Neurofibromatosis type 1 (NF1) is a genetic disorder that causes typically non-cancerous tumors to grow along nerves, primarily influencing the skin, nervous system, and bones. The disorder can manifest in a wide variety of ways, with symptoms ranging from mild to more significant. NF1 is one of the more common genetic conditions, affecting people of all races and sexes worldwide.
Genetic Causes and Inheritance
Neurofibromatosis type 1 is caused by a mutation in the NF1 gene on chromosome 17. This gene holds the instructions for creating a protein called neurofibromin. Neurofibromin acts as a tumor suppressor, which means it helps regulate cell growth and prevent cells from dividing in an uncontrolled way. When a mutation occurs in the NF1 gene, the loss of functional neurofibromin allows cells to grow without proper control, leading to the formation of tumors.
The genetic change for NF1 can arise in two ways. In about half of all cases, the condition is inherited from a parent with NF1. This follows an autosomal dominant pattern, meaning only one copy of the altered gene from one parent is needed to cause the disorder. A parent with NF1 has a 50% chance of passing the gene to each child.
The other half of NF1 cases result from a new, or spontaneous, mutation. In these instances, the change in the NF1 gene occurs for the first time in the affected individual. This spontaneous mutation can happen during the formation of the sperm or egg cell or early in embryonic development. Once the mutation has occurred, that individual can then pass the condition on to their future children.
Key Signs and Symptoms
The most common signs of NF1 often appear in childhood and can vary greatly in severity. One of the earliest indicators is the presence of multiple flat, light brown skin patches known as café-au-lait macules. While many people have one or two of these spots, having six or more is a strong indicator of NF1. These spots are often present at birth or appear within the first few years of life.
Freckling in unusual areas, such as the armpits or the groin area, is another distinctive feature. This type of freckling is not seen in the general population and usually develops between the ages of 3 and 5. These clusters of small spots are similar in color to café-au-lait macules but are much smaller. Their appearance in skin folds is a specific clue for clinicians.
Neurofibromas are a hallmark of the condition. These are benign growths that develop on or under the skin and can also form inside the body. Cutaneous neurofibromas are soft, pea-sized bumps on the skin’s surface, while plexiform neurofibromas are larger tumors that grow along nerves. Plexiform neurofibromas can sometimes cause disfigurement or other medical issues depending on their location.
Other signs involve the eyes and bones. Tiny, harmless bumps on the iris called Lisch nodules can develop, which do not affect vision and are only visible during a specialized eye exam. Tumors known as optic pathway gliomas can also grow on the optic nerve. NF1 can also cause specific bone abnormalities, such as the bowing of the lower leg or developmental issues with the bone behind the eye.
The Diagnostic Process
Diagnosing NF1 involves a thorough clinical evaluation by a healthcare provider. The process relies on a set of internationally recognized diagnostic criteria. A diagnosis is confirmed when an individual displays two or more specific signs, such as multiple café-au-lait spots, skinfold freckling, or the presence of neurofibromas.
A comprehensive physical examination is the foundation of the process, allowing a doctor to identify the characteristic skin findings. This is often supplemented by a detailed ophthalmology exam to look for Lisch nodules on the iris or evidence of an optic pathway glioma. These two examinations alone can often provide enough evidence to make a diagnosis.
In some situations, imaging studies like an MRI may be used to assess for plexiform neurofibromas or optic pathway gliomas that are not visible externally. While diagnosis is most often made clinically, genetic testing is also available. This can confirm a suspected diagnosis when clinical signs are ambiguous or be used for family planning to identify the specific NF1 gene mutation.
Managing NF1 Throughout Life
Because NF1 affects multiple body systems and its manifestations can change over time, management focuses on regular monitoring and addressing symptoms as they arise. There is no single cure, so care is tailored to the individual’s specific health needs. This approach often involves a multidisciplinary team of specialists, including neurologists, dermatologists, ophthalmologists, and orthopedic surgeons.
Routine surveillance helps detect potential issues early. This includes annual physical examinations to monitor blood pressure and check for new neurofibromas. Regular eye exams are also recommended, especially in young children, to screen for optic pathway gliomas and other changes.
When specific symptoms require intervention, various treatments are available. Problematic neurofibromas that cause pain, nerve compression, or disfigurement can often be surgically removed. For inoperable plexiform neurofibromas, targeted medications known as MEK inhibitors have been developed. Since learning disabilities are common in children with NF1, management includes ensuring access to appropriate educational support and resources.
Potential Health Complications
Individuals with NF1 have an increased risk of developing certain health complications beyond the more common signs. While most people with NF1 live full lives, vigilance for these potential issues is a part of their long-term care. The lifelong management strategies are designed to catch and address these complications early.
One of the more significant risks is the development of cancer. Plexiform neurofibromas have a small chance of transforming into a cancerous tumor called a malignant peripheral nerve sheath tumor (MPNST). People with NF1 also have a higher risk for other cancers, including breast cancer, leukemia, and certain brain tumors. For this reason, cancer screening, such as mammograms for women, may be recommended at an earlier age.
Other health issues can also arise. High blood pressure is more common and can be caused by narrowing of the arteries to the kidneys or a benign adrenal gland tumor. Skeletal problems, like scoliosis, can progress and may require bracing or surgery to correct.