Neurofibromatosis

Neurofibromatosis

This is the commonest neurocutaneous syndrome and is transmitted as an autosomal dominant characteristic.

Two gene defects have been identified:

• NF-1 (Chromosome 17): Mainly cutaneous features and peripheral nerve abnormalities.
• NF-2 (Chromosome 22): Mainly central nervous system involvement and acoustic neuroma formation after the age of 20.

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Neurofibromatosis Type 1 (NF1)

Also known as von Recklinghausen disease.

NF1 has an incidence of 1 in 3000 live births. It is caused by an autosomal dominant gene on Chromosome 17.

• 50% are inherited from an affected parent.
• 50% result from sporadic (de novo) gene mutation.

Clinical Manifestations & Diagnostic Criteria

The disease is clinically diagnosed when ≥ 2 of the following seven features are present:

1. Café-au-lait Macules (≥ 6)

• Size: > 5 mm in greatest diameter in prepubertal individuals; > 15 mm in postpubertal individuals.
• They are the hallmark of neurofibromatosis and are present in almost 100% of patients.
• Typically the 1st manifestation to appear (present at birth but increase in size, number, and pigmentation).
• Note: They are not specific for NF1 and may be observed in other disorders.

2. Axillary or Inguinal Freckling (Crowe Sign)

• Consists of multiple hyperpigmented areas 2–3 mm in diameter.

3. Lisch Nodules (Iris Hamartomas) (≥ 2)

• Hamartomas located within the iris.
• Best identified by slit lamp examination.

4. Neurofibromas (≥ 2) or Plexiform Neurofibroma (1)

• Neurofibromas are the most common type of benign tumor in NF1.
  • Benign tumors of peripheral nerve sheath.
  • Most visible on the skin (small rubbery lesions with slight purplish discoloration), but may occur on any peripheral nerve including blood vessels and GI tract.
• Plexiform neurofibromas:
  • Typically congenital and result from diffuse thickening of nerve trunks and surrounding soft tissues.
  • May produce overgrowth of an extremity and deformity of the corresponding bone.
  • Pathognomonic for NF1 and has a risk of malignant transformation.

Dermal vs. Plexiform Neurofibroma:

5. Osseous Lesions

• Distinctive osseous lesions such as:
  • Sphenoid dysplasia (may cause pulsating exophthalmos).
  • Cortical thinning/thickening of long bones.
  • Tibial pseudoarthrosis.

6. Optic Glioma

• The most frequently observed CNS tumor in NF1.

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7. A First-Degree Relative with NF1

Complications of NF1

• Learning Disability: The most common complication, affecting > 50% of individuals.
• Seizures.
• Cerebral Vascular Abnormalities: Aneurysm or stenosis leading to CVA, hemiparesis, and cognitive defect.
• Malignancies: Higher incidence of pheochromocytoma, leukemia, and Wilms tumor.
• Scoliosis: A common complication.
• Hypertension: Results from renal vascular stenosis or pheochromocytoma.

Diagnosis & Management

Diagnosis:

• History and physical examination.
• MRI findings.

Management:

• There is no specific treatment; therapy is symptomatic.
• Multidisciplinary follow-up is necessary.
• Annual Assessments:
  • Vision exam (Ophthalmologic).
  • Neurologic assessment.
  • Blood pressure monitoring.
  • Full physical examination (Scoliosis evaluation, tumor surveillance).
• Treat complications.
• Neuropsychological and educational testing should be considered.
• Genetic counseling.

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Neurofibromatosis Type 2 (NF2)

Also known as MISME syndrome (Multiple Inherited Schwannomas, Meningiomas, and Ependymomas).

• Less common than NF1.
• Inheritance: Autosomal Dominant (Gene on Chromosome 22).
• Incidence: 1 in 25,000.
• Note: Café-au-lait macules can be seen but are much less frequent. NF2 is not associated with cognitive impairment (unlike NF1).

Clinical Manifestations

• Symptoms often appear during childhood: Tinnitus, hearing loss, facial weakness, headache, or unsteadiness.
• First manifestation: Typically Cataracts.
• Most common tumor: Schwannomas.
• Most common affected cranial nerve: CN VIII (Vestibulocochlear nerve).

Diagnostic Criteria

Diagnosed when one of the following sets is present:

1. Bilateral Vestibular Schwannomas (Acoustic Neuromas)

2. Unilateral Vestibular Schwannoma AND First-Degree Relative with NF2

3. Unilateral Vestibular Schwannoma OR First-Degree Relative with NF2 AND any two of the following:

• Meningioma
• Non-vestibular schwannoma
• Ependymoma
• Cataract

Management

• Multidisciplinary team approach.

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Schwannomatosis

• A form of neurofibromatosis clinically distinct from NF1 and NF2.
• Characterized by multiple Schwannomas in the absence of bilateral vestibular schwannomas.
• Incidence: ~0.47 in 1,000,000 persons.

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