Neurofibromatosis type I (NF1), also known as von Recklinghausen disease, is a genetic disorder affecting the nervous system, skin, and other organs. It is a neurocutaneous disorder involving abnormalities of the skin and the nervous system. Neurofibromatosis type I is caused by mutations in the NF1 gene.
Neurofibromatosis type I genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of neurofibromatosis type I include:
- Neurofibromas: Neurofibromas are tumors that arise from the peripheral nerves and can develop anywhere in the body. They can be noncancerous (benign) but may cause various symptoms depending on their location and size.
- Café-au-Lait Spots: Café-au-lait spots are flat, brown skin spots often present from birth. They are a hallmark feature of neurofibromatosis type I and may increase in number with age.
- Freckling in Armpits or Groin: Freckling in areas such as the armpits or groin is another characteristic skin finding in neurofibromatosis type I.
- Lisch Nodules: Lisch nodules are tiny, harmless nodules that may appear on the eye's iris. They do not affect vision.
- Optic Gliomas: Some individuals with neurofibromatosis type I may develop tumors called optic gliomas in the optic nerve, which can lead to vision problems.
- Skeletal Abnormalities: Skeletal abnormalities, such as scoliosis (curvature of the spine), may occur in individuals with neurofibromatosis type I.
- Learning Disabilities: Learning disabilities, attention deficits, and cognitive impairments are more common in individuals with neurofibromatosis type I.
- Macrocephaly: Some individuals with neurofibromatosis type I may have a larger-than-average head size (macrocephaly).
- Tumors in the Central Nervous System: In addition to peripheral nerve tumors, tumors can also develop in the central nervous system, including the brain and spinal cord.
- Autosomal Dominant Inheritance: Neurofibromatosis type I follows an autosomal dominant inheritance pattern, meaning a child has a 50% chance of inheriting the mutated gene from an affected parent.
Diagnosis of NF1 is often based on clinical criteria, including characteristic features such as café-au-lait spots and neurofibromas. Genetic testing can confirm the diagnosis by identifying mutations in the NF1 gene.
While there is currently no cure for neurofibromatosis type I, management involves addressing symptoms and complications. Regular monitoring, especially in childhood, is important for early detection and intervention. Treatment may include surgery to remove problematic tumors, orthopedic interventions for skeletal issues, and educational support for learning disabilities.
Genetic counseling is recommended for individuals with NF1 and their families to understand the inheritance pattern, assess the risk of passing the condition to offspring, and discuss available management strategies.
More Information
Neurofibromatosis (NF) is a disease that causes tumors in nervous tissue, including the brain, spinal cord, and peripheral nerves. It is classified into three subtypes: NF1, NF2, and schwannomatosis (SWN). NF1 is the most frequent subtype, accounting for 96% of NF cases.
Neurofibromatosis type I is caused by pathogenic mutations in the NF1 gene that produces neurofibromin, a tumor suppressor GTPase protein that regulates the RAS/MAPK signaling pathway. For this reason, neurofibromatosis type I is classified within the group of RAS-opathies and has in common specific clinical manifestations with other diseases that are part of this group, such as Noonan syndrome.
More than 2.000 pathogenic variants in the NF1 gene have been identified in patients with the disease. Most pathogenic mutations in the NF1 gene reduce the total expression of the neurofibromin protein by premature truncation or microdeletion. It has been shown that there are various phenotypes and that different mutations could influence them. For example, patients with p.Met992del have a mild phenotype, while those with substitutions such as p.Arg1276 and p.Arg1809Cys have Noonan syndrome-like features, including cardiovascular abnormalities. Patients carrying microdeletions in the NF1 gene have a more severe phenotype.
Neurofibromatosis type I genetic testing analyzes the 98 most frequent pathogenic mutations of the NF1 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
