Ocular manifestations of von Hippel-Lindau disease: clinical and genetic investigations.

PURPOSE: To describe the clinical spectrum of lesions involving the visual system in von Hippel-Lindau (VHL) disease, the genetic alterations, and the molecular genetic properties of retinal hemangioblastomas.
METHODS: In this prospective case-series, 406 patients with VHL disease had systemic and ocular evaluations. Genetic mutations within six pathological specimens were evaluated, using microdissection and polymerase chain reaction amplification.
RESULTS: Half of the 406 patients (199 families) with VHL disease had ocular involvement. Visual acuity was 20/20 or better in 170 patients (84.5%) with hemangioblastomas; six (3%) were legally blind. Thirty-three (8.2%) had unilateral enucleations. Genetic mutations were detected in all VHL patients. The patients with complete deletion were less likely to have ocular VHL compared with those patients with partial deletion, missense, and nonsense mutation (9% versus 45%) (P < .0001), suggesting the importance of the gene or areas of genes on chromosome 3 for the development of retinal hemangioblastomas. The molecular genetic assessments of the pathology specimens showed that the foamy "stromal" cells were affected with the genetic mutations. There is an up-regulation of vascular endothelial growth factor, which was expressed in the ocular lesions.
CONCLUSIONS: In this series, the largest of its kind, patients with ocular lesions of VHL disease are referred mostly from physicians. The systemic genetic mutation evaluations suggest that a certain gene or groups of genes in chromosome 3p are crucial for both the development and maintenance of the retinal tumor. This is the first series to find a difference between the phenotype and genotype.