Neurofibromatosis

Question 1

What is Neurofibromatosis?

Answer 1

Neurofibromatoses are genetic disorders characterised by tumour formation on nerves, associated with other changes such as skin lesions and bone deformities. There are inherited in an autosomal dominant pattern.

There are two main types: Neurofibromatosis Type 1, and Neurofibromatosis Type 2.

Reference: Nelson’s Paediatrics [20th Edition], p.2874.

Question 2

What is the underlying genetic defect in the Neurofibromatoses?

Answer 2

Neurofibromatosis Type 1

1 in 3000 live births

>50% are de novo mutations

NF-1 gene (17q11.2)

The NF-1 gene encodes for Neurofibromin protein which inhibits Ras, an oncogene.

Neurofibromatosis Type 2

1 in 25000 live births

NF-2 gene (22q11.2)

The NF-2 gene encodes for Merlin/Schwannomin.

Reference: Nelson’s Paediatrics [20th Edition], p. 2877.

Question 3

How does Neurofibromatosis Type 1 present?

Answer 3

Any two of the following seven features are diagnostic:

Café au Lait Spots (~100%)

Six or more (>5mm in prepubertal children, >15mm in postpubertal children)

Present in nearly all cases of NF-1; note that can be indicative of other conditions, e.g. Noonan Syndrome, Peutz-Jeghers Syndrome.

Axillary or Inguinal Freckling (~80% by 6 years)

Lisch Nodules (~74%)

>=2 nodules

Hyperpigmented iris hamartomas

Not a characteristic of NF-2.

Neurofibroma

>=2 Neurofibroma or 1 x Plexiform Neurofibroma

Small, rubbery with purplish colour.

Osseous Lesion

Examples include sphenoid dysplasia (can result in a pulsating exophthalmos), or thinned cortex of long bones.

Optic Glioma (~15%)

Mostly low-grade astrocytomas

Extension can affect hypothalamus causing endocrinopathies and failure to thrive.

First-degree relative with NF-1

For whom diagnosis was founded in above criteria.

Reference: Nelson’s Paediatrics [20th Edition], p. 2874-2876; PasTest.

Question 4

What are the complications of Neurofibromatosis Type 1?

Answer 4

• Learning disability (~30%)
• Neurological:
  
  • Seizures (~8%)
  • Cerebral aneuryms/stenosis > Moyamoya
  • TIA
  • Precocious Puberty
  • Spinal Cord Compression
• Neoplasms:
  
  • Astrocytomas
  • Phaechromocytoma
  • Wilm’s
  • Leukaemia
• Ophthalmological:
  
  • Astrocytic hamartomas
  • Congenital glaucoma
• Skeletal
  
  • Scoliosis
• Renal
  
  • Renal Artery Stenosis

NB: Moyamoya is a condition in which the internal carotid arteries become stenosed, resulting in the formation of collateral vessels in the formation of a ‘puff of smoke’ or ‘moyamoya’.

Reference: Nelson’s Paediatrics [20th Edition], p. 2876; NINDS, PasTest.

Question 5

How does Neurofibromatosis Type 2 present?

Answer 5

Any one of the following four features is diagnostic:

1. Bilateral Vestibular Schwannomas (90-95%)
2. First-degree relative with NF-2 and:
   
   • Unilateral vestibular schwannoma, or;
   • 2 of meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
3. ​Unilateral Vestibular Schwannoma and:
   
   • 2 of meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
4. Multiple meningiomas (2+) and:
   
   • ​Unilateral vestibular schwannoma, or;
   • 2 of schwannoma, glioma, neurofibroma, cataract.

Reference: Nelson’s Paediatrics [20th Edition], p. 2877.

Question 6

How is Neurofibromatosis Type 1 managed?

Answer 6

Multidisciplinary team approach including:

• Annual ophthalmology review
• Neurology
• Blood pressure monitoring
• Scoliosis evaluation
• Neuropsychology
• Educational testing

Reference: Nelson’s Paediatrics [20th Edition], p. 2876.