Neurofibromatosis Type 2 Clinics and Genetics


Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by multiple benign tumours of the nervous system. More than 90% of the patients develop bilateral vestibular schwannomas, which are the hallmark of NF2 and lead to progressive hearing loss in adult patients. Spinal tumours are as frequent as bilateral vestibular schwannomas, whereas approximately one‐third of them cause neurological symptoms. Cranial nonvestibular schwannomas, meningiomas and ependymomas are also frequent in NF2, as well as ophthalmological lesions and peripheral polyneuropathy. With a birth incidence of around 1 in 25 000, the genetic cause for NF2 is the heterozygous inactivation of the NF2 tumour suppressor gene on 22q. More than half (50–80%) of NF2 patients are founders who bear de novo mutations among whom mosaicism is frequent (at least 25–30%). NF2 is a complex syndrome and demands interdisciplinary care, experienced specialists, social and psychological support and rehabilitation measures.

Key Concepts

  • NF2 is a tumour suppressor gene syndrome and is characterised by multiple benign cerebral and spinal tumours.
  • Bilateral vestibular schwannomas are the hallmark of NF2.
  • The genetic cause for NF2 is the heterozygotic inactivating mutation of the NF2 gene on 22q.
  • Mosaicism is frequent among de novo NF2 patients (>25–30%).
  • NF2 is a complex syndrome and demands interdisciplinary care, experienced specialists, coordinated social and psychological supports and rehabilitation measures.

Keywords: NF2; schwannoma; meningioma; hearing loss; LOH

Figure 1. Bilateral vestibular schwannomas (VS), a cerebral meningioma (M) and multiple spinal tumours (SPT) revealed by MRI in an NF2 patient.
Figure 2. Cutaneous schwannomas in an NF2 patient.
Figure 3. Subcapsular cataract in an NF2 patient.
Figure 4. From classical inherited NF2 to case of sporadic NF2‐related tumours. In between are mosaicism of various timing of mutation, various size of affected cell population, various mutation detecting rate and various severity of the disease.
Figure 5. Tumour‐LOH (loss of heterozygosity) analysis enables identification of the mutation‐bearing allele. Microsatellite marker D22S268 is linked to the NF2 gene. In the blood of the index patient, this marker has two different alleles (with 194 and 196 bp) and is thus heterozygous. The allele 196 bp is lost in the tumour, implying that the tumour retained allele 194 bp bears the genetic defect. Examining the blood DNA (deoxyribonucleic acid) of the offspring of this patient revealed that the patient passed the defective allele 194 bp to offspring No. 1. The other allele 202 bp in offspring No. 1 originates from the other parent. In offspring No. 2, both alleles of the marker were 196 bp. Therefore, this offspring inherited the healthy allele (196 bp) from the affected parent. The other 196 bp allele originates from the other healthy parent.


Ahronowitz I, Xin W, Kiely R, et al. (2007) Mutational spectrum of the NF2 gene: a meta‐analysis of 12 years of research and diagnostic laboratory findings. Human Mutation 28 (1): 1–12.

Baser ME, Friedman JM, Aeschliman D, et al. (2002) Predictors of the risk of mortality in neurofibromatosis 2. American Journal of Human Genetics 71 (4): 715–723.

Baser ME, Kuramoto L, Woods R, et al. (2005) The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. Journal of Medical Genetics 42 (7): 540–546.

Bäumer P, Mautner VF, Bäumer T, et al. (2013) Accumulation of non‐compressive fascicular lesions underlies NF2 polyneuropathy. Journal of Neurology 260: 38–46.

Blakeley J (2012) Development of drug treatments for neurofibromatosis type 2‐associated vestibular schwannoma. Current Opinion in Otolaryngology & Head and Neck Surgery 20 (5): 372–379.

Bosch MM, Boltshauser E, Harpes P and Landau K (2006) Ophthalmologic findings and long‐term course in patients with neurofibromatosis type 2. American Journal of Ophthalmology 141 (6): 1068–1077.

Curto M and McClatchey AI (2008) Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. British Journal of Cancer 98 (2): 256–262.

Ellis JR Jr, Heinrich B, Mautner VF and Kluwe L (2011) Effects of splicing mutations on NF2‐transcripts: transcript analysis and information theoretic predictions. Genes, Chromosomes & Cancer 50: 571–584.

Evans DGR, Huson S, Donnai D, et al. (1992) A clinical study of type 2 neurofibromatosis. Quarterly Journal of Medicine 84: 603–618.

Evans DG, Trueman L, Wallace A, Collins S and Strachan T (1998a) Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. Journal of Medical Genetics 35: 450–455.

Evans DG, Wallace AJ, Wu CL, et al. (1998b) Somatic mosaicism: a common cause of classic disease in tumor‐prone syndromes? Lessons from type 2 neurofibromatosis. American Journal of Human Genetics 63: 727–736.

Evans DGR, Birch JM and Ramsdem RT (1999) Paediatric presentation of type 2 neurofibromatosis. Archives of Disease in Childhood 81: 496–499.

Evans DG, Birch JM, Ramsden RT, Sharif S and Baser ME (2006) Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. Journal of Medical Genetics 43 (4): 289–294.

Evans DGR (2009) Neurofibromatosis type 2 (NF2): A clinical and molecular review. Orphanet Journal of Rare Diseases 19 (4): 16.

Farschtschi S, Kollmann P, Dalchow C, Stein A and Mautner VF (2015) Reduced dosage of bevacizumab in treatment of vestibular schwannomas in patients with neurofibromatosis type 2. European Archives of Oto‐Rhino‐Laryngology 272 (12): 3857–3860.

Fisher LM, Doherty JK, Lev MH and Slattery WH (2009) Concordance of bilateral vestibular schwannoma growth and hearing changes in neurofibromatosis 2: neurofibromatosis 2 natural history consortium. Otology & Neurotology 30: 835–841.

Gripp KW, Baker L, Kandula V, et al. (2017) Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager. Clinical Genetics 14 (in press).

Hagel C, Lindenau M, Lamszus K, et al. (2002) Polyneuropathy in neurofibromatosis 2: clinical findings, molecular genetics and neuropathological alterations in sural nerve biopsy specimens. Acta Neuropathologica 104 (2): 179–187.

Karajannis MA, Legault G, Hagiwara M, et al. (2012) Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro‐Oncology 14 (9): 1163–1170.

Karajannis MA, Legault G, Hagiwara M, et al. (2014) Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro‐Oncology 16 (2): 292–297.

Kluwe L, Bayer S, Baser ME, et al. (1996) Identification of NF2 germ‐line mutations and comparison with neurofibromatosis 2 phenotypes. Human Genetics 98: 534–538.

Kluwe L, MacCollin M, Tatagiba M, et al. (1998) Phenotypic variability associated with 14 splice‐site mutations in the NF2 gene. American Journal of Medical Genetics 77 (3): 228–233.

Kluwe L and Mautner VF (1998) Mosaicism in sporadic neurofibromatosis 2 patients. Human Molecular Genetics 7: 2051–2055.

Kluwe L, Friedrich RE, Tatagiba M and Mautner VF (2002) Presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients: a method based on tumor analysis. Genetics in Medicine 4 (1): 27–30.

Kluwe L (2003) Method for the determination of data for the preparation of the diagnosis of phakomatosis. US patent 6,660,477.

Kluwe L, Mautner V, Heinrich B, et al. (2003) Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. Journal of Medical Genetics 40 (2): 109–114.

Kluwe L, Nygren AO, Errami A, et al. (2005) Screening for large mutations of the NF2 gene. Genes, Chromosomes & Cancer 42 (4): 384–391.

MacCollin M and Mautner VF (1998) The diagnosis and management of neurofibromatosis 2 in childhood. Seminars in Pediatric Neurology 5 (4): 243–252.

Mathieu D, Kondziolka D, Flickinger JC, et al. (2007) Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates. Neurosurgery 60: 468–470.

Mautner VF, Tatagiba M, Guthoff R, Samii M and Pulst SM (1993) Neurofibromatosis 2 in the pediatric age group. Neurosurgery 33 (1): 92–96.

Mautner VF, Tatagiba M, Lindenau M, et al. (1995) Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. American Journal of Roentgenology 165 (4): 951–955.

Mautner VF, Lindenau M, Baser ME, et al. (1996) The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery 38 (5): 880–885, discussion 885–886.

Mautner VF, Lindenau M, Baser ME, Kluwe L and Gottschalk J (1997) Skin abnormalities in neurofibromatosis 2. Archives of Dermatology 133 (12): 1539–1543.

Mautner VF, Baser ME, Thakkar SD, et al. (2002) Vestibular schwannoma growth in patients with neurofibromatosis type 2: a longitudinal study. Journal of Neurosurgery 96 (2): 223–228.

Mautner V‐F, Nguyen R, Kutta H, et al. (2010a) Bevacizumab induces regression of vestibular schwannomas leading to improved hearing in patients with neurofibromatosis type 2. Journal of Neuro‐Oncology 12 (1): 14–18.

Mautner VF, Nguyen R, Knecht R and Bokemeyer C (2010b) Radiographic regression of vestibular schwannomas induced by bevacizumab treatment: sustain under continuous drug application and rebound after drug discontinuation. Annals of Oncology 21 (11): 2294–2295.

Merel P, Hoang‐Xuan K, Sanson M, et al. (1995) Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas. Genes, Chromosomes & Cancer 13: 211–216.

Moyhuddin A, Baser ME, Watson C, et al. (2003) Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. Journal of Medical Genetics 40 (6): 459–463.

Parry DM, Eldridge R, Kaiser‐Kupfer MI, et al. (1994) Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. American Journal of Medical Genetics 52: 450–461.

Parry DM, MacCollin MM, Kaiser‐Kupfer MI, et al. (1996) Germ‐line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. American Journal of Human Genetics 59: 529–539.

Plotkin SR, Singh MA, O'Donnell CC, et al. (2008) Audiologic and radiographic response of NF2‐related vestibular schwannoma to erlotinib therapy. Nature Clinical Practice. Oncology 5: 487–491.

Plotkin SR, Stemmer‐Rachamimov AO, Barker FG 2nd, et al. (2009) Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. New England Journal of Medicine 361 (4): 358–367.

Plotkin SR, Halpin C, McKenna MJ, et al. (2010) Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otology & Neurotology 31 (7): 1135–1143.

Plotkin SR, Merker VL, Halpin C, et al. (2012) Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients. Otology & Neurotology 33 (6): 1046–1052.

Rouleau GA, Merel P, Lutchman M, et al. (1993) Alteration in a new gene encoding a putative membrane‐organizing protein causes neuro‐fibromatosis type 2. Nature 363 (6429): 515–521.

Rowe J, Radatz M, Kemeny A, et al. (2008) Radiosurgery for type II neurofibromatosis. Prog Neurol Surg. 21: 176–182.

Samii M, Gerganov V and Samii A (2008) Microsurgery management of vestibular schwannomas in neurofibromatosis type 2: indications and results. Progress in Neurological Surgery 21: 169–175.

Schulz A, Baader SL, Niwa‐Kawakita M, et al. (2013) Merlin isoform 2 in neurofibromatosis type 2‐associated polyneuropathy. Nature Neuroscience 16 (4): 426–433.

Sperfeld AD, Hein C, Schroder JM, Ludolph AC and Hanemann CO (2002) Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2. Brain 125 (part 5): 996–1004.

Trofatter JA, MacCollin MM, Rutter JL, et al. (1993) A novel moesin‐, ezrin‐, radixin‐like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72 (5): 791–800.

Wellenreuther R, Kraus JA, Lenartz D, et al. (1995) Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. American Journal of Pathology 146: 827–832.

Wentworth S, Pinn M, Bourland JD, et al. (2009) Clinical experience with radiation therapy in the management of neurofibromatosis‐associated central nervous system tumors. International Journal of Radiation Oncology, Biology, Physics 73: 208–213.

Further Reading

Antonarakis SE and Cooper DN (2006) Mutations in Human Genetic Disease (Encyclopedia of Life Science). John Wiley & Sons Ltd. DOI: 10.1038/npg.els.0005471.

Asthagiri AR, Parry DM, Butman JA, et al. (2009) Neurofibromatosis type 2. Lancet 73 (9679): 1974–1986.

Evans DG, Baser ME, O'Reilly B, et al. (2005) Management of the patient and family with neurofibromatosis 2: a consensus conference statement. British Journal of Neurosurgery 19 (1): 5–12.

Evans DG (2009) Neurofibromatosis 2 [bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genetics in Medicine 11 (9): 599–610.

Lu‐Emerson C and Plotkin SR (2009) The neurofibromatoses. Part 2: NF2 and schwannomatosis. Reviews in Neurological Diseases 6 (3): E81–E86.

Skolnik JM and Fisher ED (2003) Tumour suppressor genes (Encyclopedia of Life Science). John Wiley & Sons Ltd. DOI: 10.1038/npg.els.0001475.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kluwe, Lan, Farschtschi, Said, and Mautner, Victor‐F(Sep 2017) Neurofibromatosis Type 2 Clinics and Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022391.pub2]