Neurofibromatosis Type I ( NF 1)

Abstract Neurofibromatosis type I (NF1) is a common, autosomal dominant condition that manifests as multiple café‐au‐lait spots, peripheral nerve sheath tumours, optic nerve pathway tumours, orthopaedic abnormalities and learning disabilities. The gene for NF1 encodes neurofibromin, a RasGTPase activating protein (RasGAP) that activates the intrinsic GTPase of Ras and negatively regulates its role in signal transduction. As a tumour suppressor, inactivating mutations in NF1 lead to increased intracellular Ras signalling. Other components of the Ras‐MAP (mitogen‐activated protein) kinase pathway are now known to be involved in other genetic conditions including Noonan syndrome, Costello syndrome, Cardio‐facial‐cutaneous syndrome and Legius syndrome. NF1 is a neurocutaneous disorder that is a paradigm for many principles in the practice of medical genetics: variable clinical expressivity, penetrance, pleiotropy, age‐dependent clinical expression and mosaicism. The development of inhibitors of the Ras‐MAPK pathway, and other Ras‐connected pathways, opens new avenues of therapeutic intervention for myriad complications of this disorder. Key concepts Tumour suppressor: The NF1 gene loosely fits the paradigm of the “two‐hit” model of tumour suppressor in that somatic inactivation of a haploinsufficient gene in a subset of cells leads to tumour development. Variability of clinical expressivity: NF1 demonstrates multiple phenotypes, even in the same family where all affected individuals have the identical gene mutation. Age‐related penetrance: The clinical manifestations of NF1 arise at different ages and the condition is fully penetrant in adults. Genomic structure: The NF1 gene is traditional in its gene structure, yet there are unique features including embedded genes transcribed in the opposite orientation and multiple disease‐causing translocation breakpoints. Value of diagnostic criteria: NF1 is one of the few genetic conditions that can be diagnosed by the application of seven diagnostic criteria. Mosaicism: NF1 has a high sporadic incidence, and somatic mutations occurring in early pregnancy can lead to a mosaic clinical presentation evident by skin manifestations. Positional cloning: The NF1 gene was identified by application of genetic and physical mapping techniques. Animal models: Animal models, particularly the conditional mice, have been instrumental in furthering our understanding of this condition. Integration of kinase pathways: The Ras‐MAPK pathway is integrated in the intracellular network of signalling that includes growth factor receptors at the cell membrane. Pathophysiology: The understanding of the biochemical pathway and processes leading to tumour formation have led to the design and application of specific therapeutics that would not otherwise have been considered in the treatment of NF1.