Introduction

• 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

  • 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

    • 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

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      Information

      Published:05 June 2024 Last Updated:05 June 2024