Monday, June 25, 2012

What Is Neurofibromatosis? What Causes Neurofibromatosis?

Neurofibromatosis, also known as NF, is a genetically inherited disorder of the nervous system (brain and spinal cord) which mainly affects the development of nerve (neural) cell tissues, causing tumors (neurofibromas) to develop on nerves, and may cause other abnormalities. The tumors may be harmless, or may compress nerves and other tissues and cause serious damage. In some rarer cases the tumors may become cancerous.

Neurofibromatosis affects all neural crest cells (Schwann cells, melanocytes, endoneurial fibroblasts). Elements from these cells proliferate in excess throughout the whole body, resulting in the formation of tumors, and abnormal function of melanocytes, causing disordered skin pigmentation. Melanocytes are pigment-producing cells in the skin, hair and eye that determine their color. The tumors may also cause bumps under the skin, colored spots, bone problems, pressure on spinal nerve roots, as well as other neurological problems.

Neurofibromatosis may affect the bones, causing severe pain. Some patients experience learning disabilities, behavioral problems, and vision and/or hearing loss. There is no cure for the disease.

Neurofibromatosis describes two entirely different diseases, as well as a much rarer form, with different causes that have similar features:
  • Type 1 neurofibromatosis (Nf1) - or von Recklinghausen's disease, von Recklinghausen NF, or peripheral neurofibromatosis. It is transmitted on chromosome 17 and is mostly caused by mutation (rather than deletion) of the Nf1 gene.

    Shortly after birth several birthmarks (hyperpigmentation) may appear in different parts of the body. During late childhood cutaneous lesions (tumors on the skin) and subcutaneous lesions (tumors under the skin) may appear, from a few to thousands. There is a slight risk that the tumors become cancerous.

    For some patients this is presents no serious medical problems apart from a skin condition. However, complications are possible, and sometimes serious.
  • Type 2 neurofibromatosis (Nf2) - or bilateral neurofibromatosis. It results mainly from a mutation (rather than a deletion) of the Nf2 gene and is transmitted on chromosome 33.

    Tumors form in the nervous system, generally within the skull, known as intracranial tumors. Tumors also develop in the spinal canal, known as intraspinal tumors. Acoustic neuromas are common - these develop on the vestibulocochlear nerve (the eighth cranial nerve). The vestibulocochlear nerve is responsible for our sense of hearing; it is also important for our sense of balance and body position. Patients may experience hearing loss, as well as losing their sense of balance. Symptoms tend to occur during late teens and early 20s. Tumors may also become cancerous.
  • Schwannomatosis - this is a much rarer form of neurofibromatosis that has only recently been recognized. It is genetically distinct from Nf1 and Nf2. According to the National Institute of Neurological Disorders and Stroke, USA, schwannomatosis accounts for about 15% of the inherited forms of neurofibromatosis. Patients develop schwannomas (tumors in the tissue around a nerve) anywhere in the body, except for the vestibulocochlear nerve (the nerve that goes to the ear). The tumors can cause severe pain, numbness, tingling, and/or weakness in the toes and fingers. Patients do not develop the neurofibromas seen in Nf1 and Nf2.

    Researchers have identified a mutation of the SMARCB1/INI1 gene that is linked to the familial form of the disease. However, nobody yet knows what causes the severe pain which is typical in this disorder.
The rest of this article focuses on Nf1 and Nf2.

Both Nf1 and Nf2 are caused by a gene mutation, which may be inherited. Sometimes the gene mutates unexpectedly (in such cases the mutation was not inherited).

Neurofibromatosis affects males, females and individuals from all ethnic groups equally.

Neurofibromatosis is the most common genetic neurological disorder that is caused by a single gene. According to the National Health Service (NHS), UK, Nf1 affects approximately 1 in every 2,500 newborns. Although the odds seem small, Nf1 is classed as a common genetic disorder. Approximately 1 in 35,000 people in the UK have Nf2. According to the CDC (Centers for Disease Control and Prevention), USA, approximately 1 in every 4,000 Americans are diagnosed with Nf1 during childhood, and 1 in every 50,000 are diagnosed with Nf2, which is mostly diagnosed later in life.

According to Medilexicon's medical dictionary:
    Neurofibromatosis"comprises two distinct hereditary disorders, formerly labeled peripheral and central neurofibromatosis, but now entitled neurofibromatosis type I and type II. Type I (peripheral) neurofibromatosis, [MIM*162200] by far the more common of the two types, is characterized clinically by the combination of patches of hyperpigmentation and cutaneous and subcutaneous tumors. The hyperpigmented skin areas, present from birth and found anywhere on the body surface, can vary markedly in size and color: those that are dark brown are called café-au-lait spots. The multiple cutaneous and subcutaneous tumors, called neurofibromas, can develop anywhere along the peripheral nerve fibers, from the roots distally. Neurofibromas can become large, causing major disfigurement, eroding bone, and compressing various peripheral nerve structures; a small hamartoma (Lisch nodule) can be found in the iris of almost all patients. Type I neurofibromatosis, also called von Recklinghausen disease, has autosomal dominant inheritance, with the gene locus on chromosome 17q11, and is caused by mutation in the NF1 gene that encodes neurofibromin. Type II (central) neurofibromatosis [MIM*101000] has few cutaneous manifestations, and consists primarily of bilateral (less often, unilateral) acoustic neuromas, causing deafness, often accompanied by other intracranial and paraspinal neoplasms, such as meningiomas and gliomas. Type II neurofibromatosis also has autosomal dominant inheritance, but the gene locus is on 22q11, caused by mutation in the NF2 gene encoding the product merlin."

What are the signs and symptoms of neurofibromatosis?

A symptom is something the patient feels and reports, while a sign is something other people, such as the doctor detect. For example, pain may be a symptom while a rash may be a sign.

Nf1 signs and symptoms - some patients just have a skin condition and do not have any other related medical problems. Signs and symptoms generally appear during early childhood, and are not usually harmful to health. Examples include:
  • Birthmarks - known as café-au-lait spots because of their coffee color. They appear on the skin, usually at birth. Babies who have one or two such spots do not necessarily have NF. However, if more than 6 of them appear by the time the child is five years old, Nf1 should be considered (even suspected). The number of café-au-lait spots can increase, they may get bigger, and might become darker with time.
  • Freckles - an outbreak of freckles in improbable places, such as the groin, under the breasts, or in the armpits may be another sign of Nf1.
  • Neurofibromas - these are generally non-cancerous tumors that grow on the nerves of the skin. Sometimes they may develop on nerves deeper inside the body. They appear as lumps under the skin. As the child gets older there can be more of them. They may grow as the patient gets older. Neurofibromas may be soft, or firm and round.
  • Lisch nodules - very small brown spots which appear in the iris of the eye. They cause no symptoms.
Nf2 signs and symptoms - this type of neurofibromatosis has more serious symptoms. Tumors grow on nerves deep inside the body.
  • Acoustic neuroma - this type of tumor develops adjacent to the brain on a portion of the eighth cranial nerve, which goes from the brain to the inner year. Also known as vestibular schwannoma, acoustic neuroma is one of the most common types of brain tumors.

    Symptoms develop when the tumor presses on the cranial nerves; the more it grows the more likely signs and symptoms will appear. However, experts say that sometimes tumor size does not always determine effects. Signs and symptoms may include:

    • Facial numbness
    • Facial weakness and sometimes paralysis
    • Gradual hearing loss. In rare cases this may be sudden, and occurs on only one side, or is more severe on one side. In most cases hearing loss develops during the patient's teens or early twenties. One ear can be worse than the other.
    • Loss of balance
    • Tinnitus - ringing in the affected ear
    • Vertigo - dizziness
    The tumor may press on the brainstem. Uncommonly, the tumor may reach such a size that the compression on the brainstem becomes life-threatening. For some patients the acoustic neuroma (the tumor) is so small that it never causes problems.
  • Other tumors - sometimes tumors can develop on the skin, brain and spinal cord, and can cause serious problems.

    Most tumors tend to grow gradually and do not cause problem for several years. However, some develop more rapidly. It is important for patients with Nf2 to be checked regularly so that any tumor can be removed before any complications happen.
  • Café-au-lait spots - these are less common in patients with Nf2. If they do occur, there are significantly fewer of them, compared to patients with Nf1.
  • Cataracts - as they are uncommon in children, their presence makes an Nf2 diagnosis easier. Cataracts are easily removed and do not usually cause problems (if treated).

What are the causes of neurofibromatosis?

What is a gene?

Every living organism has genes. Genes are a set of instructions that decide what the organism is like, how it survives, and how it behaves in its environment. The genes lie in long strands of DNA (deoxyribonucleic acid) called chromosomes. Humans have 23 pairs of chromosomes - or a total of 46.

A faulty gene causes neurofibromatosis

Both Nf1 and Nf2 are caused by a defective gene, which may either be inherited from a parent or can sometimes suddenly change (mutate) for no apparent reason. The defective gene that causes Nf1 is found on chromosome number 17, while the faulty one that cases Nf1 is found on chromosome number 22.
  • Inherited genetic conditions - these can be passed on by a parent (or both). If one parent carries the faulty gene there is a 50% chance the condition will be passed onto an offspring.
  • Spontaneous mutation - in cases where there is no family history of Nf1 or Nf2 the doctors will conclude that the neurofibromatosis patient's gene mutated (changed) spontaneously. In most cases the mutation occurred just before the sperm fertilized the egg (conception) - in either the sperm or the egg.

How is neurofibromatosis diagnosed?

In order to reach a diagnosis a doctor needs to identify signs and symptoms linked to neurofibromatosis, as well as checking any family history of the condition.

Diagnosis of Nf1 - the birthmarks (café-au-lait marks), freckles and skin lumps are the main signs that will make the doctor suspect neurofibromatosis. If a patient has at least two of the signs and symptoms below, a diagnosis of Nf1 will be made:
  • A family history of Nf1
  • A glioma - a tumor on the optic nerve. This tumor hardly ever affects eyesight, and usually has no symptoms.
  • Abnormal development of the spine (scoliosis), the temple (sphenoid) bone of the skull, or the tibia (long shin bone)
  • At least six café-au-lait spots measuring more than 5 millimeters in diameter in children or more than 15 millimeters across in adolescents and adults.
  • At least two benign lumps under the skin (neurofibromas)
  • At least two Lisch nodules - small brown spots in the iris (colored part of the eye)
  • Freckling in the armpits, under the breast, or in the groin area
A special lamp is used to check for skin marks. The doctor may also order the following tests:
  • X-rays
  • CT (computed tomography) scan
  • MRI (magnetic resonance imaging) scan
  • A genetic test - a blood sample is taken
Diagnosis of an adult is much more straightforward than of children. It may take several years for the number of symptoms needed for an accurate diagnosis to develop.

Diagnosis of Nf2 - if a GP (general practitioner, primary care physician) suspects Nf2, the patient will be referred to a specialist, a neurologist, for more tests. An Nf2 diagnosis is made when:
  • There is an acoustic neuroma in one ear, and two or more typical symptoms, such as cataracts and brain tumors, and there is a family history of the condition (a first-degree relative, i.e. mother, father, brother, sister, or child, with NF2).
  • There are acoustic neuromas in both ears
A CT (computed tomography) or MRI (magnetic resonance imaging) scan of the brain can detect the presence of an acoustic neuroma, as well as brain or spinal tumors.

A blood sample is taken and sent to a lab to detect the faulty gene. If it is identified, diagnosis is confirmed.

If an Nf2 diagnosis is confirmed the patient will probably have hearing and eye tests to check for cataracts, other eye problems, and hearing problems.

What are the treatment options for neurofibromatosis?

Nf1 treatment - a significant number of patients with Nf1 have only mild symptoms and are able to live a normal healthy life. Even so, they will need careful monitoring so that any looming complications may be treated early on. Below are some possible symptoms and their treatments:
  • Neurofibromas - these are non-cancerous lumps on the skin. They are not generally painful. Sometimes, however, they may graze or catch on things if they are located on certain parts of the body, increasing the risk of itching, infection, numbness and general discomfort. These may be removed (there is a risk they grow back).

    If the neurofibromas are located in places where surgery is not an option, the doctor can prescribe standard painkillers, as well as more specifically-designed ones.

    Depending on the severity and characteristics of the discomfort, some patients say they have had good results with physical therapy (UK: physiotherapy), relaxation techniques, reflexology and acupuncture.
  • Hypertension - patients with Nf1 have a greater risk of suffering from high blood pressure (hypertension). Hypertension will be treated with either medication or lifestyle changes (or both). The National Health Service (NHS), UK, recommends that patients with Nf1 have an annual blood pressure check, even if they do not suffer from high blood pressure.
  • Optic gliomas - this is a tumor that grows on the optic nerve, the nerve that sends signals to the eye. If the patient's eyesight is affected the tumor can be surgically removed.
  • Scoliosis - curvature of the spine. The patient will either undergo surgery or wear a back brace.
Nf2 treatment - in most cases the tumors are monitored regularly. If any of them start causing problems, or problems are likely to occur, then treatment is required.
  • Acoustic neuromas - these are tumors that grow on the vestibulocochlear nerve (the nerve to the ear). Surgery does not always improve hearing; in fact hearing is sometimes lost or worse after the operation. Hence, recommending surgery depends not only on how badly hearing is affected, but also on the size of the tumor and how rapidly it is growing.
  • Radiotherapy - sometimes radiotherapy may be used to shrink a tumor.
  • An ABI (auditory brain stem implant) may be implanted to help hearing. Removal of vestibulocochlear nerve tumors and placement of auditory brain stem implants is often done at the same time. The surgeon makes an incision in the skin of the side of the head, and removes some of the bone behind the ear. This exposes the tumor so that it can be removed and also allows access to the brain stem beneath it. Sometimes the surgeon approaches the brain stem through the back of the head. People with auditory brain stem implants wear an external receiver and speech processor. This device converts sounds into electrical signals, which are then sent to the implant.
  • A cochlear implant may be placed after the tumor has been safely removed. This is a small, complex electronic device that can help to provide a sense of sound to a person who is profoundly deaf or severely hearing impaired. The implant consists of an external portion that is placed behind the ear and a second portion that is surgically placed under the skin. The implant has:

    • A microphone, which picks up sound.
    • A speech processor, which selects and arranges the sounds which the microphone collected.
    • A transmitter and receiver/stimulator, which receive signals from the speech processor and convert them into electric impulses.
    • A group of electrodes that collects the stimulator impulses and sends them to different parts of the auditory nerve.
    Although the implant cannot restore normal hearing, it can give a deaf person a useful representation of sounds around him/her, helping him/her to understand speech.
  • A hearing therapist can help the patient manage problems associated with tinnitus (ringing in the ears) as well as balance. In some cases the patient may be taught how to lip-read and use sign-language.

What are the possible complications of neurofibromatosis?

Nf1 possible complications
  • Eyesight and hearing - if a tumor (neuroma) presses on the nerves that lead to the ears or eyes there is a risk of vision and hearing problems. In children this can lead to learning difficulties and behavioral problems.
  • Short-term memory - patients with neurofibromatosis have a higher risk of having short-term memory problems.
  • Coordination - spatial awareness and coordination may be challenging for some patients.
  • Plexiforms - these are neurofibromas which spread around large nerves as they grow, causing the nerve to become thick and misshapen. They feel like knots or cords under the skin and can become quite large, painful and disfiguring. If plexiforms are going to occur, they will start doing so during childhood.

    Approximately one third of patients with Nf1 may also have one or more of the following complications:

    • A higher risk of epilepsy
    • A large head
    • A small percentage of Nf1 patients eventually develop malignant (cancerous) tumors
    • Benign skin tumors
    • Curvature of the spine (scoliosis)
    • Gliomas - tumors on the eye nerves. Rarely do they cause symptoms or affect eyesight.
    • Hypertension (high blood pressure)
    • Problems with speech
    • Short stature
    • Skeletal problems
Nf2 complications
  • Skin tumors - similar to the ones seen in patients with NF1. They are benign (non-cancerous). However, they should be monitored in case they get bigger, change, or cause pain.
  • Brain tumors - in most cases these are benign (non-cancerous). However, they may put pressure on parts of the brain and cause convulsions, eyesight problems and balance problems.
  • Spinal cord tumors - tumors may also develop on the nerves surrounding the spine. Patients may experience trembling, numbness and pain in their limbs. If the tumor is higher up, around the neck area there, may be facial problems; the patient may find smiling or blinking harder. Sometimes there may be problems swallowing.

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