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. 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.
- Incidence is 1:36,000.
- The inheritance is autosomal dominant with high penetrance.
- About 20% of cases are new mutations.
Von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene, which is a tumour suppressor gene. 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 renal cell carcinoma (RCC).
- Type 2B - high risk of RCC.
- Type 2C - phaeochromocytoma only with no other neoplasms.
Diagnostic criteria for clinical diagnosis
- Family history of von Hippel-Lindau (VHL) disease PLUS a tumour (CNS/retinal haemangioblastoma or clear cell renal cell carcinoma (RCC)); OR
- If no family history, ≥2 CNS/retinal haemangioblastomas plus visceral tumour (RCC, phaeochromocytoma or pancreatic tumour).
- 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.
- May be diagnosed from family history and genetic testing.
- May present with symptoms of the various tumours (see below).
Investigations and monitoring
This is a key part of von Hippel-Lindau (VHL) disease management and involves:
- Regular and lifelong surveillance for tumours, using a screening protocol (below).
- Genetic counselling/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.
- New symptoms should be investigated immediately.
- Screening for phaeochromocytoma is essential in patients undergoing surgery (because of the risk of hypertensive crisis).
Screening protocol for von Hippel-Lindau diseaseThe following protocol is used by Leung et al:
- Annual blood pressure and neurological examination.
- Annual direct and indirect ophthalmoscopy from age 5 years, ± fluorescein angiography.
- Annual 24-hour measurement of the urinary vanillylmandelic acid (VMA) level from age 10 years.
- Annual abdominal ultrasound from age 10 years.
- Baseline MR imaging of the brain and spine at age 20 years; low threshold for repeat if any symptoms/signs.
- Auditory questionnaire - if positive, audiogram. MRI if audiogram abnormal.
- The most common tumour in von Hippel-Lindau (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.
- 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.
- 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.
- 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.
- 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 a new option).
- 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.
- Surgical removal, preferably early surgical intervention sparing the adrenal cortex.
- Preoperative evaluation and treatment is important to prevent hypertensive crisis.
Renal cell carcinoma (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.
- Present at the average age of 35 years.
- Most are asymptomatic and diagnosed on imaging.
- There are 2 types:
- Pancreatic cysts and serous cystadenomas:
- 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.
- Managed by surgical resection, depending on size and location of tumour.
- Pancreatic cysts and serous cystadenomas:
Endolymphatic sac tumours
- These are tumours of the inner ear which are rare in the general population.
- They are nonmalignant but can erode nearby bone.
- Occur in 11% of VHL disease patients at the 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.
- 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 Hippel-Lindau (VHL) disease patients was 50 years; the main causes of death were renal cell carcinoma (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).
Further reading & references
- VHLCG; Von Hippel Lindau Contact Group. Website for patients and families
- Gulani A; von Hippel-Lindau Disease, eMedicine, Nov 2008
- Hayden MG, Gephart R, Kalanithi P, et al; Von Hippel-Lindau disease in pregnancy: a brief review. J Clin Neurosci. 2009 May;16(5):611-3. Epub 2009 Mar 3.
- Calzada MJ; Von Hippel-Lindau syndrome: molecular mechanisms of the disease. Clin Transl Oncol. 2010 Mar;12(3):160-5.
- Lonser RR, Glenn GM, Walther M, et al; von Hippel-Lindau disease. Lancet. 2003 Jun 14;361(9374):2059-67.
- Maher ER; Orphanet rare diseases, von Hippel-Lindau disease webpage. Updated October 2009
- Priesemann M, Davies KM, Perry LA, et al; Benefits of screening in von Hippel-Lindau disease--comparison of morbidity associated with initial tumours in affected parents and children. Horm Res. 2006;66(1):1-5. Epub 2006 Apr 27.
- Leung RS, Biswas SV, Duncan M, et al; Imaging features of von Hippel-Lindau disease. Radiographics. 2008 Jan-Feb;28(1):65-79; quiz 323.
- MD Anderson Cancer Centre; University of Texas, USA. Von Hippel-Lindau Disease (Accessed July 2010)
- Butman JA, Linehan WM, Lonser RR; Neurologic manifestations of von Hippel-Lindau disease. JAMA. 2008 Sep 17;300(11):1334-42.
- Von Hippel-Lindau Syndrome, Online Mendelian Inheritance in Man (OMIM)
|Original Author: Dr Huw Thomas||Current Version: Dr Naomi Hartree|
|Last Checked: 25/08/2010||Document ID: 2927 Version: 21||© EMIS|
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