Neurofibromatosis Type 1

  • Epidemiology
    • 1 in every 3000 to 3500 births
  • Inheritance pattern
    • AD
    • ~50% de novo mutations
      • If ≥ 2 affected children of unaffected parents consider germline mosaicism or (false paternity)
    • Can have segmental/mosaic disease
    • 100% penetrance (by age 8)
  • Mutation
    • NF1 gene is located on 17q11.2 of chromosome 17 (tumoral supressor gene)
    • Neurofibromin protein é produzida em múltiplos tecidos
      • Sobretudo crista neural
        • Neurónios
        • Schwann cells
        • Melanocytes
      • Outras células
        • Astrócitos
        • Células musculares lisas vasculares e células endoteliais
        • Fibroblastos
        • Osteoblastos
        • Queratinócitos
    • Inhibition of cell growth and proliferation via inhibition of the Ras signal transduction pathway (Ras activity is inhibited by the stimulation of GTPase)
    • Activation of the AKT/mTOR and Raf/MEK/ERK pathways
    • Non functional neurofibromin protein influences the growth of neurofibromas along the nerves of the whole body
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  • Clinical presentation
    • Skin
      • Multiple neurofibromas: benign peripheral nerve sheath tumors that originate from neural crest cells and affect the myelinated nerves.
        • Soft, painless nodules: typically manifest under or on the skin
        • Dermal and subcutaneous neurofibromas onset: adolescence
        • Malignant transformation possible
        • Plexiform neurofibromas have a risk of malignant degeneration
          • Plexiform neurofibromas
            • Likely congenital, grow over time
            • Cutaneous “bag of worm” or dark brown plaque with overlying hypertrichosis
            • Deeper nodules
            • Degeneration into malignant peripheral nerve sheath tumor (2-11%) - concern if rapid increase in size, pain
          • FDA approved selumetinib in 2020 for treatment of inoperable plexiform neurofibromas (oral MEK inhibitor)
      • Features due to melanocyte dysfunction:
        • Café au lait spots
          • Brown (hyperpigmented), flat macule or patch
          • Age of onset: before 2 years
        • Lisch nodules
          • Pigmented iris hamartomas
          • Age of onset: between 5–10 years
        • Axillary and inguinal freckling
          • Crowe-sign
          • Age of onset is between 3–5 years
      • Há quem ache que também deviam estar nos critérios de diagnóstico:
    • Neurologic
      • Seizures and/or focal neurologic signs due to brain lesions (especially meningiomas)
      • Intellectual disability
      • Macrocephaly
    • Bone involvement
      • Dysplasia of long bones, particularly tibia
      • Scoliosis
      • Sphenoid wing dysplasia - associated with orbital plexiform neurofibroma, can lead to exophtalmos or enophtalmos
      • Vertebral dysplasia with accentuation of the posterior concavity (scalloping) of the vertebral body → scoliosis and kyphoscoliosis
        • May be associated with meningoceles or paravertebral neurofibromas
      • Short stature
      • Cortical thinning
      • Fractures
      • Pseudoarthrosis
    • Ocular
      • Optic pathway glioma (most commonly involving optic nerve) causing unilateral vision loss, proptosis, or precocious puberty
        • Histologically is a low grade pilocytic astrocytoma
    • Other organ systems
      • Associated with certain tumors
      • Vascular complications
        • Renovascular Hypertension
        • Aneurysms
        • Pulmonary stenosis
        • Stenosis of the aorta, renal arteries, mesenteric arteries
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    • Timing of onset of finding
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  • Neurofibromatosis Type I Diagnostic criteria
    • At least one of the two pigmentary findings (café-au-lait macules or freckling) should be bilateral
    • A: the dignostic criteria for NF1 are met in an individual who does not have a parent diagnosed with NF1 if two or more of the following are present
      • Six or more café-au-lait macules (>5mm diameter in prepubertal individuals and >15mm in post pubertal individuals)
        • May not be born with. Need continuous assessment.
      • Freckling in axillary or inguinal regions
      • Two or more neurofibromas of any type, or one plexiform neurofibroma
      • At least two Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities
      • Optic pathway glioma
      • A distinctive osseous lesion, such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone
      • A heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells
    • B: A child of a parent who meets the diagnostic criteria specified in A merits a diagnosis of NF1 if one or more of the criteria in A are present
  • DDx
    • McCune-Albright syndrome
    • Fanconi anemia
    • Tuberous sclerosis
    • Ataxia telangiectasia
    • Noonan syndrome
      • Cadiopatia congénita com estenose pulmonar
      • Manchas café com leite mais escuras
      • Fascies
    • Bloom syndrome
    • Legius syndrome
    • Neurofibromatosis type 2
  • Complicações
    • Malignant degeneration of peripheral or plexiform neurofibromas
      • Increase in size or pain should raise suspicion of a malignant tumor → biopsy
    • Principal: neurofibromas plexiformes → learning difficulties in 30-40%
    • Pseudarthrosis and scoliosis requiring surgery
    • Hydrocephalus
    • Pheocromocitoma, carcinoid tumors
    • Aggressive optic pathway gliomas
    • Cerebral glioblastoma (high grade malgnant astrocytoma)
    • Malignant tumors of the nerve sheat
    • Association of juvenile xanthogranuloma and myelomonocytic leukemia
    • Vascular complications
  • Abordagem
    • Follow up should be primarily clinical, systematic examinations are not cost-effective
    • Controversial: MRI of the brain and spine with contrast: to detect e.g., neurofibromas, meningiomas, optic pathway glioma
    • Ophthalmological exam: to detect optic glioma in NF type 1
    • Auditory testing: to detect acoustic neuromas in NF type 2
    • Genetic testing: mutations in NF1 gene or NF2 gene (se necessário para completar critérios de diagnóstico ou para aconselhamento familiar)
  • Treatment
    • Excision or resection of tumors (e.g., meningiomas)
      • Plexiform neurofibroma excision usually hemorragic
    • Surgery for kyphoscoliosis in NF type 1
    • Drugs targeting the mTOR pathway (e.g., sirolimus) to reduce tumor growth
  • Prognosis
    • Increased mortality due to malignant transformation of tumors
    • Unpredictable course throughout life
    • Average life expectancy
      • NF type 1: ∼ 60 years
      • NF type 2: ∼ 40 years
  • Planeamento familiar
    • It is not possible to assess the future severity of NF1: intra-family variations are the norm
    • Prenatal diagnosis is only possible if the mutation is identified, which is possible in 90% of cases
    • Couples who are planning to have children and are aware of this risk are increasingly opting for prenatal or preimplantation diagnosis
  • Vigiar em idade adulta
    • Justifica consulta de dermatologia ou vigilância no médico de família?