Neurofibromatosis Type 1 (NF1)

What causes NF1

The NF1 gene makes neurofibromin, a protein that keeps cell growth in check by turning off the RAS signaling pathway. A change in one copy of the gene leads to uncontrolled growth when the other copy is damaged in a cell. NF1 is autosomal dominant: a parent with NF1 has a 50% chance of passing it to each child. About half of cases come from a new gene change with no family history.

Signs and symptoms

Skin

• Café-au-lait macules: flat, light-brown patches, often present at birth or appearing in the first years. Six or more is a key sign. See café-au-lait macules
• Freckling in the armpits or groin, usually by age 3 to 5
• Cutaneous neurofibromas: soft, flesh-colored bumps on or under the skin, typically appearing in the teens and increasing in adulthood, sometimes in large numbers
• Plexiform neurofibromas: larger, deeper tumors along nerves, present in about 30 to 50% of people, which can cause disfigurement, pain or loss of function. See plexiform neurofibroma

Eyes

• Lisch nodules: harmless pigmented spots on the iris
• Optic pathway gliomas: in about 15% of children, usually under 7. Most cause no symptoms, but some affect vision or trigger early puberty

Bones

• scoliosis
• bowing of the lower leg (tibial dysplasia), which can lead to fracture and a false joint
• short stature and a larger head size
• low bone density

Learning and development

• learning disabilities in about half of children
• ADHD in up to about 40%
• autism spectrum features in some
• delayed motor and speech skills

Other

• high blood pressure, from renal artery stenosis or pheochromocytoma
• headaches and seizures
• blood vessel problems (vasculopathy)

Cancer risk

People with NF1 have a higher risk of:

• Malignant peripheral nerve sheath tumor (MPNST): lifetime risk around 8 to 15%, often arising in a plexiform neurofibroma
• breast cancer in women under 50
• gliomas, gastrointestinal stromal tumors, pheochromocytoma and juvenile myelomonocytic leukemia

Diagnosis

The revised 2021 international criteria diagnose NF1 when a person without a parent with NF1 has two or more of:

• 6 or more café-au-lait macules over 5 mm before puberty, or over 15 mm after puberty
• freckling in the armpit or groin
• 2 or more neurofibromas of any type, or 1 plexiform neurofibroma
• optic pathway glioma
• 2 or more Lisch nodules, or 2 or more choroidal abnormalities
• a characteristic bone lesion
• a pathogenic NF1 gene variant

A child of a parent with NF1 needs only one feature. Genetic testing confirms the diagnosis and helps distinguish NF1 from Legius syndrome, which also causes café-au-lait spots.

Treatment and monitoring

There is no cure, but care is coordinated by NF specialists:

• Annual checkups: skin, growth, development, spine, blood pressure
• Yearly eye exams in children up to about age 8, then regularly
• Developmental and school assessments, with educational support
• MRI scans when symptoms suggest a tumor
• Selumetinib and mirdametinib, MEK inhibitor tablets, can shrink inoperable symptomatic plexiform neurofibromas
• Surgery to remove painful or disfiguring neurofibromas, and laser or electrodesiccation for small skin neurofibromas
• Chemotherapy for optic gliomas that threaten vision
• Breast screening with yearly mammograms from age 30, and breast MRI from 30 to 50 per NCCN guidance
• Genetic counseling for family planning

Outlook

Most people with NF1 lead full lives. Life expectancy is somewhat reduced on average, mainly because of malignant tumors and vascular problems, which is why monitoring and prompt evaluation of new symptoms matter.

Frequently asked questions

What are the first signs of NF1?

The first sign is usually multiple café-au-lait spots, flat light-brown patches on the skin, often present at birth or appearing in the first year or two. Freckling in the armpits or groin often follows by age 3 to 5. Neurofibromas usually appear later, around puberty.

Is neurofibromatosis type 1 inherited?

It can be. NF1 is autosomal dominant, so each child of an affected parent has a 50% chance of inheriting it. However, about half of people with NF1 have a new gene change and no family history.

Are neurofibromas cancerous?

Most neurofibromas are benign. Plexiform neurofibromas can, rarely, turn into malignant peripheral nerve sheath tumors. Warning signs include rapid growth, hardening, persistent pain or new nerve problems, which need urgent assessment.

How is NF1 treated?

Care focuses on regular monitoring and treating complications as they arise. Surgery can remove troublesome neurofibromas, MEK inhibitors such as selumetinib can shrink inoperable plexiform neurofibromas, and children receive support for learning and attention difficulties.

How many café-au-lait spots are normal?

Having 1 to 3 café-au-lait spots is common in healthy people. Six or more spots larger than 5 mm in a child, or 15 mm after puberty, raise the possibility of NF1 and should be evaluated by a doctor.