Merck Manual

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M. Cristina Victorio

, MD, Akron Children's Hospital

Reviewed/Revised Dec 2023
Topic Resources

Neurofibromatosis is a group of genetic disorders in which many soft, fleshy growths of nerve tissue (neurofibromas) form under the skin and in other parts of the body, and flat spots that are the color of coffee with milk (café-au-lait spots) often develop on the skin.

  • Neurofibromatosis is caused by mutations in certain genes.

  • In addition to growths under the skin and café-au-lait spots on the skin, people may have abnormalities in bone, incoordination, weakness, abnormal sensation, or hearing or vision problems.

  • Doctors do a physical examination, consult established criteria, and sometimes do an imaging test of the head to check for lumps and growths.

  • Growths can be removed surgically or, if cancerous, may be treated with radiation therapy or chemotherapy.

Neurofibromatosis is a neurocutaneous syndrome. A neurocutaneous syndrome causes problems that affect the brain, spine, and nerves (neuro) and the skin (cutaneous).

Neurofibromas are flesh-colored, noncancerous (benign) growths of Schwann cells (which form a wrapping around peripheral nerve fibers) and other cells that support peripheral nerves Overview of the Peripheral Nervous System The peripheral nervous system refers to the parts of the nervous system that are outside the central nervous system, that is, those outside the brain and spinal cord. Thus, the peripheral nervous... read more (the nerves outside the brain and spinal cord).

Typical Structure of a Nerve Cell

A nerve cell (neuron) consists of a large cell body and nerve fibers—1 elongated extension (axon) for sending impulses and usually many branches (dendrites) for receiving impulses. The impulses from the axon cross a synapse (the junction between 2 nerve cells) to the dendrite of another cell.

Each large axon is surrounded by oligodendrocytes in the brain and spinal cord and by Schwann cells in the peripheral nervous system. The membranes of these cells consist of a fat (lipoprotein) called myelin. The membranes are wrapped tightly around the axon, forming a multilayered sheath. This myelin sheath resembles insulation, such as that around an electrical wire. Nerve impulses travel much faster in nerves with a myelin sheath than in those without one.

Typical Structure of a Nerve Cell

Neurofibromas, which can be felt under the skin as small lumps, usually start appearing after puberty.

Types of Neurofibromatosis

There are 3 types of neurofibromatosis.

Neurofibromatosis type 1 (NF1)

NF1 (also known as von Recklinghausen disease) affects about 1 of 4,650 people. Neurofibromas develop along peripheral nerves—for example, under or within the skin and just outside the spinal cord. Sometimes tumors develop in the nerves that connect the brain to the eyes (optic nerves). Bone and soft tissues (such as muscle) may also be affected.

NF2-related schwannomatosis (NF2)

NF2 affects about 1 of 25,000 people. It causes tumors of the auditory nerve (which connects the inner ear and the brain), called vestibular schwannomas (acoustic neuromas) Vestibular Schwannoma A vestibular schwannoma (also called an acoustic neuroma) is a noncancerous (benign) tumor that originates in the cells that wrap around the vestibular nerve (Schwann cells). Vestibular schwannomas... read more Vestibular Schwannoma , and sometimes tumors in the brain or in the tissues that cover the brain or spinal cord (meninges). Tumors in the meninges are called meningiomas. They are not cancerous.

Non-NF2 schwannomatosis (schwannomatosis)

Schwannomatosis is rare. Schwannomas are growths composed mainly of Schwann cells. They develop around spinal, cranial, and peripheral nerves, but vestibular schwannomas do not develop.

Causes of Neurofibromatosis

About half the people with neurofibromatosis inherit it. Only 1 gene for neurofibromatosis—from 1 parent—is required for the disorder to develop (dominant inheritance Inheritance of Single-Gene Disorders Genes are segments of deoxyribonucleic acid (DNA) that contain the code for a specific protein that functions in one or more types of cells in the body or code for functional RNA molecules.... read more ), and each child of an affected parent has a 50% chance of inheriting the disorder. Most of the genes involved in neurofibromatosis have been identified.

In the rest of the people, neurofibromatosis results from a spontaneous (not inherited) gene mutation. Thus, these people have no family history of the disorder.

Different types of mutations—whether inherited or spontaneous—may occur. The severity of the disorder depends on the type of mutation.

Symptoms of Neurofibromatosis

Neurofibromatosis type 1 (NF1)

NF1 usually causes no symptoms, but most people with NF1develop the characteristic café-au-lait spots or lumps under the skin. People may not notice these spots or lumps. However, if neurofibromas put pressure on the nerve they surround, people may notice tingling or weakness in areas near the lumps.

Café-au-lait spots develop in about 90% of affected children. They are the medium-brown color of coffee with milk (café-au-lait) and develop on the skin of the chest, back, pelvis, and creases of the elbows and knees. These flat spots typically exist at birth or appear during infancy. Children who do not have neurofibromatosis may have 2 or 3 café-au-lait spots, but children who have NF1 have 6 or more of these spots.

Neurofibromas that develop in the skin are common. Between ages 10 and 15, neurofibromas of varying sizes and shapes may begin to appear. There may be fewer than 10 of these growths or up to thousands of them. They may be the color of skin or have a pink or tan discoloration and usually do not cause other symptoms.

Neurofibromas that develop under the skin can cause structural abnormalities, such as an abnormally curved spine (kyphoscoliosis), rib deformities, enlarged long bones in the arms and legs, and bone defects of the leg bones or skull. If the bone surrounding an eyeball is affected, the eye bulges. Neurofibromas that develop under the skin can also affect the nerves that lead from the brain to various parts of the head, neck, and trunk (cranial nerves Overview of the Cranial Nerves Twelve pairs of nerves—the cranial nerves—lead directly from the brain to various parts of the head, neck, and trunk. Some of the cranial nerves are involved in the special senses (such as seeing... read more ).

Neurofibromas that develop in the nerves may affect any nerve in the body. They frequently grow on spinal nerve roots (the parts of the spinal nerve that emerge from the spinal cord through the spine). There, they often cause few or no problems. However, if they put pressure on (compress) the spinal cord, they can cause paralysis or disturbances in sensation in different parts of the body, depending on which part of the spinal cord is compressed. If neurofibromas compress peripheral nerves, the nerves may not function normally, and pain, tingling, numbness, or weakness may result. Tumors that affect nerves in the head can cause blindness, dizziness, incoordination, or weakness.

Other problems may develop. They include

Optic gliomas may not cause any symptoms, or they may enlarge enough to put pressure on the optic nerve and impair vision or even cause blindness. These tumors can usually be identified by the time children are 5 years old and rarely develop after age 10.

Neurofibromatosis usually progresses slowly. As the number of neurofibromas increases, more neurologic problems may develop.

NF2-related schwannomatosis (NF2)

Non-NF2 schwannomatosis (schwannomatosis)

In schwannomatosis, benign tumors (called schwannomas) can develop on almost any nerve in the body, except the auditory nerves, so people with non-NF2 schwannomatosis do not have vestibular schwannomas. Some people have many schwannomas, but others have only a few.

The first symptom of schwannomatosis is usually pain, which can occur anywhere in the body and which may become chronic and severe. Some people have numbness, tingling, or weakness in the fingers and toes. Other symptoms may develop, depending on the location of the schwannomas. Symptoms develop when schwannomas compress nerves in the head, spine, or trunk.

Diagnosis of Neurofibromatosis

  • A doctor's evaluation

  • Magnetic resonance imaging or computed tomography

  • Sometimes genetic testing

In most people, neurofibromatosis is identified when people have a routine examination, see the doctor because of cosmetic complaints about the spots, or need to be evaluated because they have a family history of neurofibromatosis.

Doctors base the diagnosis of all 3 types of neurofibromatosis on findings noted during a detailed physical examination, such as café-au-lait spots or lumps under the skin along nerves. Doctors use established criteria to help them determine which type a person may have.

Doctors do genetic testing in people who they think might have neurofibromatosis but who do not meet all the necessary criteria.

Treatment of Neurofibromatosis

  • For neurofibromas that cause symptoms, possibly surgery or removal by laser or electrocautery

  • For cancerous tumors, chemotherapy

  • For vestibular schwannomas, sometimes bevacizumab

  • For non-NF2 schwannomatosis, pain management

No known treatment can stop the progression of neurofibromatosis or cure it.

Individual neurofibromas that cause severe symptoms can usually be removed surgically or, if small, by laser or an electrical current (electrocautery). Sometimes surgical removal of the neurofibroma requires removing the nerve as well.

If cancerous tumors develop, chemotherapy is done.

Treatment of vestibular schwannomas is primarily surgical removal. Slow-growing tumors may not require immediate surgery. Fast-growing tumors may be treated with injections of a medication called bevacizumab, which blocks vascular endothelial growth factor. Because vestibular schwannomas can affect hearing, all people who have NF2-related schwannomatosis should be evaluated by an audiologist (a health care professional who identifies, assesses, and manages disorders of hearing and balance).

Treatment of schwannomas in non-NF2 schwannomatosis is often with long-term pain management. Schwannomas are surgically removed only if a person has uncontrolled pain or if the schwannomas cause neurologic problems such as weakness or tingling.

Because neurofibromatosis can be hereditary, genetic counseling Genetic Counseling and Genetic Testing Before Pregnancy Genetic disorders are caused by abnormalities in one or more genes or chromosomes. Some genetic disorders are hereditary and others are spontaneous. Hereditary genetic disorders are passed down... read more is recommended when people with this disorder are considering having children. The child of a person with neurofibromatosis has a 50% chance of having the disorder. For people who have a child with the disorder but do not have the disorder themselves, the risk of having another child with the disorder is very small.

Drugs Mentioned In This Article

Generic Name Select Brand Names
Alymsys, Avastin, MVASI, Zirabev
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