Neurofibromatosis type II - AbsoluteAstronomy.com

Neurofibromatosis Type II (or "MISME Syndrome", for "Multiple Inherited Schwannoma

Schwannoma

A schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....

s, Meningioma

Meningioma

The word meningioma was first used by Harvey Cushing in 1922 to describe a tumor originating from the meninges, the membranous layers surrounding the CNS ....

s, and Ependymoma

Ependymoma

Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...

s") is an inherited disease. The main manifestation of the disease is the development of symmetric, non-malignant

Malignant

Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...

brain tumours in the region of the cranial nerve VIII, which is the auditory-vestibular nerve that transmits sensory information from the inner ear

Inner ear

The inner ear is the innermost part of the vertebrate ear. In mammals, it consists of the bony labyrinth, a hollow cavity in the temporal bone of the skull with a system of passages comprising two main functional parts:...

to the brain

Human brain

The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

. Most people with this condition also experience problems in their eye

Human eye

The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...

s. NF II is caused by mutation

Mutation

In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s of the "Merlin"

Merlin (protein)

Merlin is a cytoskeletal protein. In humans, it is a tumor suppressor protein involved in Neurofibromatosis type II. Sequence data reveal its similarity to the ERM protein family....

gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

, which, it seems, influences the form and movement of cell

Cell (biology)

The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

s. The principal treatments consist of neurosurgical

Neurosurgery

Neurosurgery is the medical specialty concerned with the prevention, diagnosis, treatment, and rehabilitation of disorders which affect any portion of the nervous system including the brain, spine, spinal cord, peripheral nerves, and extra-cranial cerebrovascular system.-In the United States:In...

removal of the tumors and surgical treatment of the eye lesions. There is no therapy for the underlying disorder of cell function caused by the genetic mutation.

Incidence, Mode of transmission, Epidemiology

NF II is an inheritable disorder with an autosomal dominant mode of transmission. Incidence of the disease is about 1 in 60,000. There is a broad clinical spectrum known, but all patients checked have been found to have some mutation of the same gene on chromosome 22

Chromosome 22 (human)

Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of Chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and representing between 1.5 and 2 % of the total DNA in cells.In 1999,...

. Through statistics, it is suspected that one-half of cases are inherited, and one-half are the result of new, de novo mutation

Mutation

Pathogenesis, Molecular Biology and pathophysiological relations

NF II is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band q11-13.1. This peptide

Peptide

Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

is thought to have a tumor-suppressive function. In a normal cell, the concentrations of active (dephosphorylated) merlin are controlled by processes such as cell adhesion

Cell adhesion

Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...

(which would indicate the need to restrain cell division). It is known that Merlin's deficiency can result in unmediated progression through the cell cycle

Cell cycle

The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

due to the lack of contact-mediated tumour suppression, sufficient to result in the tumors characteristic of Neurofibromatosis type II. The NF II gene is presumed to result in either a failure to synthesize Merlin or the production of a defective peptide that lacks the normal tumor-suppressive effect. The Schwannomin-peptide consists of 595 amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s. Comparison of Schwannomin with other protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s shows similarities to proteins that connect the cytoskeleton

Cytoskeleton

The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

to the cell membrane

Cell membrane

The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

. Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition.

Pathology

The so-called acoustic neuroma

Acoustic neuroma

A vestibular schwannoma, often called an acoustic neuroma, is a benign primary intracranial tumor of the myelin-forming cells of the vestibulocochlear nerve . The term "vestibular schwannoma" involves the vestibular portion of the 8th cranial nerve and arises from Schwann cells, which are...

of NF II is in fact a Schwannoma

Schwannoma

A schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....

of the nervus vestibularis, or vestibular schwanomma. The misnomer of acoustic neuroma is still often used. The vestibular Schwannoma

Schwannoma

A schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....

s grow slowly at the inner entrance of the internal auditory meatus (meatus acousticus internus). They derive from the nerve sheaths of the upper part of the nervus vestibularis in the region between the central and peripheral myelin (Obersteiner-Redlich-Zone) within the area of the porus acousticus, 1 cm from the brainstem.

Genotype-Phenotype-Correlation

Many patients with NF II were included in studies that were designed to compare disease type and progression with exact determination of the associated mutation. The goal of such comparisons of genotype and phenotype is to determine whether specific mutations cause respective combinations of symptoms. This would be extremely valuable for the prediction of disease progression and the planning of therapy starting at a young age. The results of such studies are the following:

In most cases the mutation in the NF II gene causes shortened peptides.
There are no mutational hot-spots.
Patients with Frameshift mutation- or Nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...

s suffer poor prognosis.
Patients with Missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...

s have a better prognosis.
In cases with Mutations in the splice-acceptor-region
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...

, there is no good correlation to determine.
Point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

s may have only minor effects.
Cases are published in which exactly the same mutation is associated with clearly different outcome.

These results suggest, that probably other factors (Environment, other mutations) will determine the clinical outcome.

Symptoms and Signs

The clinical spectrum of the disease is broad. In other words, people with NF II may develop a wide range of distinct problems.

Acoustic nerve: 90% of the patients show bilateral acoustic neuroma
Acoustic neuroma
A vestibular schwannoma, often called an acoustic neuroma, is a benign primary intracranial tumor of the myelin-forming cells of the vestibulocochlear nerve . The term "vestibular schwannoma" involves the vestibular portion of the 8th cranial nerve and arises from Schwann cells, which are...

s on magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

(MRI).
Other cranial nerves and meninges: About 50% of patients develop tumours in other cranial nerves or Meningiomas.
Spinal cord: About 50% of the patients develop spinal lesions. Only 40% of the spinal lesions are symptomatic. The spinal tumours in NF II are separated in two groups. Intramedullary lesions are located within the spinal tissue and usually belong to the so-called spinal astrocytoma
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...

s or ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...

s. The extramedullary lesions are located within the small space between the surface of the spinal cord and the bony wall of the spinal canal. These tumours belong to the Schwannoma
Schwannoma
A schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....

s and Meningiomas.
Skin: If children show neurofibromas, a diagnostic procedure should be performed to decide which form of neurofibromatosis
Neurofibromatosis
Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...

causes the alterations.
Eyes: Studies on patients with NF II show that more than 90% of the affected persons suffer eye lesions. The most common alteration in NF II is the juvenile subcapsular cataract
Cataract
A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...

(opacity of the lens) in young people.

"Presenting symptoms" (initial concern that brings a patient to a doctor) of a lesion of the nervus vestibulocochlearis due to a tumour in the region of the cerebello-pontine angle are the following: hearing loss (98%), tinnitus

Tinnitus

Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

(70%), dysequilibrium (67%), headache (32%), facial numbness and weakness (29% and 10% respectively).

"Clinical signs" (alterations that are not regarded by the patient and that can be detected by the doctor in a clinical examination) of the lesion in discussion are: abnormal corneal reflex (33%), nystagmus (26%), facial hypesthesia (26%).

Evaluation (study of the patient with technical methods) shows the enlargement of the porus acousticus internus in the CT scan, enhancing tumours in the region of the cerebello-pontine angle in gadolinium-enhanced MRI scans, hearing loss in audiometric studies and perhaps pathological findings in Electronystagmography

Electronystagmography

Electronystagmography is a diagnostic test to record involuntary movements of the eye caused by a condition known as nystagmus. It can also be used to diagnose the cause of vertigo, dizziness or balance dysfunction by testing the vestibular system....

. Some times there are elevated levels of protein in liquor study.

Diagnosis

NF II can be diagnosed with 65% accuracy prenatally with chorionic villus sampling

Chorionic villus sampling

Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it...

or amniocentesis

Amniocentesis

Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...

.

Bilateral acoustic neuromas are diagnostic of NF2.

The diagnostic criteria for NF II are the following:

Detection of bilateral acoustic neuroma by imaging-procedures
First degree relative with NF II and the occurrence of Neurofibroma
Neurofibroma
A neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I , an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability...

, Meningiomas, Glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...

, or Schwannoma
Schwannoma
A schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
First degree relative with NF II and the occurrence of juvenile posterior subcapsular cataract.

The criteria have varied over time.

Progression of the disease

In NF II Acoustic neuroma

Acoustic neuroma

s usually affect young people, whereas, in sporadic forms of Acoustic neuroma

Acoustic neuroma

s, the appearance of the tumour is limited to the elderly.

There are two forms of the NF II:

The Wishart-Phenotype is characterized by multiple cerebral and spinal lesions in patients younger than 20 years and with rapid progression of the tumours.
Patients that develop single central tumours with slow progression after age of 20 are thought to have the Feiling-Gardner-Phenotype.

Overview

Early diagnosis allows better planning of therapy in young patients with NF II. In many cases, the hearing loss is present for 10 years before the correct diagnosis is established. Early in the disease, surgery for an acoustic neurinoma can protect facial nerve function in many patients. In selected cases of patients with very small tumors and good bilateral hearing, surgery may offer the possibility of long-term hearing preservation.

Patients with the Wishard phenotype suffer multiple recurrences of the tumour after surgical treatment. In the case of facial nerve palsy, the muscles of the eyelids can lose their mobility, leading to conjunctivitis and corneal injury. "Lidloading" (implantation of small magnets, gold weights, or springs in the lid) can help prevent these complications. Other means of preserving corneal health include tarsorrhaphy, where the eyelids are partially sewn together to narrow the opening of the eye, or the use of punctal plugs, which block the duct that drains tears from the conjunctival sac

Conjunctiva

The conjunctiva covers the sclera and lines the inside of the eyelids. It is composed of rare stratified columnar epithelium.-Function:...

. All these techniques conserve moisture from the lacrymal glands, which lubricates the cornea and prevents injury. Most patients with NF II develop cataracts, which often require replacement of the lens. Children of affected parents should have a specialist examination every year to detect developing tumors. Learning of sign-language is one means of preparation for those that will most probably suffer complete hearing loss.

The St. Louis Children's Hospital Neurofibromatosis Center maintains a comprehensive list of current NF research studies.

Operative therapy of acoustic neuroma

There are several different surgical techniques for the removal of acoustic neuroma

Acoustic neuroma

. The choice of approach is determined by size of the tumour, hearing capability, and general clinical condition of the patient.

The retrosigmoid approach offers some opportunity for the retention of hearing.
The translabyrinthine approach will sacrifice hearing on that side, but will usually spare the facial nerve. Post-Operative cerebrospinal fluid leaks are more common.
The middle fossa approach is preferred for small tumours, and offers the highest probability of retention of hearing and vestibular function.
Less invasive endoscopic techniques have been done outside of the United States for some time. Recovery times are reported to be faster. However, this technique is not yet mainstream among surgeons in the US.

Larger tumors can be treated by either the translabyrinthine approach or the retrosigmoid approach, depending upon the experience of the surgical team. With large tumors, the chance of hearing preservation is small with any approach. When hearing is already poor, the translabyrinthine approach may be used for even small tumors. Small, lateralized tumours in patients with good hearing should have the middle fossa approach. When the location of the tumour is more medial a retrosigmoid approach may be better.

Auditory canal decompression is another surgical technique that can prolong usable hearing when a vestibular schwannoma has grown too large to remove without damage to the cochlear nerve. In the IAC (internal auditory canal) decompression, a middle fossa approach is employed to expose the bony roof of the IAC without any attempt to remove the tumor. The bone overlying the acoustic nerve is removed, allowing the tumour to expand upward into the middle cranial fossa. In this way, pressure on the cochlear nerve is relieved, reducing the risk of further hearing loss from direct compression or obstruction of vascular supply to the nerve.

Radiosurgery

Radiosurgery

Radiosurgery is a medical procedure that allows non-invasive treatment of benign and malignant tumors. It is also known as stereotactic radiotherapy, when used to target lesions in the brain, and stereotactic body radiotherapy when used to target lesions in the body...

is a conservative alternative to cranial base or other intracranial surgery. With conformal radiosurgical techniques, therapeutic radiation focused on the tumour, sparing exposure to surrounding normal tissues. Although radiosurgery can seldom completely destroy a tumor, it can often arrest its growth or reduce its size. While radiation is less immediately damaging than conventional surgery, it incurs a higher risk of subsequent malignant change in the irradiated tissues, and this risk in higher in NF2 than in sporadic (non-NF2) lesions.

Chemotherapy

A 2009 clinical trial at Massachusetts General Hospital

Massachusetts General Hospital

Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...

used the cancer drug Bevacizumab

Bevacizumab

Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....

(commercial name: Avastin) to treat 10 patients with neurofibromatosis type II. The result was published in The New England Journal of Medicine. Of the ten patients treated with bevacizumab, tumours shrank in 9 of them, with the median best response rate of 26%. Hearing improved in some of the patients, but improvements were not strongly correlated with tumour shrinkage. Bevacizumab works by cutting the blood supply to the tumours and thus depriving them of their growth vector. Side effects during the study included alanine aminotransferase, proteinuria

Proteinuria

Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...

, and hypertension

Hypertension

Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

(elevated blood pressure) among others. A separate trial, published in The Neuro-oncology Journal, show 40% tumour reduction in the two patients with NF2, along with significant hearing improvement.

Overall the researchers believed that bevacizumab showed clinically significant effects on NF2 patients. However, more research is needed before the full effects of bevacizumab can be established in NF2 patients.

Management of Hearing Loss in NF2

Because hearing loss in those with NF2 almost always occurs after acquisition of verbal language skills, patients do not always integrate well into the Deaf culture

Deaf culture

Deaf culture describes the social beliefs, behaviors, art, literary traditions, history, values and shared institutions of communities that are affected by deafness and which use sign languages as the main means of communication. When used as a cultural label, the word deaf is often written with a...

and are more likely to resort to auditory assistive technology

Assistive technology

Assistive technology or adaptive technology is an umbrella term that includes assistive, adaptive, and rehabilitative devices for people with disabilities and also includes the process used in selecting, locating, and using them...

.
The most sophisticated of these devices is the cochlear implant

Cochlear implant

A cochlear implant is a surgically implanted electronic device that provides a sense of sound to a person who is profoundly deaf or severely hard of hearing...

, which can sometimes restore a high level of auditory function even when natural hearing is totally lost. However, the amount of destruction to the cochlear nerve caused by the typical NF2 schwannoma often precludes the use of such an implant. In these cases, an auditory brainstem implant

Auditory brainstem implant

An Auditory Brain Stem Implant is a surgically implanted electronic device that provides a sense of sound to a person who is profoundly deaf, due to sensorineural hearing impairment .The auditory brain stem implant uses similar technology as the cochlear implant, but...

(ABI) can restore a primitive level of hearing, which, when supplemented by lip reading

Lip reading

Lip reading, also known as lipreading or speechreading, is a technique of understanding speech by visually interpreting the movements of the lips, face and tongue with information provided by the context, language, and any residual hearing....

, can restore a functional understanding of spoken language.

Drug therapy for NF2-related meningioma

Sunitinib

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that was approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor on January 26, 2006...

is being studied for treatment of meningioma

Meningioma

The word meningioma was first used by Harvey Cushing in 1922 to describe a tumor originating from the meninges, the membranous layers surrounding the CNS ....

which is associated with Neurofibromatosis

Neurofibromatosis

Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...

Drug therapy for vestibular schwannoma

Lapatinib

Lapatinib , used in the form of lapatinib ditosylate, is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway. It is used in combination therapy for HER2-positive breast cancer...

is being studied by Jeffrey Allen at NYU Langone Medical Center for treatment of vestibular schwannoma in Neurofibromatsis type II.

External links

General: http://www.neuroguide.com/
GeneReview/NCBI/NIH/UW entry on Neurofibromatosis 2
Society for Neuroscience
Description of surgical management: Acoustic Neuroma Patient Archive
Research/Advocacy: Advocure
Information about auditory brainstem implants: House Ear Institute
Research/Advocacy: Children's Tumor Foundation: Ending Neurofibromatosis Through Research Website
NF KONTAKT.be (a nonprofit organization providing information and resources for families, Schools and Health Care workers dealing with NF1, NF2, and tumour-related neurofibromatosis in Belgium and providing awareness and support of Neurofibromatosis in Europe)

The source of this article is wikipedia, the free encyclopedia. The text of this article is licensed under the GFDL.

Incidence, Mode of transmission, Epidemiology

Pathogenesis, Molecular Biology and pathophysiological relations

Pathology

Genotype-Phenotype-Correlation

Symptoms and Signs

Diagnosis

Progression of the disease

Overview

Operative therapy of acoustic neuroma

Chemotherapy

Management of Hearing Loss in NF2

Drug therapy for NF2-related meningioma

Drug therapy for vestibular schwannoma

See also

External links