NF Criteria

Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), and Schwannomatosis (SWN/NF3)

The three forms of neurofibromatosis are; neurofibromatosis 7ype 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (NF3/SWN)

It is important to understand that while NF is rare, it is statistically unlikely to have more than one form of NF. It is also statistically likely for a person with any of the three types to be told they might have more than one type of NF. Since tumor growth for each is different, it is important to know for a fact which type a person has. Due to similarities between the three forms, the accidental diagnosis of more than one form of NF is an easy one for doctors to make.

1. Reason for Confusion

All three forms of NF can result in tumors that may be seen as bumps just below the surface of the skin, cutaneous and subcutaneous tumors. In a person with NF1, these tumors are neurofibroma. In people with NF2 or Schwannomatosis, they would be schwannoma. It is argued by some doctors, that it is possible for neurofibroma to also grow in individuals with NF2. The distinction between the Neurofibroma and Schwannoma can only be determined by a biopsy but cannot with the use of an MRI alone. Some of these tumors are painful, some are not, and there is typically a considerable amount more of skin surface tumors for people with NF1.

Skin discoloration spots of café-au-lait macules is also primarily an NF1 concern, but people with NF2 and SWN, sometimes developing these, typically fewer than 6. These marks are not part of diagnosis criteria for NF2, or SWN.

2. Criteria for Neurofibromatosis Type 2 Diagnosis - the Baser Criteria^[2]

There have been different standards for diagnosis of NF2 since it was acknowledged as a condition different from NF1 and again when Schwannomatosis was classified as a separate condition.

NF2 Diagnostic Criteria as of 2018 (December 2018 - now)

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

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

3. Neurofibromatosis Type 1^[3]

NF1: Diagnostic Criteria

In 2003 it was determined that NF1 was caused by damage to Chromosome 17q11.2 and can be found there in genetic testing.

The NIH diagnostic criteria for NF1 in an individual who has two or more of the following features:

• Six or more Café-au-lait Macule Spots over 5mm in greatest diameter in prepubertal individuals and over 15mm in greatest diameter in post pubertal individuals
• Two or more neurofibromas of any type or one Plexiform Neurofibroma
• Freckling in the Axillary or Inguinal Regions
• Optic Glioma
• Two or more either Lisch Nodules (Iris Hamartomas)
• A distinctive osseous lesion such as sphenoid Dysplasia, or Tibial Pseudarthrosis
• A first-degree relative (parent, sibling, or offspring) with NF1 as defined by the above criteria

The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas.^[18]

4. Schwannomatosis (SWN/NF3) ^[4]

A percentage of individuals with NF2 were displaying symptoms differently. In 2005 the development of genetics found out why when these individuals had a different genetic mutation. While some issues are in fact the same with individuals who have NF2, Schwannomatosis ( SWN / NF3 ) is, in fact, its own condition.

Schwannomatosis is caused by a mutation in the SMARCB1 gene (SWI/SNF) or the LZTR1 gene.

SWN: Diagnostic Criteria

The diagnostic criteria for a person to be diagnosed with schwannomatosis, congenital neurilemmomatosis, follow a strict guideline established by the NIH. A diagnosis for Schwannomatosis may be established if a person meets one of the conditions identified below.

Confirmed (Definite) Diagnosis of Schwannomatosis:

• Two (2) or more Non-Intradermal Schwannomas (at least one (1) with histological confirmation)
• No evidence of a vestibular tumor on high-quality MRI scan no known constitutional NF2 mutation
• One (1) pathologically confirmed Non-Vestibular Schwannoma plus a first-degree relative who meets the above criteria

Presumed (Probable) Diagnosis of Schwannomatosis:

• Two (2) or more non-intradermal schwannomas (at least one (1) with histological confirmation)
• No evidence of vestibular tumor on high quality MRI scan
• No known constitutional NF2 mutation
• No symptoms of 8th Cranial Nerve dysfunction
• Radiographic evidence (image scans) of a Non-Vestibular Schwannoma plus a first-degree relative meeting the criteria for definite Schwannomatosis

NF3: Genetic Criteria

In 2013, individuals showing signs of Schwannomatosis with no markers for the SMARCB1 protein were finally established to have an alteration of the LZTR1 protein.

Other Names

1. Multiple Neurilemmomas
2. Multiple Schwannomas
3. Neurilemmomatosis
4. Neurilemmomatosis, Congenital Cutaneous
5. Neurinomatosis
6. Neurofibromatosis Type 3
7. NF3
8. SWN

5. CALMS

These can be dark brown, or light brown, contrast areas of different skin pigmentation, and may be about 1". Often such a mild difference in skin tone they may be unnoticed or difficult to see in pictures. These can also fade over the years. No treatment is necessary.

If an individual in a family has Neurofibromatosis (NF); Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), or Schwannomatosis (SWN/NF3) also develop these marks, medical review of health for the same form of NF.

• NF1 more than 6 CALMS
• NF2 unlikely to develop 6 CALMS
• SWN unlikely to develop CALMS

The presence of Café-au-lait Macules (CALMs) should raise the suspicion of a genetic condition and physical examination for cause is important.

Also the result of:

1. Ataxia Telangiectasia
2. Basal Cell Nevus Syndrome
3. Bloom Syndrome
4. Chiak-Higashi Syndrome
5. Fanconi Anemia
6. Gaucher Disease
7. Hunter Syndrome
8. Legius Syndrome
9. Maffucci Syndrome
10. McCune-Albright Syndrome
11. Multiple Mucosal Neuroma Syndrome
12. Silver-Russell Syndrome
13. Tuberous Sclerosis
14. Watson Syndrome

6. Sources

1. Hoa, M., & Slattery III, W. H. (2012). "Neurofibromatosis 2." Otolaryngologic Clinics of North America, 45(2), 315.
   Source: http://books.google.com/books?hl=en&lr=&id=kwdw7RQHeKcC&oi=fnd&pg=PA315&dq=nf2,+NIH,+Natural+History+Study&ots=1JzDOLvv__&sig=9mPRcLKT7aqMbU14304wCtlmaf8 | DOI: 10.1016/j.otc.2011.12.005
2. "NF Storyboard." National Institute of Health (2010). Available from: NIH Complete NF2 Timeline: 2010
3. NF1: Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [Updated 2012 May 3]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1109
4. Schwannomatosis: Bacci, C., Sestini, R., Provenzano, A., Paganini, I., Mancini, I., Porfirio, B., ... & Papi, L. (2010). Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation. Neurogenetics, 11(1), 73-80. Available from: http://link.springer.com/article/10.1007/s10048-009-0204-2#page-1
5. Piotrowski, Arkadiusz, et al. "Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas." Nature genetics 46.2 (2014): 182. "Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas." http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2855.html
6. Ruttledge, M. H., & Rouleau, G. A. (2005). Role of the neurofibromatosis type 2 gene in the development of tumors of the nervous system. Neurosurgical focus, 19(5), 1-5. http://thejns.org/doi/abs/10.3171/foc.2005.19.5.7
7. Chen, H., Zhang, X., Zhang, Z., Yang, T., Wang, Z., & Wu, H. (2014). The role of NF2 gene mutations and pathogenesis-related proteins in sporadic vestibular schwannomas in young individuals. Molecular and cellular biochemistry, 1-8. http://link.springer.com/article/10.1007/s11010-014-2011-9
8. Evans, D. G., et al. "A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity." Journal of medical genetics 29.12 (1992): 841-846. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1016198/
9. Gerber, P. A., Antal, A. S., Neumann, N. J., Homey, B., Matuschek, C., Peiper, M., ... & Bolke, E. (2009). Neurofibromatosis. European journal of medical research, 14(3), 102. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352057
10. Congressionally Directed Medical Research Programs. NF2 Storyboard. (2010) http://cdmrp.army.mil/nfrp/pdf/NF2storyboard.pdf
11. Chung, Kwanghun, et al. "Structural and molecular interrogation of intact biological systems." Nature 497.7449 (2013): 332-337. http://www.nature.com/nature/journal/v497/n7449/abs/nature12107.html
12. Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., ... & Messiaen, L. M. (2013). Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nature genetics. http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2855.html
13. Baser, M. E., Friedman, J. M., Joe, H., Shenton, A., Wallace, A. J., Ramsden, R. T., & Evans, D. G. R. (2011). Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genetics in Medicine, 13(6), 576-581. http://www.nature.com/gim/journal/v13/n6/abs/gim9201192a.html
14. 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. http://journals.sagepub.com/doi/abs/10.1177/0883073816666736
15. National Institute of Health. Genetics Home Reference. "Schwannomatosis" (MArch 2017) https://ghr.nlm.nih.gov/condition/schwannomatosis#synonyms
16. Cherian, Ajith, et al. "Segmental schwannomatosis: An uncommon cause of crural monoparesis." Journal of neurosciences in rural practice 3.3 (2012): 420.
    https://search.proquest.com/openview/784a9898e5b150e0d8ee6c06fe240d29/1?pq-origsite=gscholar&cbl=226476
17. Merker, Vanessa L., et al. "Clinical features of schwannomatosis: a retrospective analysis of 87 patients." The oncologist 17.10 (2012): 1317-1322.
    http://theoncologist.alphamedpress.org/content/17/10/1317.full
18. Luscan, Armelle, et al. "The activation of the WNT signaling pathway is a Hallmark in neurofibromatosis type 1 tumorigenesis." Clinical Cancer Research 20.2 (2014): 358-371.
    http://clincancerres.aacrjournals.org/content/20/2/358.short
19. OMIM - Online Mendelian Inheritance in Man. "#101000 NEUROFIBROMATOSIS, TYPE II; NF2" https://www.omim.org/entry/101000
20. OMIM - Online Mendelian Inheritance in Man. "#162091 SCHWANNOMATOSIS 1; SWNTS1" https://www.omim.org/entry/162091
21. Celano, Emma, et al. "Spinal cord ependymoma: a review of the literature and case series of ten patients." Journal of neuro-oncology 128.3 (2016): 377-386.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705940/ | doi: 10.1007/s11060-016-2135-8
22. Genetic Home Reference "NF1 gene, neurofibromin 1" https://ghr.nlm.nih.gov/gene/NF1
23. OMIM - Online Mendelian Inheritance in Man. " * 613113 - NEUROFIBROMIN 1; NF1"
    https://www.omim.org/entry/613113