Diagnosis of Neurofibromatosis Type 2 (NF2)

1. Introduction

The earlier life diagnosis of neurofibromatosis type 2 (NF2) can help manage NF2 specific health problems.

For the condition of neurofibromatosis type 2 (NF2), there are two different standards for diagnosis:

1. Baser Pediatric Criteria
2. Manchester Criteria

Baser Pediatric Criteria

The Baser Pediatric Criteria is a newer method of diagnosis and can helps find individuals with NF2 early in life, in an older individual this standard could help determine if a child developing NF2 problems may have a parent with NF2 symptoms (spontaneous-mosaic NF2) but not enough issues for diagnosis of NF2 with the previous diagnosis criteria.

Manchester Criteria

Many with NF2 do not meet the Manchester Criteria for diagnosis until either late teens or adulthood and diagnosis that late can result in missed opportunities to manage problems an individual might face as a result of NF2.

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2. Criteria for NF2 Diagnosis ^{[Baser, M. E., 2016]}

There have been different standards for diagnosis of NF2 since it was acknowledged as a condition different from NF1, again when Schwannomatosis (SWN/NF3) was classified as a separate condition, and recently in 2016 as a result of a study in the UK.

As of 2016, the criteria for the diagnosis of NF2 is the baser criteria which is a revision of the manchester criteria. Michael E Baser, M.D. works with the team in Manchester UK, who have had a significant part in understandings of genetics and layout of criteria for the help of the diagnosis of the neurofibromatosis (NF) conditions.

It is important for doctors to know about the Manchester Criteria as well as the baser pediatric criteria since NF2 is not the only reason for Vestibular Schwannoma tumors, but the only condition that results in bilateral (left/right) vestibular schwannoma. Bilateral vestibular schwannoma trumors are not always seen in MRI's until later in life.

The 2018 revision of diagnosis for neurofibromatosis type 2 (NF2) change the tumor type of glioma, to ependymoma, and remove of neurofibroma. ^{[Evans, 2018]}

2.1. NF2: Schwannomatosis (July 2022)

NF2 Merlin is not neurofibromatosis type 2 but one of the three forms of schwannomatosis: Ring Chromosome 22, and SMARCB1(LZTR1).

2.1. Neurofibromatosis Type 2 (NF2) Diagnostic Criteria as of 2018 (December 2018 - now)

Primary Finding	Added Features needed for Diagnosis
Bilateral Vestibular Schwannoma	None
First-degree relative with NF2	Unilateral Vestibular Schwannoma, or Any two (2) other NF2-Associated lesions: Meningioma, Schwannoma, Ependymoma, or Juvenile Cataracts
Unilateral Vestibular Schwannoma	Any two (2) other NF2-Associated lesions: Meningioma, Schwannoma, Ependymoma, or Juvenile Cataract
Multiple Meningiomas	Unilateral Vestibular Schwannoma, or Any two (2) other NF2-Associated lesions: Schwannoma, Ependymoma, or Juvenile Cataracts

2.2. NF2 Baser Pediatric Diagnostic Criteria (2016 - December 2018)

The 2016 revision helped with the diagnosis of individuals with neurofibromatosis type 2 (NF2) at childhood years. The criteria from 1997 helped with diagnosis later in life. Early diagnosis of NF2 is important to monitor change and progression of NF2 issues.

Primary Finding	Added Features needed for Diagnosis
Bilateral Vestibular Schwannoma	None
First-degree relative with NF2	Unilateral Vestibular Schwannoma, or Any two (2) other NF2-Associated lesions: Meningioma, Schwannoma, Glioma, or Cataracts
Unilateral Vestibular Schwannoma	Any two (2) other NF2-Associated lesions: Meningioma, Schwannoma, Glioma, Neurofibroma, or Cataract
Multiple Meningiomas	Unilateral Vestibular Schwannoma, or Any two (2) other NF2-Associated lesions: Schwannoma, Glioma, Neurofibroma, or Cataracts

2.3 Manchester Criteria (1997 - 2016)

The 1997 manchester criteria required one of the following three conditions to apply for diagnosis of NF2:

• Bilateral Vestibular Schwannoma (VS)
• 1 or more 1st degree relative with NF2 + unilateral Vestibular Schwannoma at <30 years
• 2 of the following: Meningioma, Glioma, Schwannoma, Juvenile Posterior Lenticular Opacities

3. Diagnosis Methods

Diagnosis can be determined definitively through the following methods:

1. Neurologist Examination: This is the most common way for a neurologist to diagnose an individual with NF2 is a review of one of the following:
• MRI - MRI - The MRI would be both with and without contrast, gadolinium (Gd), and require a scan of the brain and spinal cord.
• Genetic Test - A genetic Test can be used to determine if not only one individual in a family has but if it is possible a parent has NF2 as well.


2. Neuro-Ophthalmologist - A neuro-ophthalmologist is a neurologist, with a specialty in vision. If they notice any of the following, an MRI is necessary for NF2 diagnosis confirmation:
• Optic Tumor Pressure (Papilledema ): An eye exam indicates tumor pressure on the eyes
• Juvenile Cataracts: Juvenile cataracts is a common eye issue at birth or shortly after for individuals with NF2.


3. Dermatologist Examination: Individuals with NF2 can develop skin irregularities of; 1) Café-au-lait Spots/Café-au-lait Macules (CALMs), as well as 2) skin surface tumors (cutaneous lesions) of schwannoma. Removal of a tumor to confirm is a schwannoma could help narrow down the condition type to either NF2 or schwannomatosis (SWN/NF3), but genetic testing of the tumor mass would be the only way for a dermatologist to determine conclusively has NF2.
   If the tumor mass is a neurofibroma, the individual more likely has NF1.


4. Otologic Examination - An ontological/ENT (ear nose throat) doctor, would have you take either or both:
• Audiometry Hearing Test - Speech Recognition/Discrimination Tests
• ABR - Auditory Brain Stem Response
• MRI - Magnetic Resonance Imaging of with and without Gadolinium of the brain and spinal cord.


5. Geneticist: To determine if a child who is known to have developed any signs of NF2, but to determine if; 1) the child is germline NF2, and 2) to determine which form exactly a child may have and how extensive their NF2 issues could be, the best method is for both parents to be tested.
   A genetic test (blood test) - There is 2/3 risk of a negative find of NF2 being wrong. It can mean not found, not that a person does not have NF2. Reason::
   • a person has Mosaic NF2, first generation NF2 with only part of the body having NF2.
   • NF2 can be the result of 200 different combinations of damage that involve the NF2 gene.
   Sometimes the only way to know for certain is from a tumor biopsy, which can make it complicated to determine if a person with spontaneous NF2 is or is not in fact germ line.

4. Additional Diagnosis Considerations

If a parent has NF2 but no tumors or eye issues are yet to be found on their child the following might justify the child may have NF2 like their parents and could justify genetic testing.

White Blood Cells

White blood cells are the component of the immune system. The amount of white blood cells increases when an individual's body is fighting something; typically, this is from germs for infections. However, if an individual is fighting tumor development, the white blood cell levels are typically higher than they should be. The white blood cell count is a statistic noted in regular blood tests.

Café-au-lait Spots

It is possible for a person with NF2 to develop Café-au-lait Spots(CALMS). However, CALMS only grow as a result of genetic conditions and justify the further medical test if a family has an NF type or otherwise.

Skin Tumors

Not all individuals with NF2 develop skin surface tumors. They are not a part of the NF2 criteria but can occur.

5. Sources

1. Evans, D. Gareth, et al. "Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing." Genetics in Medicine (2018): 1.
   https://www.nature.com/articles/s41436-018-0384-y
2. Ardern-Holmes, Simone, Gemma Fisher, and Kathryn North. "Neurofibromatosis Type 2: Presentation, Major Complications, and Management, With a Focus on the Pediatric Age Group." Journal of Child Neurology. 32.1 (2017): 9-22.
   Source: http://journals.sagepub.com/doi/abs/10.1177/0883073816666736 | DOI: 10.1177/0883073816666736
3. Baser, M. E., Friedman, J. M., Joe, H., Shenton, A., Wallace, A. J., Ramsden, R. T., & Evans, D. G. R. "Empirical development of improved diagnostic criteria for neurofibromatosis 2." Genetics in Medicine, 13(6), 576-581. (2011)
   Source: http://www.nature.com/gim/journal/v13/n6/abs/gim9201192a.html | DOI: 10.1097/GIM.0b013e318211faa9
4. Hoa, Michael, and William H. Slattery. "Neurofibromatosis 2." Otolaryngologic Clinics of North America 45.2 (2012): 315-332.
   Source: https://www.oto.theclinics.com/article/S0030-6665(11)00227-1/abstract | DOI: 10.1016/j.otc.2011.12.005
5. N., Miller, J. "NF2 Storyboard." CDMRP. National Institute of Health. (2010).