1065
EDITORIALS
von
Hippel-Lindau disease
Hippel-Lindau (VHL) disease is an inherited disorder characterised by a predisposition to tumour development in the retina, cerebellum, spinal cord, pancreas, and kidneys. In this issue (p 1052) Dr Neumann and Dr Wiestler report a prevalence in the Freiburg district of Germany of about 1 in 40 000. If this figure applies elsewhere, then in the UK, for example, there will be at least 20 affected patients in the catchment area of a large teaching hospital. Since inheritance is autosomal dominant, as many as four or von
five times this number will run a risk of 1 in 4 or greater of harbouring the gene. Consequently establishing this diagnosis is important not only for the patient but also for the extended family. 12 The most comprehensive clinical study was undertaken by the Cambridge group,3who analysed data on 152 previously unreported patients. Age at onset varied from 4 to 68 years with a mean of 26-3. Retinal angiomatosis was the most common presenting feature and the only complication seen in children under 10 years. 51 patients died; mean age at death was 41 years. The commonest severe complications were retinal angiomatosis and cerebellar haemangioblastoma (both 59%), renal cell carcinoma (28%), spinal cord haemangioblastoma (13%), and phaeochromocytoma (7%). Life-table analysis indicated that renal cell carcinoma would develop eventually in most long-term survivors. More unusual and probably less serious complications included renal, pancreatic, and epididymal cysts, although the malignant potential of these lesions, especially those in the kidneys,4 remains unclear. Information about genetic aspects of this pleotropic disorder has also been provided. At the clinical level the Cambridge group3 concluded, as a result of careful screening techniques, that penetrance is almost complete by the age of 60 years. This fmding confirms an earlier estimate based on a study of a very large kindred of Puerto Rican origin.’ Variable expression within a family is customary, although some families seem to have a propensity for phaeochromocytoma.This observation would be consistent with Neumann and Wiestler’s suggestion of a complex genetic locus or contiguous gene syndrome. Further analysis of interfamilial and intrafamilial variation is needed to determine the validity of this novel and attractive hypothesis, which could have important implications for the planning of
screening programmes.
At the molecular level research has focused on the short arm of chromosome 3, after reports of deletions from this region in both sporadic7 and VHL8renal cell carcinomas. Linkage analysis has confirmed that the VHL locus is close to the locus of the RAF-11 oncogene on chromosome 3p25.9 Both statistical analysis of age of onsettO and DNA parental origin studies" suggest that the normal VHL gene acts as a tumour suppressor; the mutant VHL gene results in tumour formation only when it is "liberated" from the effects of its normal homologue by an event such as somatic deletion or recombination. When closely linked DNA markers are discovered, very reliable preclinical diagnosis in close relatives of affected individuals should be possible. This will almost certainly be a contentious issue at a time when the ethical aspects of presymptomatic testing in children for allied disorders such as polyposis coli and multiple endocrine adenomatosis are under scrutiny. Skilled counselling based on full knowledge of the disease and its natural history will be essential, as will the guarantee of lifelong monitoring and support. Meanwhile, there can be no excuse for lengthy delay in the implementation of screening protocols, both for the patients and for their close relatives. Several groups have drawn up guidelines for precisely this purpose,’-3,12 starting with ophthalmoscopy from the age of 5 years and proceeding to annual abdominal ultrasonography and urine analysis for catecholamines. Supplementary cranial and abdominal computed tomographic scanning are required less frequently. The case for establishing regional registers of inherited cancers13 has never been
stronger. SM, Harper PS, Hourihan MD, Cole G, Weeks RD, Compston DAS. Cerebellar haemangioblastoma and von Hippel-Lindau disease. Brain 1986; 109: 1297-310. 2. Jennings AM, Smith C, Cole DR, et al. von Hippel-Lindau disease in a large British family: clinicopathological features and recommendations for screening and follow-up. Q J Med 1990; 66: 233-49. 3. Maher ER, Yates JRW, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990; 77: 1151-63. 4. Solomon D, Schwartz A. Renal pathology in von-Hippel-Lindau disease. Hum Pathol 1988; 19: 1072-79. 5. Go RCP, Lamiell JM, Hsia YE, Yuer WM, Paik Y. Segregation and linkage analyses of von Hippel Lindau disease among 220 descendants from one kindred. Am J Hum Genet 1984; 36: 131-42. 6. Green JS, Bowmer MI, Johnson GJ. von Hippel-Lindau disease in a Newfoundland kindred. Can Med Assoc J 1986; 134: 133-42. 7. Zbar B, Brauch H, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 1987; 327: 721-24. 8. King CR, Schimke RN, Arthur T, Davoren B, Collins D. Proximal 3p deletion in renal cell carcinoma cells from a patient with von Hippel-Lindau disease. Cancer Genet Cytogenet 1987; 27: 345-48. 9. Seizinger BR, Rouleau GA, Ozelius LJ, et al. von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 1988; 332: 268-69. 10. Maher ER, Yates JRW, Ferguson-Smith MA. Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. J Med Genet 1990; 27: 311-14. 11. Norby S, Pedersen B, Hjorth JP, Jensen AM. Partial deletion of 3p in von Hippel-Lindau renal cell carcinoma. Clin Genet 1990; 37: 387. 12. Choyke PL, Filling-Katz MR, Shawker TH, et al. von Hippel-Lindau disease: radiologic screening for visceral manifestations. Radiology 1990; 174: 815-20. 13. Littler M, Harper PS. A regional register for inherited cancer. Br Med J 1. Huson
1989; 298: 1689-91.
EDITORIALS
von
Hippel-Lindau disease
Hippel-Lindau (VHL) disease is an inherited disorder characterised by a predisposition to tumour development in the retina, cerebellum, spinal cord, pancreas, and kidneys. In this issue (p 1052) Dr Neumann and Dr Wiestler report a prevalence in the Freiburg district of Germany of about 1 in 40 000. If this figure applies elsewhere, then in the UK, for example, there will be at least 20 affected patients in the catchment area of a large teaching hospital. Since inheritance is autosomal dominant, as many as four or von
five times this number will run a risk of 1 in 4 or greater of harbouring the gene. Consequently establishing this diagnosis is important not only for the patient but also for the extended family. 12 The most comprehensive clinical study was undertaken by the Cambridge group,3who analysed data on 152 previously unreported patients. Age at onset varied from 4 to 68 years with a mean of 26-3. Retinal angiomatosis was the most common presenting feature and the only complication seen in children under 10 years. 51 patients died; mean age at death was 41 years. The commonest severe complications were retinal angiomatosis and cerebellar haemangioblastoma (both 59%), renal cell carcinoma (28%), spinal cord haemangioblastoma (13%), and phaeochromocytoma (7%). Life-table analysis indicated that renal cell carcinoma would develop eventually in most long-term survivors. More unusual and probably less serious complications included renal, pancreatic, and epididymal cysts, although the malignant potential of these lesions, especially those in the kidneys,4 remains unclear. Information about genetic aspects of this pleotropic disorder has also been provided. At the clinical level the Cambridge group3 concluded, as a result of careful screening techniques, that penetrance is almost complete by the age of 60 years. This fmding confirms an earlier estimate based on a study of a very large kindred of Puerto Rican origin.’ Variable expression within a family is customary, although some families seem to have a propensity for phaeochromocytoma.This observation would be consistent with Neumann and Wiestler’s suggestion of a complex genetic locus or contiguous gene syndrome. Further analysis of interfamilial and intrafamilial variation is needed to determine the validity of this novel and attractive hypothesis, which could have important implications for the planning of
screening programmes.
At the molecular level research has focused on the short arm of chromosome 3, after reports of deletions from this region in both sporadic7 and VHL8renal cell carcinomas. Linkage analysis has confirmed that the VHL locus is close to the locus of the RAF-11 oncogene on chromosome 3p25.9 Both statistical analysis of age of onsettO and DNA parental origin studies" suggest that the normal VHL gene acts as a tumour suppressor; the mutant VHL gene results in tumour formation only when it is "liberated" from the effects of its normal homologue by an event such as somatic deletion or recombination. When closely linked DNA markers are discovered, very reliable preclinical diagnosis in close relatives of affected individuals should be possible. This will almost certainly be a contentious issue at a time when the ethical aspects of presymptomatic testing in children for allied disorders such as polyposis coli and multiple endocrine adenomatosis are under scrutiny. Skilled counselling based on full knowledge of the disease and its natural history will be essential, as will the guarantee of lifelong monitoring and support. Meanwhile, there can be no excuse for lengthy delay in the implementation of screening protocols, both for the patients and for their close relatives. Several groups have drawn up guidelines for precisely this purpose,’-3,12 starting with ophthalmoscopy from the age of 5 years and proceeding to annual abdominal ultrasonography and urine analysis for catecholamines. Supplementary cranial and abdominal computed tomographic scanning are required less frequently. The case for establishing regional registers of inherited cancers13 has never been
stronger. SM, Harper PS, Hourihan MD, Cole G, Weeks RD, Compston DAS. Cerebellar haemangioblastoma and von Hippel-Lindau disease. Brain 1986; 109: 1297-310. 2. Jennings AM, Smith C, Cole DR, et al. von Hippel-Lindau disease in a large British family: clinicopathological features and recommendations for screening and follow-up. Q J Med 1990; 66: 233-49. 3. Maher ER, Yates JRW, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990; 77: 1151-63. 4. Solomon D, Schwartz A. Renal pathology in von-Hippel-Lindau disease. Hum Pathol 1988; 19: 1072-79. 5. Go RCP, Lamiell JM, Hsia YE, Yuer WM, Paik Y. Segregation and linkage analyses of von Hippel Lindau disease among 220 descendants from one kindred. Am J Hum Genet 1984; 36: 131-42. 6. Green JS, Bowmer MI, Johnson GJ. von Hippel-Lindau disease in a Newfoundland kindred. Can Med Assoc J 1986; 134: 133-42. 7. Zbar B, Brauch H, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 1987; 327: 721-24. 8. King CR, Schimke RN, Arthur T, Davoren B, Collins D. Proximal 3p deletion in renal cell carcinoma cells from a patient with von Hippel-Lindau disease. Cancer Genet Cytogenet 1987; 27: 345-48. 9. Seizinger BR, Rouleau GA, Ozelius LJ, et al. von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 1988; 332: 268-69. 10. Maher ER, Yates JRW, Ferguson-Smith MA. Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. J Med Genet 1990; 27: 311-14. 11. Norby S, Pedersen B, Hjorth JP, Jensen AM. Partial deletion of 3p in von Hippel-Lindau renal cell carcinoma. Clin Genet 1990; 37: 387. 12. Choyke PL, Filling-Katz MR, Shawker TH, et al. von Hippel-Lindau disease: radiologic screening for visceral manifestations. Radiology 1990; 174: 815-20. 13. Littler M, Harper PS. A regional register for inherited cancer. Br Med J 1. Huson
1989; 298: 1689-91.
