Neurofibromatosis

What is neurofibromatosis?

Neurofibromatosis (NF) refers to a group of genetic conditions involving the development of tumors that may affect the brain, spinal cord, and the nerves that send signals between the brain and spinal cord and all other parts of the body. Most tumors are non-cancerous (benign), although some may become cancerous (malignant). 

NF is not a single disorder. NF includes:

• Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease .
• All types of Schwannomatosis (SWN), including NF2-related schwannomatosis (NF2-SWN), which is the most common form of SWN  

Types of Neurofibromatosis

Neurofibromatosis Type 1

While NF1 is rare, it is the most common type of NF. Symptoms can develop slowly, so getting the correct diagnosis may take several years. But most people are diagnosed during early childhood. Most people with NF1 have an average life expectancy.

Children and adults with NF1 have different symptoms and medical problems that can develop throughout their lives. Signs and symptoms of NF1 include:

• Flat, light brown spots on the skin (“café au lait” spots). These are the most common sign of NF1. People with NF1 almost always have more than six of these spots. The spots are smaller in children than in adults (at least half a centimeter versus over 1.5 centimeters). Café au lait spots are not always present at birth and may appear more often and spread to more areas of the body over time. These spots are not dangerous but may indicate the presence of an NF1 gene change in the person. However, they also appear in other conditions, so a doctor must see and diagnose them.
• Freckling in the armpits or the groin. This usually appears by age 5. Freckles are similar in appearance to café au lait spots but smaller. Freckling can happen in other conditions, but the freckling alongside other common symptoms can indicate NF1.
• Soft, pea-sized bumps called neurofibromas. These are common and can appear on the skin (known as cutaneous), under the skin’s surface (subcutaneous), or on any nerve throughout the body. Although some cutaneous neurofibromas develop in childhood, most appear during or after the teenage years and may occur more often with age.
• Plexiform neurofibromas. These happen in about 50% of patients with NF1 and involve multiple nerves and surrounding tissues near nerves and organs in the body. About 10-15% of the neurofibromas can become dangerous over a person’s lifetime and turn into a malignant tumor of nerve coverings.
• Growths on the iris of the eye (known as Lisch nodules or iris hamartomas). Typically, these nodules only appear in the teen years. They are harmless and do not require monitoring or treatment. 
• A tumor of the optic pathway (optic pathway glioma). This happens in about 15-20% of children with NF1. Children ages 1 to 6 years are at the greatest risk for these tumors.  Most of the time, optic gliomas do not cause symptoms. Sometimes, optic pathway gliomas can affect vision and require chemotherapy.
• Bone deformities. These are not common in NF. If they happen, these deformities are often present at birth. They include the abnormal development of the eye socket, which leads to a slight bulge of the eye or facial asymmetry. They also include bowing (curving) of the bones of the shin.
• Shorter than average height and a larger head size. Children with NF1 are shorter than most children their age and may have unusually large heads.
• Learning difficulties and attention deficit hyperactivity disorder. These conditions happen in over half of people with NF1. These conditions may vary in their severity. Also, difficulty with social relationships (social cognition) is common.

Complications of NF1 include:

• Vascular conditions, such as congenital heart defects, high blood pressure (hypertension), stenosis (hardening) of the arteries to the kidneys (called renal artery stenosis), or narrowing of the major blood vessels to the brain (called Moyamoya disease)
• Poor visuospatial skills (which refers to the ability to know where objects are in space) and poor performance on academic achievement tests, including those that measure reading and math skills 
• More common and aggressive scoliosis, or curvature of the spine
• Increased risk of gastrointestinal stromal tumors (GIST) and neuroendocrine tumors, like pheochromocytoma and benign nerve tumors, called glomus tumors
• Higher risk for developing breast cancer before age 50 in women

NF2-Schwannomatosis

Signs and symptoms of NF2-SWN usually appear between the teenage years and age 30, although they can begin at any age.

The most common features of NF2-SWN are benign (non-cancerous), slow-growing tumors affecting the cranial, spinal, and peripheral nerves, as well as the covering of the brain and spinal cord (called the meninges). The common tumors seen in NF2-SWN include: 

• Schwannomas. Schwannomas are tumors made up of a specific type of cell called Schwann cells. Schwann cells produce myelin, the substance that covers and protects peripheral nerves throughout the body. Schwannomas cause problems because they often happen on the eighth cranial nerve, an important nerve for hearing and balance. The eighth cranial nerve has two branches: the acoustic branch, which carries the signals for hearing to the brain, and the vestibular branch, which carries signals for sense of position and balance. Vestibular schwannomas are the most common form of schwannoma in people with NF2-SWN, but schwannomas can involve any cranial or peripheral nerves. Schwannomas are also found in the skin and appear as bumps under or on the skin. Schwannomas may or may not progress over time, and many never require treatment.
• Meningioma. Meningioma is the second most common tumor type in people who have NF2-SWN. Meningiomas are tumors that form in the meninges. People with NF2-SWN can develop multiple meningiomas in the covering of the brain and along the spinal column. 
• Ependymoma tumors. Ependymomas develop within the spinal cord. In many individuals, these tumors cause no symptoms.

Complications of NF2-SWN can include:

• Hearing loss or ringing in the ears (tinnitus) and problems with balance related to vestibular schwannomas. These are often the first symptoms and may appear with weakness in the facial muscles
• Vision problems like cataracts (clouding of the lens) beginning in childhood, or changes in the retina that can affect vision
• 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
• Schwannomas on the skin

Other forms of SWN can be associated with chronic pain located anywhere in the body.

Who is more likely to have neurofibromatosis?

About half of people with NF inherit the condition from one of their parents. The other half develops NF due to a spontaneous (also called sporadic) change in the gene. Each child who inherits the NF1 genetic variant will have symptoms of the condition. There is a 50% chance that a person with NF1 will pass it on to their children. 

It's not completely known why tumors develop in people with NF. However, tumor development is partly due to genetic changes that affect proteins responsible for controlling the growth of nervous system cells. Without the normal function of these proteins, cell growth increases, leading to the formation of tumors. 

How is neurofibromatosis diagnosed and treated? 

Diagnosing neurofibromatosis

To diagnose neurofibromatosis (NF), a doctor begins with a review of a patient’s personal and family medical history and a physical exam. Doctors can check for characteristic signs and symptoms to diagnose a person suspected of having NF.

NF1 is usually diagnosed during childhood, as symptoms appear at birth or shortly after, usually by age 10. To make a diagnosis of NF1, an individual must have two or more of the following:

• Six or more café au lait spots
• Freckling in the armpit or groin
• Two or more neurofibromas or one plexiform neurofibroma
• Two or more Lisch nodules or iris hamartomas (bumps on the iris of the eye)
• Optic pathway glioma
• Curving of the bones of the shin
• An NF1-associated gene variant on genetic testing 
• A parent with NF1

Doctors will likely monitor a child with only one symptom and no family history of NF1 for any other symptoms. To diagnose NF1 using skin changes (café au lait spots or freckling), at least one of these skin conditions needs to appear on both sides of the body. 

To make a diagnosis of NF2-SWN, the person must have one of the following:

• Vestibular schwannomas on both sides of the body
• The same disease-causing variant in at least two different NF2-related tumors (including schwannoma, meningioma, and/or ependymoma)
• Either two major or one major and two minor criteria:
  • Major criteria include unilateral vestibular schwannoma, a parent with NF2-SWN, two or more meningiomas, or an NF2-pathogenic variant in blood or saliva
  • Minor criteria include ependymoma, schwannoma, juvenile cataract, retinal hamartoma, or epiretinal membrane (both seen by a skilled ophthalmologist)

An eye exam can help diagnose neurofibromatosis and show Lisch nodules, cataracts, and vision loss caused by NF1. To diagnose NF2 and SWN, doctors may order hearing tests.

Imaging tests such as X-rays, CT scans (computed tomography scan), or MRIs (magnetic resonance imaging) can help identify bone changes, tumors in the brain or spinal cord, and very small tumors elsewhere in the body. An MRI might be used to diagnose optic gliomas in NF1 or help find tumors in the person's nervous system and skin in NF2. Additional imaging based on symptoms may reveal schwannomas on peripheral nerves.

Genetic testing may be needed to correctly diagnose individuals with features of these conditions who do not have a known family history or bilateral vestibular schwannomas (those that happen on both sides of the body). Genetic testing can be useful in some situations, such as when a person is pregnant or when the clinical diagnosis is inconclusive.

Treating neurofibromatosis

There is no cure for NF1 or SWN, but treatments are available to help manage symptoms and address other conditions that may develop. 

Many people with NF won't require lengthy treatment for any single symptom during their lives. However, people with neurofibromatosis should get regular screenings to detect signs and symptoms, such as routine eye and physical exams. They should be seen regularly by a specialist, even if they don't have any symptoms. A specialty clinic should see people with NF and provide them with an initial screening and annual follow-up evaluations (more frequent if the condition is severe).

Medications

The U.S. Food and Drug Administration (FDA) approved selumetinib (Koselugo) as a treatment for children ages two and older with NF1 who have plexiform neurofibromas that are causing symptoms and cannot be addressed with surgery. The drug helps to stop tumor cells from growing. Currently, there is no approved medical treatment or drug to treat SWN directly, but medications can help manage pain, headache, seizures, and other symptoms. Medications to treat complications, such as vestibular schwannomas and meningiomas, are in development.  

Surgery

Surgeons may remove tumors that are growing or causing symptoms directly related to the tumor. Surgeons may also remove tumors if there is concern about cancer or if the tumors cause significant discomfort. Doctors have no general agreement about when surgery should be performed or which surgical option is best. Some bone malformations, such as scoliosis, can be corrected surgically or by stabilizing the spine with a brace. Surgical options for vestibular schwannomas depend on tumor size and the extent of hearing loss. 

However, because vestibular schwannomas are located on the nerve that controls hearing and balance, surgeons must carefully weigh the potential risk of nerve damage against the potential benefits of surgery.

Cancer treatment

Chemotherapy, surgery, or radiation therapy may be used to treat tumors that become cancerous or to prevent tumors from growing. Chemotherapy may be used to treat optic pathway or other brain gliomas. It is a standard treatment for cancers that may arise with NF1, including malignant peripheral nerve sheath tumor (MPNST) and breast cancer. 

Devices and other therapeutic support

Because children with NF1 have a higher risk for a variety of learning disabilities, such as ADHD and delayed speech, they should be evaluated by a care team knowledgeable in NF1. Children with NF1 benefit from formal neuropsychological assessments to assist in creating individualized educational plans for school. 

For people with NF2-SWN, cochlear implants, hearing aids, or auditory brain stem implants might improve hearing loss. Mobility devices and corrective eyewear can help manage movement and vision problems associated with neurofibromatosis.

What are the latest updates on neurofibromatosis?

NINDS, a part of the National Institutes of Health (NIH), is the leading federal funder of research on NF. NINDS supports new and innovative research to understand and better, prevent, diagnose, and treat NF. NINDS-supported research projects cover a wide range of topics on neurofibromatosis, such as interventions to reduce health disparities in NF, risk factors, and effective ways to reduce a person's risk of NF. Other NIH institutes, the Department of Defense (DOD), and private foundations have also provided critical support for NF research and clinical trials. 

Current laboratory and clinical research aims to understand how genetic defects cause the diverse conditions and medical problems that happen in people with neurofibromatosis, and also how to predict which clinical features will develop in any given person (known as personalized or precision medicine). In addition, studies in NF1 and SWN have revealed many important insights for investigators working in other fields, including brain cancer, sarcoma, autism, learning disabilities, nerve regeneration, chronic pain, and targeted therapies.

Clinical trials

NINDS supports clinical trials aimed at understanding tumor growth and cognitive impairments in children:

• NINDS-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 on the impact of NF2-SWN on individuals and to understand disease progression better. Studying the natural history of tumors in NF2-SWN can help scientists determine possible factors that may regulate their growth.
• NINDS supports clinical trials involving a large group of children with NF1 to find associations between brain abnormalities and specific cognitive disabilities. Understanding these links could help doctors anticipate NF1-related cognitive impairments and inform early intervention programs.

Several options have been tested or are under investigation for treating neurofibromatosis tumors. Ongoing clinical studies on drugs that block an enzyme that affects how some cells grow and develop, called mitogen-activated protein kinase, show promise in treating NF1-associated tumors, especially in children. Because schwannomas are particularly hard-to-treat tumors, NINDS researchers are developing and testing a new treatment option that uses a virus to kill tumor cells. Researchers are also testing chemotherapy drugs as treatments for NF2-related schwannomas.

More information about research on neurofibromatosis can be found using NIH RePORTER, a searchable database of current and past research projects supported by NIH and other federal agencies. RePORTER also includes links to publications and resources from these projects. For articles on NF research, search PubMed, which contains citations from medical journals and other sites. 

How can I or my loved one help improve care for people who have experienced neurofibromatosis?

Clinical trials increase our understanding of NF and improve how doctors treat it. Consider participating in a clinical trial, so clinicians and scientists can learn more about NF and related disorders. Clinical research with human study participants helps researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of participants are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible and that treatments will be safe and effective for everyone who will use them.

For information about clinical research participation, visit the NINDS Clinical Trials site and NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with TIAs at Clinicaltrials.gov, a searchable database of current and past federal and private clinical trials.

Donate brain tissue

NINDS supports the Human Brain and Spinal Fluid Resource Center. This center supplies researchers worldwide with tissue from individuals with neurological and other disorders. Tissue from people with NF1, NF2, or SWN is needed to help scientists study these disorders more effectively. 

People with neurofibromatosis also can support research by pre-registering to donate their brain tissue before death. Human brain tissue is essential to understanding how the nervous system functions.

The NIH NeuroBioBank is an effort to coordinate the network of brain banks it supports across the country to advance research through the collection and distribution of post-mortem brain tissue to qualified research teams. 

Registering to donate brain tissue can help scientists learn more about how the brain affects the body.