Von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is an inherited disorder causing multiple tumours, both benign and malignant, in the central nervous system (CNS) and viscera. The most common tumours are retinal and CNS haemangioblastomas, renal cell carcinoma (RCC), renal cysts and phaeochromocytoma.¹²

Tumours also arise in the pancreas, epididymis or broad ligament of the uterus, and the inner ear (endolymphatic sac). The age at which the tumours present ranges from early childhood to the seventh decade of life. Early diagnosis, screening of family members and lifelong surveillance of VHL patients for tumours is recommended.

Epidemiología³

• Incidence is about 1:36,000 live births.

• The inheritance is autosomal dominant with high penetrance.⁴

• About 20% of cases are new mutations.

VHL disease is caused by mutations of the VHL tumour suppressor gene (3p25-26). The resulting tumours are highly vascular.

• Type 1 families - risk of phaeochromocytoma is low, but can develop all other von Hippel-Lindau tumour types.

• Type 2 families - have phaeochromocytomas with:
  

  • Type 2A - low risk of RCC.

  • Type 2B - high risk of RCC.

  • Type 2C - phaeochromocytoma only with no other neoplasms.

Diagnostic criteria for clinical diagnosis

• Family history of VHL disease PLUS a tumour (CNS/retinal haemangioblastoma or clear cell RCC); OR

• If no family history, ≥2 CNS/retinal haemangioblastomas plus visceral tumour (RCC, phaeochromocytoma or pancreatic tumour).

Pruebas genéticas

• In affected families, genetic testing can detect almost all cases of VHL disease.

• For new mutations (the first affected member of a family), genetic diagnosis is more complex. This is due to the possibility of mosaicism (not all tissues carry the mutation), where the VHL mutation may be absent from blood leukocytes and the genetic test can be falsely negative.

• Antenatal testing is possible if a VHL mutation has been found in a family member.⁸

• May be diagnosed from family history and genetic testing.

• May present with symptoms of the various tumours (see 'Tumours - presentation and management', below).

• The hormonal and haemodynamic effects of pregnancy accelerate the growth of haemangioblastomas in VHL syndrome, leading to increased symptoms and risk to both the mother and fetus.⁹

This is a key part of VHL disease management and involves:¹⁰

• Regular and lifelong surveillance for tumours, using a screening protocol (below).

• Asesoramiento genético/testing of family members - because of the need for lifelong tumour surveillance.

• If a genetic test cannot exclude VHL disease, then family members should receive regular screening for VHL tumours.

• A multidisciplinary approach to screening. The team may be led by a geneticist, and includes specialists in urology, gastroenterology, neurology, ophthalmology, and radiology.¹¹

• New symptoms should be investigated immediately.

• Screening for phaeochromocytoma is essential in patients undergoing surgery (because of the risk of hypertensive crisis).¹²

60-80% of patients with VHL disease have haemangioblastomas, and 10-15% will develop endolymphatic sac tumours.¹⁴

CNS haemangioblastomas

• The most common tumour in VHL disease; affects about 70% of patients; presents at the average age of 33 years.

• Usually in the cerebellum, spinal cord or brainstem; can also occur in lumbosacral nerve roots or the supratentorial region.

• A benign tumour but can cause significant morbidity and mortality.

• Presentation - depends on the tumour location - eg, headache, ataxia, inco-ordination, nausea/vomiting, sensory loss, weakness, hyperreflexia.

• Manejo:
  

  • Surgical excision is curative; most tumours can be removed safely.

  • Unnecessary surgery should be avoided, as tumours may be multiple and their growth rate is unpredictable. Therefore surgery may be deferred, depending on symptoms.

Retinal haemangioblastomas

• Common in VHL disease - found in 60% of patients. Can occur in children aged <10 years; the average age at presentation is 25 years.

• Usually asymptomatic until complications arise (exudates, subretinal oedema, retinal detachment or glaucoma), causing loss of vision.

• Manejo:
  

  • For peripheral retinal tumours - laser photocoagulation or cryotherapy.

  • Optic disc lesions should be monitored but are difficult to treat (anti-vascular endothelial growth factor (anti-VEGF) therapy may be an option).

Phaeochromocytomas

• May be adrenal or extra-adrenal (eg, paragangliomas in carotid body and extra-aortic tissues).

• Most are benign; 5% are malignant.

• Symptoms/signs - headaches, palpitations, episodic sweating, pallor and nausea; intermittent or sustained hypertension; may have no symptoms.

• Manejo:
  

  • Surgical removal - preferably early surgical intervention sparing the adrenal cortex.

  • Pre-operative evaluation and treatment is important to prevent hypertensive crisis.

RCC and renal cysts

• Common in VHL disease - RCC or renal cysts occur in 60% of patients.

• Renal cysts are usually asymptomatic and rarely need treatment; complex cysts need monitoring as they may contain RCC.

• Serial imaging aids detection of RCC.

• Surgery is required for RCC. For smaller tumours, nephron-sparing surgery can preserve renal tissue, to prevent or delay the need for nephrectomy.

Pancreatic tumours¹²

• Present at the average age of 35 years.

• Most are asymptomatic and diagnosed on imaging.

• There are 2 types:
  

  • Pancreatic cysts and serous cystadenomas:
    

    • Benign.

    • Occur in 20-50% of patients.

    • Rarely need treatment unless they impinge on other organs.

  • Pancreatic neuroendocrine tumours:
    

    • Have metastatic potential.

    • Occur in 15% of patients.

    • Are managed by surgical resection, depending on size and location of tumour.

Endolymphatic sac tumours

• These are tumours of the inner ear which are rare in the general population.

• They are non-malignant but can erode nearby bone.

• Occur at an average age of 22 years.

• Present with hearing loss, tinnitus, vertigo or facial weakness.

• Surgery is curative, can relieve vertigo and may prevent progression of hearing loss. However, once hearing loss occurs, it is usually irreversible.

Epididymal cystadenomas

• Common in men with VHL disease (found in 25-60%).

• Usually asymptomatic; may be found on palpation.

• Diagnosis/monitoring is by ultrasound. Usually no treatment is required.

Broad ligament cystadenomas

• Prevalence is unknown; usually asymptomatic and found on imaging.

• Treatment is rarely required unless symptomatic.

Previously, the average life expectancy for von VHL disease patients was 50 years; the main causes of death were RCC or CNS haemangioblastoma. Current screening protocols and treatment have improved this prognosis.

The syndrome is named after Eugene von Hippel, who described the retinal tumours (1904), and Arvid Lindau, who described their association with other tumours (1926).