What is neurofibromatosis type 2?

Neurofibromatosis type 2 (NF2) is a hereditary condition that makes a person susceptible to developing tumors called schwannomas (benign tumors that form on the connective tissue surrounding nerves). Patients with neurofibromatosis type 2 may develop schwannomas along nerves in the brain, spinal cord, and other areas of the body. The most commonly affected nerve is the vestibular nerve, which connects the inner ear to the brain. Almost every individual with NF2 develops bilateral (both-sided) vestibular schwannomas by age 30.

Other typical features of neurofibromatosis type 2 include:

• Tumors of the central nervous system, especially:
  • Meningiomas (benign tumors that develop on the membrane surrounding the brain and spinal cord)
  • Ependymomas (benign tumors that form in the brain or spinal cord)
  • Astrocytomas (benign tumors that form in the brain or spinal cord)
• Eye problems, such as cataracts at a young age or retinal hamartomas (benign eye tumors)
• Mononeuropathy or polyneuropathy (damage to one or multiple nerves) 

Because neurofibromatosis type 2 is hereditary, the risk to develop the features associated with the condition may be passed from generation to generation in a family. The type and severity of the disorder is usually similar in affected relatives.

Causes

Neurofibromatosis type 2 is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.

In the vast majority of patients with neurofibromatosis type 2, the disorder develops as the result of alterations in a specific gene known as NF2, which is located on chromosome 22 at position q12.2. NF2 is the only gene known to be associated with neurofibromatosis type 2. The protein produced by the NF2 gene acts as a “tumor suppressor," which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. It also has a fundamental role in controlling cell movement, cell shape, and communication between cells.

With the exception of egg and sperm cells, each cell of the body normally has two working copies of the NF2 gene. Patients with neurofibromatosis type 2 generally carry an alteration in one copy of the NF2 gene in all the cells of their body. Individuals with neurofibromatosis type 2 are born and develop normally, but are at an increased risk to develop benign and malignant tumors. These tumors are believed to develop because, over time, the second working copy of the NF2 gene may become altered within one or more cells. The loss of function of the second NF2 gene copy leads to abnormal growth of the affected cells, increasing their chance to become cancerous.

How is neurofibromatosis type 2 inherited?

Approximately 50 percent of patients with neurofibromatosis type 2 inherit an altered copy of the NF2 gene from a parent who also has neurofibromatosis type 2. In the remaining 50 percent of patients, neurofibromatosis type 2 results from the development of a “new” mutation in the NF2 gene in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter scenario, the affected individuals will be the first ones in their family to carry this genetic change. All individuals who carry an alteration in one copy of the NF2 gene in all the cells of their body have a 50 percent (or 1 in 2) chance of passing this same alteration on to each of his or her children. Children who inherit the altered gene copy will have neurofibromatosis type 2 and will therefore be at risk to develop the features associated with this disorder.

Genetic mosaicism in neurofibromatosis type 2

About 25 to 30 percent of individuals with no family history of neurofibromatosis type 2 are genetically “mosaic” for an NF2 mutation. A person with NF2 mosaicism has two different populations of cells that make up the body. One population contains two working copies of the NF2 gene (these cells are normal) and the second population contains one working and one non-working NF2 gene copy (these cells are abnormal). Individuals with NF2 mosaicism may show signs of disease only in areas of the body that contain the abnormal cells.

The phenomenon of mosaicism may occur in the following way: 

• An individual inherits two working copies of the NF2 gene, one from each parent via the egg and sperm at the time of conception. As the first cell of the fetus divides, each new cell will receive two working copies of the NF2 gene.
• After several cell divisions, a mutation in one copy of the NF2 gene occurs in one cell of the developing fetus. This cell will now divide and create more cells like itself that carry one normal and one abnormal NF2 gene copy. However, there still remains a population of normal cells that will continue to divide and produce cells with two working copies of NF2. Thus, as the baby grows, a proportion of the cells will contain two normal NF2 gene copies and a second set of cells will be at risk to develop the features of NF2.
• If the egg or sperm cells of a genetic mosaic carry the altered NF2 gene copy, the mosaic individual can pass the mutation on to future children. Because it is difficult to know which cells of the body of a mosaic individual are affected, it is not possible to predict the exact risk to develop tumors or pass the altered gene copy on to future children.

Diagnosis

For an individual with no known family history of neurofibromatosis type 2, the occurrence of one or more of the following features confirms a diagnosis of the condition:

• Bilateral (both-sided) vestibular schwannomas
• Unilateral (one-sided) vestibular schwannoma, and any two of the following: meningioma, schwannoma, glioma, neurofibroma, cataract
• Multiple meningiomas and either of the following:
  • Unilateral vestibular schwannoma
  • Any two of: schwannoma, glioma, neurofibroma, cataract 

For an individual with a positive family history of neurofibromatosis type 2, a clinical diagnosis is established by the presence of any one of the following:

• Vestibular schwannoma (unilateral or bilateral)
• Any two of: meningioma, schwannoma, glioma, neurofibroma, cataract

A detailed review of an individual’s medical and family history is important in diagnosing neurofibromatosis type 2. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed clinical manifestations of neurofibromatosis type 2, such as vestibular schwannomas or cataracts. If the pattern of clinical features is suggestive of neurofibromatosis type 2, the physician or counselor may recommend that genetic testing be performed.

Genetic testing

In order to confirm on a molecular level that an individual has neurofibromatosis type 2, he or she can undergo genetic testing:

• Generally, a sample of blood is obtained from an affected individual.
• DNA is isolated from this sample, and the two copies of the NF2 gene are analyzed using a variety of methods and compared to the normal reference sequence for the NF2 gene.
• If an alteration in one NF2 gene copy is identified, the genetic counselor can examine whether the alteration has been previously reported in other individuals with neurofibromatosis type 2.

It is estimated that about 93 percent of individuals with familial neurofibromatosis type 2 will have a mutation involving NF2. In patients with no family history of neurofibromatosis type 2, the mutation detection rate drops to 60 to 75 percent. This is because some of these patients may be mosaic and not have an identifiable alteration of NF2 in their blood cells. Therefore, the failure to identify an alteration in the NF2 gene does not exclude a clinical diagnosis of neurofibromatosis type 2.

NF2 genetic test results can also provide important information for other family members. If a mutation responsible for neurofibromatosis type 2 syndrome is identified, at-risk relatives (first or second degree relatives) can be tested for the same genetic alteration. Individuals with a mutated NF2 gene typically show symptoms of neurofibromatosis type 2 by early adulthood, so genetic testing would be most informative for younger relatives.

Reproductive options

A person with neurofibromatosis type 2 who does not wish to pass this disorder on to future children has several options, including:

• Prenatal diagnosis: DNA is obtained from the cells of the embryo through chorionic villus sampling (CVS) or amniocentesis. The DNA is analyzed for alterations in the NF2 gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
• Preimplantation Genetic Diagnosis (PGD): For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the NF2 gene would be implanted.

Before one can proceed with prenatal testing or PGD, an NF2 mutation must be identified in a parent with neurofibromatosis type 2.

Tumor risks

Individuals with neurofibromatosis type 2 typically develop tumors along nerves in the brain, spinal cord, and other parts of the body. Often, these tumors must be removed to prevent serious medical problems, but they are usually benign (non-cancerous). In some cases, these tumors undergo malignant changes and behave like cancers, but the overall rate of malignant transformation is low.  

Tumor screening protocol for NF2

While the tumors associated with NF2 are almost always benign, they should be followed closely or treated as their growth can cause other problems. For example, vestibular schwannomas may lead to hearing loss, and certain central nervous system tumors cause paralysis. Furthermore, it is important to monitor schwannomas for signs of growth, change or pain, which can rarely indicate malignant transformation.

Individuals with neurofibromatosis type 2 should be screened regularly for these issues through:

• Annual brain MRIs starting at age 10 years and continuing until at least 40 years of age
• Baseline spine MRIs to screen for tumors should be performed at time of diagnosis and repeated if symptoms develop
• Annual hearing evaluation, beginning at time of diagnosis
• Annual eye examination starting in childhood

Adults with NF 2

Adults who have neurofibromatosis type 2 or who would like more information about neurofibromatosis type 2 may contact the Medical Genetics Team at The Hospital of the University of Pennsylvania.