62 Neurofibromatosis Type 1

Case 62 Neurofibromatosis Type 1


Jean-Pierre Farmer and Abdulrahman J. Sabbagh


Image Clinical Presentation



  • A 3-year-old child is referred to you because of the presence of multiple café-au-lait spots.
  • His parents have a normal phenotype.
  • History does not reveal any developmental delay.
  • His physical examination shows macrocrania, multiple café-au-lait spots, 12 in total, greater than 0.5 cm.
  • There is no scoliosis.
  • He has pulsatile proptosis of the right eye without chemosis or pupillary changes.

Image Questions




  1. What are the diagnostic criteria for neurofibromatosis type I (NF-1)?
  2. What are other NF-1 associated conditions?
  3. What are types of cutaneous neurofibromas?
  4. How would you proceed with investigations?
  5. Which additional consultants would you involve?
  6. Which lesions, if present, would likely require more frequent surveillance and imaging in this patient?
  7. What is the cause of pulsatile proptosis?
  8. What is the chance of occurrence of optic pathway gliomas in NF patients?
  9. What are the rates of optic glioma progression in NF patients?
  10. What imaging characteristics of optic glioma might help in determining the prognosis?
  11. What is the usual cause of aqueductal stenosis in NF-1 patients?
  12. How frequent are academic difficulties in patients with NF?
  13. Assuming the magnetic resonance imaging (MRI) of the brain and spine are normal, what would be your recommended follow-up scan frequency?
  14. Is the age at diagnosis significant with respect to prognosis in patients with NF-1?
  15. What is the NF-1 gene and where is it located?
  16. What is neurofibromin? What are its functions?
  17. Describe the Ras signaling pathway (Rat sarcoma) and its relation to neurofibromin.

Image Answers




  1. What are the diagnostic criteria for NF-1?


    • NF-1 criteria include the following:1


      • Six or more café-au-lait spots (over 5 mm in pre-pubertal individuals, over 15 mm in postpubertal individuals)
      • Two or more neurofibromas of any type or one plexiform neurofibroma
      • Freckling in the axillary or inguinal region
      • Optic glioma
      • Two or more Lisch nodules (iris hamartomas)
      • Osseous lesions such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis
      • A first-degree relative (parent, sibling, or off spring) with NF-1 by the above criteria

  2. What are other NF-1-associated conditions?


    • NF-1 associated conditions include the following:1,2


      • Aqueductal stenosis
      • Macrocephaly
      • Unilateral superior orbital defect (pulsatile exophthalmos)
      • Cognitive impairment and learning disabilities
      • Kyphoscoliosis
      • Syringomyelia
      • Intracranial tumors


        • Astrocytoma, hemispheric
        • Meningioma, solitary or multicentric (adults)

      • Extracranial tumors


        • Schwann cell tumors
        • Neuroblastoma
        • Sarcoma
        • Leukemia
        • Wilms’ tumor
        • Pheochromocytoma

      • Moyamoya disease

  3. What are types of cutaneous neurofibromas?


    • Types of neurofibromata (Friedman and Riccardi classification)3–5:


      • Discrete cutaneous: Soft and fleshy nodules located in epidermis, dermis, and trunk mainly, but in the face and extremities as well. Usually more than a 100 lesions are seen by age 40.
      • Discrete subcutaneous: These are firm and rubbery.
      • Deep nodular (plexiform nodular): involve nerves beneath the dermis; they are fusiform; may involve the entire nerve.
      • Diffuse plexiform: congenital in origin, evident in infancy or childhood. They are locally invasive and have poorly defined margins. They may be precancerous.

  4. How would you proceed with investigations?


    • MRI of the brain, spine, and orbits
    • Formal visual acuity, visual fields, and extraocular movement testing.
    • Genetic testing

  5. Which additional consultants would you involve?


    • Ophthalmologist
    • Pediatrician
    • Geneticist

  6. Which lesions, if present, would likely require more frequent surveillance and imaging in this patient?


    • Lesions requiring frequent follow-ups include6,7


      • Brainstem gliomas
      • Paraspinal gliomas
      • Craniofacial neurofibromas
      • Symptomatic lesions
      • Extraoptic glioma

    • Every 2 years for asymptomatic gadolinium-enhancing lesions7


      • Optic pathway and parenchymal gliomas
      • Cranial nerve and visceral neurofibromas

  7. What is the cause of pulsatile proptosis?


    • The most likely cause of pulsatile proptosis is sphenoid wing hypoplasia.

  8. What is the chance of occurrence of optic pathway gliomas in NF patients?


    • The chance of occurrence of optic pathway gliomas in NF patients is 15 to 30%.7,8

  9. What are the rates of optic glioma, progression in NF patients?


    • Optic pathway gliomas progress in 12% of NF patients that harbor them.

  10. What imaging characteristics of optic glioma might help in determining the prognosis?


    • The main characteristic that indicates a smaller chance of progression is lack of enhancement.7

  11. What is the usual cause of aqueductal stenosis in NF-1 patients?


    • The usual cause of aqueductal stenosis in NF-1 patients is the occurrence of midbrain unidentified bright objects (UBOs).9,10

  12. How frequent are academic difficulties in patients with neurofibromatosis?


    • Academic difficulties in patients with NF-1 are as common as 30 to 46%.11,12

  13. Assuming the MRI of the brain and spine are normal, what would be your recommended follow-up scan frequency?


    • Assuming the MRI of the brain and spine are normal, young patients require annual MRIs.13

  14. Is the age at diagnosis significant with respect to prognosis in patients with NF-1?


    • Age at diagnosis below 6 years carries a significantly worse prognosis in patients with NF-1.

  15. What is the NF-1 gene and where is it located?


    • The NF-1 gene has the following characteristics12,14:


      • Located on chromosome 17, band q12.2
      • Base pairs 26,446,242 to 26,725,589
      • 335,000 chemical bases
      • 60 exons, alternative splicing at exons 9a, 23a, 48a
      • It is a tumor suppressor gene that encodes neurofibromin.

  16. What is neurofibromin? What are its functions?


    • Neurofibromin15


      • It is a protein (2818 amino acids, molecular mass 327 kDa)16 that is mainly expressed in


        • Astrocytes and oligodendrocytes of the central nervous system
        • Sensory neurons of the peripheral nervous system
        • Schwann cells
        • Other cells originating from the neural crest such as melanocytes

      • It functions by inactivating Ras by stimulating intrinsic Ras-GTPase to hydrolyze Ras attached guanosine triphosphate (GTP) to guanosine diphosphate (GDP).

  17. Describe the RAS signaling pathway (Rat sarcoma) and its relation to neurofibromin.


    • RAS when activated can lead to tumor formation.
    • Neurofibromin functions to deactivate RAS.
    • See Fig. 62.1 for further details.
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Jul 16, 2016 | Posted by in NEUROSURGERY | Comments Off on 62 Neurofibromatosis Type 1

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