Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects approximately 1:2500 individuals worldwide. The hallmark manifestation is the neurofibroma, a benign tumor of the nerve sheath, but many other tumor and nontumor manifestations occur, including malignant peripheral nerve sheath tumors, gliomas, skeletal dysplasia, learning disabilities, etc. The disorder is due to pathogenic variants in the NF1 gene, a large gene that encodes the protein neurofibromin. The gene functions as a tumor suppressor, at least in the pathogenesis of tumor-related manifestations. Genetic testing is available and has revealed over 3000 distinct pathogenic variants. Most lead to loss of function of the gene product, with only a small number of genotype–phenotype correlations identified. Neurofibromin is a complex protein that interacts with multiple other proteins in the cell. Its principal function, at least regarding the disorder NF1, appears to be the regulation of the conversion of RAS-GTP to RAS-GDP through a GTPase activating protein domain. Hyperactive RAS signaling can be demonstrated in tumors associated with NF1. Recognition of this mechanism has led to the development of treatments based on MAP-kinase kinase (MEK) inhibition, with one drug approved by the US Food and Drug Administration for the treatment of plexiform neurofibromas.