Neurofibromatosis
Overview
Neurofibromatosis (NF) is a genetic neurological disorder that affects cell growth in nerve tissue. NF produces tumors of the skin, internal organs, and nerves that may become cancerous (malignant). It also can affect bones, causing severe pain and debilitation and may result in learning disabilities, behavioral dysfunction, and hearing and vision loss. There is no cure for neurofibromatosis.
Types
Neurofibromatosis can be inherited as an autosomal dominant trait (a parent with the disorder has a 50% chance of passing it to an offspring) or can result from a spontaneous genetic mutation.
Type 1 neurofibromatosis, also called von Recklinghausen NF, is transmitted on chromosome 17 and is caused by mutation (or rarely, deletion) of the NF1 gene. This type causes multiple areas of hyperpigmentation (i.e., birthmarks) that appear shortly after birth. In late childhood, a few to thousands of tumors appear on the skin (called cutaneous lesions) and under the skin (called subcutaneous lesions). These tumors may become cancerous.
Type 2 neurofibromatosis results from mutation (or rarely, deletion) of the NF2 gene and is transmitted on chromosome 22. In this type, tumors form in the nervous system, usually within the skull (intracranial tumors) and spinal canal (intraspinal tumors). Tumors on the eighth cranial nerve (vestibulocochlear nerve), which are sometimes referred to as acoustic neuromas, are most common. This type causes hearing loss and loss of sense of balance (equilibrium), usually during the late teens or early 20s. These tumors may become cancerous.
Schwannomatosis is a rare form of NF in which multiple benign tumors (schwannomas) form in peripheral nerve fiber cells (called Schwann cells). Schwannomatosis does not cause neurological disabilities or malignant tumors. The hallmark of this condition is chronic pain, which can occur in any part of the body, depending on which peripheral nerves are affected.
Incidence and Prevalence
Neurofibromatosis is the most common genetic neurological disorder that is caused by a single gene. It affects more than 100,000 people in the United States. Type 1 NF affects 1 in 4000 people and is usually diagnosed during childhood. Type 2 affects 1 in 50,000 and is usually diagnosed in early adulthood. Schwannomatosis is rare.
NF occurs throughout the world and affects men and women of all races and ethnic groups.
Risk Factors and Causes
Neurofibromatosis is an inherited disease caused by one of two genetic processes. In 50% of cases, a parent passes the defective NF gene (i.e., NF1 or NF2) to an offspring, resulting in autosomal dominant transmission. The NF1 and NF2 genes have tumor suppressor function. Rarely, neurofibromatosis is caused by deletion of the NF1 or NF2 gene.
In the other 50% of cases, a spontaneous genetic mutation occurs with no known cause, no hereditary link, and no family history of the disease.
Other disorders (e.g., epilepsy, scoliosis) have been linked to NF.
Signs and Symptoms
Type 1 NF
Early symptoms of Type 1 neurofibromatosis include multiple skin lesions (called cafe au lait spots) that appear during infancy. These lesions can occur anywhere on the body and become more numerous during childhood. Cafe au lait spots also occur in healthy infants and about 10% of the general population has one or two.
During adolescence, benign tumors may develop on the skin (cutaneous), under the skin (subcutaneous), and in connective nerve tissue (neurofibromas). These tumors may be painful and in about 2-5% of cases, they become malignant. Some cutaneous lesions can be pressed into the skin manually (called buttonholing).
Other symptoms of Type 1 NF include the following:
- Curvature of the spine (scoliosis)
- Dizziness
- Enlargement and deformity of the bones (may cause chronic pain)
- Hearing loss
- Learning disabilities
- Tumors of the optic nerve, or optic gliomas (may cause blurry vision, vision loss, and Lisch nodules on the iris)
Type 2 NF
In Type 2 neurofibromatosis, tumors frequently develop on the eighth cranial nerve (called the vestibulocochlear nerve), causing symptoms such as dizziness, ringing in the ears (tinnitus), loss of balance, and significant hearing loss. Symptoms of this type usually develop during adolescence or early adulthood. Skin lesions do not always appear in Type 2 NF.
Schwannomatosis
The hallmark of this condition is severe chronic pain, which can occur in any part of the body. In about 33% of patients with schwannomatosis, only one part of the body (e.g., one arm, one leg) is affected.
Diagnosis
Family history, physical examination for clinical signs of the disease (e.g., multiple cutaneous and subcutaneous lesions), and magnetic resonance imaging (MRI) are used to diagnose neurofibromatosis. Diagnosis can be confirmed through genetic testing.
Physical Examination
Six or more flat areas of hyperpigmentation on the skin (cafe au lait spots) are the most common clinical sign of NF. These spots usually appear by 2 years of age and increase in number over time. They are tan in light-skinned people, darker than surrounding skin in dark-skinned people, and they usually darken with age.
Small hyperpigmented spots that are difficult to distinguish from freckles may appear on the skin. Freckling usually occurs in areas of skin exposed to sun, but NF may cause freckling in other areas, including the armpit (axilla) and the groin.
Cutaneous tumors caused by NF often can be pressed into the skin manually, leaving a vacant space under the skin that may remain for some time (called buttonholing). Buttonholing distinguishes NF tumors from benign fatty tumors unrelated to NF (lipomas).
An eye specialist (ophthalmologist) may examine the eyes with a slit-lamp microscope to detect benign lesions on the iris (Lisch nodules), which may be caused by optic gliomas.
Magnetic resonance imaging (MRI scan) of the brain and spine may be used to detect tumors caused by neurofibromatosis (e.g., optic gliomas, vestibulocochlear nerve tumors, tumors of the spinal canal) and schwannomas. If multiple schwannomas are detected, high quality MRI of the base of the brain is performed to rule out Type 2 NF and diagnose schwannomatosis.
Tumors of the vestibulocochlear nerve that are detected by MRI may be evaluated using audiometry tests. These tests evaluate hearing and help to determine nerve function and detect tumor changes (e.g., growth).
Genetic Testing
Genetic testing (e.g., gene linkage, mutation analysis) detects neurofibromatosis in about 90% of cases. These blood tests can be used to confirm diagnosis by identifying genetic abnormalities, to provide early detection for people with a family history of the disease who do not have symptoms, and to determine the risk for passing the disease to offspring.
Treatment
There is no cure for neurofibromatosis and the goal of treatment is to relieve symptoms. Painful cutaneous and subcutaneous tumors and those that occur on visible areas of the body may be removed surgically. Surgery also may be performed to remove schwannomas and nerve tissue tumors (neurofibromas) that cause pain, sensory loss, and loss of function.
In Type 2 neurofibromatosis, surgery using magnification and very small instruments (microsurgery) may be performed to remove tumors of the vestibulocochlear nerve.
When surgery cannot be performed without risking damage to nerve function, high energy x-rays (radiation) may be used to shrink tumors.
Neurofibromatosis often results in psychological and social issues for patients and their families. Counseling and support groups may help patients cope with the disease.
Prognosis
Prognosis for patients with neurofibromatosis depends on the type. Type 1 NF may reduce life expectancy by up to 15 years, usually due to malignant tumors. Early diagnosis and treatment (e.g., surgery, radiation) may reduce mortality rates.
Prognosis for patients with Type 2 NF depends on age of onset and the number and location of tumors. Prompt diagnosis and treatment (surgery) may improve life expectancy to more than 15 years following diagnosis.
Prevention
Neurofibromatosis cannot be prevented. People with a family history of the disease may choose to undergo genetic testing and counseling to determine if they are at risk for transmitting NF to their offspring.