NF2-Related Schwannomatosis (Neurofibromatosis Type 2)

Definition and epidemiology

NF2-related schwannomatosis (formerly neurofibromatosis type 2, NF2) is an autosomal dominant tumour predisposition syndrome caused by pathogenic variants in the NF2 gene, in which nerve sheath tumours (schwannomas), meningiomas and ependymomas develop. An international consensus published in 2022 retired the name ‘neurofibromatosis 2’ to reduce confusion with neurofibromatosis type 1 and improve diagnostic specificity, renaming the condition ‘NF2-related schwannomatosis’ under the umbrella term schwannomatosis. The same umbrella covers subtypes such as SMARCB1-related, LZTR1-related and 22q-related schwannomatosis (Plotkin et al., 2022).

The new criteria combine clinical features with genetic data and include mosaic forms. Diagnosis requires bilateral vestibular schwannomas, an identical NF2 variant in at least two anatomically distinct NF2-related tumours, or a defined combination of major and minor criteria (Plotkin et al., 2022). Birth incidence has been reported as high as 1 in 25,000 in England, with a population prevalence of about 1 in 60,000 (Evans, 2009). Penetrance is complete and the average age at symptom onset is 22 years (Plotkin et al., 2022).

Symptoms and signs

Most adults present with hearing loss, which usually starts in one ear. Tinnitus and imbalance may accompany it. A further 20-30% present with symptoms from a meningioma, spinal tumour or skin tumours (Evans, 2009). Skin tumours are found in about 70% of patients, though usually in small numbers. Juvenile posterior subcapsular or cortical cataract occurs in 60-80% of patients and is an important diagnostic clue (Evans, 2009).

In childhood-onset disease, vestibular schwannomas account for only 15-30% of presenting symptoms; the first sign is often a skin or other nerve tumour or an eye finding (Evans, 2009). Early cataract, retinal hamartoma or an unexplained mononeuropathy in a child should therefore raise the possibility of NF2-related schwannomatosis. The lifetime risk of meningioma approaches 80%, and 20-35% of patients develop intramedullary spinal ependymomas (Plotkin et al., 2022). Earlier age at onset and multiple meningiomas are associated with a more severe course (Evans, 2009).

Causes and risk factors

The NF2 gene encodes the tumour suppressor protein merlin. Affected people carry an inherited or newly arisen pathogenic variant in one copy; a tumour develops when the second copy is also lost in a Schwann cell. Inheritance is autosomal dominant: each child of an affected parent has a 50% chance of inheriting the condition (Evans, 2009). In families with typical disease and bilateral vestibular schwannomas, a germline NF2 variant is found in blood in about 96% (Plotkin et al., 2022).

More than half of cases arise from new (de novo) variants (Evans, 2009). Based on a study of more than 1,000 de novo cases, about 60% of these patients are estimated to be mosaic (Plotkin et al., 2022). In mosaic individuals, the variant is present in only some body cells, so blood testing may be negative and the variant may be demonstrable only in two separate tumours. The risk of a mosaic parent passing the condition on is below 50% (Evans, 2009). Variant type also affects the course: truncating variants are associated with more severe disease (Evans, 2009).

Audiological and clinical assessment

The diagnosis is made with MRI and genetic testing, and the criteria are summarised in the table below. Because tumour growth and hearing change do not always run in parallel, MRI and audiological monitoring are planned together. Under recommended surveillance, children of affected families can be assessed from birth; cranial MRI starts at about 12 years (10 years in severely affected families), is repeated every two years until 20, then every 3-5 years, and annually once tumours are present. Annual audiology including ABR is recommended alongside MRI (Evans, 2009).

• Pure-tone audiometry: bilateral, often asymmetric sensorineural loss. Tumour size and degree of loss are not closely related, and the loss may be stepwise, fluctuating or sudden.
• Speech audiometry: word recognition may be disproportionately poor relative to thresholds; this matters for predicting benefit from hearing aids and cochlear implants. Word recognition is one of the key measures guiding treatment decisions during follow-up.
• Tympanometry and acoustic reflexes: the tympanogram is normal; with retrocochlear involvement, reflex thresholds are raised or reflexes are absent.
• OAEs: present while cochlear function is preserved; they may disappear later as cochlear blood flow is affected.
• ABR: prolonged I-V interpeak latency, an interaural wave V latency difference or absent waves; part of annual monitoring (Evans, 2009).
• Vestibular tests: vHIT, caloric testing and VEMPs assess nerve involvement and compensation after surgery; with bilateral involvement, bilateral vestibulopathy may develop.

The most important differential diagnosis is sporadic vestibular schwannoma. NF2-related schwannomatosis should be considered, and genetic assessment offered, in a young person with a unilateral vestibular schwannoma, multiple meningiomas or early cataract. Molecular data are decisive in distinguishing it from other schwannomatosis subtypes whose clinical features may overlap (Plotkin et al., 2022).

Treatment and audiological rehabilitation

Treatment should be planned in an experienced centre that brings together neurosurgery, ENT, oncology, audiology and genetics. The guiding principle is to preserve function, especially hearing, for as long as possible. Options are active surveillance with MRI and hearing tests, microsurgery, radiosurgery and drug treatment; the decision depends on growth rate, hearing level, brainstem compression and the person’s preferences, and rests with the medical team. Radiosurgery results in NF2-related tumours are more limited than in sporadic tumours; Evans (2009) reported tumour control of about 50% and hearing preservation for at least three years in about 40%.

Bevacizumab, which targets vascular endothelial growth factor (VEGF), is the main drug used for growing vestibular schwannomas. In the first series it reduced tumour volume in 9 of 10 patients, and hearing improved in 4 of the 7 patients whose hearing could be assessed (Plotkin et al., 2009). A systematic review of ten studies including 200 patients found a radiological response rate of 38% and a hearing response rate of 45%; the commonest side effects were hypertension and heavy menstrual bleeding (Chiranth et al., 2023). Indication, dose and monitoring are decisions for the doctor; during treatment, hearing tests are the main tool for judging response.

Hearing rehabilitation should be planned at every stage. Hearing aids are fitted once hearing loss begins, and CROS or BiCROS options are considered for asymmetric loss. If the cochlear nerve is anatomically and functionally preserved (after surveillance, radiosurgery or nerve-sparing surgery), a cochlear implant (CI) can be used. If the nerve cannot be preserved, an auditory brainstem implant (ABI) is the option. In a single-centre series, 77% of CI users and 12% of ABI users achieved open-set speech perception; the authors recommended a CI where disease and anatomy allow and stressed tumour management that preserves the possibility of CI use (Dornhoffer et al., 2024). For most users, an ABI provides awareness of environmental sound that supports lipreading. Communication options such as sign language and lipreading training should be discussed before hearing is lost completely.

Genetic counselling should be offered at diagnosis. The 50% risk to children of an affected person, the lower transmission risk in mosaic individuals, presymptomatic genetic testing, prenatal and preimplantation genetic diagnosis, and surveillance of at-risk relatives should all be discussed in detail with the family (Evans, 2009).

Impact on quality of life and advice

NF2-related schwannomatosis begins at a young age, lasts for life and may require several treatments. Progressive bilateral hearing loss deeply affects communication, education, work, relationships and emotional well-being. Facial nerve weakness, loss of balance and visual problems may be added. Uncertainty, frequent MRI and test appointments, and decisions about family planning can increase anxiety, and psychological support and patient organisations are helpful.

Practical advice: plan communication options while your hearing is still good; learning lipreading or sign language protects communication if the loss progresses. Use your hearing aids and remote microphone systems consistently, and ask for adjustments at school or work. Keep your hearing test and MRI appointments, and seek review straight away if your hearing changes suddenly. If you have balance problems, take care in the dark and on slippery surfaces. If you are planning a family, ask for genetic counselling. If your child is at risk, start the recommended surveillance, including eye examinations and hearing tests, at an early age.