Aberrant cutaneous expression of the angiogenic factor midkine is associated with neurofibromatosis type-1

Neurofibromatosis type 1 is a common autosomal dominant disorder (incidence 1:3500) characterized by lesions that include neural crest derivatives such as Schwann cells and melanocytes. A critical event in the pathogenesis of neurofibromatosis type 1 is the heterozygous germ-line loss of the tumor suppressor gene NF1. Additional genetic and/or epigenetic events have been posited, including various alterations in growth factor expression. By in situ hybridization and immunohistochemistry, we demonstrate aberrant expression of the angiogenic and tumorigenic growth factor midkine in the skin of patients with neurofibromatosis type 1, but not normal individuals. We demonstrate that midkine expression is independent of the presence of neurofibromas, and thus appears to be associated with mutations in the NF1 gene. Furthermore, midkine-containing culture media is shown to stimulate the growth of human endothelial and neurofibroma-derived cells. In conclusion, we introduce the skin as a source of dysregulated growth factors in neurofibromatosis type 1, and suggest the further study of the angiogenic factor midkine in neurofibromatosis type 1 pathogenesis.