Summary

Von Hippel-Lindau (VHL) disease is an autosomal dominant tumour syndrome caused by a mutation in the VHL tumour suppressor gene on Chromosome 3p. The gene normally regulates HIF (Hypoxia Inducible Factor). Without VHL, the body thinks it is hypoxic, leading to uncontrolled angiogenesis (blood vessel growth). The hallmark is the development of highly vascular tumours in specific organs:

• CNS: Haemangioblastomas (Cerebellum, Spinal Cord, Brainstem).
• Eye: Retinal Haemangioblastomas (Angiomas).
• Kidney: Renal Cell Carcinoma (Clear Cell RCC).
• Adrenal: Phaeochromocytoma. Management is lifelong surveillance ("The VHL Protocol") to detect and treat these tumours early. A new class of drugs, HIF-2$\alpha$ Inhibitors (Belzutifan), has revolutionized treatment, often avoiding multiple surgeries. [1,2]

Key Facts

• Genetics: Autosomal Dominant (VHL gene). 20% are de novo.
• The "VHL Complex": VHL protein ubiquitinates HIF-1$\alpha$ for destruction. Lack of VHL = High HIF = High VEGF = Tumours.
• Haemangioblastomas: Benign but dangerous. They are cystic nodules in the cerebellum or spine. They secrete EPO (Polycythaemia) and can bleed/compress.
• Renal Cell Carcinoma: Occurs in 40-60%. It is usually bilateral and multifocal.
• Phaeochromocytoma: Can be the presenting feature. Often bilateral.

Clinical Pearls

"The Polycythaemia Clue": If a cerebellar tumour patient has a high Haemoglobin (Hb > 180), suspect a Haemangioblastoma secreting Erythropoietin (EPO).

"Don't Biopsy the Adrenal": A Phaeochromocytoma can look like an incidentaloma. If you biopsy it without alpha-blockade, you can precipitate a hypertensive crisis. Check Metanephrines first.

"3 cm Rule": For VHL Renal Cell Carcinomas, we watch them until they reach 3cm. Why? Because the risk of metastasis is low under 3cm, and we want to preserve kidney function (avoiding dialysis) for as long as possible.

"HIF-2$\alpha$ Inhibition."

• Mechanism: A small molecule that blocks the dimerization of HIF-2$\alpha$ with HIF-1$\beta$. It directly targets the molecular defect.
• Trial: The LITESPARK-004 study.
• Results:
  • Shrank RCCs in 49% of patients.
  • Shrank CNS haemangioblastomas in 30%.
  • Shrank Pancreatic tumours in 77%.
• Impact: Patients who were facing "inevitable" surgery or dialysis now have a medical option. Many have avoided surgery for years.
• Side Effects: Anaemia (blocks EPO), Hypoxia.

"Saving the Nephrons."

• In VHL, the patient will develop new kidney tumours forever. We cannot just remove the kidney (Radical Nephrectomy) or they will need dialysis by age 30.
• Technique:
  • Open or Robotic approach.
  • Clamp the renal artery (Warm Ischaemia Time must be under 20 mins).
  • "Shell out" the tumours (Enucleation) keeping a thin rim of normal margin.
  • Repair the defects.
• Repeat Surgery: VHL patients often undergo 3-4 partial nephrectomies on the same kidney over a lifetime. It is technically demanding ("Hostile abdomen").

"Stopping the VHL line."

• VHL is a defined genetic burden with high penetrance.
• Many patients choose PGD (IVF with embryo selection).
• Debate: VHL is treatable (unlike Huntington's). Is it ethical to discard embryos for a manageable condition? Most authorities say Yes, given the burden of surgeries and cancer risk.

Genotype-Phenotype Correlation:

• Type 1: High risk of RCC/Haemangioblastoma. LOW risk of Phaeo. (Deletion/Nonsense mutations).
• Type 2: HIGH risk of Phaeochromocytoma. (Missense mutations).
  • 2A: Phaeo + Haemangioblastomas. Low RCC risk.
  • 2B: Phaeo + Haemangioblastomas + High RCC risk.
  • 2C: Phaeo Only.

What is VHL?

It is a genetic condition where your body's "oxygen sensor" switch is stuck in the "ON" position. This makes blood vessels grow too much, forming cysts and tumours in the brain, eyes, and kidneys.

Is it cancer?

Ideally, we catch the kidney tumours before they act like aggressive cancers. The brain tumours (haemangioblastomas) are benign (they don't spread), but they squash the brain.

The Protocol

You are now the CEO of your own body. You must have your scans every year. If you stick to the schedule, we can catch everything early and deal with it. If you disappear for 5 years, things grow large and become dangerous.

Common Exam Questions

1. Radiology:

• Q: What is the classic appearance of a Haemangioblastoma?
• A: A cystic mass with an enhancing mural nodule.

2. Oncology:

• Q: What is the threshold for operating on a VHL kidney tumour?
• A: 3cm.

3. Haematology:

• Q: Why do these patients get polycythaemia?
• A: Ectopic EPO secretion by the haemangioblastoma.

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.