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Path 19.06 notes > 19.06.06 NF1/2 > Flashcards

19.06.06 NF1/2 Flashcards

1
Q

What is the most common autosomal dominant neurocutaneous disorder associated with tumour predisposition

A

Neurofibromatosis type 1

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2
Q

Prevalence of NF1

A

1 in 3-4,000 people affected worldwide

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3
Q

What is NF1 gene

A

A tumour suppressor gene

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4
Q

Main phenotypic features of NF1

A

Café au lait spots and neurofibromas. Features increase with age so can be difficult to diagnose in young patients.

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5
Q

Common cause of death in patients with NF1

A

Malignancy and vasculopathy

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6
Q

What are the diagnostic criteria developed by National Institute of Health

A

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
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7
Q

What is a café au lait (CAL) spot

A

Flat, pale coffee-coloured patches on skin.

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8
Q

What percentage of the general population has CALs

A

10%

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9
Q

What is a neurofibroma

A

Small benign lumps on the skin. Number increase with age. Can develop into larger plexiform neurofibromas.

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10
Q

What are Lisch nodules

A

Small lumps on the iris. Often asymptomatic and do not require treatment

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11
Q

What proportion of NF1 patients develop malignant tumours

A

5%. Often around brain, spinal cord, on optic nerve (glioma)

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12
Q

Other phenotypic features in NF1 patients

A
  • High blood pressure
  • Scoliosis, osteopenia and osteoporosis.
  • Cognitive impairment.
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13
Q

What is segmental NF1

A

NF1 features restricted to one part of the body. Due to somatic mosaicism

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14
Q

Treatment for NF1

A

MRI monitoring, ophthalmological examination, blood pressure monitoring.

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15
Q

How many alternative transcripts does NF1 gene have

A

3

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16
Q

Where is NF1 located

A

17q11.2

17
Q

Function of NF1

A
  • Produces neurofibromin
  • Expressed by oligodendrocytes, Schwann cells, nerve cells
  • Neurofibromin is a negative regulator of RAS.
  • Activates RasGTPase which converts RASGTP to inactive RASGDP.
18
Q

What happens when NF1 is mutated

A
  • Mutations result in increased active RAS and increased signalling (MAPK pathway)
  • Leads to cell proliferation
19
Q

Differential diagnoses

A

-NF1 mutations can also cause Noonan syndrome, LEOPARD syndrome, Legius syndrome, Costello syndrome.

20
Q

When is molecular testing essential to confirm a diagnosis of NF1

A

in young children

21
Q

Detection rate using sequencing and MLPA

A
  • sequencing= 90%

- MLPA= 4-5%

22
Q

Does NF1 have a high or low mutation rate

A

High. As a result somatic mosaicism is common

23
Q

Is testing DNA extracted from blood ideal for NF1 testing

A
  • No, due to high rate of somatic mosaicism (especially segmental mosaicism).
  • Testing of tumour DNA is ideal (is there LOH).
24
Q

Complication of testing tumour DNA

A

Potentially high levels of acquired mutations may complicate analysis

25
Q

Genotype phenotype correlation

A
  • 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.
26
Q

Is there a high degree of clinical variability amongst related and unrelated patients.

A
  • Yes
  • Due to allelic heterogeneity
  • modifying genes
27
Q

How common is NF2

A

1 in 25,000 (rarer than NF1= 1 in 3-4,000)

28
Q

NIH guidelines clinical criteria

A

One of the following

  • Bilateral vestibular schwannomas
  • First degree relative with NF2 and a schwannoma or other tumour (glioma, neurofibroma)
29
Q

What is a vestibular schwannoma

A

benign intracranial tumour of the myelin forming cells of the vestibulocochlear nerve

30
Q

What does a vestibular schwannoma cause

A
  • Gradual hearing loss
  • Tinnitus
  • Balance problems
31
Q

What is NF2 gene

A

A tumour suppressor

32
Q

What is the function of NF2

A

Encodes neurofibromin 2. Produced by the nervous system, such as Schwann cells

33
Q

What do mutations in NF2 cause

A
  • to produce non-functional neurofibromin 2.

- Leads to increased growth and cell division (e.g. of Schwann cells).

34
Q

Detection rate with sequencing and MLPA

A

Combined= 72% for simplex cases and 92% of familial cases

35
Q

Is somatic mosaicism an issue with NF2

A
  • Yes, similar to NF1. Testing lymphocyte DNA may miss mosaic variants.
  • Testing tumour DNA may detect both constitutional variant and the acquired variant

Path 19.06 notes (29 decks)

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