Neurofibromatosis 1

In the words of Kaleb Yohay:

Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurocutaneous disorder with a predisposition to the development of benign and malignant tumors. Mutations in the NF1 gene result in loss of function of neurofibromin 1, a guanosine triphosphatase-activating protein that helps maintain the proto-oncogeneRas in its inactive form. Loss of neurofibromin results in increased proliferation and tumorigenesis. As a result, people with NF1 are at increased risk for the development of nervous and non-nervous system malignancies. Malignancy is a major source of morbidity and mortality in NF1. The natural history of NF1-associated malignancies is often different than that of their sporadic counterparts and, as such, management strategies need to be adjusted accordingly.

So,  broken NF1 genes lead to failure of MEK inhibition.  NF1 lies in the class of RASopathies, developmental syndromes caused by germlinemutations in genes that alter the Ras subfamilyand Mitogen-activated protein kinases that control signal transduction.  Mouse and zebrafish models have been produced for some aspects of NF1.  NF1 was sequenced and patented at the U. of Michigan in 1991. Patent holders Peggy Wallace and David Gutmann have continued to lead in NF1.  Patient registry, tissue samples, mutation databases, candidate drug lines and collaborative research protocols are available at Washington U, U of Alabama and CTF. Nancy Ratner at U. of Cincinatti is also a leader in the field and Indiana U is active.  Principal funding for NF1 research comes from the US Army CDMRP. There are 4 or 5 charities which support NF1 work, including

NF1 can be inherited or arise as a spontaneous mutation, for example in aging parents. 50% of mutations are spontaneous.  NF1 occurs in 1 of 3000 live births. It is more prevalent than Cystic Fibrosis.

The first clinical sign of NF1 is observation of café au lait spots and freckling in newborns.

Another diagnostic but benign sign is Lisch nodules (hamartomas of the iris).

Definitive diagnosis is done by sequencing NF1 gene and discovering a mutation, such as Y489C.  See Neurofibromatoses in Clinical Practice by Ferner, Huson and Evans, a comprehensive short guide to clinical manifestations.

The prognosis is highly variable and unpredictable.  Many complications can arise from an NF1 mutation and little has been established regarding the genotype-phenotype correlation. Limited GWAS have been done.   Complications include:

  • Congenital cardiac abnormalities and vasculopathy
  • Scioliosis, bone dysplasia, macrocephaly, early onset
  • Learning delays and ADHD, preschool onset.
    • Up to 60% of children with NF-1 have problems with some areas of learning or attention span.
    • Children with NF-1 can have problems with coordination that can make it harder for them to write or draw
    • Some children with NF-1 have problems with speech that make it harder to understand what they say
    • Children with NF-1 can show weaknesses with socialization and peer relationships that can affect school
  • Optic glioma, preschool onset
  • Many small skin tumors, puberty onset
  • Plexiform neurofibroma, adolescence and adulthood
  • Malignant peripheral nerve sheath tumors (MPNST), adolescence and adulthood
  • Increase risk of brain tumors
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