von Hippel-Lindau disease type 2A in a family with a duplicated 21-base-pair in-frame insertion mutation in the VHL gene.

Background: von Hippel-Lindau disease (VHL), also called angiomatosis retinae, is inherited as an autosomal dominant trait. It is frequently associated with other tumors in the central nervous system, kidneys, or adrenal glands. In order to investigate the relationship between genotype and corresponding phenotypes, we performed molecular genetic analysis in a Japanese patient with VHL type 2A.

Methods: After informed consent had been obtained, the three exons of the VHL gene were PCR-amplified and sequenced either directly or after subcloning. Clinical features were also examined.

Results: A novel in-frame duplication of the 21 base pairs at nucleotide 806 (the position of codon 198) of the VHL gene was found in our patient. The clinical phenotype of the patient included retinal hemangiomas associated with vitreous hemorrhage and traction retinal detachment, pheochromocytoma, and hemangioma-like lesions in the cerebellum which corresponded to those of VHL type 2A. Abnormal diffuse vascular leakage was observed in the apparently intact retina by fluorescein angiography.

Conclusion: An insertion mutation of the VHL gene is a rare association with VHL type 2. This insertion mutation may interfere the binding between the VHL gene and elongins. Abnormal retinal vascular leakage suggests the possible effects of overexpressed vascular permeability factors such as vascular endothelial growth factor from hemangiomas associated with defective VHL gene.