Neurofibromatosis 2 (NF2)

Roughly one-third of people who develop NF2 may also have the disease called mosaic NF2. This diagnosis results in milder symptoms restricted to just one part of the body.

Although many people with neurofibromatosis 2 (NF2) inherit the gene that causes the condition, some cases arise from a spontaneous genetic mutation in the NF2 gene for unknown reasons.

Once this mutation has occurred, the abnormal gene can be inherited. Each child of an affected parent has a 50 percent chance of inheriting the gene mutation. Only one parent needs to have the faulty gene for their child to be at risk of developing NF2.

Couples with a family history of neurofibromatosis 2 (NF2) should discuss their risk factors with medical professionals before becoming pregnant. With the guidance of a genetic counselor, options may include working with an egg or sperm donor, adoption, in utero tests (such as chorionic villus sampling or amniocentesis) or pre-implantation genetic tests (for those becoming pregnant using IVF).

Neurofibromatosis occurs in both biological sexes and in all races and ethnic groups. Why tumors develop in these conditions isn't completely known, but it appears to be caused in part by mutations in genes that play key roles in suppressing growth in nervous system cells. These mutations keep the genes — identified as NF1, NF2, SMARCB1 and LZTR1 — from making normal proteins that control the ability of the cells to function properly. Without the normal function of these proteins cell growth increases, leading to the formation of tumors.

Genetic testing and screening are available for pregnant mothers to help determine risk for NF2. These tests may be conducted during pregnancy, or prior to transferring an embryo (for those using IVF). Because many of the clinical features of NF2 develop as an individual ages, getting the correct diagnosis can take several years. Prevention is limited to those choosing to genetically screen embryos prior to implantation. 

While teenagers and adults often are first seen for hearing and balance problems, young children with NF2 more commonly seek initial medical attention due to vision problems and meningiomas.

Signs of NF2 may be present in childhood but can be overlooked, especially in children who do not have a family history of NF2. Children are often first seen by a doctor because of schwannomas in the skin, vision loss from retinal abnormalities or tumors, seizures or weakness related to spinal cord compression. More commonly, symptoms of NF2 are first noticed in the second decade of life.

The most common first symptom is hearing loss or ringing in the ears (tinnitus) related to vestibular schwannomas. Less often, the first visit to a doctor will be because of disturbances in balance, visual impairment, focal weakness in an arm or leg, seizures or skin tumors.

Nearly all individuals with NF2 will develop tumors along the nerves that are responsible for balance and hearing, causing symptoms like trouble walking, buzzing or ringing in the ears and hearing loss that worsens progressively. 

Signs and symptoms of NF2 result from the development of:

• Benign, slow-growing tumors affecting the cranial, spinal and peripheral nerves, as well as the covering of the brain and spinal cord (called the meninges)
  • Schwannomas are tumors made up of Schwann cells, the cells that produce the myelin that covers and protects peripheral nerves throughout the body. They often occur on the eighth cranial nerve, which has two branches: The acoustic branch carries the signals for hearing to the brain, and the vestibular branch carries signals for sense of position and balance. Vestibular schwannomas (also known as acoustic neuromas) are the most recognized form of schwannoma in people with NF2, but schwannomas can involve any of the cranial or peripheral nerves in someone with NF2. Schwannomas also can occur in the skin and appear as bumps under the skin or on the skin surface. Most tumors are benign, although very rarely they may become cancerous. Schwannomas may or may not progress over time and many never require treatment.
  • Meningioma is the second most common tumor type in people who have NF2. Meningiomas form in the tissue covering that surrounds the brain and spinal cord. People with NF2 have both a higher rate of meningiomas than the general population and can develop multiple meningiomas within the skull and along the spinal column.
  • Ependymoma tumors occur more frequently in people with NF2 than in the general population. Ependymomas arise within the spinal cord (as opposed to on the surface) and are benign. In many individuals, these tumors produce or show no symptoms.
• People with NF2 may develop vision problems like cataracts at an earlier age or have changes in the retina that can affect vision
• Individuals with NF2 may develop peripheral neuropathy, or problems with nerve function, usually numbness and weakness on both sides of the body (with or without muscle loss) in the arms and legs

While teenagers and adults often are first seen for hearing and balance problems, young children with NF2 more commonly seek initial medical attention due to vision problems and meningiomas.

Signs of NF2 may be present in childhood but can be overlooked, especially in children who do not have a family history of NF2. Children are often first seen by a doctor because of schwannomas in the skin, vision loss from retinal abnormalities or tumors, seizures or weakness related to spinal cord compression. More commonly, symptoms of NF2 are first noticed in the second decade of life.

The most common first symptom is hearing loss or ringing in the ears (tinnitus) related to vestibular schwannomas. Less often, the first visit to a doctor will be because of disturbances in balance, visual impairment, focal weakness in an arm or leg, seizures or skin tumors.

To diagnose NF2, a doctor will look for the following:

• Vestibular schwannomas
• A parent, sibling or child with NF2

It may be impossible to distinguish someone with NF2 from SWN based on clinical features alone. Genetic testing may be needed to correctly diagnose individuals with features of these conditions who lack a known family history or bilateral vestibular schwannomas (those that occur on both sides of the body). Genetic testing can be useful in some situations, such as for prenatal testing or when the clinical diagnosis is inconclusive. 

Detailed imaging of the brain and spinal cord by MRI is necessary, and additional imaging based on symptoms may reveal schwannomas on peripheral nerves.

Signs of NF2 may be present in childhood but can be overlooked, especially in children who do not have a family history of NF2. Children are often first seen by a doctor because of schwannomas in the skin, vision loss from retinal abnormalities or tumors, seizures or weakness related to spinal cord compression. More commonly, symptoms of NF2 are first noticed in the second decade of life.

The most common first symptom is hearing loss or ringing in the ears (tinnitus) related to vestibular schwannomas. Less often, the first visit to a doctor will be because of disturbances in balance, visual impairment, focal weakness in an arm or leg, seizures or skin tumors.

To diagnose NF2, a doctor will look for the following:

• Vestibular schwannomas
• A parent, sibling or child with NF2

They will also look for a unilateral vestibular schwannoma (on one side of the body) before age 30 or any of the following:

• Ependymoma
• Juvenile cataract or retinal abnormalities
• Meningioma
• Schwannoma of non-vestibular nerves

There is no known cure for NF2, and it is best managed at a specialty clinic with an initial screening and annual follow-up evaluations (more frequent if the disease is severe). Improved diagnostic technologies, such as magnetic resonance imaging (MRI), can reveal tumors of the vestibular nerve as small as a few millimeters in diameter. Vestibular schwannomas grow slowly, but they can grow large enough to engulf one of the eight cranial nerves as well as cause brain stem compression and damage to surrounding cranial nerves.

Surgical options depend on tumor size and the extent of hearing loss. There is no general agreement among doctors about when surgery should be performed or which surgical option is best. Individuals considering surgery should carefully weigh the risks and benefits of all options to determine which treatment is right for them.

As NF2 worsens over time, its progression is different in each individual case. Most people with NF2 will lose their hearing completely, and may also lead to requiring assistance of a mobility device such as a wheelchair.

Some tumors associated with NF2 may be removed with surgery, though risk still exists for deafness or facial weakness. Some benefit from learning sign language orlip-reading skills or the use of a hearing aid or special implants. 

Surgical options depend on tumor size and the extent of hearing loss. There is no general agreement among doctors about when surgery should be performed or which surgical option is best. Individuals considering surgery should carefully weigh the risks and benefits of all options to determine which treatment is right for them.

Studying the natural history of tumors in NF2 can help scientists determine possible factors that may regulate their growth. National Institute of Neurological Disorders and Stroke-supported researchers are using a variety of tests — including diagnostic imaging, eye examinations, hearing and balance tests, neurologic examinations, blood and genetic testing, and quality of life assessments — to characterize the impact of NF2 on individuals and better understand disease progression.

Current basic and clinical research is not only aimed at understanding how genetic defects cause the diverse conditions and medical problems encountered people with NF, but also how to predict which clinical features will arise in any given person (personalized or precision medicine). In addition, studies in NF1, NF2 and SWN have revealed numerous important insights for investigators working in other fields, including brain cancer, sarcoma, autism, learning disabilities, nerve regeneration, chronic pain and targeted therapies.