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Neurofibromatosis is a genetic disease that produces tumors which can be found in nerves in different areas of the body.

Neurofibromatosis encompasses three related but genetically different disorders that affect the nervous system. This disorder leads to tumors located in nerves in different areas of the body. It mainly affects the skin, bones, and nervous system. The tumors are usually originated from the tissue surrounding nerves. Most of these tumors are benign, but some of them can eventually become malign.

There are three types of neurofibromatosis:

This type of neurofibromatosis is also known as von Recklinghausen’s disease, or peripheral neurofibromatosis. Neurofibromatosis type 1 (NF1) is the most common of the three types of this disease.

One of the most characteristic symptoms is the presence of coffee-coloured patches (cafe-au-lait spots) on the skin, which appear during childhood. In many affected individuals, this may be the only symptom present. These spots usually increase in number and size with age. Freckles can sometimes be observed in the groin and armpit areas as well.

Most adults usually develop benign tumors on or immediately under the skin, which are usually located in nerves close to the spine or in other areas of the body. A symptom that often develops during childhood is the presence of benign growths in the iris, known as Lisch nodules, which do not affect vision. Some individuals may develop tumors in the optic nerve (optic nerve gliomas), which can lead to total or partial loss of vision, although they sometimes do not affect vision at all. Other symptoms of this disorder are hypertension, short stature, head larger than normal (macrocephaly), skeletal abnormalities such as abnormally curved legs or abnormally curved spine (scoliosis). Children with this disorder often present with learning difficulties, such as attention deficit and hyperactivity (ADHD).

NF1 is a progressive disorder whose symptoms usually worsen with time, reaching moderate to severe degree, although a small number of patients may present with symptoms that remain unaltered. When complications derived from the disease arise, they usually do not threaten the patient’s life; in fact, individuals with this disorder have a normal life expectancy.

Although no cure for neurofibromatosis type 1 exists, some of its symptoms can be treated. Tumors can be surgically removed, although they often reappear; likewise, optic nerve gliomas can be treated with surgery and/or chemotherapy. Scoliosis and abnormally curved legs can also be treated with surgery or orthopedics.

This type is much more uncommon than NF1. One of the main symptoms are vestibular schwannomas, which are benign tumors located in the nerve that connects the brain and the ear (the eighth cranial nerve) and which usually occur around age 30. Their name is due to the fact that they are originated from Schwann cells, whose function is to protect nerve cells. These tumors sometimes press and damage the nerves around them and, depending on their location, can be highly dangerous.

Individuals with neurofibromatosis type 2 (NF2) are at a higher risk of suffering from other benign tumors in the nervous system, such as brain or spinal tumors. Patients can also suffer from tumors (schwannomas) in the skin, as well as eye disorders such as cataracts, but the presence of cafe-au-lait spots or neurofibromas is not as common. Symtpoms usually start presenting between ages 18 and 22, and the most common first symptom is often hearing loss or ear buzzing.

As in the case of NF1, there is no cure for neurofibromatosis type 2, but surgery can help manage the resulting symptoms. Early surgery when vestibular schwannomas are still small is sometimes recommended in order to remove the whole tumor and preserve hearing and balance. Radiosurgery and chemotherapy treatments are being tested for this type of tumors, but the risks of these procedures in relation to their efficiency are yet to be assessed. Surgery can also be used to correct cataracts and potential retinal abnormalities, as well as for spinal tumors, although they often do not cause any symptoms.

It is a recently recognized type of neurofibromatosis that was formerly included within NF2. It is the least common form of the disease. The main feature is the development of schwannomas in different areas of the body, excluding the vestibular nerve. When schwannomas increase in size, they cause very severe pain, which is the main symptom of this disorder; the intensity of the pain varies among individuals. Other symptoms such as numbing, tingling, or weakness in fingers and toes are sometimes present. These patients never present with neurofibromas. Approximately one third of people affected by this disorder have tumors restricted to only one area of the body. The number of tumors varies among individuals.

Surgery is again the most effective treatment. Schwannomas are usually removed to mitigate pain, although they sometimes develop again. Treatment often includes painkillers to manage pain.

Neurofibromatosis type 1 is caused by mutations in the NF1 gene, which generates a protein called neurofibromin, which acts as a tumor suppresant, protecting cells from the rapid and uncontrolled growth and division typical of tumors. In about 5% of patients, a large portion of the NF1 gene or even the whole gene is missing, while the remaining patients show only small changes. All this alters the formation of neurofibromin, which, therefore, does not properly fulfil its regulatory function, leading to the occurrence of neurofibromas that are characteristic of this disorder. The mechanism by which mutations in this gene cause other symptoms of this disease, such as cafe-au-lait spots or learning disorders, is not well known.

Neurofibromatosis type 2 is caused by mutations in the NF2 gene, which generates a protein known as schwannomin or merlin, which also acts as a tumor suppressant and which is produced in the nervous system, specifically in Schwann cells. While its exact function is not well known, it seems to be involved in controlling cell movement and shape, as well as communication among cells. An abnormal function of this protein leads to uncontrolled multiplication of Schwann cells, generating the tumors typical of this disorder.

Schwannomatosis seems to be caused by somatic mutations in the NF2 gene. Somatic mutations are acquired during an individual’s life and are only present in certain cells; this type of mutations cannot be inherited. Despite this, researchers do not believe that this type of mutations are the cause for this disease and are working on finding other genetic changes that may be involved.

Neurofibromatosis type 1 can be considered one of the most common rare diseases, affecting 1 in 3,000 people.

Neurofibromatosis type 2 affects 1 in 25,000 people.

Schwannomatosis, the least common of the three, affects approximately 1 in 40,000 newborns.

In Spain, there are around 15,000 people affected by some type of neurofibromatosis. All forms of the disease affect all ethnic groups equally, and there are no differences between men and women.

The inheritance pattern of this disease is autosomal dominant, which means that inheriting one altered copy of the gene from one of the parents is sufficient for the disease to occur. Therefore, if any of the parents is affected, there is a 50% risk of a child also suffering from the disease.

Currently, 50% of cases are due to spontaneous mutations, also known as de novo mutations, in the involved genes. Therefore, in these cases, the parents are not affected and there is no family history of the disease. In the case of schwannomatosis, the inheritance mechanism is still not well understood, but 85% of cases are known to be caused by new mutations.

AEENF –  Neurofibromatosis Patients Association

ACNefi – Catalonian Neurofibromatosis Association

NF Network – American Neurofibromatosis Organization