Neurofibromatosis

Neurofibromatosis is a group of genetic conditions that causes tumors to grow on nerves throughout the body. While most tumors are not cancerous, they can affect the skin, nervous system, eyes, and bones, causing a wide range of symptoms from mild skin changes to serious complications that require careful monitoring throughout life.

Table of contents

• What is neurofibromatosis?
• Types of neurofibromatosis
• Signs and symptoms
• What causes neurofibromatosis?
• How is neurofibromatosis diagnosed?
• Treatment and management
• Living with neurofibromatosis
• Outlook and life expectancy

What is neurofibromatosis?

Neurofibromatosis (NF) is a group of genetic conditions that affect the nervous system and skin.^[1] The condition causes tumors to develop on nerve tissue throughout the body, including the brain, spinal cord, and the nerves that send signals between the brain and all other parts of the body.^[1] Tumors are abnormal clusters of cells that form a solid mass of tissue.^[2]

Most tumors in neurofibromatosis are not cancerous (these are called benign tumors), although some may become cancerous (called malignant tumors).^[1] These tumors are typically benign and often involve the skin or surrounding bone.^[5]

Neurofibromatosis is not a single disorder but includes several distinct types.^[1] While symptoms are often mild, each condition presents differently.^[5] About one-third of people with NF notice no symptoms at all.^[4]

Types of neurofibromatosis

There are three main types of neurofibromatosis, each caused by different genetic changes and affecting people in different ways.^[1]

Neurofibromatosis type 1 (NF1)

NF1 is the most common type of neurofibromatosis, making up about 96% of all cases.^[2] It occurs in approximately one out of every 3,500 births.^[4] NF1 is also known as von Recklinghausen disease.^[1]

While NF1 is rare, most people are diagnosed during early childhood.^[1] Symptoms often appear at birth or shortly afterward, and almost always by age 10.^[3] Children and adults with NF1 have different symptoms and medical problems that can develop throughout their lives.^[1]

NF1 causes café au lait spots (light brown flat patches on the skin), nerve tumors called neurofibromas, armpit and groin freckles, eye nerve tumors, and bone deformities like scoliosis (a curved spine).^[2]

Neurofibromatosis type 2 (NF2-related schwannomatosis)

Neurofibromatosis type 2, now called NF2-related schwannomatosis, affects about 3% of all neurofibromatosis cases.^[2] It occurs in approximately one out of every 40,000 births.^[4]

NF2 may appear during childhood, adolescence, or early adulthood.^[4] Symptoms may not become apparent until early adulthood.^[5] This type is primarily characterized by benign tumors of the nerves that transmit sound impulses and balance signals from the inner ears to the brain.^[4] Tumors commonly affect both the left and right hearing and balance nerves.^[4]

NF2-related schwannomatosis causes slow-growing nerve tumors, hearing changes, vision changes (such as cataracts), and numbness or weakness called peripheral neuropathy.^[2]

Schwannomatosis

Schwannomatosis is the least common type, accounting for around 1% of all neurofibromatosis cases.^[2] It occurs in an estimated one out of every 40,000 births.^[4] Current evidence suggests that it is a distinct genetic disease from NF1 and NF2.^[4]

This disorder is more frequently diagnosed in adults aged 30 and older.^[4] Some cases don’t cause symptoms, while in others, it causes slow-growing nerve tumors called schwannomas, sometimes located only on one part of the body.^[2] Schwannomatosis often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression.^[5]

von Recklinghausen disease, von Recklinghausen’s disease, NF1, NF2, bilateral acoustic neurofibromatosis, peripheral neurofibromatosis, central neurofibromatosis

Signs and symptoms

Symptoms of neurofibromatosis vary depending on the type and can range from mild to severe.^[2] Symptoms tend to be mild to moderate, but they can vary greatly from person to person.^[3] Some types won’t cause symptoms, while others may cause severe symptoms.^[2]

Common symptoms across all types

The most common symptoms that can occur in all three types include:^[2]

• Tumors that grow slowly on nerves, which are usually benign but some can turn into cancer
• Skin growths, including birthmarks and freckles in unusual places
• Hearing or vision loss
• Spine curvature (scoliosis)
• Muscle weakness
• Numbness or tingling
• Pain and headaches
• Learning difficulties
• Behavioral changes like attention-deficit/hyperactivity disorder
• Seizures

Symptoms specific to NF1

Signs and symptoms of NF1 include:^[1]

Café au lait spots: These are flat, light brown spots on the skin and are the most common sign of NF1.^[1] People with NF1 almost always have more than six of these spots.^[1] The spots are smaller in children than in adults (at least half a centimeter versus over 1.5 centimeters).^[1] 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.^[1]

Freckling: Freckling in the armpits or groin usually appears by age 5.^[1] Freckles are similar in appearance to café au lait spots but smaller.^[1] They may also appear under the breast.^[6]

Neurofibromas: These are soft, pea-sized bumps that are common and can appear on the skin (known as cutaneous), under the skin’s surface (subcutaneous), or on any nerve throughout the body.^[1] Although some cutaneous neurofibromas develop in childhood, most appear during or after the teenage years and may occur more often with age.^[1]

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.^[1] About 10-15% of these neurofibromas can become dangerous over a person’s lifetime and turn into a malignant tumor of nerve coverings.^[1]

Lisch nodules: These are growths on the iris of the eye (the colored part of the eye).^[1] These are tiny bumps that typically appear only in the teen years.^[1] They can’t easily be seen and don’t affect vision.^[3]

Other symptoms may include skeletal abnormalities such as bowing of the legs, thinning of the shin bone, or scoliosis.^[4] Some people may develop a larger than average head, lower than average weight, and abnormal bone development.^[2]

What causes neurofibromatosis?

The cause is a genetic mutation (a change in the genetic code).^[5] These can be inherited, or in about half of cases, they occur spontaneously during early development for unknown reasons.^[5]

NF1

NF1 is caused by mutations in the gene that controls production of a protein called neurofibromin.^[4] This gene is believed to function as a tumor suppressor.^[4] In about 50% of people with NF1, the disorder results from gene mutations that occur for unknown reasons (spontaneous mutation).^[4] In others with the disorder, NF1 is inherited in what’s called an “autosomal dominant inheritance pattern.”^[4]

NF2 and Schwannomatosis

NF2 results from mutations in a different tumor-suppressing gene.^[4] Some people with NF2 experience a gene mutation that occurs for unknown reasons (spontaneous mutation), while others inherit it from their parents.^[4]

While schwannomatosis is not well understood, it is estimated that 85% of cases have no known cause (spontaneous) and 15% are inherited.^[4]

Inheritance pattern

There is a 50-percent chance that each child of a parent with NF1 or NF2 will inherit the gene and develop NF1 or NF2 (respectively).^[4] This is known as autosomal dominant inheritance pattern.^[4] However, up to 50% of cases happen randomly, without any biological family history.^[2]

How is neurofibromatosis diagnosed?

If a doctor thinks you or your child might have neurofibromatosis, they will refer you to a specialist for tests.^[6] To diagnose neurofibromatosis, a healthcare professional begins with a review of your personal and family medical history and a physical exam.^[9]

Diagnosis is typically based on symptoms, examination, medical imaging, and biopsy.^[5] The skin is checked for café au lait spots, which can help diagnose NF1.^[9]

Tests used to diagnose NF1

If other tests are needed to diagnose NF1, these may include:^[9]

• Eye exam: An eye exam can reveal Lisch nodules, cataracts, and vision loss
• Imaging tests: X-rays, CT scans, or MRIs can help identify bone changes, tumors in the brain or spinal cord, and very small tumors. An MRI might be used to diagnose optic gliomas (tumors on the optic nerve)
• Genetic tests: Genetic testing for NF1 can help support the diagnosis. Genetic tests also can be done during pregnancy before a baby is born

Tests used to help confirm NF1 include eye tests to check vision, an MRI scan to check for tumors in areas of the body such as the brain, spine, and abdomen, and genetic tests.^[6]

For a diagnosis of NF1, at least two symptoms of the condition must be present.^[9] A child who has only one symptom and no family history of NF1 is likely to be monitored for any other symptoms.^[9] A diagnosis of NF1 is usually made by age 4.^[9]

Treatment and management

There is currently no cure for neurofibromatosis.^[6] However, many of its complications aren’t life threatening, and there are treatments that can help manage the symptoms.^[16] Treatment focuses on supporting healthy growth and development in children and early management of complications.^[3]

Monitoring and regular checkups

If your child has NF1, often yearly age-appropriate checkups are recommended to:^[9]

• Check the skin for new neurofibromas or changes in existing ones
• Check for signs of high blood pressure
• Check growth and development, including measuring height, weight, and head circumference
• Look for signs of skeletal abnormalities

You’ll be supported by different healthcare professionals, which may include a brain specialist (neurologist), an eye specialist (ophthalmologist), and a skin specialist (dermatologist).^[6] Children will also be under the care of a doctor who specializes in the treatment of children (pediatrician).^[6]

Children with NF1 should have their eyes checked every year (adults every 2 years).^[6] Blood pressure should be checked every year.^[6]

Treatment options

Treatment will depend on your symptoms and may include:^[6]

Medicine to stop tumors growing: New targeted therapies, called MEK inhibitors, are being developed to target plexiform neurofibromas.^[16] A therapy called Selumetinib is approved for children under 18 and is in clinical trials for adults.^[16] It can shrink plexiform neurofibromas, improving pain and quality of life.^[16]

Surgery: Surgery may be done to remove tumors that are causing problems or have become cancerous.^[5] If NF1 causes large tumors or tumors that press on a nerve, surgery can reduce symptoms.^[3] Removal of neurofibromas for medical or cosmetic indications is one of the most common procedures on individuals with NF1.^[13]

Radiotherapy: Using a beam of radiation to treat small tumors or pieces of a larger tumor that are left after surgery.^[6] Radiation and chemotherapy may also be used if cancer occurs.^[5]

If your symptoms are not causing any problems, your doctor may suggest waiting to see if any problems develop before starting treatment.^[6]

Support for learning and mental health

Children with NF1 often have learning difficulties and may need extra help and support at school.^[6] If required, therapy might be helpful to cope with self-consciousness about visible marks or other challenges.^[16] There are also NF summer camps for children to build self-esteem and bond with others who are going through similar circumstances.^[16]

Living with neurofibromatosis

For many, living with neurofibromatosis can be a challenge for the person with the condition and their caregivers.^[17] For some patients with NF1, symptoms can be mild and cause no serious health issues.^[17] Most people with NF1 have no or few medical problems and live normal lives, with no need for treatment.^[13]

However, because every person with NF1 is at risk of complications from this disorder, it is important that they are regularly reviewed by a doctor who is familiar with the condition.^[8] Young children should be seen every six to 12 months, and older children every year.^[8] You or your child should have a check-up at least once a year so the symptoms can be monitored.^[6]

Possible complications

Sometimes neurofibromatosis can lead to further problems or serious complications.^[6] These can include:^[6]

• High blood pressure
• Bone and joint problems – some children have weak bones that can cause bowed legs or a curved spine (scoliosis)
• A tumor on the nerve to the eye (optic nerve), which can cause vision problems
• Depression, anxiety, and low self-esteem caused by large tumors or tumors on your face
• Cancer – some tumors can become cancerous and there’s a higher risk of developing certain types of cancer, including breast cancer and brain cancer

Tumors in these disorders are overwhelmingly benign; they may become malignant in 3 to 5 percent of all cases.^[4]

Women with NF1 should have a breast scan (mammogram) each year from the age of 40 to check for breast cancer.^[6]

Impact on daily life

NF1-PN can cause some challenges throughout the body, including pain, weakness or numbness, limited physical mobility or strength, visual impairment, breathing problems, disfigurement, and bowel or bladder changes as a result of neurofibromas on or near the spinal cord or in the abdomen.^[17]

At times, NF1 may make people feel socially isolated.^[17] For example, children with NF1 may experience difficulties socializing.^[17] This could be because they feel self-conscious about visible marks, or pain may restrict their social life.^[17] However, there is support available for both you and your child, so seek help if either of you are facing any mental health challenges.^[17]

Outlook and life expectancy

While the condition typically worsens with time, most people with NF1 have a normal life expectancy.^[5] Most people with NF1 have an average life expectancy.^[1]

As the condition gets gradually worse and can cause serious problems, it can affect life expectancy in some cases.^[6] Your care team will be able to speak to you about this if you want to know more.^[6]

In NF2, symptoms may not become apparent until early adulthood, and NF2 increases the risk of early death.^[5]

Every period of life has its own NF challenges. It’s about working on the symptoms and living the best life you can.^[16]