Neurofibromatosis Type 1 Molecular Basis of Disease

Neurofibromatosis type 1 (NF1) is an autosomal dominant progressive disorder with high penetrance but extremely variable expressivity (reviewed in References 1, 3, and 4). The cardinal features are café au lait macules, intertrige-nous freckling, Lisch nodules, and multiple neurofibromas, although numerous other features and complications are common. Criteria for diagnosis of NF1 were established in 1987 by a National Institutes of Health Consensus Conference and are widely used.5 Neurofibromas are benign nerve sheath tumors that arise on peripheral nerves. Cutaneous neurofibromas develop in virtually all cases of NF1, typically appear in the second decade of life, grow slowly, increase in number with age, and are considered at low risk for transformation to a malignant peripheral nerve sheath tumor (MPNST; previously known as neurofibrosarcoma). In contrast, diffuse plexiform neuro-fibromas and deep nodular plexiform neurofibromas are considered at increased risk for transformation to MPNST. Individuals affected with NF1 have a lifetime risk for MPNST of 8% to 13%.6 Other neoplasms epidemiologically associated with NF1 include medulloblastoma, pheochro-mocytoma, astrocytoma, and adenocarcinoma of the ampulla of Vater. Children affected with NF1 are at increased risk for optic pathway and brainstem gliomas, rhabdomyosarcomas, and malignant myeloid leukemias. NF1 patients also are at increased risk for a second malignancy, some of which may be treatment related.

NF1 is caused by inactivating mutations in one copy of the NF1 gene resulting in haploinsufficiency for the gene product neurofibromin (Table 21-1). About 85% to 90% of constitutional mutations are nonsense, splicing, and missense; they are distributed throughout the gene, although some exons appear to be mutation rich (Figure 21-1). An estimated 5% of mutations are large contiguous gene deletions typically of 1.4 megabases (Mb) that delete one entire NF1 allele (reviewed in Reference 7). About one half of cases are familial (inherited from an affected parent) and one half are sporadic, resulting from a de novo NF1 mutation. An unknown fraction of sporadic cases are due to postzygotic mutation of the NF1 gene, which complicates mutation detection and genetic counseling. Neurofibromin functions as a negative regulator of the RAS oncogene by stimulating the conversion of active guanosine 5'-triphosphate (GTP)-bound RAS to the inactive guanosine 5'-diphosphate (GDP)-bound form by hydrolyzing GTP. Biochemical, cell culture, and genetic studies in both NF1 patients and mouse models are consistent with a model whereby a somatic mutation inactivates the remaining functional NF1 gene (leading to increased activated RAS) in a progenitor Schwann cell as an early, probably initiating, event in the development of neurofibromas (reviewed in Reference 8). Biallelic inactivation of NF1 also occurs in other types of progenitor cells that give rise to NF1-associated tumors such as gliomas and myeloid malignancies.

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