Von Hippel-Lindau disease
Updates to Article Attributes
Von Hippel-Lindau (vHL) disease is characterised by the development of numerous benign and malignant tumours in different organs (at least 40 types 1) due to mutations in the VHL tumour suppressor gene on chromosome 3.
Epidemiology
The disease is rare with an estimated prevalence of 1:35,000-50,000. Most patients are diagnosed with their first tumour at age 26 10.
Clinical presentation
Clinical presentation is varied, depending on the site of disease manifestation (see below). Most commonly these are either within the abdominal cavity or affect the central nervous system.
Pathology
Distribution
Patients may develop some or all of the various lesions which include:
Abdominopelvic
-
renal lesions (>67% of patients 10)
-
renal cell carcinomas (RCCs)
- usually of the clear cell type 7 and frequently bilateral 10
- 70% lifetime risk 9
- RCCs present at an earlier age (mean = 39 years) in those with vHL 10
-
renal cysts
- can occur in up to 75% of patients 5
- often tend to be bilateral and multiple
- can simple, complex or cystic RCC 10
- renal angiomyolipomas
-
renal cell carcinomas (RCCs)
-
adrenal
- phaeochromocytomas: 25-30% of patients 10
- extra-adrenal phaeochromocytoma / paraganglioma: 15% 8,10
-
pancreas (may be the earliest manifestation 3)
- pancreatic cysts: ~40% of patients 10
-
pancreatic neuro-endocrine tumours (pNET)
- ~12.5% of patients (range 9-17%) 10
- usually non-functional 9
- frequently multiple
- pancreatic serous cystadenoma: ~12.5% of patients (range 9-17%)
- pancreatic adenocarcinoma: rare
- liver
Urogenital
- epididymal cysts 10
- papillary cystadenoma of the epididymis: ~35% of patients (range 25-60%) 10
- broad ligament cystadenomas 10
CNS
-
CNS haemangioblastoma(s): occur in ~70% of patients (range 60-80%) 9,10
- cerebellar (~60%; range 44-72%)
- spinal cord (~30%; range 13-50%); most commonly in cervical and thoracic cord
- brainstem
- choroid plexus papilloma
Head and neck
-
retinal haemangioblastoma(s)
- most common presenting feature, occurring in 45-60% of patients 9,10
- vision loss in 35-55% of patients 9
-
endolymphatic sac tumours (ELST)
- occurs in 10-15% of patients 10
- bilateral in 30% 10; considered pathognomonic for vHL 9
A mnemonic to help remember the features of vHL is: HIPPEL.
Genetics
The disease carries an autosomal dominant inheritance with high expression and penetrance - ~80% of cases occur via this pathway with ~20% arising de novo 10. It results from an inactivation of VHL, a tumour suppressor gene located on chromosome 3p25.5. However, no mutation is identified in up to 30% of cases.
Classification
VHL can be classified according to clinical phenotypes, and the classification correlates with particular genotypes 10:
- type 1: low-risk for pheochromocytoma but higher-risk for CNS haemangioblastoma, RCC, pancreatic cyst, and pNET
- type 2A: high-risk for pheochromocytoma; low-risk for RCC
- type 2B: high-risk for pheochromocytoma and RCC
- type 2C: high-risk for pheochromocytoma only
Radiographic features
Please refer to articles on individual lesions for specific imaging characteristics.
Treatment and prognosis
Most lesions from vHL are treatable and surveillance is recommended with various regional guidelines 10. Some experts advocate routine screening starting in adolescence. Prognosis is poor, with a median survival of ~50 years, with the most common cause of death being RCC and cerebellar haemangioblastomas 1.
History and etymology
Eugen von Hippel (1867-1939) was a German ophthalmologist who had described a rare disorder of the retina in 1904 and seven years later reported the basis of this disease, named as "angiomatosis of the retina".
Arvid Vilhelm Lindau (1892-1958) was a Swedish pathologist and bacteriologist who described the association between angiomatosis of the retina and haemangioblastomas of the cerebellum and other parts of the CNS and other visceral components of a disease, calling it "angiomatosis of the central nervous system".
In 1964 the disease was renamed Von Hippel-Lindau disease.
-<li>usually of the clear cell type <sup>7 </sup>and frequently bilateral <sup>10</sup>- +<li>usually of the <a title="Clear cell renal cell carcinoma" href="/articles/clear-cell-renal-cell-carcinoma">clear cell type</a> <sup>7 </sup>and frequently bilateral <sup>10</sup>
-</ul><p>A mnemonic to help remember the features of vHL is: <a href="/articles/von-hippel-lindau-disease-mnemonic">HIPPEL</a>.</p><h5>Genetics</h5><p>The disease carries an autosomal dominant inheritance with high expression and penetrance - ~80% of cases occur via this pathway with ~20% arising <em>de novo</em> <sup>10</sup>. It results from an inactivation of VHL, a tumour suppressor gene located on chromosome 3p25.5. However, no mutation is identified in up to 30% of cases.</p><h5>Classification</h5><p>VHL can be classified according to clinical phenotypes, and the classification correlates with particular genotypes <sup>10</sup>:</p><ul>- +</ul><p>A mnemonic to help remember the features of vHL is: <a href="/articles/von-hippel-lindau-disease-mnemonic-1">HIPPEL</a>.</p><h5>Genetics</h5><p>The disease carries an autosomal dominant inheritance with high expression and penetrance - ~80% of cases occur via this pathway with ~20% arising <em>de novo</em> <sup>10</sup>. It results from an inactivation of VHL, a tumour suppressor gene located on chromosome 3p25.5. However, no mutation is identified in up to 30% of cases.</p><h5>Classification</h5><p>VHL can be classified according to clinical phenotypes, and the classification correlates with particular genotypes <sup>10</sup>:</p><ul>
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