Neurofibromatosis type 1 (NF1)

ALSO KNOWN AS: Von Recklinghausen’s neurofibromatosis, Von Recklinghausen disease, peripheral neurofibromatosis,

RELATED CONDITIONS: Neurofibromas, iris Lisch nodules, optic gliomas, café-au-lait spots, freckling, learning disabilities, bone complications such as scoliosis or bone overgrowth, osteoporosis

DEFINITION: Neurofibromatosis type 1 (NF1) is a hereditary disorder of the nervous system that affects the growth and development of nerve cell tissues. This disorder is associated with neurofibromas (bumplike tumors under the skin or elsewhere in the body that develop anywhere along a nerve), café-au-lait spots (flat spots on the skin that are darker than the surrounding area), freckling in places not exposed to the sun (such as the armpit and groin), eye developments such as optic glioma (a tumor growing on the nerve to the eye) and Lisch nodules (harmless growths on the colored part of the eye), and bone problems such as scoliosis (curvature of the spine) or bone overgrowth. Up to 10 percent of affected individuals have peripheral nerve sheath tumors (tumors that form along the protective covering around nerves located outside the brain and spinal cord), the most common malignant tumors associated with NF1. Although rare, malignant peripheral nerve sheath tumors do occur. Fewer than 1 percent of people with NF1 have pheochromocytomas (adrenal gland tumors that release stress hormones) that cause dangerously high blood pressure. Approximately half of individuals with NF1 have a learning disability, although it is usually mild. The severity of the disorder varies within families, between families, and even within an individual at different times during life.

Risk factors: Because NF1 is hereditary, the main is having a family history of this disorder. Each child of a person with NF1 has a 50 percent chance of inheriting the disorder. However, NF1 can develop spontaneously in individuals with no family history of the condition.

Etiology and the disease process: The underlying genetic cause of NF1 is a mutation, or a genetic change, in the NF1 gene. The purpose of the protein made by the NF1 gene is not fully understood, but it most likely helps stop uncontrolled cell growth and proliferation. Mutations in the NF1 gene either prevent the protein from being made or cause the protein to be made incorrectly, and the multistep process of tumorigenesis (formation or production of tumors) is left unchecked.

Usually, each person has two normal copies of the NF1 gene. A mutation in one copy of the gene is sufficient to cause NF1, which is why this condition is referred to as autosomal dominant (autosomal means the NF1 gene is located on one of the twenty-two pairs of autosomes, which are the nonsex chromosomes). An affected person has an NF1 gene mutation from conception, but symptoms of the disease may be present at birth or not manifest until later in life. Nearly all individuals with NF1 have signs and symptoms of the disorder by the end of childhood. The average life expectancy of affected individuals is reduced by about fifteen years.

Incidence: Approximately 1 in 3,000 people has NF1, which makes it one of the most common dominantly inherited genetic disorders. Nearly half of people with NF1 inherit the disorder. The other 50 percent have a new gene mutation, meaning the mutation occurred for the first time in those individuals.

Symptoms: Symptoms vary and are usually mild to moderate and not life-threatening. Most symptoms appear in infancy through age ten, but the disease is progressive. Adults with NF1 may have only a few neurofibromas, but some have hundreds or even thousands. These tumors continue to develop throughout life and can affect any organ in the body. Neurofibromas can cause pain and disfigurement and, more rarely, cause problems with organ function. Malignant peripheral nerve sheath tumors can cause pain, numbness, or paralysis. Optic gliomas can lead to blindness. Visual-spatial performance and attention deficits are the most common learning disabilities observed in individuals with NF1.

Screening and diagnosis: Doctors diagnose NF1 based on certain criteria, which include having two or more of the following: six or more café-au-lait spots, two or more neurofibromas or one plexiform neurofibroma (weblike neurofibroma that entwines surrounding tissues), freckling in the armpit or groin, optic glioma, two or more Lisch nodules, an unusual bone complication, or a first-degree relative (parent, sibling, or child) with NF1.

Genetic testing can confirm a suspected diagnosis because mutations in the NF1 gene cause NF1. However, diagnostic genetic testing is rarely needed because doctors can easily diagnose the disease based on clinical findings. Genetic testing detects more than 95 percent of NF1 gene mutations in individuals clinically diagnosed by a physician.

Treatment and therapy: The main focus of treatment for NF1 is controlling symptoms. Surgery can be performed to treat bone malformations or to remove tumors that cause pain or disfigurement. In the case of malignancy, the tumor is surgically removed if possible, and the patient may also have adjuvant and radiotherapy.

Prognosis, prevention, and outcomes: The way neurofibromatosis affects a person over a lifetime varies widely. Because NF1 is a genetic condition, its manifestations cannot be prevented. However, physicians recommend that individuals with NF1 have monitoring that includes a yearly physical examination, a yearly ophthalmologic examination (eye exam) for children (less frequently for adults), regular blood pressure checks, and regular assessment of development for children.

Bibliography

Barke, Jenny, Diana Harcourt, and Jane Coad. "'It's Like a Bag of Pick and Mix—You Don't Know What You Are Going to Get': Young People's Experience of Neurofibromatosis Type 1." Journal of Advanced Nursing , vol. 70, no. 7, 2014, pp. 1594–603. doi:10.1111/jan.12319.

Yap, Yoon-Sim, et al. “The NF1 Gene Revisited - From Bench to Bedside.” Oncotarget , vol. 5, no. 15, 2014, pp. 5873-92. doi:10.18632/oncotarget.2194.

Friedman, Jan M. "Neurofibromatosis 1." National Library of Medicine, 2022, www.ncbi.nlm.nih.gov/books/NBK1109. Accessed 20 June 2024.

Korf, Bruce R., and Allan E. Rubenstein. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. Thieme Medical, 2005.

"Neurofibromatosis." MedlinePlus, medlineplus.gov/neurofibromatosis.html. Accessed 20 June 2024.

"Neurofibromatosis, Type 1." National Library of Medicine, www.ncbi.nlm.nih.gov/medgen/18013. Accessed 20 June 2024.

"Neurofibromatosis Type 1." MedlinePlus, 1 July 2020, medlineplus.gov/genetics/condition/neurofibromatosis-type-1. Accessed 20 June 2024.