What is neurofibromatosis type 2?

Neurofibromatosis type 2 (NF2), or central neurofibromatosis, is a genetic – or hereditary – disease that typically appears during young adulthood and is associated with the development of benign tumors of the central nervous system. What is characteristic in patients with NF2 is the development of benign tumors of the 8th cranial nerve, typically on both sides, referred to as bilateral vestibular schwannomas and previously called acoustic neuromas as well. Since the 8th cranial nerve is responsible for hearing and equilibrium, these tumors lead to increasing hearing loss and sometimes to impaired balance or an unsteady gait. Other benign tumors, brain tumors, and spinal tumors may occur as well. A decline in visual acuity, triggered by a special form of juvenile cataract, is also characteristic. NF2 is classified as a tumor disposition disease.

How is neurofibromatosis type 2 diagnosed?

Manchester criteria for diagnosing NF2

NF2 can be clinically diagnosed on the basis of the following criteria:

  • Vestibular schwannomas (VS) on both sides
    or
    a positive family history of NF2 (in a first-grade relative = parent, sibling, child)

    plus

  • VS on one side
    or
    2 of the following features: meningiomas / gliomas / neurofibromas / schwannomas / juvenile cataracts

Clinical Signs

Tinnitus (ringing in the ears) and increased hearing loss during early adulthood are often the first symptoms that motivate people to see a doctor. Impaired balance, unsteady gait, headaches, and a feeling of numbness kin or even paralysis of the optic nerve are also described.

Around 30% of patients develop the symptoms during late childhood. At this age, the initial symptoms are more frequently caused by benign tumors of the meninges (called meningiomas). Moreover, damage to a nerve caused by schwannomas can lead to pain or a loss of function. Sometimes it is also visual impairment because of a juvenile cataract that is the first indication of the diagnosis.

The clinical signs vary greatly and can be subtle, with the first symptoms not usually occurring before early adulthood. Below is a list of typical findings:

  • Skin tumors, which can be found in a little over two thirds of all patients. They are mainly schwannomas, although neurofibromas have also been reported in rare cases. These tumors present in three forms:

    • Plaque-like schwannomas within the skin, slightly raised, pigmented (more color), and with more hair
    • Nodular tumors beneath the skin, which may be noticed as spindle-shaped, rough areas of swelling
    • Neurofibromas located directly in the skin
  • Latte-colored, irregularly delimited café au lait spots that are characteristic of NF1 are also found more frequently with NF2 than in healthy people, although they are much less pronounced than with NF1.

  • Schwannomas, neurofibromas, meningiomas, and gliomas are benign tumors arising from cells that surround, protect, insulate, and supply the nerve – called nerve sheaths.

  • Juvenile subcapsular cataract is a specific form of cataract that already occurs during adolescence and can cause a decline in visual acuity.

What is the risk of cancer?

It is common for benign nerve sheath tumors to develop – mainly schwannomas, which commonly grow on both sides along the 8th cranial nerve and can lead to tinnitus (ringing in the ears), hearing loss, and impaired balance. These nerve sheath tumors also grow in other areas, such as along peripheral nerves in the skin or central nervous system, in the brain, or along the spinal cord. Other benign tumors of the nervous system occur as well – meningiomas, astrocytomas, and even low-grade ependymomas, which may be located in the spinal canal, trigger pain and neurological failures, and cause an unsteady gait. Around half of these findings are diagnosed by chance; there are usually no symptoms at all.

What causes neurofibromatosis type 2?

Neurofibromatosis type 2 is a genetic disease caused by a mutation, i.e. a change in the genetic material. The affected gene encodes a protein called merlin, or sometimes schwannomin as well. Merlin is mainly present in nerve tissues and functions as a tumor suppressor; in other words, it counteracts the development of tumors by inhibiting growth.

NF2 occurs in around 1:25.000-33.000 people. Somewhat more than one third of the cases are passed down by parents to their children; heredity is therefore autosomal dominant. This means that the probability of passing on the disease (heredity) is 50%. Somewhat fewer than 2/3 of the cases are due to a spontaneous or new mutation, called a de novo mutation. This means that the gene change has newly occurred in the patient himself or herself.

Genetic testing is possible and recommended for everyone with the clinical diagnosis and for all patients with tumors typical of NF2 (meningiomas, schwannomas) to verify the diagnosis. Genetic testing of people who are potentially affected but do not have symptoms is advised from the age of 10-12.

Is there a treatment?

With growing vestibular schwannomas (VS) and imminent hearing loss, an operation and radiation are regarded as a treatment option if the risk of increased damage due to the tumor itself is higher than the risk of the operation or radiation. In children, radiation is to be avoided if possible, as there is a risk that they will develop a secondary tumor. The medication bevacizumab (brand name Avastin), which has not yet been approved in Germany for this indication, is currently giving very good treatment results in rapidly growing VS. A brainstem or cochlear implant is worth considering if deafness occurs.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

The goal is to detect developing complications early on in order to achieve the best possible treatment results. To this end, regular doctor’s visits are recommended (recommendations from AACR 2016):

  • Annual medical history and clinical checkup, audiometry (tone and speech audiometry)

  • Annual MRI of the skull (2x/year in the year of the diagnosis to determine the tumor growth rate) from the age of 10 (earlier for the high-risk genotype and if there are clinical symptoms)

  • MRI of the spine every 2-3 years (as soon as tumor growth is detected, with the first checkup recommended after 6 months to determine the tumor growth rate)

  • Consider performing a whole-body MRI.

  • No recommendation for routine screening with F-FDG-PET/CT or MRI if there are no symptoms

Self-Care and Support

What should I pay special attention to?

If you have the impression that your child’s hearing has become worse in one or both ears or if he or she complains more about headaches, and nausea in the morning, quickly gets tired after reading a little, complains of a feeling of numbness or paralysis in the face (asymmetrical facial features), or exhibits loss of hand extension or weak foot dorsiflexion, please set up an appointment with your attending ophthalmologist or pediatrician or at a special NF clinic.

Support Groups and Additional Information