Neurofibromatosis

Neurofibromatosis (NF) is a neurocutaneous syndrome that can affect many parts of the body, including the brain, spinal cord, nerves, skin, and other body systems. NF can cause growth of non-cancerous tumors on nerve tissue, producing skin and bone abnormalities.

The two different forms of this disorder are neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). NF1 accounts for approximately 90% of all cases.

Of the two types of neurofibromatosis – NF1 and NF2 – NF1 is more common, occurring in 1 of every 2,500-3,000 births and affecting an estimated 100,000 Americans. It is also known as von Recklinghausen disease.

NF2 is characterized by the presence of bilateral acoustic neurofibroma-like tumors and is rarer, seen in 1 in 25,000 births. People with NF2 usually develop benign tumors on the nerves in their ears, causing hearing loss, eventual deafness, and problems with balance.

The severity of both types of neurofibromatosis varies greatly. In families where more than one person has NF, it can present with different physical signs and complications for each person. At diagnosis, it isn't possible to know right away whether a case will be mild or lead to severe complications.

Neurofibromatosis Type 1

NF1 (also known as von Recklinghausen disease) occurs in about 1 in 4,000 babies born in the United States. To diagnose NF1, doctors take a thorough medical and family history because children with NF1 often have a parent with the disease.

The classic sign of NF1 are skin pigment findings known as "café-au-lait" spots. These light brown or coffee-colored patches may be present at birth and can look like freckles at first. They often increase in size and number during the first few years of life. A child diagnosed with NF1 will usually have at least six café-au-lait spots that are larger than freckles. The spots are flat, don't itch or hurt, and do not turn into anything more serious.

Another common sign is the presence of Lisch nodules, tiny, benign (noncancerous) tumors found on the iris of the eye. In some cases, tumors can develop along the optic nerves and affect vision. During puberty, benign tumors called neurofibromas develop on or under the skin or along the nerves of the body. Bone deformities also may develop.

NF1 treatment focuses on managing the symptoms. A child with complications involving the eye, nervous system, spine, or bones will be referred to an appropriate specialist for treatment. In cases where these neurofibromas are causing chronic pain, growing into vital body organs, or causing infections, the growths can be removed through surgery.

Children with NF1 also have a high prevalence of seizures, learning disabilities, attention deficit disorder (ADHD), and speech problems. Therapy and specialists can help manage those symptoms.

Neurofibromatosis Type 2

Neurofibromatosis type 2 is less common, occurring in about 1 in 40,000 births. Kids who have it usually develop tumors on the auditory nerves (the nerves leading to the ear), but not until adolescence or as young adults.

NF2 symptoms, which appear in the teen years or early twenties, can include hearing loss, ringing of the ears, and problems with balance. Different treatment options can help manage these problems.

Both types of neurofibromatosis, NF 1 and NF2, are autosomal dominant genetic disorders, which means an affected person has 1 chance in 2 of passing it on with each pregnancy.

Neurofibromatosis also can be the result of a spontaneous change (mutation) in the genetic material of the sperm or egg at conception in families with no previous history of NF. About half of cases are inherited, and the other half are due to spontaneous genetic mutation.

NF 1 and NF 2 are each related to changes in separate genes:

• The NF1 gene is located on chromosome 17.
• NF2 has been traced to chromosome 22.

These findings are important because they have led to the development of a genetic test that can reliably confirm NF in affected individuals.

Approximately one in every 2,500-3,000 babies born has NF1. Approximately 100,000 people in the United States have NF. NF occurs in equal numbers of men and women, and in every racial and ethnic group. Neurofibromatosis is usually inherited, but up to half of cases occur because of spontaneous changes (mutations) within a person's genes. Once a mutation occurs, the changed (mutant) gene can then be passed on to succeeding generations. The child of a parent with neurofibromatosis has a 50% chance of inheriting the disorder.

Neurofibromas often first appear in childhood, especially during puberty. NF is occasionally diagnosed in infancy (in children with more apparent cases), but more often in kids between 3 and 16 years old.

The first noticeable sign is almost always the presence of brown café au lait spots. These distinctive spots don't hurt or itch and never progress to anything more serious than spots. They can be found anywhere on the body, though not usually on the face. Tiny ones – freckles – may be seen under the arms or in the groin area.

If your child has already been diagnosed with NF and you notice that a growing tumor is beginning to cause a problem, tell your doctor immediately.

NF1 is sometimes diagnosed in younger children, especially those with more severe forms of the disorder. One key to early diagnosis of mild NF is the appearance of café au lait spots on the skin.

Many people who do not have NF have a few café-au-lait spots. But if a young child has five or more, at least ½ inch in size (roughly the size of a dime), a doctor will look for other clues that may indicate NF, including neurofibromas – tumors on, under, or hanging off the skin – and Lisch nodules, tiny, noncancerous tumors on the iris (the colored part of the eye). Lisch nodules are of no clinical significance except that they help confirm a diagnosis of NF.

Neurofibromas often become evident on various parts of the body, beginning at the arms, around 10 years of age. A child may also develop freckling in the folds of the skin of the armpit or groin or on other parts of the body where the skin creases.

Abnormalities of the skeleton, such as the thinning or overgrowth of the bones in the arms or lower leg, curvature of the spine (scoliosis), and other bone deformities also may be features of NF1.

NF2 is usually not diagnosed until a child is older. Hearing loss in the late teens and early twenties is often among the first symptoms of the disorder, and is caused by tumors growing on the auditory nerves (which carry electrical impulses from the inner ear to the brain, allowing us to hear) on one or both sides.

Other symptoms of NF2 include continuous ringing in the ears, headache, facial pain or weakness, and feeling unsteady or off balance.

Neurofibromatosis is usually diagnosed based on a combination of findings. A child must have at least two of the following signs to be diagnosed with NF1:

• Cafe-au-lait spots of a certain number, size, and location
• Appearance of two or more neurofibromas (often resembling pea-sized bumps on the skin)
• Lisch nodules on the irises
• Optic glioma (tumor along the main nerve of the eye that is responsible for sight)
• Certain skeletal abnormalities
• Family member with NF1
• Freckling under the arms or in the groin

Tests like magnetic resonance imaging (MRI) and X-rays may be used to screen for tumors or evidence of skeletal problems. A child's head circumference will be measured, as kids with symptoms of NF can have a circumference that's larger than normal for their age. Blood pressure will be monitored. Doctors also take a detailed personal history, looking for signs of learning difficulties.

To diagnose NF2, doctors will check for any evidence of hearing loss. They'll order audiometry (hearing tests) as well as imaging tests to look for tumors in the nerves of the ears, spinal cord, or brain. They'll also determine if there's a family history of NF2.

Genetic testing is now available for people with a family history of either NF1 or NF2. Although testing is still not 100% sensitive, recent advances have increased sensitivity to over 90%. Amniocentesis or chorionic villus sampling can sometimes determine if an unborn child has the condition.

Treatment for NF1 includes removal of the neurofibromas for cosmetic purposes, treating the complications, and getting intervention for children with learning disabilities. Kids will be referred to appropriate medical specialists to monitor and treat complications, which may include:

• seizures (up to 40% of children with NF1 have them)
• high blood pressure
• scoliosis
• speech impairment
• optic nerve tumors (which can cause vision problems leading to blindness)
• early or delayed onset of puberty

Rarely, neurofibromas can become cancerous (3%-5% of cases). In these occurrences, surgery, chemotherapy, or radiation may be necessary.

With NF2, surgeons will likely need to remove the auditory nerve tumors, which may cause deafness afterward. When parts of the auditory nerve are removed, hearing aids won't work.

In 2000, the U.S. Food and Drug Administration (FDA) approved an auditory brainstem implant for people with NF2 who have lost their hearing. This device transmits sound signals directly to the brain, enabling the person to hear certain sounds and speech.

Currently, our neurosciences team are actively involved in research and conducting clinical trials with medications in the hopes they'll be able to offer more treatment options–and perhaps, someday soon, a cure.