NF2-Related Schwannomatosis
Original Editor - Wendy Walker
Lead Editors - Wendy Walker, Kim Jackson, WikiSysop, Rishika Babburu and Lucinda hampton
Introduction
NF2-related schwannomatosis (NF2-SWN) is the name of the condition which prior to 2022 was known as Neurofibromatosis Type 2.[1] The name was changed because the NF2-SWN does not cause neurofibromas. The term "NF2" is retained as this is the name of the responsible gene.
NF2-SWN is a rare genetic tumour predisposition syndrome, which is. characterised by development of multiple benign nerve sheath tumours, known as schwannomas, particularly affecting the vestibular nerve.[2]
Birth incidence is approximately 1 in 28,000 (1 in 27.956 in the most recent UK estimate).[3] Average age of onset is in the 20s, and many affected individuals develop bilateral vestibular schwannomas by 30 years.
Clinically Relevant Anatomy
NF2-SWN is inherited as an autosomal dominant condition; approximately 50% of affected individuals are traditionally reported to have NF2-SWN as a result of a new (de novo) gene mutation. However, recent UK epidemiological data using contemporary diagnostic criteria suggest that the proportion of clearly inherited cases is approximately 23%, with a substantial portion of patients having mosaic NF2-SWN.[4]
The manifestations of NF2-SWN result from mutations in (or, occasionally, deletion of) the NF2 gene, located on the long arm of chromosome 22. Inheriting one pathogenic NF2 variant is enough to predispose a person to the condition, with tumours developing when the remaining normal copy is lost or inactivated in a cell.
The NF2 gene product known as merlin is a tumour suppressor protein which helps stop cells dividing when they touch neighbouring cells (contact inhibition) and restrains growth-promoting signalling pathways; when both copies of NF2 in a cell are lost or inactivated, merlin function is lost and cells can grow unchecked, causing tumours such as schwannomas and meningiomas.[5]
Mechanism of Injury / Pathological Process
NF2-SWN is an autosomal dominant genetic disorder caused by mutations on chromosome 22[6]. Patients usually have multiple Central Nervous System tumours; most typically a patient will be found to have bilateral Acoustic Neuromas (AKA Vestibular Schwannomas).
It is caused by mutations of the "Merlin" gene[7] which influences the form and movement of cells, and acts as a tumour suppressor; so reduced action of this protein, or decreased production of it causes tumours in both the central and peripheral nervous systems to develop.[5]
Histological findings in NF2-SWN tumours show distinct characteristics which differ from non-NF2-SWN Vestibular Schwannomas/Acoustic Neuromas. Depending on the severity of the underlying mutation, multiple other CNS tumours can also be found, especially meningiomas, schwannomas, and gliomas, some of them involving cranial nerves.
Clinical Presentation
Presenting symptoms
These may include the following:
- Hearing loss, ringing in the ears, and balance problems associated with vestibular nerve lesions
- Visual deficits
- Cranial nerve palsies
NF2-SWN is associated with significant morbidity and decreased life span. Furthermore, diagnosis in childhood is often difficult because of the absence of central nervous system (CNS) involvement at a young age[8].
Although the genetic change causing NF2-SWN is present at conception, the clinical manifestations occur over many years. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire life span.
Complications of NF2-SWN
The following complications frequently occur:
Unilateral or, frequently, bilateral vestibular schwannomas leading to tinnitus, hearing loss, and/or problems with balance
Spinal cord schwannomas are common in NF2 and result in significant morbidity. Intracranial meningiomas are common.
Spinal cord ependymomas, astrocytomas, and meningiomas also occur, but less frequently.
Gliomas, ependymomas, and other cerebral, cerebellar, or spinal cord lesions that may result in neurologic deficits, seizures, and/or hydrocephalus
Peripheral nerve schwannomas, mixed tumors, and, occasionally, neurofibromas
Peripheral neuropathies
Visually significant juvenile cataracts
Nonvestibular schwannomas occur in more than half of patients, and are often diagnosed in patients with an earlier age at diagnosis of NF2-SWN. Cranial nerves 3 and 5 are most commonly involved.
Diagnostic Criteria
The clinical diagnosis of NF2 related schwannomatosis is established when an individual has one of the following:
- Bilateral eighth nerve tumours (vestibular schwannoma, also known as acoustic neuroma)
- An identical NF2 variant in at least two anatomically distinct NF2 related tumours (schwannoma, meningioma and/or ependymoma)
- An NF2 pathogenic variant in an unaffected tissue such as blood, with a diagnosis of mosaic NF2-schannomatosis when the variant is present at less than 50%
OR when either two Major OR one Major and two Minor criteria are present:
Major criteria:
- Unilateral vestibular schwannoma
- First degree relative other than sibling with NF2 schwannomatosis
- NF2 pathogenic variant in an unaffected tissue such as blood
- Two or more meningiomas
Minor criteria:
- Ependymoma
- Schwannoma (require at least one dermal if major criterion is unilateral vestibular schwannoma
- Juvenile sub scapular or cortical cataract
- Retinal hamartoma
- Epireretinal membrane aged less than 40 years
- Single meningioma
Diagnosis of NF2-SWN involves the following:
Genetic testing
Imaging studies
Auditory, ophthalmic, and histologic examinations
Management / Interventions
Medical care for patients with NF2-SWN consists of routine examinations focusing on early detection of some of the potential complications related to CNS or spinal cord lesions[9].
Guidelines for the care of the patient with NF2-SWN:
Annual testing as follows:
- Neurologic examination to identify changes in neurologic status which suggest progression of the disease
- Hearing test and when indicated, referral to an audiologist
- Ophthalmologic testing
- MRI to monitor existing lesions and/or look for new lesions
Treatment of symptomatic tumours, including:
Surgical resection is most common, especially for acoustic neuromas.
Occasionally, radiation and/or chemotherapy may be recommended.
Differential Diagnosis
Neurofibromatosis Type 1 (NF1) differs from NF2-SWN in that NF1 patients have large numbers of skin lesions, whereas NF2 patients generally have fewer skin lesions.
Brainstem Gliomas
Intracranial Ependymomas
Physiotherapy
Customized vestibular rehabilitation incorporating adaptation, habituation, balance and mobility has been demonstrated to improve balance in patients with Acoustic Neuroma[10].
If the Facial Nerve is affected, causing facial palsy, then physiotherapy is indicated, as set out on the Facial Palsy page.
References
- ↑ Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genet Med. 2022 Sep;24(9):1967-1977. doi: 10.1016/j.gim.2022.05.007. Epub 2022 Jun 9. PMID: 35674741.
- ↑ Forde C, King AT, Rutherford SA, Hammerbeck-Ward C, Lloyd SK, Freeman SR, Pathmanaban ON, Stapleton E, Thomas OM, Laitt RD, Stivaros S, Kilday JP, Vassallo G, McBain C, Kerrigan S, Smith MJ, McCabe MG, Harkness EF, Evans DG. Disease course of neurofibromatosis type 2: a 30-year follow-up study of 353 patients seen at a single institution. Neuro Oncol. 2021 Jul 1;23(7):1113-1124. doi: 10.1093/neuonc/noaa284. PMID: 33336705; PMCID: PMC8248850.
- ↑ Evans DG, Plotkin SR. Clinical epidemiology of NF2-related schwannomatosis. Handb Clin Neurol. 2025;212:129-134. doi: 10.1016/B978-0-12-824534-7.00013-5. PMID: 41052833.
- ↑ Forde C, Smith MJ, Burghel GJ, Bowers N, Roberts N, Lavin T, Halliday J, King AT, Rutherford S, Pathmanaban ON, Lloyd S, Freeman S, Halliday D, Parry A, Axon P, Buttimore J, Afridi S, Obholzer R, Laitt R, Thomas O, Stivaros SM, Vassallo G, Evans DG. NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study. J Med Genet. 2024 Aug 29;61(9):856-860. doi: 10.1136/jmg-2024-110065. PMID: 38925914.
- ↑ 5.0 5.1 Cooper J, Giancotti FG. Molecular insights into NF2/Merlin tumor suppressor function. FEBS Lett. 2014 Aug 19;588(16):2743-52. doi: 10.1016/j.febslet.2014.04.001. Epub 2014 Apr 12. PMID: 24726726; PMCID: PMC4111995.
- ↑ Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, 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. J Med Genet 1992;29:841-6
- ↑ Striedinger K, VandenBerg SR, Baia GS, McDermott MW, Gutmann DH, Lal A (November 2008). "The neurofibromatosis 2 tumor suppressor gene product, merlin, regulates human meningioma cell growth by signaling through YAP". Neoplasia 10 (11): 1204–12
- ↑ Matsuo M, Ohno K, Ohtsuka F. Characterization of early onset neurofibromatosis type 2. Brain Dev. Feb 13 2013
- ↑ Aboukais R, Baroncini M, Zairi F, Bonne NX, Schapira S, Vincent C, et al. Prognostic value and management of spinal tumors in neurofibromatosis type 2 patients. Acta Neurochir (Wien). May 2013;155(5):771-7.
- ↑ Vereeck L, Wuyts FL, Truijen S, De Valck C, Van de Heyning PH. The effect of early customized vestibular rehabilitation on balance after acoustic neuroma resection.. Clin Rehabil. 2008 Aug;22(8):698-713