Neurofibromatosis Type I (NF1) is a genetic disorder affecting multiple body systems, including the skin, nervous system, and eyes. It is characterized by the growth of non-cancerous tumors along nerves, as well as changes in skin pigmentation. Symptoms vary widely among individuals, from mild to severe.
Genetic Basis and Causes
Neurofibromatosis Type I is caused by a mutation in the NF1 gene, located on chromosome 17. This gene provides instructions for making a protein called neurofibromin. Neurofibromin acts as a tumor suppressor, helping to regulate cell growth and division. When the NF1 gene is mutated, the neurofibromin protein may be nonfunctional or absent, leading to uncontrolled cell proliferation and the formation of tumors.
NF1 can be acquired in two primary ways. Approximately half of all individuals with NF1 inherit the mutated gene from a parent who also has the condition. This follows an autosomal dominant inheritance pattern, meaning only one copy of the altered gene is sufficient for the disorder to develop.
The remaining cases, about 50%, arise from spontaneous, or de novo, mutations in the NF1 gene. These mutations occur randomly during the formation of sperm or egg cells, or in early embryonic development, in individuals with no prior family history of NF1. A person with a spontaneous mutation still has a 50% chance of passing the altered gene to their children.
Recognizing the Signs
NF1 signs include characteristic changes on the skin, in the eyes, and in bone development, which can appear at different ages.
Café-au-lait spots are flat, light brown patches on the skin. While many people without NF1 may have one or two such spots, individuals with NF1 typically have six or more. These spots are often present at birth or appear within the first year of life, increasing in size and number throughout childhood.
Neurofibromas are benign tumors that grow on nerves, appearing as bumps on or under the skin. They typically emerge during teenage years or early adulthood and can increase in number and size. Plexiform neurofibromas are a larger, more extensive type of tumor that can grow deeper within the body, potentially causing disfigurement, pain, or functional problems.
Freckling in unusual areas, specifically the armpits (axillary freckling) and groin (inguinal freckling), is another common sign. These small, clustered freckles typically develop between three and five years of age.
Eye involvement includes Lisch nodules, which are small, benign bumps on the iris. These nodules usually do not affect vision and become more common with age. Optic pathway gliomas are tumors that can develop on the optic nerve. While often slow-growing and asymptomatic, some can cause vision loss, a squint, or a bulging eye.
Bone abnormalities are also observed in individuals with NF1. These can include bowing of the tibia, which may lead to fractures. Scoliosis, a sideways curvature of the spine, is another common skeletal issue, varying from mild to severe.
Neurological aspects frequently affect individuals with NF1. Learning disabilities are common, impacting up to 80% of children with NF1. These difficulties can affect academic achievement, including reading, writing, and math skills. Attention-deficit/hyperactivity disorder (ADHD) is also frequently observed.
Diagnosis and Medical Management
Diagnosis involves a clinical evaluation, including medical history and physical examination. NF1 is generally diagnosed if an individual meets two or more specific clinical features.
These diagnostic criteria include:
Six or more café-au-lait spots of specific sizes.
Two or more neurofibromas or one plexiform neurofibroma.
Freckling in the armpit or groin regions.
Two or more Lisch nodules in the iris or an optic pathway glioma.
Distinctive bone lesions, such as sphenoid dysplasia or thinning of the long bone cortex.
A first-degree relative who already meets these criteria.
Genetic testing for the NF1 gene mutation can confirm the diagnosis, particularly in atypical cases or for prenatal diagnosis.
Medical management of NF1 requires a multidisciplinary approach. This team includes specialists such as neurologists, dermatologists, ophthalmologists, and orthopedists. Regular monitoring is a cornerstone of care, with yearly check-ups to track new or worsening symptoms. These visits include assessing skin for new neurofibromas, checking blood pressure, and monitoring growth and development. Annual eye exams screen for issues like optic gliomas. Imaging tests, such as MRIs, are used if specific clinical concerns arise, but are not routinely recommended for screening all patients.
Treatment focuses on managing symptoms and preventing complications. For problematic neurofibromas, surgical removal may be considered, and drug therapies like MEK inhibitors are approved for certain plexiform neurofibromas. Bone deformities like scoliosis may be managed with observation, bracing, or surgery. Learning disabilities and ADHD are addressed with individualized education programs, behavioral therapies, and medication. Early intervention programs are often beneficial for developmental delays.
Understanding Potential Complications
Individuals with NF1 have an increased risk of developing various tumors. A more serious concern is the elevated risk of malignant peripheral nerve sheath tumors (MPNSTs), which are cancerous tumors that can arise from pre-existing neurofibromas. Other cancers, such as brain tumors and certain types of leukemia, are also seen at higher rates in the NF1 population.
Cardiovascular issues can also arise. High blood pressure is more common, and can sometimes be caused by conditions like renal artery stenosis or pheochromocytomas. Blood vessel abnormalities, known as vasculopathy, can affect vessels throughout the body.
Bone issues include pseudarthrosis, where a fractured bone fails to heal properly, and osteoporosis, a reduction in bone mineral density leading to weaker bones. These skeletal complications can impact mobility.