Neurofibromatosis, type 1

Once one individual in a family has been identified as having a gene change causing NF1, other members of the family can have targeted genetic testing to look for the presence or absence of that gene change. Children of an individual with NF1 have a 1 in 2 (50% chance) of inheriting the NF1 gene change from their affected parent. A parent of an individual known to have NF1 may also have an NF1 gene change and be affected with the condition, or the gene change may have occurred for the first time in the affected individual (known as de novo). Approximately 50% of individuals with NF1 have an affected parent, and approximately 50% have a de novo gene change and neither parent is affected. Once an individual has been diagnosed with NF1, It is recommended that their relatives be informed of their risk and seek medical evaluation as appropriate.

Hypothetical example: "John" has NF1 and his specific disease causing NF1 gene mutation has been identified by genetic testing. His brother "Tom" then has testing for the specific NF1 mutation that "John" has, and "Tom’s" test is negative (normal). This negative result in Tom can be used to provide the family information that Tom does not have the NF1 gene change causing John’s NF1. Tom’s children do not then need to receive genetic testing for John’s NF1 mutation. Tom could not have passed down the NF1 mutation, because he did not inherit it himself. You cannot pass on a gene mutation you do not have.

Families with questions about the genetics of NF1 may benefit from genetic counseling. The National Society of Genetic Counselors "Find a Genetic Counselor" searchable directory can be used to locate genetic counselors throughout the United States and Canada.

Other people with Neurofibromatosis Type 1 (NF1) can be found through online support groups, including:
Children’s Tumor Foundation (http://www.ctf.org)
The Neuro Foundation (http://www.nfauk.org)
Neurofibromatosis Network (http://www.nfnetwork.org)
Neurofibromatosis Midwest (http://www.nfmidwest.org)
Texas Neurofibromatosis Foundation (http://texasnf.org)
Neurofibromatosis Mid-Atlantic (http://www.nfmidatlantic.org)

There may also be local support groups in your area. A genetic counselor may be able to assist you in identifying local resources for families with individuals with NF1. The National Society of Genetic Counselors has a searchable "Find a Genetic Counselor" directory which can be used to locate genetic counselors throughout the United States and Canada.

Medical geneticists and genetic counselors can assist families with questions about diagnosis and management of NF1. The National Society of Genetic Counselors website has a searchable "Find A Genetic Counselor" directory that can be used to locate genetic counselors throughout the Untied States and Canada.

A medical geneticist or another physician familiar with NF1 can help ensure that an individual with NF1 receives care from a multi-disciplinary team of healthcare providers, dependent upon the specific symptoms of NF1 an individual patient experiences. In addition to routine primary care, this team may include dermatology (skin), orthopedics (bone), ophthalmology (vision), neurology (brain and nervous system), and a developmental pediatrician.

In general, there are no significant lifestyle changes that are recommended for people with NF1. There are certain symptoms potentially associated with NF1 which, if present in an individual, may require lifestyle modifications for that individual (eg, tibial dysplasia or dysplastic scoliosis). However, in those cases, any recommended changes for the individual’s lifestyle would be based on the symptoms present, not because of the underlying diagnosis of NF1.

Radiation therapy may be associated with increased risk to develop a malignant peripheral nerve sheath tumor, so people with NF1 may want to avoid this therapy if possible.

The general population risk of a couple unaffected with NF1 to have a child with NF1 is approximately 1 in 7000. Approximately 1 in 3500 children are born with NF1.

NF1 may be clinically suspected in individuals with clinical symptoms such as café-au-lait spots (has the appearance of a brown birthmark on the skin), neurofibromas (a tumor formed on a nerve sheath cell, typically benign), freckling in the groin area or in the armpits, optic glioma (a type of brain tumor), Lisch nodules (an eye finding which gives a freckling appearance to the colored part of the eye (iris)), an osseous lesion (a change in a bone), and/or a parent/ sibling/ child with NF1

Individuals suspected to have NF1 may benefit from an evaluation by a medical geneticist and genetic counseling. If you are interested in locating genetic services in your area, your primary care provider may be able to provide you with a referral, or you can use the National Society of Genetic Counselors "Find a Genetic Counselor" searchable directory to locate a genetic counselor in the United States or Canada. ‘

There are key differences between analyzing the DNA from a tumor and analyzing DNA from the germline. Germline refers to the DNA sequence present in the egg or sperm that is inherited by a child from his or her parents. Genetic testing is increasingly performed on tumor samples, and in some cases, the results of genetic testing on tumor cells can help guide treatment options. Most of the genetic changes found in a tumor sample are new changes present in the tumor but not present in the cells in the rest of the body (called somatic changes). Somatic mutations are not inherited from a parent or present at birth, but rather they arise randomly in only certain tissues in the body later in life. Many somatic changes occur during the growth of a tumor. An NF1 gene mutation found in a tumor does not confirm that a person has Neurofibromatosis Type 1 (NF1), as the NF1 gene mutation identified in the tumor may be present only the tumor cells and not throughout the body.

NF1 is caused by germline mutations. These are genetic changes present from the time of conception of an affected individual. Germline mutations should be present throughout the body, and can be identified by genetic testing of blood cells, as well as saliva, skin and other tissue types.

In April of 2020, the US Food and Drug Administration (FDA) approved the first therapy for neurofibromatosis type 1 (NF1) called selumetinib (brand name: Koselugo). The medication is specifically designed to treat pediatric patients living with NF1 who have plexiform neurofibromas (nerve sheath tumors) that cause medical issues and are unable to be surgically removed. Selumetinib is a kinase inhibitor that blocks a key enzyme that is needed for the plexiform neurofibroma growth.

Neurofibromatosis Type 1 (NF1) is a genetic condition that can cause skin findings and tumors, or growths, in different parts of the body. The majority of the tumors that NF1 can cause are benign (do not cause cancer). Individuals with NF1 may also develop an eye finding called iris Lisch nodules, which do not affect vision but can be an important diagnostic clue. People with NF1 can be affected very differently from one another, even in the same family. Some individuals with NF1 may have very mild health issues and may never be diagnosed on the basis of their symptoms, while others with NF1 have much more severe health and/or cosmetic issues on the basis of their symptoms.

Genes contain the instructions that the body uses to direct growth and development (like a set of blueprints). The NF1 gene is what is known as a tumor suppressor gene. There are two copies of the NF1 gene in each cell of our body. One copy of the NF1 gene is inherited from each parent. The typical function of the NF1 gene and other tumor suppressor genes is to help to reduce the occurrence of random growths (tumors) in the body. Individuals with NF1 have a gene change (mutation) in one of their two copies of the NF1 gene. The gene change in the NF1 gene causes the gene to not work properly. A nonworking copy of the NF1 gene can lead to an increased chance of the individual developing the tumors that are frequently seen as part of NF1. Most of these tumors are not cancer (benign). However, they can sometimes cause other problems in the body. The other skin findings and related symptoms in NF1 also result from the presence of a nonworking copy of the NF1 gene in the cells of the affected individual’s body.

NF1 is a genetic condition caused by changes in a gene called NF1.NF1 is an autosomal dominant condition, which means that the presence of an NF1 disease causing gene change in one of an individual’s two copies of the NF1 gene is sufficient to cause the condition.

Genetic testing for NF1 consists of sequencing the NF1 gene, or spelling out the "letters’" that form the gene. Some types of gene changes, known as mutations, which are detected by genetic testing as spelling errors in the gene, are known to change the function of the gene in such a way that they are known to cause NF1 (called pathogenic). This is what is known as a positive test result for NF1. A positive test result for NF1 confirms the diagnosis of NF1.

A negative genetic test result means that the laboratory analyzed the DNA of an individual and found no genetic changes known to cause NF1. This result has different implications depending on the situation of the person who was tested.

NF1 is named for the neurofibromas that many individuals with NF1 develop. Neurofibromas are tumors that grow on nerves in the body. While the majority of these neurofibromas are not malignant (cancerous), they can cause discomfort, cosmetic issues and other problems if they grow too large. If a neurofibroma grows on the optic nerve in the eye (optic glioma), this can potentially affect vision.

Many people with NF1 have dermatological (skin) findings. Multiple café-au-lait spots (similar to flat birthmarks) are often found. Also, many people with NF1 have freckling in non-sun exposed areas, like in the armpit (axillary freckling) or around the groin area (inguinal freckling). Lisch nodules are clumps of pigment in the colored part of the eye (iris) that have the appearance of freckles that do not affect vision but can be detected by an eye examination. Nearly all (97%) of individuals with NF1 develop Lisch nodules.

Some individuals with NF1 may have attention deficit hyperactivity disorder (ADHD) or problems learning in school as well. Other symptoms can include macrocephaly (large head size), early or late puberty, scoliosis (curvature of the spine) and other orthopedic problems, high blood pressure, brain tumors, and leukemia.

There are published medical management guidelines which outline recommendations for individuals diagnosed with NF1, broken down by age. These guidelines include:

Following a diagnosis of Neurofibromatosis Type 1(NF1) at any age, an individual should have:

Most of the skin findings associated with NF1 are benign (noncancerous). People with NF1 may have a somewhat higher risk for certain rare malignant tumors (in the brain, nerves or spinal cord), but are estimated to have the same risk as individuals in the general population without NF1 for more typical cancers found in the general population (ie, breast, lung, stomach). While most individuals with NF1 do not develop cancer thought to be related to NF1, the most common type of cancer found in individuals with NF1 is malignant peripheral nerve sheath tumor (cancer along a nerve), which occurs in approximately 10% of individuals with NF1.

The main risks for malignancy in childhood with NF1 include leukemia (blood cancer) and brain tumors, while in adolescence the primary cancer seen is malignant peripheral nerve sheath tumors. The risk for cancer in adults with NF1 is primary malignant peripheral nerve sheath tumor and breast cancer.

There have been guidelines published regarding the medical management and surveillance of individuals with NF1 by multiple professional organizations, including the American Academy of Pediatrics (2008), the National Society of Genetic Counselors (2007), and other expert groups. These guidelines often include recommendations for assessments following the diagnosis of NF1, and then ongoing evaluations broken down by the age of the individual with NF1.

Some recommended surveillance guidelines include:

Reduced (incomplete) penetrance and variable expressivity relate to the symptoms that an individual with a genetic condition, including NF1, experience in their lifetime. In this context, penetrance refers to how many people with a disease causing gene change show clinical features of the condition (look to be affected). If it is known that there are individuals who have a disease causing change (mutation) in the gene but do not seem to develop any symptoms of the condition, then the condition is described as being incompletely penetrant, or having reduced penetrance.

Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition.

NF1 is fairly highly penetrant, meaning that nearly all people with a disease causing mutation (change) in an NF1 gene develop clinical signs and symptoms of NF1 before adulthood. NF1 is a condition with a large amount of variable expressivity, meaning that affected individuals may have a wide range of what symptoms related to NF1 they develop and how severe these symptoms are. Even individuals with NF1 in the same family may have a high amount of variability in the signs and symptoms of NF1 that they each experience.

There is controversy over whether individuals diagnosed with NF1 with no specific neurological symptoms should routinely have brain MRIs at the time of diagnosis, and whether regular ongoing brain MRIs should be a part of standard management for individuals with NF1 or not. One argument for regular brain MRIs is that they can help screen for the development of certain possible symptoms of NF1. The argument against believes that the possible negatives (such as high costs, the possibility of findings of uncertain clinical significance and unnecessary family anxiety) outweigh the potential benefit.

Your healthcare provider may have her/his own opinion on what type of medical management is right for you and your situation.

There are medical management guidelines that could alter the care of children known to be affected with NF1, and so it is reasonable to evaluate and potentially consider genetic testing of an individual at any age suspected to have NF1.

Families with questions about medical management and genetic testing options for families with individuals known or suspected to have NF1 may benefit from consultation with a medical geneticist and genetic counseling. The National Society of Genetic Counselors website includes a "Find a Genetic Counselor" searchable directory which can be used to locate genetic counselors across the United States and Canada.

Around 97% of people with NF1 have Lisch nodules in the colored part of their eye (iris). Lisch nodules have the appearance of freckling in the colored ring of the eye.

Most individuals with NF1 develop a skin finding such as multiple café-au-lait spots (similar to a flat birthmark) or freckling in area without sun exposure (ie. under the arm or near the groin, known as axial and inguinal freckling).

As of January 2016, NF1 is not on the Recommended Uniform Screen Panel (RUSP). The RUSP is created by the Health Resources and Services Administration, and guides individual states in their determination of what conditions are recommended to be included as part of state based newborn screening programs. More information about newborn screening, including which disorders are included in the newborn screening panel in a particular state, is available at http://www.babysfirsttest.org.

If there is reason to suspect that an individual has NF1, genetic testing would be an option at any age.

A diagnosis of NF1 can be made by a medical geneticist or other physician familiar with NF1 on the basis of an individual fulfilling diagnostic criteria from the National Institutes of Health. There are several genetic testing options for individuals with a known or suspected diagnosis of NF1 commercially available at genetic testing laboratories. The type of testing for NF1 with the highest detection rate is a multi-step protocol that involves analyzing DNA (genomic DNA) as well as mRNA (a temporary copy of the information found on DNA that takes information from the DNA to another part of the cell where proteins are made), as well as checking for a deletion of the NF1 gene (missing genetic information). This multi-step protocol is estimated to detect disease causing gene changes in over 95% of individuals who meet clinical criteria for NF1 and are therefore believed to be affected. Alternatively, there are also genetic tests that sequence the genomic DNA for spelling errors (approximately 61% detection rate in clinically affected individuals), do deletion/duplication analysis (missing or extra pieces of genetic information involving the NF1 gene – approximately 5% detection rate in affected individuals), and cytogenetic testing which is a type of chromosome analysis that could detect a chromosome rearrangement that disrupts the NF1 gene and causes NF1 (less than 1% of affected individuals).

Once the disease causing gene change has been identified in one individual with NF1 in a family, targeted testing for that specific gene change can be offered to other individuals in the family as appropriate.

As with all genetic testing, there are possible benefits, risks and limitations to genetic testing for NF1. Individuals or families interested in genetic testing for NF1 or with questions about interpretation of genetic testing results may benefit from genetic counseling. The National Society of Genetic Counselors website includes a "Find A Genetic Counselor" directory which may be used to locate genetic counselors throughout the United States and Canada.

There is research being conducted on Neurofibromatosis Type 1 (NF1). ClinicalTrials.gov can provide up-to-date information on current clinical trials. In 2020, there were 144 studies at various stages listed on clinicaltrials.gov. The Children’s Tumor Foundation website also contains information about research in NF1.

In April of 2020, the US Food and Drug Administration (FDA) approved the first therapy for neurofibromatosis type 1 (NF1) called selumetinib (brand name: Koselugo). The medication is specifically designed to treat pediatric patients living with NF1 who have plexiform neurofibromas (nerve sheath tumors) that cause medical issues and are unable to be surgically removed. Selumetinib is a kinase inhibitor that blocks a key enzyme that is needed for the plexiform neurofibroma growth.

Other than selumetinib, there are also treatments for individual symptoms of NF1 that may be present to a variable degree in affected individuals. There are recommended surveillance and management guidelines for individuals with NF1. Surveillance recommendations are dependent on the age of the affected individual.

Prenatal testing is available for NF1 if there is a known mutation present in the family. Prenatal testing is available through procedures known as chorionic villus sampling (CVS) and amniocentesis. In these procedures, cells are collected from the placenta (CVS) or amniotic fluid (amniocentesis), and genetic testing can be performed on the DNA found in those cells. Since the placenta is derived from the same egg and sperm cell used in the conception of a baby, DNA found in the cells of a placenta is generally the same as DNA found in cells from a baby. DNA collected by CVS or amniocentesis can be analyzed for the presence or absence of a known NF1 gene change, if present in a family.

Approximately 50% of individuals with NF1 inherit the gene change from a parent who is also affected by NF1, and approximately 50% of the time the NF1 gene change occurs for the first time in the affected individual (de novo). De novo gene changes occur randomly in egg or sperm cells and are not caused by any known lifestyle or environmental factors.

NF1 is inherited in what is known as a autosomal dominant manner. Genetic information is organized in the cells of the body on structures called chromosomes. Most cells in the body typically have 46 chromosomes which are organized into 23 pairs of 2. The first 22 pairs of chromosomes, which are numbered 1-22, are the same in males and females and are called autosomes. The 23rd pair of chromosomes is called the sex chromosomes and are what determine gender (XX for female and XY for male). An individual receives one chromosome from each pair from each parent at the time of conception. This means that everyone has two copies of all of the genetic information found on chromosomes 1-22, with one copy coming from each parent.

NF1 being inherited in an autosomal dominant manner means that the gene change that causes NF1 is located on one of the first 22 pairs of chromosomes (called autosomes). Specifically the NF1 gene is located on chromosome number 17. Since the NF1 gene is located on an autosome, NF1 affects both males and females. Dominant refers to an individual needing a disease causing gene change on only one of their two copies of the NF1 gene to be affected with NF1.

If an individual is affected with NF1, this means that there is disease causing gene change on one of their two number 17 chromosomes. The children of an individual with NF1 each have a 1 in 2, or 50%, chance of inheriting the disease causing gene change from the affected parent and also being affected with the condition.

Genetic testing for NF1 consists of sequencing the NF1 gene, or spelling out the "letters’" that form the gene. Some types of gene changes, known as mutations, which are detected by genetic testing as spelling errors in the gene, are known to change the function of the gene in such a way that they are known to cause NF1 (called pathogenic). Other types of gene changes in the NF1 gene consist of spelling errors that result in the gene sequence being different than what is typically found, but do not seem to affect the function of the NF1 gene or cause an individual to have NF1. Finally, there is the possibility with gene sequencing of identifying gene changes (spelling errors) within the NF1 gene whose effects on the gene are unclear. In these cases, the gene change is categorized as a "variant of uncertain significance", since it is known that there is a gene change (variant) in the gene, but the effect of that gene change is unclear (uncertain significance).

A gene change categorized as a "variant of uncertain significance" (VOUS) cannot be used to confirm or exclude a diagnosis of NF1 in an individual. As more people have genetic testing for NF1 and more data is available to the laboratory, a result that was once a variant of uncertain significance may later be reclassified as either pathogenic (disease causing) or benign (normal).

A medical geneticist or genetic counselor can provide assistance in the interpretation of genetic test results. The National Society of Genetic Counselors webpage includes a "Find a Genetic Counselor" searchable directory that can be used to locate genetic counselors throughout the United States and Canada.

There are multiple ways to help support research and individuals living with NF1 through financial contributions. You can donate to a support group like The Neuro Foundation (http://www.nfauk.org), Neurofibromatosis Network (http://www.nfnetwork.org), Neurofibromatosis Midwest (http://www.nfmidwest.org), Texas Neurofibromatosis Foundation (http://texasnf.org), or Neurofibromatosis Mid-Atlantic (http://www.nfmidatlantic.org). Support groups will use their funds differently. Some will help to raise awareness, assist people with Neurofibromatosis, or donate to medical research. The Children’s Tumor Foundation also raises money for Neurofibromatosis research (http://www.ctf.org).

A medical geneticist or other physician familiar with NF1 can make the diagnosis of NF1 in an individual based upon clinical examination and history. There are diagnostic criteria developed by the National Institutes of Health (NIH) that, if met, can be used to diagnose an individual with NF1 without doing genetic testing.

However, genetic testing is becoming more common to assist in the diagnosis of an individual known or suspected to have NF1 and for genetic counseling and family testing purposes. Genetic testing for NF1 is most typically performed on a blood sample, though other tissue types may be used. Specifically, there is an important distinction between testing the blood of an individual for a gene change causing NF1, or testing tumor tissue of an individual for the same purpose.

There are several laboratories that offer genetic testing for NF1. A medical geneticist or genetic counselor can coordinate genetic testing for NF1. The National Society of Genetic Counselors website includes a searchable "Find a Genetic Counselor" directory which can be used to locate genetic counselors across the United States and Canada.

You can find a doctor that specializes in Neurofibromatosis Type 1 through the Children’s Tumor Foundation website .

Medical geneticists and genetic counselors can assist families with questions about diagnosis and management of NF1. The National Society of Genetic Counselors website has a searchable "Find A Genetic Counselor" directory that can be used to locate genetic counselors throughout the Untied States and Canada.

ClinicalTrials.gov can provide up-to-date information on research being conducted. You can also learn about current research news through the Children’s Tumor Foundation website.

NF1 is a rare disease, estimated to affect around 1 in 3,000 to 1 in 4,000 people.

Genetic testing for NF1 is most commonly performed on a blood sample. Depending on the requirements of a specific genetic testing laboratory, genetic testing for NF1 may also be able to be performed on saliva or other tissue samples. There are specific circumstances where it can be beneficial to look for gene changes in more than one tissue type (for example, blood versus skin cells), or to look for changes to the NF1 gene in tissue from an NF-1 related tumor.

A medical geneticist or genetic counselor can assist in coordinating or interpreting genetic testing results. The National Society of Genetic Counselors website includes a "Find a Genetic Counselor" searchable directory which can be used to locate genetic counseling services throughout the United States and Canada.

People with NF1 generally have average intelligence, though around 50% – 75% of people with NF1 may have a learning disability. Intellectual disability is much less commonly found. Only about 6% of individuals with NF1 have intellectual disability.

Around 30% of individuals with NF1 have some symptoms of autism spectrum disorder, but do not necessarily meet criteria for a clinical diagnosis of autism. Individuals with NF1 may have an impaired ability to interact socially with others. Awareness, early intervention, and a detailed learning plan like an Individualized Education Program (IEP) can help individuals with NF1 do better in school and improve their social interactions.

Neurofibromas that are disfiguring to an individual’s appearance or are located in an inconvenient location (such as belt or collar lines) found on or just below the skin may be removed by surgery, laser, or electrocautery. The recommended method may be influenced by the size of the neurofibroma.

Plexiform neurofibromas are more of a challenge to remove, as it is difficult to clear all of the growth when it is rooted in the nerves, and many plexiform neurofibromas grow back after surgical removal. Carboplatin chemotherapy or tyrosine kinase inhibitors may be of benefit in some cases.

When neurofibromatosis is associated with vascular disorders, it is often known as vascular neurofibromatosis. Although the vascular involvement of NF1 is well described it is rarely seen in the large vessels. Neurofibromin, the protein that is made by the NF1 gene, is expressed in a variety of tissues, including the brain, blood vessels, muscle, and skin. This gene is known as a tumor suppressor gene, meaning that its job is to prevent the cells from replicating too quickly and forming tumors. When the gene is not working correctly, as is the case in people with NF1, it can cause tumors such as neurofibromas. The cells in the blood vessels can also replicate too quickly and cause the walls of the vessels to thicken and become fragile. When these vessels are fragile, aneurysms are more likely to occur.

Neurofibromatosis Type 1 is often abbreviated as NF1. Neurofibromatosis Type 1 may also be referred to as von Recklinghausen disease, peripheral neurofibromatosis, and Recklinghausen disease, nerve.

There are good support groups for people with Neurofibromatosis Type 1 (NF1), including:

Children’s Tumor Foundation (http://www.ctf.org)
The Neuro Foundation (http://www.nfauk.org)
Neurofibromatosis Network (http://www.nfnetwork.org)
Neurofibromatosis Midwest (http://www.nfmidwest.org)
Texas Neurofibromatosis Foundation (http://texasnf.org)
Neurofibromatosis Mid-Atlantic (http://www.nfmidatlantic.org)

There may also be local support groups in your area. A genetic counselor may be able to assist you in identifying local resources for families with individuals with NF1. The National Society of Genetic Counselors has a searchable "Find a Genetic Counselor" directory which can be used to locate genetic counselors throughout the United States and Canada.

There are not different forms of NF1 with different ages of onset of symptoms. However, in NF1, symptoms typically become more apparent as a person ages, and different symptoms are typically found at various ages. There is a lot of variability in the types and severity of symptoms seen in individuals with NF1, even in the same family, with some individuals having such minor clinical findings that they never come to medical attention to be diagnosed, while others have much more significant health, cosmetic and developmental problems as a result of NF1.

There are more than 100 genetic conditions and multiple congenital anomaly syndromes that include café-au-lait spots (flat, pigmented birth marks) or other typical findings of NF1. However, based on the other clinical features of NF1 and these other syndromes, medical geneticists and other physicians familiar with these conditions can generally distinguish NF1 from other conditions clinically. Some of the more common rare disorders which share clinical features in common with NF1 include: