Neurofibromatosis type I

Overview

Neurofibromatosis type I (NF1), also known as von Recklinghausen disease, is a common genetic disorder that affects the growth and development of nerve cell tissues. It is characterized by the formation of benign tumors along nerves in the skin, brain, and other parts of the body. The condition can also cause skin changes, skeletal abnormalities, learning difficulties, and an increased risk of certain cancers.

NF1 is part of a group of disorders known as neurocutaneous syndromes and affects approximately 1 in 3,000 individuals worldwide. Symptoms typically appear during childhood, and the severity of the condition can vary widely, even among affected members of the same family. While most tumors associated with NF1 are benign, they can sometimes cause significant complications depending on their size and location.

Causes

Neurofibromatosis type I is caused by mutations in the NF1 gene located on chromosome 17. This gene produces a protein called neurofibromin, which functions as a tumor suppressor by helping to regulate cell growth and prevent uncontrolled proliferation.

When the NF1 gene is mutated, neurofibromin function is impaired, leading to the formation of tumors along nerves. These tumors, known as neurofibromas, can grow anywhere in the nervous system, including the brain and spinal cord.

NF1 is inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene is needed to cause the disorder. However, up to 50% of cases result from a de novo (new) mutation, meaning the affected individual has no family history of the disorder.

Symptoms

The clinical features of NF1 are highly variable, ranging from mild to severe. The most common symptoms include:

Cutaneous and Pigmentary Signs

• Café-au-lait spots: Light brown skin patches; typically six or more larger than 5 mm in children or 15 mm in adults

• Freckling: Especially in unusual areas such as the armpits (axillary) or groin (inguinal)

Neurologic and Tumor-Related Features

• Neurofibromas: Soft, benign tumors on or under the skin

• Plexiform neurofibromas: Larger, deeper nerve sheath tumors that can become disfiguring or compress vital structures

• Optic pathway gliomas: Tumors of the optic nerve, which may lead to vision problems

Musculoskeletal Abnormalities

• Scoliosis (curvature of the spine)

• Bone dysplasia (especially of the tibia or sphenoid bone)

• Short stature and joint laxity

Ophthalmologic Features

• Lisch nodules: Benign iris hamartomas detectable on eye examination

Other Features

• Learning disabilities and attention-deficit/hyperactivity disorder (ADHD)

• Delayed speech and motor development

• Increased risk of malignant peripheral nerve sheath tumors (MPNSTs)

• Seizures (in a small subset of patients)

• Headaches and behavioral problems

Diagnosis

NF1 is primarily diagnosed based on clinical criteria established by the National Institutes of Health (NIH). A diagnosis is confirmed if two or more of the following are present:

• Six or more café-au-lait macules

• Two or more neurofibromas of any type, or one plexiform neurofibroma

• Freckling in the axillary or inguinal regions

• Optic glioma

• Two or more Lisch nodules

• A distinctive osseous lesion (e.g., sphenoid wing dysplasia, tibial pseudoarthrosis)

• A first-degree relative with NF1 diagnosed using the above criteria

Additional Diagnostic Tools

• Genetic testing: Can identify NF1 mutations, especially useful in atypical or early presentations

• MRI or CT scans: To evaluate tumors in the brain, spine, or optic pathways

• Ophthalmologic examination: Slit-lamp exam for detecting Lisch nodules

• Developmental assessments: For learning disabilities and behavioral issues

Treatment

There is no cure for NF1, and treatment is primarily symptomatic and supportive. A multidisciplinary approach is often necessary, involving neurologists, dermatologists, geneticists, ophthalmologists, orthopedic specialists, and psychologists.

Management Strategies

• Regular monitoring: Annual exams to assess growth, vision, skin changes, and neurologic development

• Neurofibroma management: Surgical removal may be needed for painful, disfiguring, or rapidly growing tumors

• Plexiform neurofibromas: May be treated with MEK inhibitors (e.g., selumetinib) in some patients, especially children

• Optic gliomas: Observation or chemotherapy for progressive or symptomatic cases

• Educational support: Special education programs for learning difficulties

• Orthopedic interventions: For scoliosis or bone dysplasia

• Psychological support: Counseling and behavioral therapy for emotional or behavioral issues

Prognosis

The prognosis of NF1 varies widely. Many individuals live normal lifespans with minimal complications, while others may face significant physical and neurological challenges. Regular follow-up and proactive management of complications are key to improving outcomes.

Most cutaneous neurofibromas are benign and may cause cosmetic or psychological concerns. However, approximately 10–15% of individuals with NF1 develop malignant peripheral nerve sheath tumors (MPNSTs), which require aggressive treatment.

Early intervention, personalized care, and patient education help manage the complexity of NF1 and improve the quality of life for those affected.