What is NF2

Neurofibromatosis type II (NF2)

Neurofibromatosis type II (NF2), or Merlin, is a rare genetic tumor predisposition condition. NF2 is best known for the growth of multiple benign (noncancerous), intracranial tumors, and central nervous system tumors, with the risk of tumor growth in other areas of the body. Not all health issues from NF2 are the result of tumors. ^[1,2]

Regular MRI review of tumors is necessary. Pattern of either tumor growth, stability-no growth can last years and change to dangerous increased rates of tumor growth, with the individual not experiencing noticeable symptoms.^[4]

Due to tumor locations individuals with NF2 die from tumor damage each year.

Not all tumors will require treatment beyond scans to monitor change over time.

There is no cure for NF2 and treatment options are limited.

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1. Introduction

Neurofibromatosis type II (NF2), or Merlin, is a condition that affects an individual with tumors throughout their life. NF2 is sometimes also known as;

• MISME Syndrome. (Multiple Inherited Schwannoma, Meningioma, and Ependymoma)
• MERLIN Syndrome. derived from the Moesin-Ezrin-Radixin-Like Protein, (Schwannomin, is the missing or nonfunctional protein that causes NF2 tumor growth.
• Bilateral Acoustic Neurofibromatosis. (BAN)
• Central Van Recklinghausen.

Neurofibromatosis type II (NF2) is a rare genetic autosomal dominant, neurological, and neurodegenerative, tumor predisposition condition which results in slow-growing typically benign (noncancerous) tumors, primarily located in the central nerve system (CNS); brain and spinal cord. NF2 typically can cause numerous issues during an individual's lifetime. However, not all issues are tumor related. Tumors can occur in other parts of the body, not just the CNS, but can also include tumors along the peripheral nervous system (PNS), nerves. PNS tumors can include tumors seen as firm bumps under the skin. NF2 tumors can result in different forms of nerve, brain, and body damage.

NF2 is a neurological disorder that results in tumor growth as well as eye issues unique to NF2; some are unrelated to tumor nerve damage, such as juvenile cataracts.

There is no cure for NF2. A cure for NF2 would need to be a treatment that:

1. permanently stops tumor growth
2. prevent additional tumors
3. destroy all of what might be potentially hundreds of tumors an individual may have
4. manage tumors without dangerous side effects

Treatment options available today can only treat one tumor at a time. Surgery to completely remove a tumor, for individual tumor management is the only way to guarantee a tumor will do no additional damage.

While NF2 is a genetic disorder, fifty percent (50%) of people born with NF2 is the result of spontaneous mutation, no family with NF2. Since NF2 is rare, it makes it difficult for early intervention of issues. Delays of problematic tumors can result in serious consequences.

Tumor growth rate at different points in the life of an individual will vary; the reasons may include; exact NF2 mutation, hormones, and life/environment factors. Each tumor in an individual will also grow at different rates.

2. Health Issues

Many NF2 health issues are the result of tumor growth and the treatments to manage growth, the exception to this are some of the eye issues that can develop.

Typical Issues

1. Tumor Development/Growth: Tumors Types and Change

NF2 tumor types can include; schwannoma, meningioma, and ependymoma The number of tumors can vary but may result in only two (2) but may result in hundreds of tumors; minimum of two (2) of bilateral hearing related tumors.

People with NF2 do not always face the same medical issues, even in the same family.

2. Vestibular Schwannoma (VS)/(Acoustic Neuroma (AN)

The most common tumors seen in NF2 are the hallmark bilateral (left/right) vestibular schwannoma (VS)/acoustic neuroma (AN) ; these are tumors that grow on the 8th cranial nerve in the brain, typically along the vestibular nerve branch which is the balance nerve. This tumor growth typically also damage the cochlear nerve the nerve branch for hearing.

The growth of VS tumors is sometimes the only tumors an individual with NF2 might develop. If treated properly, hearing loss and balance issues. Treatment to soon might risk requirement of multiple treatments to the same tumor mass years later; the second treatment can have a higher risk of additional complications.

But when tumors grow over a few centimeters, and the individual would be at risk of additional complications noted further below are more likely to occur.

1. Cochlear Nerve and Hearing Loss
2. Vestibular Nerve and Poor Balance (Disequilibrium)

3. Tinnitus

Tinnitus is a phantom sound people start to hear when hearing loss develops. Once it starts, it does not go completely away, but things can be done to make it manageable or even make it worse. NF2 tinnitus is either subjective tinnitus or somatosensory tinnitus (gaze-evoked tinnitus.)

4. Headaches

There are different types of headaches. There are also different types of migraines. As a result of the brain tumors, individuals with NF2 are likely to have occurrences of headaches and migraines. Common migraine individuals with NF2 may have include vestibular migraines, and ocular migraines (retinal migraines). Migraine types indicate different brain tumor issues and when it may be time to discuss tumor treatment options.

5. Eye Problems: Vision Issues

Since NF2 is a neurodegenerative condition, everyone with NF2 should see a neuro-ophthalmologist to check for optic neurological issues.

A neuro-ophthalmologist is a doctor trained in two (2) branches of medicine, neurology and ophthalmology. This class of doctor specialize in different conditions that affecting vision that originate from the nervous system. It is not that an ophthalmologist would not be familiar enough with some of the neurological issues that are a result of NF, but tests that need to be done and reviewed require seeing a Neuro-Ophthalmologist, including but not limited to the review of actual MRI scans.

NF2 can result in a variety of eye issues which can result in either poor vision or blindness.

Common Issues

Note: Before reading further, it is possible issues mentioned after this point may not occur or are less likely to occur.

6. CN7: Facial Nerve Damage

Vestibular schwannoma, are schwannoma tumors along cranial nerve 8 (CN8) and are an issue that develops in many individuals with NF2. Cranial Nerve 8 travels a similar path as Cranial Nerve 7, the Facial Nerve, extending out of the brainstem right next to each other. The purpose of CN8 is hearing and balance. Individuals who develop vestibular schwannoma commonly develop damage to the facial nerve; also known as facial nerve damage, or facial paralysis. Facial nerve damage problems with; 1) inability to close eyelid, 2) tear duct and tear production issue (no tears or excess), 3) closing mouth lips for eating, 4) speech (letter pronunciation), 5) sinus, 6) appearance, 7) lack of saliva production (dry mouth), and 8) tooth decay.

Individuals with any form of face weakness should also review Trigeminal Neuralgia, as issues are similar but associated with Cranial Nerve 5.

7. Anemia: Poor Immune System Poor Immune System

There are many different reasons a person with cancer might have anemia. Some common causes are: 1) The tumor condition itself. 2) Tumor treatment, such as radiation, chemotherapy, or surgery. 3) Blood loss (this can be slow constant bleeding such as from the intestine or bladder; or fast bleeding, like heavy menstruation or bleeding from a stomach ulcer). 4) Missing certain vitamins or minerals in the diet.

Some Symptoms Include: 1) dizziness, 2) extreme tiredness (fatigue), 3) swelling in the hands or feet, 4) pale skin on extremities (hands or feet), 5) yellow eyes, 6) trouble breathing when doing things like; walking, climbing stairs, or even talking.

8. Vitamin B12 deficiency - Vitamin Deficiency and Nerve Healing

Many NF2 Issues will require physical therapy. Some issues like walking after balance issues from vestibular schwannoma damage require proper guidance by a therapist.

9. Permanent Side Effects from Extreme Fatigue

Some issues a person with NF2 has can be from attempts to manage NF2 issues. Surgery, radiation/radiosurgery, tumor-drug treatment, and scan contrast can have side effects, but long-term use of prescription medication and over-the-counter (OTC) medication can also have long-term risks.

An often overlooked problem was the risk potential of supplements for alternative treatments when the treatment was not in an NF2-based study long enough to learn side effects, particularly when taken at higher doses than commonly used.

The Food and Drug Administration (FDA), does not monitor if supplements from bottle to bottle and brand to brand. Contents of non-pharmaceutical items may include the logos for; NSF, USP, or Consumer Labs.

Most unseen dangers are from commonly used over the counter (OTC) medications and prescriptions individuals with NF2 might need to take more frequently than the average person and therefore puts them at a higher risk of side effects noted for any medication.

10. Cerebrospinal-Fluid Flow (CSF) Issues

Cerebrospinal fluid (CSF), is a clear and colorless fluid that needs to continuously move through a membrane that surrounds the Central Nervous System; brain and spinal cord. Constant CSF movement from the brain to spinal cord needs to remain continuous.

Tumor growth can result in issues blocking the necessary flow of CSF from the brain into the spine. There are two forms of CSF issues that can occur from brain tumor growth; intracranial pressure (obstructive hydrocephalus) and CSF leak (intracranial hypotension).

CSF leak had been a common occurrence in the ten (10) days following brain tumor surgery, but surgical methods are available to lower the chances of occurrence.

11. Kidney Failure (Renal Failure)

The kidneys are a pair of vital organs that perform many functions to keep the blood clean and chemically balanced. It is easier to maintain healthy kidneys than it is to recover from poor kidney health. The most common reasons an individual with NF2 may suffer from kidney failure include; pain medication, MRI contrast (Gd), and tumor-drug treatments.

12. CN5: Trigeminal Neuralgia

Trigeminal neuralgia, damage to CN5, is often confused with damage to CN7, the facial nerve. The facial nerve only controls movement, feeling in the face which is the function of Cranial Nerve 5, the trigeminal nerve.

13. CN10: Vagus Nerve: Swallowing Difficulties

Cranial Nerve 10 is the vagus nerve. Swallowing difficulties are typically the first signs there are problems with this nerve. However, this nerve controls much more. It must be watched and handled properly if it shows signs of weakness.
Functions of the vagus nerve include:

• Muscle Control: muscles control of; heart rate, sweating, esophagus, and digestion, as well as many involuntary muscle movements in the mouth, including speech and breathing.
• Sensory Control: feeling in the ear canal

The vagus nerve is not the only possible reason for swallowing difficulties; other reasons may be considerably less dangerous.

14. Additional Cranial Nerve Damage

For individuals with NF2, tumors are expected to grow on Cranial Nerve 8 (CN 8) the vestibulocochlear nerve, which controls hearing and balance. It is not uncommon for tumors on CN 8, to also damage CN 7 the facial nerve. Tumors also commonly grow on; CN 2 the optic nerve, CN 5 the trigeminal nerve, and CN 10 the vagus nerve. However; it is possible for tumors to grow and damage any other cranial nerves as well.

There are twelve (12) pairs of nerves in the central nervous system, a left and a right nerve for each. Some control muscles and others control senses.

15. Traumatic Brain Injury (TBI)

People with NF2 are at risk to develop traumatic brain injury (TBI) as the result of; 1) fast tumor growth, 2) tumor-drug treatments, 3) surgery or 4) radiotherapy treatments (Gamma knife, CyberKnife, or Proton Therapy). NF2 brain matter issues are; brain injury, brain trauma, cognitive issues, damaged regions or regions of the brain that do not function properly for some reason.

Cognitive issues from tumor growth can be temporary particularly if the result of tumor growth or surgery. Cognition is less likely to recover following radiation/radiotherapy treatments, particularly when used as a treatment for younger individuals.

16. Epilepsy/Seizures.

Epilepsy is a brain condition in which a person has repeated Seizures over time. Seizures are episodes of disturbed brain activity that cause changes in temporary attention or behavior. A person is considered epileptic (to have epilepsy); if more than one seizure occurs.

Epilepsy occurs when permanent changes in the brain cause it to be irregular concerning neuronal activity. As a result, the brain sends out abnormal signals, which can lead to repeated, unpredictable seizures. A single Seizure incident that does not happen again is not Epilepsy.

17. Strokes - An Aneurysm, Embolism, and Transient Ischemic Attack (TIA)

As a result of tumor growth, individuals with NF2 are at risk of having Strokes. A stroke is a "brain attack." It can happen to anyone at any time. It occurs when blood flow to an area of the brain is cut off. When this happens, brain cells are deprived of oxygen and begin to die. When brain cells die during a stroke, abilities controlled by that area of the brain such as memory and loss of muscle control can occur.

Strokes are the result of damage to an artery from; 1) diabetes, 2) high blood pressure or 3) lesion growth. The damage could be on an artery, inside an artery, or pressing on an artery. NF2 brain tumors are either; schwannoma or meningioma; these tumors can compromise arteries in the brain.

18. Spinal Cord and Body

• Spinal Cord and Peripheral Nerves
  • Peripheral Nerve Issues
  • Radiculopathy
  • Peripheral Neuropathy
• Vertebrae Damage
  • Scoliosis
  • Ketosis
• Mobility Issues
  • Paraplegia: damage to part of the spine and body
  • Tetraplegia (Quadriplegia): damage to top and therefore complete spine and body.
  • Hemiplegia
  • Diplopia
  • Drop Foot / Foot Drop

19. Skin Irregularities: Café-au-lait Spots

Café-au-lait Spots also known as Café-au-lait Macules (CALMS), are irregularities of the skin that could cover a 1-inch area. Café-au-lait spots are a hyperpigmented plaque-like lesion on the skin, no issue related to skin discoloration. These are not painful; they are simply a discoloration of the skin. Individuals with NF2, who have CALMS, usually have fewer than six. CALMS can also fade over time.^[13]

Opioid-induced Hyperalgesia

Harvard

PubMd

3. Tumor Treatments

While tumors are typically slow growing and Benign, there is no treatment to stop and destroy all tumors an individual might develop as a result of the NF2 condition. Drug-Based treatments are only available in clinical trial stages at this time. Treatments are; 1) surgical tumor resection or debulking, or 2) radiation/radiosurgery of gamma knife, cyberknife or proton therapy for intervention methods for individual tumor care.

Not every tumor that grows will need medical management other than observation by regularly checked MRI scans. Tumor growth can be inconsistent, and long-term stability can easily change to rapid growth.

If you require help with surgical management of vestibular schwannoma or the growth of another tumor from NF2, contact the National Institute of Health (NIH). NIH can help review MRI's for recommendations of treatment options and surgical management of tumors.

4. Genetics

4.1. Introduction

NF2 is a genetic autosomal dominant condition. A child can be afflicted with NF2 in one of two ways. He or she can 1) inherit NF2 from a mother or father who has NF2, or NF2 can be initiated by 2) spontaneous mutation. NF2 is not a disorder that can spread or someone can catch. NF2 is a condition that an individual has at birth, even though symptoms are seen later in life.

4.2. NF2 gene and MERLIN

The NF2 gene provides instructions for the production of a protein called Merlin (moesin-ezrin-radixin-like protein), also known as Schwannomin. This protein is made in the nervous system, particularly in specialized cells called Schwann cells that wrap around and insulate nerves.

Merlin helps regulate several signaling pathways that are important for controlling cell shape, cell growth, and the attachment of cells to one another (cell adhesion). This protein functions as a tumor suppressor, preventing cells from growing and dividing too fast or in an uncontrolled way.

The NF2 gene mutations that cause Neurofibromatosis Type 2 are classified as Germline, which means they are present in all of the body's cells. Most NF2 gene mutations result in an abnormally shortened version of the merlin protein. This short protein cannot perform its normal tumor suppressor function in cells. Research suggests that the loss of Merlin's function allows certain cells in the nervous system, especially Schwann cells, to multiply too frequently and form tumors.

More than four-hundred (400) mutations in the NF2 gene have been identified in people with the condition Neurofibromatosis Type 2 (NF2). ^{[Genetics Home Reference, NF2 gene - neurofibromin 2]}

Cytogenetic Location: 22q12.2

5. Diagnosis

Early in life diagnosis, and proper follow up of NF2 dysfunctions can make it easier to manage NF2 issues. Once diagnosed with NF2, doctors can begin to monitor issues with Neurological Exams and MRIs and can help look for options to slow down tumor development.

6. Family Planning

Family planning and birth control is not just prevention of pregnancy but considering advantages and disadvantages of natural and alternative options to become pregnant. Knowledge of advantages and disadvantages are important since there are dangers to mothers with NF2, not just the potential child.

Sometimes the issues to the child can even be more than just development of stronger case of NF2 than their parent. Discussion with doctors about prescriptions and other medications is important for a safe pregnancy.

7. Recent News

'NF2 Information and Services' pages are meant to be shared with doctors and others with NF2 in hopes of helping more people.

8. NF2 Information & Services Request

'NF2 Information and Services' content is meant to be shared with doctors and others with NF2 in hopes to help more people. 'NF2 Information and Services' is not run by medical professionals.

9. Sources

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