Neurofibromatosis Type 1

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  • Neurofibromatosis types 1 (NF1) and 2 (NF2) are neurocutaneous syndromes (phakomatoses). Although they share a name, they are unrelated.
    • NF1, the most common of the phakomatoses, is a multisystem disorder that may affect any organ: It is characterized by café au lait spots, axillary and inguinal freckling, neurofibromas, Lisch nodules, choroidal freckling.
    • NF2 is a rare condition that causes bilateral vestibular schwannomas.
  • System(s) affected: musculoskeletal; nervous; skin/exocrine; cardiovascular; neuro-ophthalmologic
  • Synonym(s): von Recklinghausen disease, formerly peripheral NF


  • Predominant sex for NF1: male = female
  • Birth incidence NF1: 1:2,500 to 3,000

1:3,000 to 1:4,000

Etiology and Pathophysiology

  • Neurofibromin is a guanosine triphosphatase–activating protein that acts as a tumor suppressor by downregulating a cellular proto-oncogene, p21-ras, which enhances cell growth and proliferation.
  • Neurofibromata are benign tumors composed of Schwann cells, fibroblasts, mast cells, and vascular components that develop along nerves.
  • The two-hit hypothesis has been invoked to explain malignant transformation in NF1.

  • Online Mendelian Inheritance in Man 162200
  • Caused by a mutation in the NF1 gene on chromosome 17q11.2; autosomal dominant inheritance; protein product is called neurofibromin.
  • 50% of cases are due to de novo mutations, mostly paternal; likelihood increases with paternal age.
  • Prenatal diagnosis is possible if mutation is known.
  • Penetrance is nearly 100%; expressivity is highly variable, even within a family.
  • Gene is large, with a variety of mutations causing NF1. Molecular technology can detect 95% of clinically important NF1 mutations, but clinical diagnosis frequently can be made in childhood.
  • ~5% of individuals with NF1 have a large deletion of the NF1 gene; usually a more severe phenotype
  • Segmental NF is limited to a single body region and is caused by mosaicism for the NF1 mutation.

Risk Factors

  • Having an affected first-degree relative is a diagnostic criterion for NF1, although relatives may be unaware that they have NF1.
  • Affected individuals with a positive family history (or a new mutation) have a 50% risk of transmitting NF1 to each offspring; 1 in 12 will be severely affected.
  • Segmental NF1: may have gonadal mosaicism and may be at risk for transmission of the mutated gene

Commonly Associated Conditions

  • Congenital heart disease, pulmonary stenosis, hypertension, renal artery stenosis
  • Learning disabilities (50–75%)

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