Neurofibromatosis

Neurofibromatosis, due to mutations of NF1 or NF2, are tumour syndromes characterised by multiple neurofibromas (NF1) or schwanommas (NF2).

Neurofibromatosis Type 1

The incidence of NF Type 1 is about ten times more common than NF2, occuring in 1/2,500-3000 people. Similarly, 50% of cases of sporadic and 50% are inherited.

Genetics

NF1 codes for a large protein neurofibromin, which acts as a tumour suppressor. It downregulates the activity of ras, and thereby the activity of c-KIT, mTOR and MAP-kinase. Total loss of neurofibromin via a second hit leads to dysregulation of cell cycle control and promotes growth of neurofibromas.

Neurofibromatosis Type 2

The incidence of NF Type 2 is about 1/25,000. It is less recognised due to a higher frequency of de novo mutations (about 50% of cases) and a reduced rate of skin conditions.

Genetics

NF type 2 is due to deactivating mutation of the NF2 gene which produces the protein merlin…. which is a cool name for a protein. This cell membrane protein functions as a tumour suppressor and therefore both genes must be lost for an NF2 neoplasm to develop. Familial cases are due to germline mutation of NF2 but about 50% of cases occur de novo.

Phenotype

Most patients present in their 20s. There are neurological, eye and skin lesions.

  • Neurological: The defining feature of the syndrome is bilateral schwannomas of the eighth cranial nerve which occur in 95% of patients by the age of 30. Scwhannomas of other cranial nerves occur frequently but less commonly (25-50%). Meningiomas develop in about 50% of patients and may occur with greater frequency in older patients. Spinal tumours include schwannomas (which are usually dumbbell shaped and arise from the dorsal root), however meningiomas are signficantly more common than in the general population and about 10% of patients develop ependymoma.
  • Eye: Cataracts develop n
  • Cutaneous: Cutaneous lesions are common (70%) but not as widespread or pathognomonic as for NF1. Plaques, subcutaneous and cutaneous schwanommas can be seen but the number of lesions is usually low.

Prognosis

The widespread scwhannomas often result in deafness and impaired mobility. The average life expectancy in the 1980s was 36 years but this may be longer now with improved surgical, anaesthetic and antibiotic techniques.

Treatment

Radiotherapy should typically be avoided as it may induce new tumours in these patients; it may be necessary for inoperable tumours. Surgery is the mainstay of treatment of schwanommas and meningiomas. Ependymomas may be observed, particularly if asymptomatic. Surgery is also the main treatment for these unless subtotal resection is achieved.

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