Neurofibromatosis Genetic Testing

By Douglas Stewart, MD, Medical Geneticist at Genome Medical

“Neurofibromatosis” can refer to one of three different genetic disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. NF1 and NF2 are associated with an increased risk to develop certain types of benign (non-cancerous) tumors as well as cancers. NF1 is also associated with distinctive skin pigment differences (some of which can overlap with NF2) and, frequently, learning problems. In schwannomatosis, benign tumors called schwannomas develop on spinal and peripheral nerves and can be painful. About 1 in 3,000 people is affected with NF1. NF2 is less common, affecting about 1 in 25,000 people. Schwannomatosis is the least common, affecting about 1 in 40,000 people.

Neurofibromatosis can be passed on from parent to child. NF1 and NF2 are known as “autosomal dominant,” which means that they arise from an abnormal gene inherited from a parent, even though the matching gene from the other parent is normal. In both NF1 and NF2, about half the people affected did not inherit the disorder from a parent. Instead, the disorder arose from a spontaneous change in the underlying gene. The inheritance patterns in schwannomatosis are more complex than those for NF1 and NF2. About 15 percent of people with schwannomatosis inherit a faulty copy of the underlying gene from a parent.

If a friend or loved one is suspected of having neurofibromatosis, he or she should be seen by a medical geneticist and/or a genetic counselor, who will collect a family history, evaluate signs and symptoms, and apply diagnostic criteria to make a determination. In addition, these genetic experts can make recommendations on how to manage the disorder and refer to specialists as needed. Neurofibromatosis genetic testing can be very useful in making a diagnosis.

Diagnosing Neurofibromatosis

Neurofibromatosis type 1 arises from changes in the NF1 gene. Neurofibromatosis type 2 arises from changes in the NF2 gene. Schwannomatosis can arise from changes in two genes (SMARCB1 or LZTR1), although other genes likely await discovery. In all three types of neurofibromatosis, only part of the body may be affected. This is called mosaic (or segmental) neurofibromatosis or schwannomatosis and may be associated with more mild symptoms.

Symptoms for Neurofibromatosis Type 1 (NF1)

There are approximately 100,000 Americans living with NF1, and it is one of the most common genetic disorders. Males and females are equally likely to be affected. NF1 is 100 percent penetrant, which means that a person with an NF1 gene mutation will develop at least some features of the disorder by early adulthood. The severity of the disorder can vary widely among affected family members. The reason for this is not clear, although other genes may play a role. NF1 is usually diagnosed in childhood, although more mild presentations may not be apparent until later. People almost always have multiple café au lait macules (“coffee with milk”-colored birthmarks) and freckling in the armpits. Pigmented lesions of the eyes (Lisch nodules) are found in almost everyone with NF1. Fleshy, benign skin tumors called neurofibromas develop in adolescence. About half of the people with NF1 also have larger, congenital benign tumors called plexiform neurofibromas, which can grow in unpredictable ways and give rise to cancer. Some children have optic pathway gliomas, a type of benign brain tumor, that can grow and affect vision. This is why younger children should be seen by an ophthalmologist regularly for monitoring. In younger children, NF1 can be difficult to distinguish from Legius syndrome, a much less common disorder that also features café au lait macules and freckling.

Symptoms for Neurofibromatosis Type 2 (NF2)

NF2 is much less common than NF1 and is estimated to affect around 12,000 Americans. It is associated with a distinct set of benign brain tumors (vestibular schwannoma, meningioma, glioma). Similar to NF1, NF2 can also feature neurofibromas and café au lait macules. For this reason, the two disorders were often confused until modern diagnostic criteria were developed in the 1980s. The vestibular schwannomas of NF2 arise in the inner ear, and thus can lead to deafness, ringing in the ear and problems with balance. Vision loss, seizures, pain and difficulty with mobility can also develop from the schwannomas and meningiomas. Surgery and new medical treatments can be effective in controlling the symptoms of NF2.

Symptoms for Schwannomatosis

Schwannomatosis is the least common neurofibromatosis and likely affects fewer than 10,000 Americans. It usually does not present until adulthood. The predominant symptom is pain arising from the schwannomas pressing on nerves. The pain can be anywhere in the body. Sometimes people also develop neurologic symptoms like tingling or numbness, weakness and headaches. Surgery can be helpful.

Genetic Testing for Neurofibromatosis

For NF1, NF2 and schwannomatosis, a diagnosis can be made based on carefully developed disorder-specific diagnostic criteria. Frequently it can be determined if a person has NF1, NF2 or schwannomatosis from their medical and family history, physical exam and careful examination (by a pathologist) of any removed tumors. However, since sometimes features of the disorder take time to develop, genetic testing can be very helpful in younger children or in uncertain situations. The genes tested depend on whether NF1, NF2 or schwannomatosis is suspected.

Testing requires a saliva sample or, in some cases, a blood draw. The test results are usually returned in one to two months. For NF1, the gene NF1 is tested. The Legius syndrome gene (SPRED1) is also commonly tested too. For NF2, the gene NF2 is tested. For schwannomatosis, the genes SMARCB1 and LZTR1 are tested, plus (frequently) NF2 since schwannomas are observed in both NF2 and schwannomatosis. If there is concern about mosaic or segmental neurofibromatosis, tumors, skin and other tissues may be sequenced.

For people who meet the diagnostic criteria for NF1 or NF2, more than 95 percent (but not 100 percent) will have a change (or mutation) in the NF1 or NF2 genes. This yield is much lower in schwannomatosis since there are very likely additional genes to be discovered.

Does Insurance Cover the Genetic Test for Neurofibromatosis?

Insurance companies are likely to cover the cost of testing if it is considered medically necessary. Willingness to pay for testing varies widely by insurance company, and thus you should always check with their own insurance provider. A geneticist and/or a genetic counselor can be very helpful in working with an insurance company to provide coverage. If testing is not covered by insurance, the out-of-pocket costs of genetic testing has decreased such that it is now more affordable for many people, and the total cost can be as low as $250 at some testing laboratories.

Genetic Counseling for Managing Neurofibromatosis

Although there is no cure for NF1, NF2 or schwannomatosis, the disorders can be treated and managed. A genetic counselor can be very helpful in explaining how neurofibromatosis can be passed along in families, ordering the proper genetic test (where appropriate), interpreting genetic test results and finding appropriate multidisciplinary clinics to develop long term care.

If you’d like to speak to a genetic counselor, click here to schedule an appointment. If you have questions about the services Genome Medical provides click here.

Topics: Blog

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