What are the associated manifestations of Von Hippel-Lindau (VHL) disease?

Von Hippel-Lindau Disease Associated Manifestations

Von Hippel-Lindau (VHL) disease is characterized by multiple benign and malignant tumors affecting various organ systems, including central nervous system and retinal hemangioblastomas, clear cell renal cell carcinoma, pheochromocytoma, pancreatic neuroendocrine tumors, endolymphatic sac tumors, and epididymal and broad ligament cystadenomas, as well as visceral cysts in the kidneys and pancreas. 1

Central Nervous System Manifestations

• CNS hemangioblastomas (60-80% of patients)

  • Cerebellar (44-72%)
  • Brainstem (10-25%)
  • Spinal (13-50%)
  • Youngest reported age: 8-9 years; mean age of diagnosis: 30-33 years 1
  • Can cause significant morbidity due to mass effect and potential hemorrhage 1

• Retinal angiomas/hemangioblastomas (25-60% of patients)

  • Can occur from birth; mean age of diagnosis: 25 years 1
  • Can lead to vision loss due to exudation, fibrosis, hemorrhage, or retinal detachment 1
  • Appear as red/grayish pinpoint lesions (<500 μm) that can progress to larger tumors with dilated feeding arterioles and draining venules 1

• Endolymphatic sac tumors (ELST)

  • Can cause hearing loss, tinnitus, and vertigo 1, 2

Renal Manifestations

• Clear cell renal cell carcinoma (RCC)
  • Major cause of mortality in VHL patients 1
  • Multiple and bilateral renal cysts are common 1
  • Requires monitoring and intervention when tumors reach 3 cm 2

Adrenal/Endocrine Manifestations

• Pheochromocytomas
  • Can cause hypertension, headaches, palpitations, and sweating 1, 3
  • May be bilateral and can occur in children 1

Pancreatic Manifestations

• Pancreatic neuroendocrine tumors (pNET)

  • Can be functional or non-functional 1
  • May cause hypoglycemia and other hormonal symptoms 3

• Pancreatic cysts

  • Common finding, often multiple 1

Reproductive System Manifestations

• Epididymal cystadenomas (in males) 1
• Broad ligament cystadenomas (in females) 1

Clinical Classification

VHL disease is clinically subdivided based on tumor spectrum:

• Type I: Low risk for pheochromocytoma
• Type II: High risk for pheochromocytoma
  • Type IIA: Low risk for RCC
  • Type IIB: High risk for RCC
  • Type IIC: Predominantly pheochromocytoma 1

Diagnostic Criteria

A clinical diagnosis of VHL can be established in:

1. An individual with family history of VHL and presence of a CNS/retinal hemangioblastoma, pheochromocytoma, or RCC
2. A person without family history who has either:
   • Two hemangioblastomas
   • Two visceral tumors
   • One hemangioblastoma and one visceral tumor 1

Genetic Testing Indications

Genetic testing is indicated for first-degree relatives of individuals with pathogenic VHL variants and any child diagnosed with:

• Retinal angioma/hemangioblastoma
• CNS hemangioblastoma
• Clear cell RCC
• Pheochromocytoma or paraganglioma
• ELST
• Epididymal or adnexal papillary cystadenoma
• Multiple pancreatic cysts or pancreatic NET
• Multiple renal cysts 1

Surveillance Recommendations

Early detection through systematic screening has improved survival in VHL patients:

• Annual ophthalmologic examination 2
• Annual blood pressure assessment 2
• Annual plasma-free metanephrines or 24-hour urine fractionated metanephrines 2
• Biennial audiogram for ELST detection 2
• Biennial MRI of brain and spine with contrast 2
• Annual abdominal MRI for RCC and pancreatic NET screening 2
• More frequent ocular examinations during pregnancy 1, 2

Treatment Advances

• Belzutifan, an oral HIF2-α inhibitor, has been FDA-approved for treatment of VHL-associated renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas 2, 4
• Early surgical excision is recommended for CNS hemangioblastomas before significant neurological damage occurs 2
• Extramacular or extrapapillary retinal hemangioblastomas should be treated promptly upon detection 1

Prognosis

Despite advances in early diagnosis and management, life expectancy for VHL patients remains reduced at 40-52 years 5, 6. However, comprehensive surveillance paradigms have led to early recognition of tumors and improved outcomes 1.