain and spine, and abdominal MRI/CT for renal and pancreatic lesions. - Treatment is surgical resection (nephron-sparing surgery for RCC, resection of hemangioblastomas, adrenalectomy for pheochromocytoma). Laser or cryotherapy is used for retinal lesions. - Belzutifan, an oral HIF-2α inhibitor, is approved for VHL-associated RCC, CNS hemangioblastomas, and pancreatic NETs. Common adverse effects are anemia and hypoxia. It is teratogenic. - For pheochromocytoma, give an alpha-blocker (phenoxybenzamine) before a beta-blocker.

**High-yield associations** - Chromosome 3 → VHL, and also RCC. - Distinguish from other phakomatoses (neurocutaneous disorders): tuberous sclerosis (angiomyolipomas, TSC1/2), NF1/NF2, and Sturge-Weber (sporadic, GNAQ). - Cerebellar hemangioblastoma + retinal angioma + RCC = VHL until proven otherwise.