The clinical manifestations and prevalence of von Hippel-Lindau syndrome (HLS) were reported from the Department of Medicine, Albert-Ludwigs-Universitat, Freiburg im Breisgau, Germany, and Department of Pathology, University of Zurich, Switzerland. A striking familial clustering of HLS lesions was discovered: angiomatosis retinae in 51% (47/92), haemangioblastoma of the CNS in 46% (42/92), renal lesions in 33% (30/92) and phaeochromocytoma in 24% (22/92). Of the 92 patients, 52 had 1, 31 had 2, and 9 had 3 of the 4 HLS lesions. Of 29 evaluated kindreds, 18 had renal lesions. Some features of HLS were frequently combined whereas others seemed to be almost exclusive. The patterns of lesions within individual kindreds were stable. Vascular lesions of the syndrome (angiomatosis retinae and haemangioblastoma of the CNS) occurred in most families and represented core features whereas phaeochromocytoma at one end of the scale, and renal lesions, pancreatic cysts and epididymal cystadenoma at the other end of the scale, were unlikely to develop in the same family and were mutually exclusive. The authors suggest that HLS is caused from different mutations within a complex genetic locus, or additional genetic lesions, which cooperate with the HLS gene on chromosome 3p. The data point to a linear sequence of features. The calculated prevalence of the disease in the district of Freiburg, Germany, with a population of 1.909 million, was 1/38951. [1]

COMMENT. These familial patterns of lesions are important in prognosis and the clinical management of HLS gene carriers. Patients with renal lesions are at a high risk for hemangioblastoma of the CNS, the principal cause of death in HLS patients. Patients presenting with renal disorders should be carefully monitored for the development of CNS lesions. Patients with pheochromocytoma are likely to develop angiomatosis retinae but are usually spared the CNS complication.

Von Hippel-Lindau disease has been associated with loss of a region of chromosome 3 that is often deleted in renal cell carcinoma. This region contains a tumor suppressor gene whose absence is associated with the development of renal cell carcinoma, hemangioblastoma and other tumors of von Hippel-Lindau disease. Deletion of the tumor suppressor gene may allow ectopic production of erythropoietin by the intracranial hemangioblastoma. Production of erythropoietin by a recurrent intracranial hemangioblastoma in a 59 year old woman was thought to explain the erythrocytosis in this patient with von Hippel-Lindau disease. [2]