Neurofibromatosis Type 1

  • What is neurofibromatosis type 1?

    Neurofibromatosis type 1 (NF1) is a genetic disorder that can affect multiple systems of the body. It is characterized by the presence of:

    • Skin differences, such as café-au-lait spots (light brown patches on the skin), and freckles on the armpits or groin
    • Iris Lisch nodules (benign growths on the colored part of the eye)
    • Skeletal abnormalities, including scoliosis and bowing of the legs
    • Large head size
    • Learning disabilities
    • Vascular (blood vessel) disorders

    Affected individuals are also at increased risk to develop certain benign or malignant tumors, especially:

    • Neurofibromas (benign or malignant tumors of the nerves that form on or under the skin)
    • Central nervous system tumors, especially optic gliomas (tumors that form on the optic nerve, which connects the eye to the brain)
    • Pheochromocytomas (tumors of the adrenal glands, the small hormone producing organs located on top of each kidney)
    • Leukemia

    Additionally, 50 percent of individuals with NF1 have learning disabilities, which persist into adulthood. Children with NF1 may also have personality and/or behavioral differences compared to children who do not have NF1.

    The incidence of NF1 is approximately one in 3,000 live births and it affects males and females of all races equally.

    Because neurofibromatosis type 1 is hereditary, the risk to develop the features associated with NF1 may be passed from generation to generation in a family. However, the type and severity of this disorder can vary widely between affected family members.

  • Causes

    NF1 is caused by alterations (mutations), at specific areas within a person's genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.

    In the vast majority of patients with neurofibromatosis type 1, the disorder develops as the result of alterations in a specific gene known as NF1, which is located on chromosome 17 at position q11.2. NF1 is the only gene known to be associated with neurofibromatosis type 1. The protein produced by the NF1 gene acts as a “tumor suppressor,” which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. This protein functions by “turning off” a second protein that stimulates cell growth and division.

    With the exception of egg and sperm cells, each cell of the body normally has two working copies of the NF1 gene. Patients with neurofibromatosis type 1 generally carry an alteration in one copy of the NF1 gene in all the cells of their body. Individuals with NF1 are born and develop normally, but are at an increased risk to develop benign and malignant tumors. These tumors are believed to develop because, over time, the second working copy of the NF1 gene may become altered within one or more cells. The loss of function of the second NF1 gene copy leads to abnormal growth of the affected cells, increasing their chance to become cancerous.

    How is neurofibromatosis type 1 inherited?

    Approximately 50 percent of patients with neurofibromatosis type 1 inherit an altered copy of the NF1 gene from a parent who also has NF1. In the remaining 50 percent of patients, neurofibromatosis type 1 results from the development of a “new” mutation in the NF1 gene in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter scenario, the affected individuals will be the first ones in their family to carry this genetic change. All individuals who carry an alteration in one copy of the NF1 gene in all the cells of their body have a 50 percent (or 1 in 2) chance of passing this same alteration on to each of his or her children. Children who inherit the altered gene copy will have neurofibromatosis type 1 and will therefore be at risk to develop the features associated with this disorder.

  • Diagnosis

    An individual with two or more of the following features carries a clinical diagnosis of neurofibromatosis type 1 (NF1):

    • Six or more café-au-lait spots measuring at least :
      • Five millimeters in greatest diameter in prepubertal individuals
      • Fifteen millimeters in greatest diameter in postpubertal individuals
    • Two or more neurofibromas or one plexiform neurofibroma (a thick, irregular neurofibroma that usually involves multiple nerves)
    • Freckles on the armpits or groin
    • Optic pathway glioma
    • Two or more iris Lisch nodules
    • Specific bone malformations, such as sphenoid wing dysplasia (abnormality in a skull bone) or thinning of the long bones
    • A first-degree relative with a diagnosis of neurofibromatosis type 1 (NF1)

    A detailed review of an individual’s medical and family history is important in diagnosing neurofibromatosis type 1 (NF1). A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed clinical manifestations of neurofibromatosis type 1 (NF1), such as café-au-lait spots or neurofibromas. If the pattern of clinical features and/or cancers is suggestive of neurofibromatosis type 1 (NF1), the physician or counselor may recommend that genetic testing be performed.

    Genetic testing

    In order to confirm on a molecular level that an individual has neurofibromatosis type 1 (NF1), he or she can undergo genetic testing:

    • Generally, a sample of blood is obtained from an affected individual.
    • DNA is isolated from this sample, and the two copies of the NF1 gene are analyzed using a variety of methods and compared to the normal reference sequence for the NF1 gene.
    • If an alteration in one NF1 gene copy is identified, the genetic counselor can examine whether the alteration has been previously reported in other individuals with neurofibromatosis type 1 (NF1).

    It is estimated that approximately 90 to 95 percent of individuals carrying a clinical diagnosis of NF1 will have a mutation involving the NF1 gene. Some individuals may be "mosaic" and not have a detectable alteration of NF1 in their blood cells. Therefore, the failure to identify an alteration in the NF1 gene does not always exclude the clinical diagnosis of neurofibromatosis type 1 (NF1).

    A person who is mosaic for NF1 has two populations of cells that make up the body. One population contains two working copies of the NF1 gene (these cells are normal) and the second population contains one working copy and one non-working copy of the NF1 gene (these cells are abnormal). Individuals with NF1 mosaicism may show signs of the disease only in parts of the body that contain abnormal cells. Because it is difficult to know which cells of the body of a person with NF1 mosaicism are affected, it is not possible to predict the exact risk to develop tumors or to pass the altered gene copy on to future children.

    Neurofibromatosis type 1 (NF1) genetic test results can also provide important information for other family members. If a mutation responsible for neurofibromatosis type 1 (NF1) syndrome is identified, at-risk relatives (first or second degree relatives) can be tested for the same genetic alteration.

  • Reproductive options

    A person with neurofibromatosis type 1 (NF1) who does not wish to pass this disorder on to future children has several reproductive options, including:

    • Prenatal diagnosis: DNA is obtained from the cells of the embryo through chorionic villus sampling (CVS) or amniocentesis. The DNA is analyzed for alterations in the NF1 gene.
    • Preimplantation Genetic Diagnosis (PGD): For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the NF1 gene would be implanted.

    Before one can proceed with prenatal testing or PGD, an NF1 mutation must be identified in a parent with neurofibromatosis type 1. Using either method, a parent can work with a genetic counselor and/or physician to decide whether to carry the pregnancy to term or to end the pregnancy.

  • Tumor risks

    Almost all individuals with neurofibromatosis type 1 (NF1) eventually develop neurofibromas, benign (non-cancerous) tumors that form along nerves on the skin, or elsewhere in the body. The tumors may be removed for cosmetic or medical reasons if needed. In some cases, however, these tumors undergo malignant changes and behave like cancers. Approximately 10 percent of individuals with neurofibromatosis type 1 (NF1) develop cancerous neurofibromas, called malignant peripheral nerve sheath tumors.

    Brain tumors are the second most common tumor that occurs in individuals with neurofibromatosis type 1 (NF1). Most of the brain tumors that occur in neurofibromatosis type 1 (NF1) are low-grade astrocytomas. They can occur anywhere in the brain, but most often occur along the optic pathway, and therefore can affect vision. Most of these tumors occur by 5 years of age. Fortunately, most of these tumors stabilize and do not affect vision.

    Although cancerous neurofibromas and central nervous system tumors are the most common malignancies in neurofibromatosis type 1 (NF1), affected women may also face a moderately increased risk of breast cancer development.

    Other cancers that neurofibromatosis type 1 (NF1) patients have a greater relative risk of developing include:

    • Leukemia, especially juvenile myelomonocytic leukemia (a blood cancer that affects young children)
    • Pheochromocytoma (tumor that forms on the adrenal gland)
    • Gastrointestinal stromal tumor (tumor that forms along the gastrointestinal tract)

    However, the incidence of these cancers in individuals with neurofibromatosis type 1 (NF1) is very low, and presymptomatic screening is not usually recommended.

    Cancer screening protocol

    Although most of the tumors associated with neurofibromatosis type 1 (NF1) are benign, individuals with neurofibromatosis type 1 (NF1) should be monitored for the development of these tumors, because they can cause complications, such as loss of vision with optic pathway gliomas. Furthermore, it is important to carefully monitor neurofibromas for signs that might indicate malignant transformation.

    • Annual physical evaluations (including blood pressure monitoring) by a physician familiar with the patient and the disorder
    • Annual ophthalmologic screening in early childhood, less frequent examination in older children and adults
    • Other evaluations depending on symptoms

    Other screening recommendations

    • Regular assessments of developmental and school progress in children
    • Monitoring of those who have abnormalities of the central nervous system, skeletal system, or cardiovascular system by an appropriate specialist
    • Investigation of clinically apparent signs and symptoms through further studies

    If possible, individuals with neurofibromatosis type 1 (NF1) should avoid unnecessary radiation exposure, which is associated with an increased risk of developing malignant peripheral nerve sheath tumors.

  • Adults with NF1

    Adults who have neurofibromatosis type 1 (NF1) or who would like more information about neurofibromatosis type 1 (NF1) may contact the Medical Genetics Team at the Hospital of the University of Pennsylvania.

Reviewed by Kristin Zelley, MS on September 03, 2012