Background: Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome. Since the identification of the VHL gene, at least 3 clinical-genetic subtypes of the disease have been recognized.
Objectives: To identify the specific abnormality in the VHL gene and to correlate it with the prevalence and severity of ocular involvement in a large family with VHL disease.
Methods: A longitudinal clinical study and DNA analysis of 24 family members.
Results: All 14 affected family members exhibited a thymine-to-cysteine change at nucleotide 505 (T505C) in exon 1 of the VHL gene, consistent with the clinical diagnosis of VHL disease subtype 2A. Two asymptomatic gene carriers were also identified. Seventy-five percent (12/16) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angioma. Five gene carriers (31%) had lost vision because of angiomatosis. Cerebellar hemangioblastomas were present in 4 patients (25%) and pheochromocytomas in 11 (69%). No patient was found to have a renal cell carcinoma.
Conclusions: The family shows a low susceptibility to renal carcinoma consistent with the clinical diagnosis of VHL disease type 2A. The prevalence and severity of ocular angiomatosis in this subtype do not significantly differ from those of the other more common subtypes of VHL. Recognition of the VHL disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene. Confirmation of this genotype increases the clinician's ability to provide favorable prognostic information to affected family members.