Neurofibromatosis Flashcards
Define neurofibromatosis.
An autosomal dominant genetic disorder affecting cells of neural crest originm resulting in the development of multiple neurocutaneous tumours.
How to remember: NF1 associated with problems with body as a whole (you only have 1 body), whereas NF2 associated with ear problems (you have 2 ears)’
How common is neurofibromatosis and who is affected?
- 1 in 3000 births for type 1 NF
- 1 in 40,000 births for type 2 NF
- No gender or racial predilection
- 50% are caused by new mutations
What is the aetiology of neurofibromatosis?
Mutations in the tumour suppressor geners NF1 and NF2
- Type 1 - NF1 gene mutation on chromosome 17 which encodes neurofibromin (a GTPase activating protein) → excessive activity of protooncogeen p21-ras
- Type 2 - mutations in NF2 gene on chromosome 22 which encodes merlin (or schwannomin)
What are the types of neurofibromatosis?
- Type 1 (von Recklinghausen disease) -
- Type 2
What are the signs and symptoms of type 1 neurofibromatosis?
-
Skin lesions =
- peripheral and spinal neurofibromas,
- >5 cafe au lait macules of >5mm (pre-puberty) or >15mm (post-puberty),
- axillary/inguinal freckling
-
Eyes =
- Optic nerve glioma (disturbed vision in 15%),
- Lisch nodules (hamartomas on iris)
- Bones = Skeletal deformities e.g. spinal scoliosis
- Kidneys = Phaeochromocytomas , renal artery stenosis
- Other = Learning difficulties (in 40%), headaches, precocious puberty (may indicate lesions of pituitary from optic glioma involving the chiasm)
What are the signs and symptoms of type 2 neurofibromatosis?
- Hearing loss - bilateral sensorineural hearing loss of acoustic neuromas by age 20
- Tinnitus
- Balance problems
- Headache
- Facial pain or numbness - facial nerve palsy
- Cerebellar signs if schwannoma is large
NB: Few/no skin lesions
What investigations would you do for neurofibromatosis?
Ophthalmological assessment - may be diagnostic in those with only a few cafe au lait spots. Slit lamp examination.
Audiometry - ?NF2
MRI brain and spinal cord - for vestibular schwannomas, meningiomas and nerve root neurofibromas show up as hyper-intense lesions on T2
Lesion biopsy - to confirm histological features of neurofibroma
Skull X-ray - sphenoid dysplasia in type 1 NF
Genetic testing - possible but difficult as the NF1 gene is very long
Describe the spots in neurofibromatosis in type 1. How are they used in diagnosis?
- Top - cafe au lait spots. Diagnosis:
- Pre-pubertal - >5 spots of >5mm each
- Post-pubertal - >5 spots of >15mm each
- Bottom left - neurofibromas
- Bottom right - Lisch nodules
What is acoustic neuroma associated with? What is it also known as?
Acoustic neuroma is good one to be aware of for written exam as it is associated with Neurofibromatosis type 2.
- It is BILATERAL
- AKA VESTIBULAR SCHWANNOMA
(this is a double misnomer as they are actually schwannomas in the vestibular nerve)
What is the diagnostic criteria for NF1 and NF2?
NF1: At least 2 of 7 of:
- >5 six café-au-lait spots, at least 5 mm wide in children, 15mm in adults.
- Axillary or inguinal freckles.
- Two or more typical neurofibromas/ one plexiform neurofibroma.
- Optic nerve glioma.
- Two or more iris hamartomas ie. Lisch nodules
- Sphenoid dysplasia or typical long-bone abnormalities such as arthrosis.
- First-degree relative with NF1.
NF2: at least 1 of 3 of:
- Bilateral 8th nerve masses on MRI scan.
- A first-degree relative with NF2 for a unilateral 8th nerve mass.
- A first-degree relative with NF2 for an individual with at least two of the following: Meningioma, Glioma, Schwannoma
What is the management of NF1?
Treatment depends on manifestations of disease
Phaeochromocytoma - surgical removal or chromaffin tumours
Malignant peripheral nerve sheath tumours - immediate referral for surgical removal or amputation as poorly responsive to chemo/radiotherapy.
Neurofibromas: grow slowly but may cause mass effect
- Surgical removal
- MEK1 /2 inhibitor e.g. selumetinib to treat inoperative plexiform neurofibromas
Cafe au lait/freckling do not require treatment
Headaches - investigate for raised ICP, vascular compromise or intracranial glioma
MDT support for learning difficulties
Lisch nodules - asymptomatic and do not need treatment
Eyes - monitor for visual compromise due to optic glioma
What is the management of NF2?
Assess hearing - annual; ophthalmology, MRI, audiology etc
Surgical removal of tumours
VEGF inhibitor e.g. bevacizumab - mAb used to shrink inoperable tumours
What are the complications of neurofibromatosis?
- Brain tumours
- Leukaemia
- Malignant change of peripheral nerve sheath tumours
etc
What is the prognosis of neurofibromatosis?
Reduced life expectancy due to malignancy and CVD
The earlier serious problems arise the greater the expectation for major long-term compromise
NF2 generally has worse prognosis
NF1 also reduces life expectancy but less than NF2; NF1 is very variable in its phenotype
