Science Timeline

Neurofibromatosis (NF), initially called Von Recklinghausen disease, is not one but three separate genetic conditions that all result in the growth of tumors and neurological issues. The three diseases are called; Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2) and Neurofibromatosis Type 3 more commonly known as Schwannomatosis.

The history of NF is complicated, and the development of genetic testing was needed for researchers to realize that there are in fact three forms, but this fact is not even commonly known today by all doctors since NF is rare and in some cases not even identified at all. The results are a common issue of inaccurate diagnosis of the wrong NF form and individuals not receiving the proper testing for treatments needed.

1. Timeline

• 1820: First cases of NF2 was reported by Dr. Wishart, predating Von Recklinghausen work defining what we now know as Neurofibromatosis Type 1 (NF1). ^[1]
  
  
• 1882: German pathologist Friedrich Daniel von Recklinghausen for the first time described a series of patients with a combination of cutaneous lesions and tumors of the peripheral and central nervous system. ^[2]
  
  
• 1930: Gardner and Frazier reported a large group of people with Bilateral Vestibular Schwannomas and in a study suggested a separate Central form of Von Recklinghausen Neurofibromatosis. This lead to the beginning of acceptance of two forms; Primary Neurofibromatosis (NF1) . and Central Neurofibromatosis (NF2). [1]
  
  
• 1956: A paper written by Crowe entitles "A Clinical Pathology and Genetic Study of Multiple Neurofibromatosis" did not include separation of identification of Primary Neurofibromatosis and Central Neurofibromatosis. The paper noted 5% of people with Von Recklinghausen Neurofibromatosis as having Acoustic Neuroma. [1,9] Because NF1 and NF2 differences extend beyond chances of Acoustic Neuroma, the guide would have had many false claims of what it meant to have NF1. NF differentiation is sometimes still ignored in writings and confused during diagnosis now in 2017.
  
  
• 1977: First science laboratory use of a Magnetic Resonance Imaging (MRI).
  
  
• 1979: Development of the first Auditory Brainstem Implant (ABI) started to make it possible for individuals with Bilateral VS nerve damage, hearing in neither ear, to have a chance at a hearing. It was only a two (2) Electrode Implant with very limited sound. The two electrode implant was not helpful enough it did not reach commercial use.
  
  
• 1980: Commercial use of MRI started to become available for use on patients.
  
  
• 1987: Mapping for genes for NF separated people with NF into two (2) separate diseases while identified the location of NF1 on Chromosome 17 and NF2 on Chromosome 22.^[1]
  
  
• 1987: Establishment of General Criteria for NF1 and NF2.^[3]

NF2 then was characterized by Schwannoma of the 8th cranial nerve, specifically the Vestibular branch of the Nerve; these are typically called Vestibular Schwannoma or Acoustic Neuroma. It was also understood that Schwannoma could also develop on other cranial nerves, tumor types including; Meningiomas, Ependymomas but NF2 can also result in Ocular Manifestations.

• 1988: Gadolinium-enhanced MRI made available for imaging, detection, and diagnosis of Vestibular Schwannoma; lesions as small as 2mm are detectable.
  
  
• 1990: Diagnostic criteria for NF2, any one of the following:^[3]
• Bilateral masses of the 8th Cranial Nerve;
• 1 or more 1st degree relative with NF2 + unilateral vestibular mass of 8th cranial nerve;
• 2 of the following: Neurofibroma, Meningioma, Glioma, Schwannoma, Juvenile Posterior Subcapsular Lenticular Opacities
  
  
• 1991: At the NIH Consensus Conference Tumor. Name change of acoustic neuroma (AN) to vestibular schwannoma (AN).^[1]
  Reason
  • The growth of tumors on cranial nerve 8 (CN8), the reason for hearing and balance issues, schwann cell overgrowth, schwannoma tumors.
  • Tumor growth is on the vestibular rather than an acoustic branch of CN8.
  • Change of name in the medical field of the hearing branch of CN8 from acoustic nerve to the cochlear nerve.
  
  
• 1992: Two types of NF2 inaccurately identified as two simple types:^[3]
1. Gardner Type: mild with late onset and few tumors other than Vestibular Schwannoma
2. Wishart Type: severe, early onset with multiple tumors
   
   
• 1992: The development of the eight (8) Electrode ABI, allowed for a wider range of sounds, this new implant was completely different from the first two (2) Electrode device developed in 1979. Implantation of the eight electrode ABI was done for twenty-five (25) individuals.
  
  
• 1993: Development of Magnetic Resonance Venography (MRV). MRI equipment used to see veins and arteries in the brain.
  
  
• 1996: It was determined numbers of individuals with NF2 were higher than previously believed due to Genetic Mosaicism. Individuals with Mosaic NF2 might only have, Unilateral Vestibular Schwannoma (VS on one side), or possibly no tumors, but can have children with all tumor types and issues.
  
  
• 1996: The condition of Schwannomatosis was defined as a separate clinical condition from other forms of NF. Individuals with Schwannomatosis developed tumors similar to individuals with the NF2 condition, except for Bilateral Vestibular Schwannoma. Often as many body tumors as NF1, except where NF1 body tumors are Neurofibromas, for people with Schwannomatosis the tumors are Schwannomas which result in chronic pain. ^[3]
  
  
• 1997: Diagnostic Method of the Manchester Criteria included important revisions of classifiers of NF2 as any one of the following:^[3]
• Bilateral Vestibular Schwannoma
• 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.
  
  
• 1999: The latest in developments of ABIs. ABIs with 21 Electrodes for sound. Since this, the only developments for ABIs is upgradable external parts for additional changes in sound quality and ease of use.
  
  
• 2000: Pre-symptomatic diagnosis with the genetic test can be helpful for ~66% of all classically affected NF2 patients.
  
  
• 2003: Schwannomatosis is molecularly and clinically distinct from NF2.^[3]
  
  
• 2003: Development of a high-resolution NF2-specific diagnostic microarray for the detection of the condition causing gene deletions. ^{[3] [7] [8]}
• NF1: Chromosome 17q11.2
• NF2: Chromosome 22q12.2


• 2005: Clear, distinctive characteristics between NF2 and Schwannomatosis finally classified, like NF2 also on Chromosome 22q12 but with a distinction in characteristics but with an alteration to the SMARCB1 protein, where NF2 is a result of the Merlin protein.^[3]
  
  
• 2005: Development of Polymerase Chain Reaction Method (PCR Method) to detect deletions and duplications of the NF2 gene.
  
  
• 2007: Chromogenic in situ hybridization (CISH) validated as a reliable method for assessing NF2 gene deletions in sporadic Schwannoma, Meningioma, and Ependymoma.
  
  
• 2007: Endoscopic Endonasal Surgery allows for tumor removal through the nose for previously inoperable tumors.
  
  
• 2009: Development of a method of Volumetric Measurements of tumors seen with MRIs.
  
  
• 2010: Transorbital Neuroendoscopic Surgery allows for tumor removal through the eye for previously inoperable tumors.
  
  
• 2011: Baser Criteria was created to help with earlier diagnosis for individuals with potential Spontaneous NF2 Mutation, to require genetic testing if an individual shows any physical signs of NF2. The Baser Criteria is named after Dr. Michael E Baser.
  
  
• 2013: 3D Camera Surgery Assistance. The use of a Laparoscopic surgery type Endoscope in the nasal cavity to see and remove tumor mass.
  
  
• 2013: Organs Made Transparent with New Imaging Technique: Mouse Stage. Method CLARITY (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging / Immunostaining / In situ hybridization-compatible Tissue-hYdrogel) ^[3]
  
  
• 2013: Individuals are showing signs of Schwannomatosis with no markers for the SMARCB1 protein were finally established to have an alteration of the LZTR1 protein.^[5]
  
  
• 2014: Genetic testing for accurate Schwannomatosis diagnosis was finally available. Some diagnosed as NF1 or NF2 were finally able to be properly diagnosed with Schwannomatosis.
  
  
• 2016: Updated diagnosis of NF2: Baser Criteria - There are variations on what issues NF2 may result in, and determination of diagnosis and the Baser Criteria says an individual has NF2 if one of the following applies:

  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. Reference Sources

1. 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/
2. 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
3. Congressionally Directed Medical Research Programs. NF2 Storyboard. (2010) http://cdmrp.army.mil
4. 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
5. 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
6. 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
7. NCBI. Gene. "NF2 neurofibromin 2 [ Homo sapiens (human) ]" (April 20, 2017) https://www.ncbi.nlm.nih.gov/gene/4771#genomic-regions-transcripts-products
8. US Department of Health and Human Services. National Institute of Health. National Library of Medicine. "NF2 gene: neurofibromin 2" (January 2017) https://ghr.nlm.nih.gov/gene/NF2
9. Crowe, F. W., Schull, W. J., and Neel, J. V., "A Clinical Pathology and Genetic Study of Multiple Neurofibromatosis" (C. C. Thomas, Springfield, 1956).