Neurofibromatosis Type 1 (NF1) – Causes, Symptoms & Treatment

What is Neurofibromatosis Type 1?

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is one of the most common genetic disorders affecting the nervous system. It occurs in approximately 1 in 3,000 people worldwide and affects males and females equally. NF1 belongs to a group of conditions called phakomatoses -- disorders that involve both the skin and the nervous system.

Causes

NF1 is caused by a mutation in the NF1 gene located on chromosome 17. This gene encodes a protein called neurofibromin, which normally acts as a tumor suppressor -- meaning it helps prevent cells from growing out of control. When neurofibromin is absent or dysfunctional, benign tumors called neurofibromas can form along nerve pathways throughout the body.

• In approximately 50% of cases, the mutation is inherited from a parent in an autosomal dominant pattern, meaning one copy of the altered gene is sufficient to cause the disorder.
• In the remaining 50% of cases, the mutation arises spontaneously as a de novo mutation, with no family history of the condition.

Symptoms

The symptoms of NF1 vary widely, even among members of the same family. Common features include:

• Cafe-au-lait spots: Flat, light-brown patches on the skin, typically present at birth or appearing in early childhood. Six or more spots larger than 5 mm (in children) or 15 mm (in adults) are considered a diagnostic criterion.
• Neurofibromas: Benign tumors that grow along nerves, appearing as soft lumps under or on the skin or deeper within the body.
• Lisch nodules: Pigmented, harmless bumps on the iris (the colored part of the eye), visible only during a specialized eye examination.
• Axillary and inguinal freckling: Freckle-like spots in the armpits and groin area, which are characteristic of NF1.
• Optic gliomas: Tumors growing on the optic nerve that can cause visual impairment, particularly in young children.
• Skeletal abnormalities: Including scoliosis (curvature of the spine) or bowing of the lower leg bones.
• Learning difficulties and developmental delays: Many individuals with NF1 experience attention deficit hyperactivity disorder (ADHD), learning disabilities, or mild delays in motor development.

Diagnosis

NF1 is primarily diagnosed clinically based on physical examination and medical history. According to the National Institutes of Health (NIH) diagnostic criteria, a person must have at least two of the following features:

• Six or more cafe-au-lait spots of the defined size
• Two or more neurofibromas of any type, or one plexiform neurofibroma
• Freckling in the axillary or inguinal region
• Optic glioma
• Two or more Lisch nodules
• A distinctive bony lesion (e.g., sphenoid dysplasia or tibial pseudarthrosis)
• A first-degree relative with confirmed NF1

Additional diagnostic tools include:

• Genetic testing: Blood tests to identify mutations in the NF1 gene
• MRI scans: To visualize tumors in the brain, spinal cord, or along nerves
• Ophthalmological examination: To detect Lisch nodules and optic gliomas

Treatment

There is currently no cure for NF1, as it is a lifelong genetic condition. Treatment focuses on managing symptoms and preventing or addressing complications.

Surgical Treatment

Neurofibromas that cause pain, grow rapidly, or impair the function of nearby organs or nerves may be surgically removed. However, they can regrow after removal.

Medication

Since 2020, the MEK inhibitor selumetinib (Koselugo) has been approved for children aged 3 and older with symptomatic, inoperable plexiform neurofibromas. This targeted therapy blocks a cell signaling pathway that drives tumor growth and has been shown to reduce tumor size in many patients.

Regular Monitoring

Individuals with NF1 require regular medical follow-up, including:

• Annual eye examinations
• Regular neurological assessments
• Blood pressure monitoring (tumors near the kidneys can cause high blood pressure)
• Imaging studies as clinically indicated

Educational and Psychosocial Support

Children with NF1 often benefit from learning support, occupational therapy, and speech therapy. Psychological counseling for both patients and their families is an important component of comprehensive care.

Outlook and Prognosis

The course of NF1 is highly variable. Many individuals lead largely normal lives with only mild symptoms. However, a small proportion of patients may develop serious complications, such as malignant transformation of neurofibromas (known as malignant peripheral nerve sheath tumors) or tumors of the central nervous system. Regular medical monitoring is therefore essential for early detection and timely treatment of any changes.

References

1. Legius E, Messiaen L, Wolkenstein P et al. - Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome. Genetics in Medicine, 2021. doi: 10.1038/s41436-021-01170-5
2. Evans DG, Howard E, Giblin C et al. - Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. American Journal of Medical Genetics, 2010. doi: 10.1002/ajmg.a.33139
3. National Institutes of Health (NIH): Neurofibromatosis Fact Sheet. National Institute of Neurological Disorders and Stroke (NINDS). Available at: https://www.ninds.nih.gov (accessed 2024)