Elsevier

The Lancet

Volume 361, Issue 9374, 14 June 2003, Pages 2059-2067
The Lancet

Seminar
von Hippel-Lindau disease

https://doi.org/10.1016/S0140-6736(03)13643-4Get rights and content

Summary

von Hippel-Lindau disease is a heritable multisystem cancer syndrome that is associated with a germline mutation of the VHL tumour suppressor gene on the short arm of chromosome 3. This disorder is not rare (about one in 36 000 livebirths) and is inherited as a highly penetrant autosomal dominant trait (ie, with a high individual risk of disease). Affected individuals are at risk of developing various benign and malignant tumours of the central nervous system, kidneys, adrenal glands, pancreas, and reproductive adnexal organs. Because of the complexities associated with management of the various types of tumours in this disease, treatment is multidisciplinary. We present an overview of the clinical aspects, management, and treatment options for von Hippel-Lindau disease.

Section snippets

Molecular genetics

VHL is a tumour suppressor gene on the short arm of chromosome 3 (3p25-26).23 Most people with the disorder inherit a germline mutation of the gene from the affected parent, and a normal (wild type) gene from the unaffected parent. According to Knudson's two-hit hypothesis of tumorigenesis, initiation of tumour formation arises when both VHL alleles are inactivated.24, 25 Germline mutations of VHL are present in all the cells of affected individuals who inherit the genetic trait. However, only

Clinical diagnosis

Diagnosis of von Hippel-Lindau disease is often based on clinical criteria. Patients with a family history, and a CNS haemangioblastoma (including retinal haemangioblastomas), phaeochromocytoma, or clear cell renal carcinoma are diagnosed with the disease. Those with no relevant family history must have two or more CNS haemangioblastomas, or one CNS haemangioblastoma and a visceral tumour (with the exception of epididymal and renal cysts, which are frequent in the general population) to meet

Genetic testing

Advances in genetic testing for the disease include qualitative and quantitative Southern blotting, which has been added to DNA sequence analysis. This improved testing has increased the detection rate of DNA mutations in peripheral blood leucocytes from 75% to nearly 100%.57 In 1996, there were more than 137 distinct intragenic germline mutations reported in affected families in North America, Europe, and Japan.51 Mutation types included missense, non-sense, microdeletion, insertion, deletion,

General features

Haemangioblastomas of the CNS are the most common tumour in von Hippel-Lindau disease, affecting 60-80% of all patients.11, 21, 59 The average age of presentation for CNS haemangioblastomas is 33 years (table 1).11 These tumours are benign, but are a major cause of morbidity. They arise anywhere along the craniospinal axis and are often associated with oedema or cysts (associated cysts occur with 30-80% of haemangioblastomas), or both. CNS haemangioblastomas are generally seen in the spinal

General features

Renal cell carcinomas are the major malignant neoplasm in von Hippel-Lindau disease and the primary cause of inherited renal cancer. These tumours are seen in 24-45% of patients, and adding renal cysts increases the finding of renal lesions to 60% (table l).2022 The mean age at presentation is 39 years (table 1). Although small renal tumours in this disease tend to be low grade and minimally invasive,73 their rate of growth varies widely.74 Renal lesions are often multiple and bilateral.

Conclusion

The new insights into the underlying mechanisms of tumour formation, greater knowledge of the natural history of the various lesions associated with von Hippel-Lindau disease, and more precise diagnostic studies (laboratory and imaging) should lead to an improved quality of life and extend the life expectancy of affected individuals. The diverse multisystem effects of this disease need careful, selective, and coordinated planning to determine the treatment of individual lesions that will

Search strategy

We searched PubMed database using the keyword von Hippel-Lindau, combined with the terms central nervous system, haemangioblastoma, pancreatic neuroendocrine tumour, pheochromocytoma, renal cell carcinoma, or treatment. We focused mainly on manuscripts published during the past 10 years, but have also referenced papers from before that time. Relevant articles that were not identified by this search were also referenced.

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