Introduction
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Forms of Neurofibromatosis:
- Neurofibromatosis Type 1 (NF1): Previously known as von Recklinghausen disease, the most common type.
- NF2-related Schwannomatosis (NF2): Formerly neurofibromatosis type 2.
- Schwannomatoses: Related to genetic variants other than NF2.
Epidemiology
- Multiple café-au-lait macules.
- Neurofibromas.
- Segmental NF1: Clinical features limited to one body area due to somatic mosaicism of a pathogenic variant in the NF1 gene.
Pathogenesis
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Incidence:
- NF1: Autosomal dominant genetic disorder with an incidence of 1:2600 to 1:3000 individuals.
- Approximately 50% of cases are familial (inherited).
- De novo mutations occur primarily in paternally derived chromosomes.
- Segmental NF1: Prevalence estimated at 1:36,000 to 1:40,000.
Clinical Manifestations
- Population-based study in Finland: Overall prevalence of NF1 approximately 1:4000.
- Prevalence decreases with age.
- Hazard ratio of death among individuals with NF1: 3.10.
Tumors
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Genetic Basis:
- Pathogenic variants in the NF1 gene located at chromosome 17q11.2.
- Protein product: Neurofibromin, a GTPase-activating protein (GAP) family member.
- Involvement in signaling pathways: SCF/c-kit signaling, mTOR, and MAPK pathways.
Optic Pathway Gliomas (OPGs)
- Pathogenic variants result in loss of production or reduced function of neurofibromin.
- Complete penetrance but highly variable expression.
- Somatic mutation or loss of heterozygosity at the NF1 locus leads to complete loss of neurofibromin expression in NF1 lesions such as pseudoarthrosis and neurofibromas.
- NF1 functions as a tumor suppressor gene.
- Haploinsufficiency may account for some phenotype aspects, such as neurocognitive problems.
Other Central Nervous System Neoplasms
- Caused by somatic mosaicism due to a postzygotic mutation in the NF1 gene.
- Some cells have two fully functional NF1 genes; other cells contain a pathogenic variant in one copy of the NF1 gene.
- Individuals with segmental NF1 do not have an affected parent.
- Adults with localized NF1 and mosaicism in somatic and gonadal tissues can transmit the mutation to offspring, resulting in non-segmental manifestations.
- Rare cases of germline mosaicism without apparent somatic features have been described.
Soft Tissue Sarcomas