19.06.06 NF1/2 Flashcards
What is the most common autosomal dominant neurocutaneous disorder associated with tumour predisposition
Neurofibromatosis type 1
Prevalence of NF1
1 in 3-4,000 people affected worldwide
What is NF1 gene
A tumour suppressor gene
Main phenotypic features of NF1
Café au lait spots and neurofibromas. Features increase with age so can be difficult to diagnose in young patients.
Common cause of death in patients with NF1
Malignancy and vasculopathy
What are the diagnostic criteria developed by National Institute of Health
Six or more café au lait macules over 5mm (prepubertal) or 15mm (post pubertal)
- Two or more fibromas or one plexiform neurofibroma
- freckling in armpit or groin
- optic glioma
- Two or more Lisch nodules
- Osseous lesion
- First degree relative with NF1 as defined above
What is a café au lait (CAL) spot
Flat, pale coffee-coloured patches on skin.
What percentage of the general population has CALs
10%
What is a neurofibroma
Small benign lumps on the skin. Number increase with age. Can develop into larger plexiform neurofibromas.
What are Lisch nodules
Small lumps on the iris. Often asymptomatic and do not require treatment
What proportion of NF1 patients develop malignant tumours
5%. Often around brain, spinal cord, on optic nerve (glioma)
Other phenotypic features in NF1 patients
- High blood pressure
- Scoliosis, osteopenia and osteoporosis.
- Cognitive impairment.
What is segmental NF1
NF1 features restricted to one part of the body. Due to somatic mosaicism
Treatment for NF1
MRI monitoring, ophthalmological examination, blood pressure monitoring.
How many alternative transcripts does NF1 gene have
3
Where is NF1 located
17q11.2
Function of NF1
- Produces neurofibromin
- Expressed by oligodendrocytes, Schwann cells, nerve cells
- Neurofibromin is a negative regulator of RAS.
- Activates RasGTPase which converts RASGTP to inactive RASGDP.
What happens when NF1 is mutated
- Mutations result in increased active RAS and increased signalling (MAPK pathway)
- Leads to cell proliferation
Differential diagnoses
-NF1 mutations can also cause Noonan syndrome, LEOPARD syndrome, Legius syndrome, Costello syndrome.
When is molecular testing essential to confirm a diagnosis of NF1
in young children
Detection rate using sequencing and MLPA
- sequencing= 90%
- MLPA= 4-5%
Does NF1 have a high or low mutation rate
High. As a result somatic mosaicism is common
Is testing DNA extracted from blood ideal for NF1 testing
- No, due to high rate of somatic mosaicism (especially segmental mosaicism).
- Testing of tumour DNA is ideal (is there LOH).
Complication of testing tumour DNA
Potentially high levels of acquired mutations may complicate analysis
Genotype phenotype correlation
- Whole gene deletion is associated with early onset neurofibromas and large number
- c.2970-2972del is associated with CALs but not neurofibromas
- Duplications may result in ID and seizures.
Is there a high degree of clinical variability amongst related and unrelated patients.
- Yes
- Due to allelic heterogeneity
- modifying genes
How common is NF2
1 in 25,000 (rarer than NF1= 1 in 3-4,000)
NIH guidelines clinical criteria
One of the following
- Bilateral vestibular schwannomas
- First degree relative with NF2 and a schwannoma or other tumour (glioma, neurofibroma)
What is a vestibular schwannoma
benign intracranial tumour of the myelin forming cells of the vestibulocochlear nerve
What does a vestibular schwannoma cause
- Gradual hearing loss
- Tinnitus
- Balance problems
What is NF2 gene
A tumour suppressor
What is the function of NF2
Encodes neurofibromin 2. Produced by the nervous system, such as Schwann cells
What do mutations in NF2 cause
- to produce non-functional neurofibromin 2.
- Leads to increased growth and cell division (e.g. of Schwann cells).
Detection rate with sequencing and MLPA
Combined= 72% for simplex cases and 92% of familial cases
Is somatic mosaicism an issue with NF2
- Yes, similar to NF1. Testing lymphocyte DNA may miss mosaic variants.
- Testing tumour DNA may detect both constitutional variant and the acquired variant
