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NF2 (Neurofibromatosis type 2) – risk management

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Neurofibromatosis type 2 (NF2) is an autosomal dominant tumour predisposition condition, characterised by the development of nerve cell tumours such as schwannomas and meningiomas, ophthalmological and skin lesions, and peripheral neuropathy. Approximately 50% of cases are de novo, and of these, one third are mosaic, often with milder, asymmetrical disease.  

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

  • Individual with a known or obligate germline NF2 pathogenic variant 
  • Individual with a pathogenic somatic/mosaic NF2 variant in whom a germline LZTR1 and SMARCB1 genotype has been excluded
  • Individual who meets revised Manchester criteria for NF2 (if tumour testing and germline next generation sequencing for NF2 variants with high-read depth is not available)
  • Individual at 50% risk of inheriting a germline NF2 pathogenic variant
  • Individual with a first degree relative who meets revised Manchester criteria for NF2, but where genetic testing is uninformative or not available

Exclusion criteria

  • Individual who has a first degree relative who meets clinical criteria for NF2, but does not have any clinical signs of NF2 after age 40 years
  • Individual who meets revised Manchester criteria for NF2, but who has a germline pathogenic variant in LZTR1 or SMARCB1
  • Individual with a variant of uncertain significance
Tumour typer Risk for individuals with a germline NF2 pathogenic variantrr General population risk by age 85 years
Neurological lesions
Bilateral vestibular schwannomas 87-95% Unable to obtain
Other cranial nerve schwannomas 24-51%
Intracranial meningiomas 45-58%

Spinal tumours

- Extramedullary (e.g. schwannomas, meningiomas)

- Intramedullary (e.g. ependymomas)

63-90%

55-90%
 

18-53%
Ophthalmological lesions
Retina hamartomas

6-22%

 Unable to obtain
Cutaneous lesions
Skin tumours

59-68%

 Unable to obtain
Subcutaneous tumours

43-48%
Intradermal tumours

Rare
Manifestation Risk for NF2 carriersr General population risk by age 85 years
Peripheral neuropathy  Up to 66% Unable to obtain
Cataracts 60-81% Unable to obtain
Epiretinal membranes 12-40% Unable to obtain
Skin plaques 41-48% Unable to obtain

Individuals with NF2 should be managed by a multidisciplinary team who have extensive experience with the condition and may include neurosurgeons, ear nose and throat surgeons, neurologists, clinical geneticists, ophthalmologists, pathologists, radiologists, audiologists, genetic counsellors and other nursing and allied health staff.rr

Individuals with possible or probable NF2 or mosaic disease may require more individualised management depending on their clinical presentation. Biologic therapies are becoming available and might be considered on an individual basis depending on local access.

Tumour type Recommendations
Bilateral vestibular schwannomas and other neurological lesions Surveillance Age Strategy and frequency
From infancy
  • Annual neurological examinationr
  • Annual speech and pure tone audiology with auditory brainstem evoked potentialsrr
From  10-20 years
  • Annual cranial and spinal MRI with gadolinium enhancement (gold standard)rr
  • Once tumours are present, MRI screening should be at least annual until the individual growth rate is established.r The ongoing interval for follow-up imaging of tumours is dependent on tumour location and growth raterr
From  20 years
  • 3rd-yearly MRI, unless tumours are presentrr
  • Cease surveillance at age 40 years iif no clinical or genetic signs of NF2
Surgery or treatment
  • Most NF2 associated tumours are managed conservatively
  • Consider tumour removal surgery, if appropriate, depending on the associated symptoms, size, location, growth rate, number of tumours, patient’s comorbidities and possible complications that may arise from surgeryrrr
  • Consider appropriateness of anti-angiogenic agents for bilateral vestibular schwannoma
Ophthalmological lesions Surveillance Age Strategy and frequency
From infancy Annual ophthalmological examination
From 40 years Cease surveillance at age 40 years if no clinical or genetic signs of NF2
Cutaneous lesions Surveillance There is no evidence to support regular surveillance of cutaneous lesionsrr

Allied health professional involvement, such as physiotherapy, occupational therapy, audiology, psychology, social work, hearing, speech and language therapy is important in managing tumour associated side effects.r

The recommendations are mostly based on established consensus guidelines.r

Neurological lesions 

Surveillance

MRI is recommended even in asymptomatic individuals as NF2 associated tumours and interval tumour growth may occur without any change in symptoms.r

Surgical 

The type, timing and degree of surgery (if any) should be carefully considered by a multidisciplinary team with experience in managing NF2, the lifelong implications of the condition, its treatments and the complications that may result from treatment. The cornerstone of care is in minimal interference, conservation of function and maintenance of quality of life.r Factors that should be considered in surgical decision making include tumour impact on the patient (such as degree of brain stem compression), size, location, growth rate, number of lesions, patient’s comorbidities (such as degree of hearing loss in each ear), suitability for auditory rehabilitation (using a cochlear implant or auditory brain stem implant) or other treatment (e.g. stereotactic radiosurgery), and the possible complications that may arise from the surgery, such as loss of cochlear, vestibular, bulbar and facial nerve function.rrr

Anti-angiogenic agents

Anti-angiogenic agents (including bevacizumab) have demonstrated disease stabilisation, tumour reduction and improved hearing in bilateral vestibular schwannoma.rr Bevacizumab was listed on the Pharmaceutical Benefits Scheme (PBS) in Australia on 1st June 2021 as an unrestricted benefit, including for use in NF2-related tumours. Prescription of bevacizumab should only occur with input from a multidisciplinary team including individuals with experience in its use.

Given the de novo rate and chance of mosaicism, first degree blood relatives (parents/brothers/sisters/children) may be at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Version 6

Date Summary of changes
13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template:

  • Summary:
    • Template sentence updated.
  • Target population:
    • Added to exclusion criteria "Individual with a variant of uncertain significance".
  • Management of associated health problems:
    • Accordion title changed to "Management of associated health issues".

Version number increased to V.6.

Version 5

Date Summary of changes
14/08/2021

Protocol discussed at the May 2021 cancer genetics reference committee meeting. Discussion continued electronically via MS Teams. Protocol approved for publication with the following changes made: 

  • Target group
    • Bullet 1: 'Known or obligate NF2 gene pathogenic variant carrier' changed to 'Individuals with a known or obligate germline NF2 pathogenic variant'
    • Bullet 2 and bullet 3 added
    • Exclusion criteria: bullet 2 added
  • Lifetime risk of tumour
    • Bilateral vestibular schwannoma changed from '90–95%' to '87-95%' and new reference added
  • Tumour risk management guidelines
    • Second paragraph: 'Biologic therapies are becoming available and might be considered on an individual basis depending on local access.' added
    • Bilateral vestibular schwannomas and other neurological lesions - Risk-reducing medication: row removed
    • Bilateral vestibular schwannomas and other neurological lesions - Surgery or treatment: 'Consider appropriateness of anti-angiogenic agents for bilateral vestibular schwannoma' added
  • Evidence for risk management guidelines
    • 'Risk-reducing medication' heading changed to 'Anti-angiogenic agents'
    • Paragraph added about anti-angiogenic agents
  • Website resources
    • Removed link to AdvocureNF2 website.

Version number increased to V.5. To be reviewed in 2 years.

Version 4

Date Summary of changes
18/12/2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.4.
11/01/2021 The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template:
  • Summary: template sentence added
  • Lifetime risk of cancer: heading changed to "Lifetime risk of tumour"
  • Tumour risk management guidelines:
    • Surveillance: "Age to begin" changed to "Age" 
    • Other table formatting changes
  • Support and information: template wording updated.

Version 3

Date Summary of changes

07/06/2016

New protocol discussed at March 2016 cancer genetics reference committee meeting.

Approved and published on eviQ. Review second yearly. 
31/05/2017 Transferred to new eviQ website. Version number changed to V.2.   
20/09/2018

Presented at May 2019 and discussion continued over email. Approved for publication with the following changes: 

  • Target group: 'Individuals meeting clinical criteria for NF2, but for whom genetic testing is uninformative or has not been performed' bullet removed
  • Lifetime risk of tumour/ Lifetime risk of non-cancer related manifestations/Non-cancer risk management guidelines: 'cancer' replaced with 'tumour'
  • Management of associated health problems: 'Management of tumour associated problems' removed
28/08/2019 Protocol title changed from 'Risk management for neurofibromatosis type 2 (NF2)' to 'NF2 (Neurofibromatosis type 2) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.3.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1910

13 Oct 2024