Neurofibromatosis 1 (NF1)

The conditions are:

1. Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease
2. Neurofibromatosis type 2 (NF2)
3. Schwannomatosis (SWN)

Neurofibromatosis 1 (NF1) is the most common of the three conditions. Although many people with NF1 inherit the gene that causes the condition, between 30 and 50 percent of cases arise from a spontaneous genetic mutation in the NF1 gene. Once this mutation has occurred, the abnormal gene can be inherited. Each child of an affected parent has a 50 percent chance of inheriting the gene mutation.

Although many people with neurofibromatosis 1 (NF1) inherit the gene that causes the condition, between 30 and 50 percent of cases arise from a spontaneous genetic mutation in the NF1 gene for unknown reasons.

Once this mutation has occurred, the abnormal gene can be inherited. Each child of an affected parent has a 50 percent chance of inheriting the gene mutation. Only one parent needs to have the faulty gene for their child to be at risk of developing NF1.

Couples with a family history of neurofibromatosis 1 (NF1) should discuss their risk factors with medical professionals before becoming pregnant. With the guidance of a genetic counselor, options may include working with an egg or sperm donor, adoption, in utero tests (such as chorionic villus sampling or amniocentesis) or pre-implantation genetic tests (for those becoming pregnant using IVF).

Neurofibromatosis occurs in both biological sexes and in all races and ethnic groups. Why tumors develop in these conditions isn't completely known, but it appears to be caused in part by mutations in genes that play key roles in suppressing growth in nervous system cells. These mutations keep the genes—identified as NF1, NF2, SMARCB1 and LZTR1—from making normal proteins that control the ability of the cells to function properly. Without the normal function of these proteins cell growth increases, leading to the formation of tumors.

Genetic testing and screening are available for pregnant mothers to help determine the risk of NF1. These tests may be conducted during pregnancy, or prior to transferring an embryo (for those using IVF). Because many of the clinical features of NF1 develop as an individual ages, getting the correct diagnosis can take several years. Prevention is limited to those choosing to genetically screen embryos prior to implantation.

NF1 is congenital, though some signs and symptoms may develop gradually over time. Most cases include:

• Problems with nervous system, bones and eyes
• Soft, non-cancerous tumors, called neurofibromas, found on or under the skin
• Light or dark brown patches (birthmarks known as “café-au-lait” spots) found anywhere on the body
• Clusters of freckles found under the breast, groin or in the armpits (or other unusual places on the body)

Children and adults with NF1 can have a variety of symptoms and medical problems that can change across a lifespan. Most people with NF1 have an average life expectancy. Because many of the other clinical features of NF1 develop as an individual ages, getting the correct diagnosis may take several years.

Children with NF1 are usually shorter than average and have larger heads. It is typical to see children with NF1 experience cardiovascular complications, such as congenital heart defects, high blood pressure (hypertension) and constricted, blocked, or damaged blood vessels.Other commonly seen symptoms are poor visuospatial skills and poor performance on academic achievement tests, including those that measure reading and math skills.

Other potential symptoms may include:

• Behavioral challenges, such as attention deficit hyperactivity disorder (ADHD) and limited social skills, which are commonly seen in children with NF1 
• Headaches, pain and seizures, which  happen more often in people with NF1 than in the general population
• Tumors that may become cancerous. An estimated 10 percent of plexiform neurofibromas may become malignant and require aggressive treatment. Cutaneous neurofibromas are not known to become malignant.
• Malignant glioma, a type of tumor that can occur (although rarely) in adults with NF1
• A higher risk for breast cancer before the age of 50 for adult young women with NF1 than women in the general public
• An increased risk of gastrointestinal stromal tumors (GIST) and neuroendocrine tumors, like pheochromocytoma. There also is an increased incidence of benign nerve tumors called glomus tumors.
• Scoliosis, or curvature of the spine, which can be more common and aggressive in people with NF1

It may be impossible to distinguish someone with NF1 from SWN based on clinical features alone. Genetic testing may be needed to correctly diagnose individuals with features of these conditions who lack a known family history or bilateral vestibular schwannomas (those that occur on both sides of the body). Genetic testing can be useful in some situations, such as for prenatal testing or when the clinical diagnosis is inconclusive.

Detailed imaging of the brain and spinal cord by MRI is necessary, and additional imaging based on symptoms may reveal schwannomas on peripheral nerves.

Because many of the clinical features of NF1 develop as an individual ages, getting the correct diagnosis may take several years.

To diagnose NF1, a doctor looks for some of the following:

• Six or more flat, light brown spots on the skin (“café-au-lait” spots), which are the most common feature of NF1: These multiple birthmarks measure more than five millimeters in diameter in children or more than 15 millimeters in adolescents and adults. They are seen at birth or develop during the first few years of life. Café-au-lait spots are not dangerous but indicate the possible presence of an NF1 gene change in the person. These skin marks also occur in other conditions such as Legius syndrome, a genetic condition that affects how cells in the body communicate.
• Two or more soft, pea-sized bumps involving the skin (cutaneous neurofibromas), or one larger neurofibroma that involves multiple nerves (plexiform neurofibroma): Neurofibromas are tumors that originate from nerve cells. Plexiform neurofibromas are nerve-associated tumors involving nerves outside of the brain and spinal cord. They can be present at birth or may not become noticeable for many years. Although some cutaneous neurofibromas arise in childhood, most start appearing during or after the teenage years.
• Freckling in the armpits or the groin: This usually appears by 3 to 5 years of age. Freckles are similar in appearance to café-au-lait spots but are smaller in size. Freckling can occur in other conditions, but those conditions do not commonly exhibit the other symptoms of NF1.
• Two or more growths on the iris of the eye (known as Lisch nodules or iris hamartomas): These nodules are harmless, not typically present until adolescence, do not affect vision and do not require monitoring or treatment.
• A tumor of the optic pathway (optic pathway glioma): These tumors typically first appear by age 6, rarely in late childhood and adolescence, and almost never in adults. Although they can affect vision, most do not become symptomatic.
• Bone deformities, such as abnormal development of the eye socket (sphenoid) or the tibia (one of the long bones of the shin)
• A parent, sibling or child with NF1

NF1 cannot be cured, but treatments can help manage signs and symptoms. Many people with NF1 will not require any prolonged treatment for any manifestation (disease signs or development) during their lives. People with NF1 should be evaluated periodically by an NF1 specialist, even if they are not experiencing symptoms, for signs  indicating a need for treatment and to provide reassurance that treatment is not needed when appropriate.

The U.S. Food and Drug Administration (FDA) approved selumetinib (Koselugo®) as a treatment for children ages 2 years and older with NF1. The drug helps to stop tumor cells from growing.

Surgery may be used to remove tumors that develop symptoms or are of concern for cancer as well as for tumors that cause significant discomfort. Several surgical options exist for many of the manifestations of NF1, but there is no general agreement among doctors about when surgery should be performed or which surgical option is best. Some bone malformations, such as scoliosis, can be corrected surgically or by stabilizing the spine with a brace. Some malformations that affect blood vessels can be successfully addressed with surgery or non-surgical procedures.

Chemotherapy may be used to treat optic pathways or other brain gliomas. The drug selumetinib (Koselugo®) has been approved by the FDA to treat children older than 2 years of age who have symptoms but inoperable plexiform neurofibromas. Chemotherapy regimens are a core part of treating cancers that may arise in the setting of NF1, including malignant peripheral nerve sheath tumor (MPNST) and breast cancer.

Treatments for other conditions associated with NF1 are aimed at controlling or relieving symptoms. Headache and seizures are treated with medications. Because children with NF1 have a higher-than-average risk for a variety of learning disabilities, ADHD, motor delays, and autism, they should be evaluated by a care team knowledgeable in NF1 and may be advised to have formal neuropsychological assessments to assist in creating individualized educational plans for school.

Treatments for other conditions associated with NF1 are aimed at controlling or relieving symptoms. Headache and seizures are treated with medications. Because children with NF1 have a higher-than-average risk for a variety of learning disabilities, ADHD, motor delays, and autism, they should be evaluated by a care team knowledgeable in NF1 and may be advised to have formal neuropsychological assessments to assist in creating individualized educational plans for school.

Current basic and clinical research is not only aimed at understanding how genetic defects cause the diverse conditions and medical problems people with NF encounter, but also how to predict which clinical features will arise in any given person (personalized or precision medicine). In addition, studies in NF1, NF2 and SWN have revealed numerous important insights for investigators working in other fields, including brain cancer, sarcoma, autism, learning disabilities, nerve regeneration, chronic pain and targeted therapies.

The gene for NF1 is located on chromosome 17. The NF1 gene makes a protein called neurofibromin, which regulates cell division in the nervous system and functions as a kind of molecular brake to keep cells from growing out of control. Ongoing National Institute of Neurological Disorders and Stroke-sponsored research continues to discover additional genes and molecular pathways that may play a role in NF-related tumor suppression or growth. Continuing research is starting to reveal how this novel family of growth regulators controls how and where tumors form and grow, which may lead to the development of new drugs and therapies for NF.