Neurofibromatosis

What Causes Neurofibromatosis?

The root cause of neurofibromatosis is a mutation in the genes that control the growth of affected cells. In a healthy cell, these genes prevent the cell from growing or reproducing too rapidly, and the genes can also determine the cell’s normal lifespan. In a tumor’s cells, the damage to the genes causes the cells to grow and reproduce rapidly, and the cells may live longer than usual. As this rapid growth and reproduction continue, the cells grow into an abnormal mass.

NF1 is caused by a mutation in the gene responsible for producing a protein called neurofibromin. Neurofibromin helps regulate normal cell growth, and the loss of this protein caused by the mutation is thought to allow cells to grow too rapidly.

NF2 results from mutations in genes responsible for a protein called merlin or schwannomin. This protein suppresses the growth of tumors, and the mutations interfere with its production.

SWN is caused by mutations in the SMARCB1 or LZTR1 genes, both of which play a role in tumor suppression.

Is Neurofibromatosis Hereditary?

About half of NF1 and NF2 cases are caused by gene mutations inherited from a parent. In the other half of the cases, the gene mutation occurs spontaneously without being present in the parents’ genes. However, when a person develops a spontaneous mutation that causes NF1 or NF2, that mutation may be passed on to the person’s children.

NF1 and NF2 are inherited in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

The inheritance pattern of SWM is not well understood, but a parent with the associated gene mutation is estimated to have a 15% chance of passing the disorder to their children.

How Is Neurofibromatosis Detected?

Sometimes symptoms of NF1, such as cafe-au-lait spots, are apparent at birth or early childhood. However, in many cases, the disorder’s symptoms develop slowly, and diagnosis may be delayed until later in childhood.

NF2 may also go unnoticed early in its early stages. The first signs of the disorder in adolescents or adults are often problems with balance, hearing impairments, or ringing in the ears. The initial signs of NF2 in younger children are more commonly vision difficulties or tumors in the central nervous system.

SWM shares many symptoms with NF2, and the early signs of both disorders can be the same. However, in some cases, SWM produces no noticeable symptoms.

How Is Neurofibromatosis Diagnosed?

Doctors may take several different diagnostic steps when suspecting a patient may have neurofibromatosis.

• Neurological exam. A basic neurological exam will test a patient’s reflexes, balance, coordination, strength, vision, and hearing. The results of this exam may prompt a doctor to look for further signs of the disorders.
• Imaging. Imaging technologies such as magnetic resonance imaging (MRI) and computerized tomography (CT) are non-invasive ways to look at the brain, spinal cord, bones, and other parts of the body. Doctors can use these technologies to look for signs of small tumors that could indicate neurofibromatosis.
• Genetic testing. If a doctor suspects that a patient may have some type of neurofibromatosis, they may request genetic testing to look for the mutations associated with the disorders, especially if there is no family history of the conditions.  

How Is Neurofibromatosis Treated?

Neurofibromatosis has no cure, but a variety of treatment options are available. The proper treatment approach differs depending on the type of disorder.

Treatment for NF1

Treatment options for NF1 include:

• Monitoring for changes in tumors and the emergence of complications
• Medication with selumetinib for children with tumors called inoperable plexiform neurofibromas
• Surgery to remove cancerous tumors or those that are causing complications
• Chemotherapy to treat cancerous tumors
• Anti-seizure drugs and other therapies to control individual symptoms

Treatment for NF2

Treatment options for NF2 include:

• Monitoring for changes in tumors and the emergence of complications
• Cochlear implants or other procedures to correct hearing loss
• Surgery to remove tumors that are causing complications
• Surgery to correct cataracts or other eye problems

Treatment for SWM

There is no standard treatment for SWM, but surgery to remove tumors may be considered in some cases if the tumors are causing significant complications.

How Does Neurofibromatosis Progress?

Most people with neurofibromatosis live an average life span. However, the disorders can cause significant complications that can be debilitating or, sometimes, life-threatening. The potential long-term impacts vary depending on the disorder and include:

• Learning disabilities
• Anxiety or depression
• Bone malformation
• Vision difficulties
• Hearing impairment or deafness
• Hormone problems
• High blood pressure
• Breathing difficulties
• Cancers, including breast cancer, brain tumors, leukemia, and colorectal cancer
• Numbness or weakness in the extremities (peripheral neuropathy)
• Chronic pain

How Is Neurofibromatosis Prevented?

There is no known way to prevent neurofibromatosis. People with a family history of any of the disorders are advised to speak with a genetic counselor to assess their risks if they plan to have children.

Neurofibromatosis Caregiver Tips

Some people with neurofibromatosis also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with these disorders:

• NF1 is sometimes associated with autism spectrum disorder.
• Children with NF1 may be at increased risk of attention-deficit/hyperactivity disorder (ADHD).
• People with NF1 or NF2 are also at increased risk of depression and anxiety.

Neurofibromatosis Brain Science

Although the small tumors associated with neurofibromatosis are usually benign, the disorders often increase the risk of cancerous tumors, including some that affect the brain, central nervous system, and nerves involved in sensory perception. Some of these tumors and cancers include:

• Acoustic neuroma. This non-cancerous tumor grows on the nerve that connects the brain to the inner ear. It is also sometimes called a vestibular schwannoma because it affects the Schwann cells (cells that surround nerves) on the vestibular nerve, the nerve responsible for our senses of hearing and balance. Acoustic neuromas are often associated with NF2.
• Glioblastoma. This is a cancerous tumor that affects the brain or spinal cord. These tumors tend to grow aggressively and invade surrounding brain tissues, making them very difficult to treat. They are most often associated with NF1.
• Meningioma. This tumor affects the thin membranes surrounding the brain or spinal cord. The tumors originate in the cells of the membranes, not the brain itself, and are thus not technically brain tumors. However, a large meningioma may exert pressure on nearby brain tissue and cause serious neurological symptoms. People with NF2 are at increased risk of developing meningiomas.
• Ependymoma. This tumor affects the ependymal cells that line the spinal column and spaces (ventricles) inside the brain. It also is sometimes associated with NF2.
• Astrocytoma. This type of brain tumor affects cells called astrocytes. People with NF1 are at increased risk of developing this type of tumor.

Neurofibromatosis Research

Title: Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1 (DoDNAC)

Stage: Recruiting

Principal investigator: Donald Gilbert, MD MS

Cincinnati Children’s Hospital Medical Center

Cincinnati, OH

Children with neurofibromatosis type 1 (NF1) commonly suffer from the effects of cognitive, behavioral, and motor impairments. At present, there is no specific treatment for this NF1 complication. In this project, the investigators will assess the safety and clinical benefit of N-acetylcysteine (NAC) as a pharmacological intervention in children with NF1. This drug choice is based on the recent findings from mouse models to study the central nervous system manifestations of NF1 at Cincinnati Children’s Hospital Medical Center (CCHMC). These findings revealed a role for myelin-forming oligodendrocytes in controlling nitric oxide synthases (NOS) and their product, nitric oxide (NO), in the maintenance of brain structure and function, including regulation of behavior and motor control. Treating these mice with NAC corrected cellular and behavioral abnormalities. This data from animal models of NF1, along with uncontrolled clinical observations in children with NF1, suggest that the antioxidant compound, NAC, may reduce these impairments. Therefore, the investigators propose performing a single-center double-blind placebo-controlled, prospective, Phase II study to explore the safety, tolerability, and efficacy of NAC on motor behavior and/or learning in children with NF1 aged 8 through 16 years old. Participants will be carefully monitored for side effects. Primary and secondary outcome measures will be administered at baseline, follow-up, and post-treatment.

Title: Natural History Study of Patients With Neurofibromatosis Type 2

Stage: Recruiting

Principal investigator: Prashant Chittiboina, MD

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Objective: With this prospective natural history study on neurofibromatosis type 2 (NF2) study, we hope to understand the factors leading to tumor progression and neurological disease burden in NF2.

Study Population: 269 participants, ages 8-75, with a clinical or genetic diagnosis of NF2 will participate in this study.

Design: Study participants will be evaluated with a thorough physical and neurologic examination upon enrollment. This initial outpatient evaluation will include magnetic resonance imaging with contrast of brain and spine and blood collection for research use. Participants with measurable hearing will have an audiology assessment performed during the initial visit. Participants with untreated vestibular schwannomas will have a vestibular assessment performed during the initial visit. Genetic studies performed outside will be acceptable as confirmation of NF2 in enrolled patients. If needed to confirm NF2 with genetic studies or for research purposes, whole-genome/whole-exome sequencing may be performed on blood obtained from subjects enrolled in this study. A speech-language pathologist will evaluate all participants.

Subjects will be followed as outpatients for up to ten years, during which clinical and radiologic evaluations will be performed annually. Auditory testing will be conducted annually for participants with measurable hearing. Participants with initially untreated vestibular schwannomas will be followed annually with vestibular testing. Speech and swallowing reassessments will be repeated if worsening of speech or swallowing is reported. Blood will be collected at each visit for blood biomarker testing.

Outcome measures: researchers hope to understand the biological basis for speech and swallowing dysfunction in patients with NF2. They will study and report the strength of association of MRI findings, clinical assessments, cranial nerve deficits, and speech/swallowing dysfunction. Researchers hope to identify imaging biomarkers of hearing loss in NF2. Third, they will attempt to discover the mode of peripheral neuropathy in patients with NF2. Lastly, they will attempt to discover previously unknown serum biomarkers associated with high tumor burden in NF2.

Title: Resiliency Training in Adolescents With NF1 and NF2

Stage: Recruiting

Principal investigator: Ana-Maria Vranceanu, PhD

Massachusetts General Hospital

Boston, MA

Neurofibromatosis (NFs) are rare genetic conditions with no cure. Adolescents with NF experience more symptoms of depression and anxiety, higher levels of stress associated with coping with NF symptoms, lower levels of self-esteem, difficulties with social skills and social support, high rates of learning disabilities, and more pain than the general population norms.

This study aims to compare the effect of two stress and symptom management programs tailored for adolescents with neurofibromatosis on quality of life and psychosocial functioning. We will also examine the degree to which treatment-dependent improvements in quality of life are mediated by improvements in depression, pain intensity, and pain interference.