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Neurofibromatosis disorders, including neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis, are complex genetic conditions that can affect many different organ systems in the body. A common feature of these disorders is the tendency for benign, or noncancerous, tumors to develop, mostly on the nerves, spine, brain, and skin. However, the types and severity of symptoms vary greatly from person to person.
Neurofibromatosis type 1 is the most common form of neurofibromatosis and one of the most common genetic conditions, arising in 1 in 3,000 births. In about half of people with neurofibromatosis type 1, the disorder is inherited from a parent. In the other half, the disorder is the result of a new, or spontaneous, mutation or loss of a portion of the neurofibromatosis 1 gene.
Human cells have 23 chromosomes, which house genetic information, and the neurofibromatosis 1 gene is located on chromosome 17. The gene produces a protein called neurofibromin, which has a number of functions, including the regulation of cell growth. It is also important for brain and bone health.
The symptoms of neurofibromatosis type 1 vary greatly, even among family members who have the condition, and most people show some, but not all, of the possible signs and symptoms.
The most common signs of the condition include flat, brown spots on the skin called café-au-lait spots. These usually appear within the first year of life and are often present at birth. They may increase in number and size with age, but often fade later in life. Having one or two café-au-lait spots is common in people who don’t have neurofibromatosis type 1. However, people with the condition typically have multiple spots.
Most people with neurofibromatosis type 1 also develop distinctive freckling in the armpits and groin area. This usually starts to develop during childhood and can become more pronounced with age.
Many people with type 1 neurofibromatosis develop neurofibromas. These are slow-growing, non-cancerous tumors that develop in the protective covering of nerve cells, also call the nerve sheath. There are three main types of neurofibromas: cutaneous, subcutaneous, and plexiform.
Cutaneous neurofibromas are soft, fleshy tumors arising from a peripheral nerve sheath very near the surface of the skin, or on the skin. Peripheral nerves are nerves that are outside the brain and spine.
Cutaneous neurofibromas often appear in late childhood or young adulthood. Many tumors may form on the skin and can cause itching or discomfort. These tumors generally do not become cancerous.
Subcutaneous neurofibromas are firm, tender tumors that occur along the peripheral nerves beneath the skin. They tend to appear during adolescence or young adulthood.
Plexiform neurofibromas are the most complex type of neurofibroma and can grow within long portions of one nerve or bundles of nerves. They may be deep inside the body and identified only with medical imaging scans—for example, an MRI scan—or they can be near the skin surface and on the arms, legs, head, and neck.
When they occur, they are usually present at birth, although they may not be easily seen or detected at first. They most commonly appear as a soft mass under the skin. Sometimes the skin overlying the neurofibroma is darker than the surrounding skin or is thickened.
These tumors usually grow slowly and may become cancerous in up to 10 percent of people with neurofibromatosis type 1 during their lifetime. Worrisome signs and symptoms include rapid growth and increasing pain or problems with the ability to perform physical functions.
Optic pathway gliomas are tumors that develop in the nerves leading from the eyes to the brain. They occur in up to 15 percent of children with neurofibromatosis type 1 and are typically slow growing. Only about one-third of optic gliomas cause symptoms, such as vision loss or a bulging eye.
Tumors that grow and cause symptoms usually do so during the first 10 years of life, so yearly visits to an ophthalmologist are important in younger children with neurofibromatosis type 1.
Lisch nodules can also develop in people with neurofibromatosis type 1. These are small bumps on the iris, the colored portion of the eye. These nodules do not adversely affect eyesight.
Some people with neurofibromatosis type 1 develop bone abnormalities. A number of bone problems are possible with this condition.
For example, pseudarthrosis, meaning a false joint, can occur when a bone breaks and doesn't heal properly, or when bowing—an abnormal curvature of a bone—becomes so extreme that it causes a severe angle of the bone. This happens most often in the weight-bearing bones, especially the tibia, the main bone of the lower leg.
Pseudarthrosis occurs in up to 5 percent of people with neurofibromatosis type 1. Half of all people with pseudarthrosis are affected before age two. The treatment can be complicated and requires the care of an orthopaedist.
Sphenoid wing dysplasia is a malformation of one of the bones behind the eye and sometimes results in the eye becoming displaced. This condition is usually present at birth.
About 80 percent of people with neurofibromatosis type 1 are shorter than their relatives or peers. One possible reason is scoliosis, or curvature of the spine. Scoliosis occurs in up to half of people with neurofibromatosis type 1. It most commonly begins just before or during puberty. If the curvature is mild, no treatment is necessary; however, in some people bracing or surgery becomes necessary.
People with neurofibromatosis type 1 may also have a condition called vertebral dysplasia, in which the bones of the spine are incorrectly shaped.
Adults and children with neurofibromatosis type 1 are at a small increased risk for the development of hypertension, or high blood pressure.
Hypertension in adults with neurofibromatosis type 1 may result from a growth on one of the adrenal glands called a pheochromocytoma. The adrenal glands are two small organs in the lower back on top of the kidneys. They provide the body with a number of important hormones.
A pheochromocytoma on the adrenal gland can cause elevated levels of stress hormones in the body, leading to very high blood pressure, increased heart rate, palpitations, and flushing.
Hypertension in children with neurofibromatosis type 1 is more likely the result of a narrowing of the blood vessels to the kidneys, called renal artery stenosis. In some people, the hypertension may have no identifiable cause. People who have neurofibromatosis should have their blood pressure checked at least two or three times every year, and additional testing may be necessary if their blood pressure is persistently high.
Learning problems are more common in people with neurofibromatosis type 1 than in the general population. One-half to two-thirds of people with neurofibromatosis type 1 have learning disorders.
Intelligence is typically normal, although scores on IQ (intelligence quotient) tests tend to be 5 to 10 points lower than in the general population or in siblings without the condition. Attention deficit hyperactivity disorder is also more common in people who have neurofibromatosis type 1.
Neurofibromatosis type 2 is much less common than type 1, occurring in about 1 in 40,000 births. People with neurofibromatosis type 2 may develop symptoms in their late teens or early 20s; however, some people may not develop any problems until they are in their 40s or older.
Only a minority of people with neurofibromatosis type 2 have café-au-lait spots or skin tumors resembling those seen in type 1. Instead, people with type 2 develop tumors on the eighth cranial nerve, which transmits hearing and balance signals from the ears to the brain and is located on both sides of the head.
These eighth cranial nerve tumors, also called vestibular schwannomas or acoustic neuromas, can cause ringing in the ears, problems with balance, and progressive hearing loss. Tumors can grow large enough to cause headaches and press on nearby nerves, causing problems with facial weakness.
In neurofibromatosis type 2, tumors also frequently occur on nerves other than the eighth cranial nerve. Tumors on other cranial nerves—the nerves that emerge from the brain stem itself—can cause swallowing problems, facial weakness or drooping, double vision, or facial numbness. These tumors can also be located on nerves throughout the body, and are called schwannomas because they develop from Schwann cells, which protect the nerve cells.
Meningiomas, or tumors arising from the linings of the brain and spinal cord, and ependymomas, which can develop within the spinal cord, are also associated with neurofibromatosis type 2.
Meningiomas, schwannomas, and ependymomas can cause a variety of symptoms, depending on their location in the body. Tumors that occur in the brain may cause headache, weakness on one side of the body, seizures, vision changes, memory loss, or problems with balance and walking. Those that grow near or on the spinal cord may cause weakness or numbness in the arms and legs. Schwannomas can also develop under the skin, causing lumps with or without pain and discomfort.
A rare form of cataract, or clouding of the lens in the eye, called a subcapsular lenticular opacity, can also form in people with neurofibromatosis type 2. For this reason, all people with type 2 should have regular appointments with an ophthalmologist.
Schwannomatosis is a rare form of neurofibromatosis that was first recognized in the 1990s. It may affect as many as 1 in 40,000 people. Similar to people with neurofibromatosis type 2, people with schwannomatosis develop multiple schwannomas, which are tumors consisting of Schwann cells, on cranial, spinal, and peripheral nerves. Symptoms most commonly arise during adulthood.
People who have schwannomatosis do not develop vestibular schwannomas, nor do they typically develop other types of tumors associated with neurofibromatosis type 1 or neurofibromatosis type 2, such as meningiomas, ependymomas, or neurofibromas.
Pain is common in people who have schwannomatosis and for some may be their only symptom.
Schwannomatosis is a genetic condition, meaning it is has been associated with changes in the genes INI1 (also known as SMARCB1) and LZTR1 in a minority of people. It does not have a clear pattern of inheritance and most commonly develops without a family history of the condition.
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