Neurofibromatosis type 1

Neurofibromatosis type 1 (NF-1) is a genetic disorder that leads to tumors forming along the nerves.

NF-1 is caused by pathogenic variants in the NF1 gene, which result in cells making less of a tumor suppressor protein called neurofibromin. Normally, neurofibromin regulates the Ras/MAPK signaling pathway, which controls cell growth and survival throughout the body. The loss of neurofibromin increases the activity of this signaling pathway.

UCSF is the only hospital in California recognized by the Children’s Tumor Foundation as both an NF-1 and schwannomatosis comprehensive center. Our pediatric and adult clinics work closely together to provide lifelong specialized care for patients with NF-1. Our multidisciplinary team includes experts across neuro-oncology, neurosurgery, radiation oncology, medical genetics, neuropathology, and otolaryngology.

What are the symptoms of NF-1?

Since the NF1 gene is present in all types of cells, NF-1 can affect various organ systems.

A physician can diagnose an individual with NF1 if they present with at least two of the following symptoms¹:

Six or more café-au-lait macules (flat brown spots on the skin)
Two or more neurofibromas
Freckling in the armpit or groin
An optic pathway glioma
Two or more Lisch nodules (small tan bumps on the surface of the iris in the eye) or two or more choroidal abnormalities (patchy spots in the vascular layer of the eye that are identified with near-infrared reflectance imaging²)
A distinctive bony lesion like sphenoid dysplasia (abnormal growth of the bone behind the eye near the base of the skull), anterolateral bowing of the tibia (shin bone), or long bone pseudoarthrosis (improper healing of the bones in the leg)
A pathogenic NF1 variant

The child of parent who has NF-1 can be diagnosed with the condition if they present with at least one of these symptoms.

Other symptoms of the condition can include:

Other bone abnormalities like scoliosis and osteoporosis
Cognitive differences and learning disabilities
Seizures
Soft tissue sarcomas like malignant nerve sheath tumors (MPNSTs) and gastrointestinal stromal tumors
Short stature
Macrocephaly (larger head size)
Hypertension
Peripheral vascular disease

How common is NF-1?

NF-1 is among the most common cancer predisposition syndromes and is estimated to occur in approximately 1 in 3,000 people^3,4. The pathogenic variants that cause NF-1 can arise spontaneously, but about half of people living with NF-1 inherited the condition from one of their parents². NF-1 is an autosomal dominant disorder³. This means if a child inherits a pathogenic variant of the NF1 gene (located on chromosome 17) from one parent, they will be affected by the disorder.

What are the treatment options for NF-1?

Unfortunately, there is no cure for NF-1. Since NF-1 is presents differently in each individual, the condition does not have a one-size-fits-all treatment.

Patients with NF1 have a higher risk of developing central and peripheral nervous system tumors, including neurofibromas and gliomas. Depending on the type, location, and size, some tumors can simply be monitored for additional growth or surgically removed. Chemotherapy or radiation therapy may also be suggested.

Plexiform neurofibromas are sometimes inoperable because they are not able to be separated from the functioning portion of the nerve. In these cases, targeted drug therapy with the MEK inhibitors selumetinib or mirdametinib may be a treatment option.

Neurocognitive rehabilitation is also available through our Neurocognitive Care Services. Our multidisciplinary team will assess each patient's needs, and devise an individualized plan to improve language, motor, or cognitive impairments caused by NF-1 related tumors.

What are the outcomes for patients with NF-1?

The symptoms of NF-1 and their severity differ from person to person, depending on the specific NF1 gene variants as well as additional genetic modifier variants they carry. For example, NF-1 microdeletions (in which the entire NF1 gene is absent) can result in a more severe presentation of the condition⁵.

NF-1 is a lifelong condition usually diagnosed in children that requires annual monitoring to manage the various cognitive, skeletal, and cardiovascular symptoms a patient may experience over the course of their life as well as the increased risk of developing cancer. Café-au-lait macules, abnormalities in bone growth, and plexiform neurofibromas typically occur in infancy. Low-grade tumors like optic pathway gliomas and brainstem gliomas can occur in early childhood. People with NF-1 can develop more aggressive malignancies like MPNSTs, breast cancer, or high-grade gliomas (including glioblastoma) as adults.

In general, individuals with NF-1 have shorter lifespans than people without this condition⁶, but the prognoses and survival rates vary greatly depending on what type of tumor an individual may develop.

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