NF1 / NF2

Question 1

What are the characteristic symptoms of NF1?

Answer 1

Cafe-au-lait spots + neurofibromas (present in >95% of cases)

Question 2

What is segmental NF1?

Answer 2

When features are restricted to specific parts of the body (caused by somatic mosaicism)

Question 3

What are some differential diagnoses for NF1?

Answer 3

Variants in this pathway cause NF1 and three overlapping neuro-cardio-facial cutaneous syndromes:

LEOPARD syndrome
Noonan syndrome
Costello syndrome

Question 4

Do children with NF1 have an increased risk of any other disorders?

Answer 4

Yes - increased risk of a malignant myeloid disorder, particularly Juvenile MyeloMonocytic Leukaemia (JMML)

Question 5

Provide some info on the genetics of NF1.

Answer 5

NF1 gene (chr17).
AD.
Majority = het LoF variants (>80% are severe truncation).
50% arise de novo.
Mosaicism is common.

Question 6

What is the disease mechanism for NF1?

Answer 6

NF1 produces neurofibromin 1 in range of cells incl. nerve, oligodendrocytes and Schwann cells.

Acts as a tumour suppressor - preventing cells from uncontrolled growth/division via RAS/RasGTP and MAPK pathways.

Question 7

What is the molecular testing strategy for NF1?

Answer 7

Sequence analysis detected ~90%, with whole gene dels ~5%.

High levels of mosaicism = not ideal to test using DNA from blood (unless inherited).

Direct testing of tumour DNA (incl. LoH) and analysis of RNA/cDNA can be applied.

Question 8

What can complicate direct tumour DNA testing in NF1?

Answer 8

Potentially high level of acquired variants.

Frequent mutation of NF1 in non-neurofibromatosis tumours.

Question 9

Are there any genotype-phenotype correlations in NF1?

Answer 9

Extreme clinical variability often seen thought to be due to a number of factors incl.:

• NF1 variant itself (e.g. whole gene del = earlier onset neurofibromas)
• Influence of modifying genes
• Random events (e.g. acquired 2nd hit variants/LoH at NF1 locus)

Question 10

What does the NF1 treatment pathway involve?

Answer 10

No cure - treat symptoms only.
Regular MRI monitoring.
Annual eye exam.
Regular developmental assessment.

Gene therapy trials ongoing.
Chemo (e.g. imatinib) showing promising results for neurofibromas.

Standard chemo/surgery for other associated tumours.

Question 11

What are the 5 approaches for NF1 gene therapy?

Answer 11

1. Gene replacement
2. Genome editing
3. RNA editing
4. Exon skipping
5. NST (nonsense suppressor tRNAs)

See image in notes for more details.

Question 12

Provide some info on NF2 disease background.

Answer 12

Less common than NF1.
AD (50% inherited, 50% de novo).

25-30% of sporadic cases = mosaic (constitutional variant plus 2nd acquitted hit seen in tumour DNA).

Question 13

What is the disease mechanism for NF2?

Answer 13

NF2 produces neurofibromin 2 in nervous system, particularly Schwann cells (surround + insulate nerve cells in brain + spinal cord).

Acts as tumour suppressor, impacting PI3 kinase/Akt, Raf/MEK/ERK + mTOR signalling pathways.

Variants in NF2 gene lead to production of non-functional protein that cannot regulate growth + division of cells.

Question 14

What is a differential diagnosis for NF2?

Answer 14

Schwannomatosis
(also caused by SMARCB1 variants).

Question 15

Provide some info on genotype-phenotype correlation in NF2.

Answer 15

Nonsense/frameshift vars = severe disease regardless of gene position.

Truncating vars also = increased prevalence of spinal tumours.

Large dels and missense variants = mild phenotype.