Developmental effects of von Hippel-Lindau gene deficiency.

The histogenetic origin and the basis of the distribution of central nervous system (CNS) hemangioblastomas in the von Hippel-Lindau (VHL) tumor suppressor gene syndrome, VHL disease, are unknown. To better understand hemangioblastoma histogenesis, we analyzed postmortem CNS tissues from four patients with well-established diagnosis of VHL disease including development of characteristic tumors and positive family history. Numerous angiomesenchymal tumorlets, which resembled hemangioblastoma, but which also consistently showed distinct histological features, were distributed in the nerve roots, spinal cord, and cerebellum. Genetic analysis consistently showed deletion of the wild-type VHL allele in these tumorlets. Most angiomesenchymal tumorlets were in the dorsal nerve roots; the anterior roots and cerebellum were less frequently affected. Tumorlet distribution was highly consistent in the four cases. In analogy to the wide morphological spectrum of lesions known to exist in VHL kidneys, nerve roots appear to harbor more wide-spread and morphologically heterogeneous changes than previously appreciated. The abundance of tumorlets, associated with highly consistent morphology and topography, suggests a developmental origin of hemangioblastoma. Therefore, in VHL disease, inactivation of the VHL wild-type allele appears necessary, but not sufficient, for the formation of tumor that produces symptoms and neurological disability.