Neurofibromatosis

NF1

• Previously known as von Recklinghausen disease
• Hallmarks multiple café au lait macules and neurofibromas

Epidemiology:

• Most common type of neurofibromatosis
• most common neurocutaneous & inherited tumour syndrome (1:3,000)
• always presents <5yo

Cause:

• AD disorder (50% hereditary, 50% sporadic/ spontaneous)
• Penetrance is complete
• Mutations of NF1 gene = chromosome 17 (q11.2) result in altered form of a protein, neurofibromin
• Caused by a loss of NF1 gene which normally functions as a tumour suppressor (mutation causes uncontrolled cell proliferation i.e. neurofibromas)

Features and pathology:

• Typical order is café au lait macules, axillary and/or inguinal freckling, Lisch nodules (iris hamartomas) and neurofibromas
• If present, osseous dysplasias usually appear by 1yo
• Symptomatic optic pathway glioma appears by 3yo
• Malignant peripheral nerve sheath tumours

NF-1 Diagnostic Criteria:

• At least two (CAFE SPOT): (this mnemonic seems too good to be true but it actually quite accurate)
  • C: cafe au lait spots (six or more is highly suggestive of NF1)
  • A: axillary or inguinal freckles (Crowe sign)
  • F: fibromas (neurofibroma (>2) or plexiform neurofibroma (1)
  • E: eye hamartomas (Lisch nodules - 2 or more)
  • S: skeletal abnormalities (sphenoid wing and occipital bone dysplasia, leg bowing from thinning of bone cortex, scoliosis)
  • P: positive FHx
  • OT: optic tumour (optic nerve glioma) or optic pathway glioma

Neoplasm risks:

• Malignant peripheral nerve sheath tumours (15%)
• Optic nerve pathway glioma (15%)
• Brain/spinal cord glioma (3%)
• Breast cancer (20-40% lifetime)
• Phaeochromocytoma (2%)
• GIST (6%)
• NET (1.5%)

Surveillance

• Breast cancer - start annual MRI aged 30
• Phaeochromocytoma - annual BP measurement and low threshold for testing biogenic amines
• Malignant peripheral nerve sheath - annual clinical exam

NFT-related schwannomatosis (formerly called NF2)

• Autosomal dominant
• Risks:
  • Neurological lesions - schwannomas
  • Skin tumours
  • Ophthalmological lesions
  • Peripheral neuropathy
• Diagnosis - one of the following:
  • Bilateral vestibular schwannomas
  • At least two anatomically distinct NFT-2 related tumours, with identical pathogenic variant
  • Either two major, or one major/two minor criteria:
    • Major
      • Unilateral vestibular schwannoma
      • First-degree relative other than a sibling with NF2-related schwannomatosis
      • Two or more meningiomas
      • NFt pathogenic variant in an unaffected tissue such as blood
    • Minor
      • Ependymoma
      • Schwannoma
      • Juvenile subcapsular or subcortical cataract
      • Retinal hamartoma
      • Epiretinal membrane age <40yo
      • Single meningioma
• Screening/management
  • 3rd-yearly MRI
  • Most nerve tumours are managed conservatively