Neurofibromatosis

Neurofibromatosis affects how the cells in your nervous system develop and grow. This inherited disease causes abnormal growths on tissues found throughout the nervous system, including the brain, spinal cord and nerves. Most of the time, these growths are benign (noncancerous).

Symptoms may vary widely in severity, but most cases are relatively mild. The life expectancy of the majority of patients with neurofibromatosis is normal.

There are three types of neurofibromatosis, including:

• Neurofibromatosis type 1 (NF1) mostly affects the skin, but it may also lead to bone deformities, which develop in early childhood, and sometimes at birth. About one in 3,000 to 4,000 people worldwide have NF1, according to the U.S. National Library of Medicine (NLM). It’s also called peripheral neurofibromatosis, Recklinghausen disease of the nerves and von Recklinghausen disease.
• Neurofibromatosis type 2 (NF2) leads to tumors developing on the nerves of the brain and spine. It develops late in the teenage years and, in most cases, leads to hearing loss. It’s also called bilateral acoustic neurofibromatosis, bilateral vestibular schwannomas and central neurofibromatosis. NF2 is much less common than NF1, occurring in about one in 33,000 people worldwide, according to the NLM.
• Schwannomatosis (SWN) is the rarest type of neurofibromatosis and leads to intense, chronic pain. Schwannomatosis is sometimes also called multiple neurilemmoma, multiple schwannomas, neurilemmomatosis (congenital cutaneous), neurinomatosis and neurofibromatosis type 3.

How neurofibromatosis is connected to cancer

Neurofibromatosis increases cancer risk in certain tissues. These vary by the type of neurofibromatosis. Neurofibromas may develop into sarcomas when there are mutations in NF1 and NF2. About 5 percent of neurofibromatosis patients develop sarcomas, according to the American Cancer Society.

With neurofibromatosis type 1, there’s an increased risk of other cancers, including:

• Malignant peripheral nerve sheath tumors
• Brain tumors
• Leukemia
• Gastrointestinal stromal tumors (GISTs)
• Neuroendocrine tumors (NETs)
• Breast cancer

With neurofibromatosis type 2, there’s an increased risk of developing brain tumors such as meningiomas, nerve tumors such as schwannomas, or spinal cord ependymomas. However, these may be benign, slow-growing tumors. Schwannomatosis doesn’t seem to be linked to any additional forms of cancer.

What causes neurofibromatosis?

All three types of neurofibromatosis are genetic diseases, but they’re caused by breaks in different genes. These disorders are usually autosomal dominant, which means they have a 50 percent chance of being passed down from parent to child.

If a person has any of these genetic mutations, the cells need to develop a second mutation in that gene or related genes to form tumors. There are no known risk factors that increase the likelihood of developing neurofibromatosis-related genetic mutations.

Neurofibromatosis type 1

At least 50 percent of NF1 cases are passed down from parent to offspring, according to the National Institute of Neurological Disorders and Stroke. The rest of the cases are caused by new mutations in the NF1 gene that develop on their own (known as a spontaneous genetic mutation).

The genetic typo that causes neurofibromatosis type 1 is in the gene called NF1. This gene instructs the nerve cells and other cells of the nervous system how to create the protein neurofibromin. This protein keeps the cells from growing out of control. If the cells can’t make this protein correctly, they can end up forming growths. that become benign or cancerous tumors.

Neurofibromatosis type 2

The gene affected in neurofibromatosis type 2 is the NF2 gene. The NF2 gene is active in the Schwann cell, which wraps around the body’s nerves. The gene codes for a protein called merlin or schwannomin, which stops uncontrolled growth of these cells. About half of cases of neurofibromatosis type 2 are inherited, and the other half develop spontaneously.

Schwannomatosis

In many cases, this rare type of neurofibromatosis can be traced to genetic defects in either the SMARCB1 or LZTR1 genes, though not always. These genes code for proteins that stop Schwann cells from growing out of control. Additional mutations in related genes, usually NF2, are required for these tumors to form.

Most cases of schwannomatosis are new mutations, not mutations inherited from a parent. It can run in families, though. In these cases, offspring have a 50 percent chance of acquiring the mutation, though not everyone with the broken gene develops symptoms.

Neurofibromatosis symptoms

The most common symptoms of neurofibromatosis type 1 include:

• Abnormal pigmentation, including flat, light brown patches called cafe-au-lait spots and freckles in the underarms and groin area
• Soft, pea-sized benign bumps on or just under the skin along the nerves called neurofibromas, usually developing in the teen years
• Benign growths in the colored part of the eye called Lisch nodules
• Tumors along the optic nerve, called optic gliomas, which develop in early childhood
• Cancerous tumors along the nerves of the body, called malignant peripheral nerve sheath tumors
• Bone abnormalities, including scoliosis resulting in a curved spine and abnormal eye socket or leg bone development
• Learning disabilities, including attention-deficit/hyperactivity disorder (ADHD)

Symptoms of neurofibromatosis type 2 include:

• Problems with balance and hearing, specifically tinnitus (ringing or other noises in the ears) and hearing loss
• Schwann cell tumors in or under the skin, causing bumps
• Cataracts early in life, or other abnormal vision changes
• Cafe-au-lait marks
• Headaches or facial weakness
• Noncancerous, slow-growing tumors around the nerves of the head, spine and body or the cells and tissues that cover them
• Peripheral neuropathy, leading to numbness or weakness in the arms or legs

Symptoms of schwannomatosis overlap greatly with those of NF2 due to the development of schwannomas. The main symptoms of schwannomatosis are chronic pain and various sensations (such as numbness, weakness or tingling) in the toes and fingers.

Diagnosis of neurofibromatosis

Doctors use the symptoms present and family history to diagnose neurofibromatosis. Special lights are used to visualize cafe-au-lait spots, and imaging scans like magnetic resonance imaging (MRI) and positron emission tomography combined with computed tomography (PET/CT) scans may help detect any hidden tumors. If neurofibromatosis is suspected, genetic testing is typically the most appropriate way to diagnose it.

Treatment for neurofibromatosis

Treatment for neurofibromatosis includes surgery, chemotherapy, radiation and medicines to control symptoms. Patients should undergo regular scans to monitor the growth of tumors and ensure they’re not developing any cancers.

With neurofibromatosis type 1, growths may be treated with surgery and chemotherapy. Other treatments are used for symptoms like headaches and seizures. Therapy for any learning disabilities or developmental delays is often recommended for children. A new drug called Koselugo^® (selumetinib) was approved to stop the growth of tumors in children with neurofibromatosis type 1.

Though many of the tumors of neurofibromatosis type 2 are benign and slow-growing, their development may eventually require treatment if they’re impinging on the nerve and causing symptoms such as hearing loss. Chemotherapy and/or radiation may help shrink tumors when they’re small. Surgery may be an option, but may damage hearing more or cause facial paralysis. Hearing can sometimes be restored with cochlear implants or a brainstem implant. Surgery can also correct cataracts and help reduce other symptoms.

For schwannomatosis patients, surgery may be used to remove tumors to address specific symptoms. However, there are otherwise no accepted treatments or drugs for this condition.