Neurofibromatosis Type II (or "MISME Syndrome", for "Multiple Inherited Schwannomas, Meningiomas, and Ependymomas") is an inherited disease. The main manifestation of the disease is the development of symmetric, non-malignant brain tumours in the region of the cranial nerve VIII, which is the auditory nerve that transmits sensory information from the inner ear to the brain. Most people with this condition also experience problems in their eyes. NF II is caused by mutations of a gene which probably influences the form and movement of cells. The principal treatments consist of neurosurgical 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. The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... Schwannomas, also referred to as Neurilomas, are slow-growing central nervous system tumours arising from the supporting cells of peripheral nerves, which include cranial and spinal nerve roots). ... Meningiomas are tumors arising from the outer part of the arachnoid mater in the meninges of the brain or the spinal cord. ... Ependymoma are tumors arising from the inner lining of the cerebral ventricles (= intracranial) and the remnants of the central canal in the spinal cord. ... A genetic disorder, or genetic disease is a disease caused, at least in part, by the genes of the person with the disease. ... In medicine, malignant is a clinical term that is used to describe a clinical course that progresses rapidly to death. ... A brain tumor is any mass created by an abnormal and uncontrolled growth of cells either found in the brain (neurons, glial cells, epithelial cells, myelin producing cells, etc. ... The vestibulocochlear nerve is the eighth of twelve cranial nerves, and also known as the auditory nerve. ... The inner ear comprises both: the organ of hearing (the cochlea) and the labyrinth or vestibular apparatus, the organ of balance located in the inner ear that consists of three semicircular canals and the vestibule. ... Comparative brain sizes In animals, the brain, or encephalon (Greek for in the head), is the control center of the central nervous system. ... Closeup of a blue-green human eye. ... In biology, mutations are changes to the genetic material (usually DNA or RNA). ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... Cells in culture, stained for keratin (red) and DNA (green). ... Old German engraving depicting a trepanation, an ancient and still performed neurosurgical procedure Neurosurgery is the surgical discipline focused on treating those central and peripheral nervous system diseases amenable to mechanical intervention. ...

Causes

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 35,000. There is a broad clinical spectrum known, but all patients checked have been found to have the same mutation of a gene on chromosome 22. It is suspected that statistically, one half of cases are inherited, and one half are the result of new, de novo mutations. An autosomal dominant gene is one that occurs on an autosomal (non-sex determining) chromosome. ... Chromosome 22 is one of the 23 pairs of chromosomes in humans. ... In law, the expression trial de novo literally means new trial. It is most often used in certain legal systems that provide for one form of trial, then another if a party remains unsatisfied with the decision. ...

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 is thought to have a tumor-suppressive function. 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 acids. Comparison of Schwannomin with other proteins shows similarities to proteins that connect the cytoskeleton to the cell membrane. Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition. Hugo is a masculine name. ... In biology and evolutionary computation, a locus is the position of a gene (or other significant sequence) on a chromosome. ... Chromosome 22 is one of the 23 pairs of chromosomes in humans. ... An amino acid residue is what is left of an amino acid once a molecule of water has been lost (an H+ from the nitrogenous side and an OH- from the carboxylic side) in the formation of a peptide bond. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... The National Center for Biotechnology Information (NCBI) is part of the US National Library of Medicine (NLM), which is a branch of the US National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... An amino acid residue is what is left of an amino acid once a molecule of water has been lost (an H+ from the nitrogenous side and an OH- from the carboxylic side) in the formation of a peptide bond. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... The eukaryotic cytoskeleton. ... Drawing of a cell membrane A component of every biological cell, the selectively permeable cell membrane (or plasma membrane or plasmalemma) is a thin and structured bilayer of phospholipid and protein molecules that envelopes the cell. ...

Pathology

The so called acoustic neuroma of NF II is in fact a Schwannoma of the nervus vestibularis. The wrong term is used despite better knowledge in the whole scientific and medical literature. The vestibular Schwannomas 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. Acoustic neuroma (or Vestibular Schwannoma) is a benign tumor of the myelin forming cells called Schwann cells of the 8th cranial nerve, known as the acoustic nerve, (or more properly the vestibulocochlear nerve) just after it has left the brainstem, in the pontine angle; also at the point where the... Schwannomas, also referred to as Neurilomas, are slow-growing central nervous system tumours arising from the supporting cells of peripheral nerves, which include cranial and spinal nerve roots). ... Schwannomas, also referred to as Neurilomas, are slow-growing central nervous system tumours arising from the supporting cells of peripheral nerves, which include cranial and spinal nerve roots). ...

Genotype-Phenotype-Correlation

Many patients with NF II were included in studies which 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 planning of therapy even at children 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 Frameshiftmutation- or Nonsense mutations suffer poor prognosis.
• Patients with Missense mutations have a better prognosis.
• In cases with Mutations in the splice-acceptor-region there is no good correlation to determine.
• Point mutations 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. Framing error is the following: Generally, a framing error is the result of reading a string of symbols which are grouped in blocks starting at the wrong point. ... In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon (also called a nonsense codon) in the transcribed mRNA, and possibly a truncated (and often nonfunctional) protein product. ... Missense mutations or nonsynonymous mutations are types of point mutations where a nucleotide is changed which results in a different amino acid. ... Diagram of the location of introns and exons within a gene. ... A point mutation, or hellboy is such a cool kid i mean come on! ride that yomer crusin up the street yeeeha! substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide. ...

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.

1. Acoustic nerve: 90% of the patients show a bilateral Acoustic neuroma in NMR-Imaging.
2. Other cranial nerves and meninges: About 50% of patients develop tumours in other cranial nerves or Meningiomas.
3. 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 astrocytomas or ependymomas. 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 Schwannomas and Meningiomas.
4. Skin: If children show neurofibromas a diagnostic procedure should be performed to decide which form of neurofibromatosis causes the alterations.
5. Eyes: Studies on patients with NF II showed, that more than 90% of the affected persons suffer eye lesions. The most common alteration in NF II is the juvenile subcapsular cataract (opacity of the lens) in young people.

"Presenting symptoms" (initial concern which 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 (70%), dysequilibrium (67%), headache (32%), facial numbness and weakness (29% and 10% respectively). Acoustic neuroma (or Vestibular Schwannoma) is a benign tumor of the myelin forming cells called Schwann cells of the 8th cranial nerve, known as the acoustic nerve, (or more properly the vestibulocochlear nerve) just after it has left the brainstem, in the pontine angle; also at the point where the... Meningiomas are tumors arising from the outer part of the arachnoid mater in the meninges of the brain or the spinal cord. ... Astrocytomas are intracranial tumors derived from astrocytes. ... Ependymoma are tumors arising from the inner lining of the cerebral ventricles (= intracranial) and the remnants of the central canal in the spinal cord. ... Schwannomas, also referred to as Neurilomas, are slow-growing central nervous system tumours arising from the supporting cells of peripheral nerves, which include cranial and spinal nerve roots). ... Meningiomas are tumors arising from the outer part of the arachnoid mater in the meninges of the brain or the spinal cord. ... Neurofibromatosis is an autosomal dominant genetic disorder. ... Human eye cross-sectional view. ... The term symptom (from the Greek syn = con/plus and pipto = fall, together meaning co-exist) has two similar meanings in the context of physical and mental health: Strictly, a symptom is a sensation or change in health function experienced by a patient. ...

"Clinical signs" (alterations which are not regarded by the patient and with 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%). Simply, a sign is an indication of some fact or quality; and, in everyday English, a medical sign is an objective indication of some medical fact or quality that is detected by a physician during a physical examination of a patient -- such as elevated blood pressure, or a clubbing of...

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. Some times there are elevated levels of protein in liquor study. CAT apparatus in a hospital Computed axial tomography (CAT), computer-assisted tomography, computed tomography, CT, or body section roentgenography is the process of using digital processing to generate a three-dimensional image of the internals of an object from a large series of two-dimensional X-ray images taken around... MRI Image Magnetic resonance imaging (MRI) is a method of creating images of the inside of opaque organs in living organisms as well as detecting the amount of bound water in geological structures. ... Electronystagmography (ENG) is a diagnostic test to record involuntary movements of the eye caused by a condition known as nystagmus. ...

Diagnosis

The "cardinal symptom" of the disease is bilateral acoustic neurinoma. (By its cardinal symptom a disorder is defined.) A cardinal symptom is the primary or major symptom by which a diagnosis is made. ...

The term "diagnostic criteria" designates the combination of symptoms which allows the doctor to ascertain the diagnosis of the respective disease. In the case of NF II the diagnostic criteria are the following: Diagnosis (from the Greek words dia = by and gnosis = knowledge) is the process of identifying a disease by its signs, symptoms and results of various diagnostic procedures. ...

• Detection of bilateral acoustic neurinoma by imaging-procedures.
• First degree relative with NF II and the occurrence of Neurofibroma, Meningiomas, Glioma or Schwannoma.
• First degree relative with NF II and the occurrence of juvenile posterior subcapsular cataract.

Neurofibromas are moderately firm, benign, encapsulated, slow-growing tumors of the nervous system arising from the supporting cells (Schwann cells) of peripheral nerves. ... Meningiomas are tumors arising from the outer part of the arachnoid mater in the meninges of the brain or the spinal cord. ... A glioma is a type of primary central nervous system (CNS) tumor that arises from glial cells. ... Schwannomas, also referred to as Neurilomas, are slow-growing central nervous system tumours arising from the supporting cells of peripheral nerves, which include cranial and spinal nerve roots). ...

Progression of the Disease

In NF II Acoustic neuromas usually affect young people whereas in sporadic forms of Acoustic neuromas the appearance of the tumour is limited to the elderly. Acoustic neuroma (or Vestibular Schwannoma) is a benign tumor of the myelin forming cells called Schwann cells of the 8th cranial nerve, known as the acoustic nerve, (or more properly the vestibulocochlear nerve) just after it has left the brainstem, in the pontine angle; also at the point where the... Acoustic neuroma (or Vestibular Schwannoma) is a benign tumor of the myelin forming cells called Schwann cells of the 8th cranial nerve, known as the acoustic nerve, (or more properly the vestibulocochlear nerve) just after it has left the brainstem, in the pontine angle; also at the point where the...

There are two forms of the NF II:

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

Treatment

Therapy

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 reccurrences of the tumour after surgical treatment. In the case of facial nerve palsy, the muscles of the eyelids can lose their mobility, leading to conjuctivitis 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. 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 who will most probably suffer complete hearing loss. The conjunctiva is a membrane that covers the sclera (white part of the eye) and lines the inside of the eyelids. ...

Operative therapy of acoustic neuroma

There are six different surgical techniques for the removal of acoustic neuroma. Three are only rarely used. The choice of approach is determined by size of the tumour, hearing capability and general clinical condition of the patient. Acoustic neuroma (or Vestibular Schwannoma) is a benign tumor of the myelin forming cells called Schwann cells of the 8th cranial nerve, known as the acoustic nerve, (or more properly the vestibulocochlear nerve) just after it has left the brainstem, in the pontine angle; also at the point where the... Acoustic neuroma (or Vestibular Schwannoma) is a benign tumor of the myelin forming cells called Schwann cells of the 8th cranial nerve, known as the acoustic nerve, (or more properly the vestibulocochlear nerve) just after it has left the brainstem, in the pontine angle; also at the point where the...

• The retrosigmoid (also known as the suboccipital) approach offers some opportunity for the retention of hearing, but is known to have more complications.
• The translabyrinthine approach will sacrifice hearing on that side, but will usually spare the facial nerve. Post-OP CSF 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.

Langer tumors can be treated by either the translabyrinthine or retrosigmoid approach, depending upon the experience of the surgical team. With large tumors, the chance of hearing preservation is small, even with the retrosigmoid 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.

Another surgical technique 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 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. Radiosurgery is a medical procedure which allows non-invasive brain surgery, i. ...

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 and are more likely to resort to auditory assistive technology. The most sophisticated of these devices is the cochlear implant, which can sometimes restore a high level of auditory function even when natural hearing is totally lost. Unfortunately, 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 (ABI) can restore a primitive level of hearing which, when supplemented by lip reading, can restore a functional understanding of spoken language. Deaf community and Deaf culture are two phrases used to refer to persons who are culturally Deaf as opposed to those who are deaf from the medical/audiological/pathological perspective. ... Assistive Technology (AT) is a generic term that includes assistive, adaptive, and rehabilitative devices and the process used in selecting, locating, and using them. ... Illustration of the internal parts of a cochlear implant A cochlear implant is a surgically implanted electronic device that can help provide a sense of sound to a person who is profoundly deaf or severely hard of hearing. ... Lip reading, also known as speech reading, is a technique of understanding spoken language without hearing its sounds. ...

References

Books

• Raymond D. Adams (Ed.): Principles of Neurology. McGraw-Hill. New York 1997. ISBN 0-07-067439-6.
• Bruce O. Berg (Ed.): Principles of Child Neurology. McGraw-Hill. New York 1996. ISBN 0-07-005193-3.
• Mark S. Greenberg: Handbook of Neurosurgery. Lakeland 1997. ISBN 0-9626384-5-5.
• Andrew H. Kaye and Edward R. Laws Jr (Ed.): Brain Tumors. An Encyclopedic Approach. Churchill Livingston. Edinburgh 1995. ISBN 0-443-04840-1.
• Olaf Rieß und Ludger Schöls (Hrsg.): Neurogenetik. Molekulargenetische Diagnostik neurologischer Erkrankungen. Springer. Berlin 1998. ISBN 3-540-63874-1.
• Lewis P. Rowland (Ed.): Merrits Textbook of Neurology. Williams and Wilkins. Baltimore 1995. ISBN 0-683-07400-8.
• T. Strachan und A.P. Read (Ed.): Human Molecular Genetics. BIOS Scientific Publishers Limited. 1996. ISBN 3-8274-0039-2.

Articles

• Baser M. et al. (1996) Presymptomatik diagnosis in neurofibromatosis 2 using genetic markers, neuroimaging und ocular examination. Neurology 47:1269-1277.
• Evans DGR. et al. (1992a) A genetic study of neurofibromatosis 2. J Med Gent 29:841-846.
• Evans DGR et al. (1992b) A clinical study of neurofibromatosis 2. QJM 304:603-218.
• Kaiser-Kupfer MI et al. (1989) The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Arch ophthalmol 107:541-538.
• Kluwe L et al. (1996) Identification of NF 2 germline mutations and comparison with neurofibromatosis 2 phenotypes. Hum Genet 98:534-538.
• MacCollin MM et al. (1994) Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet 55:314-320.
• Mautner VF et al. (1993) Neurofibromatosis 2 in the pediadric age group. Neurosurgery 33:92-96.
• Mautner VF et al. (1995) Spinal tumors in patients with neurofibromatosis 2. AJR 165:951-955.
• Mautner VF et al. (1996) The neuroimaging and ocular spektrum of neurofibromatosis 2. Neurosurgery 38:880-886.
• Merel P et al. (1995) Screening for germline mutations in the NF 2 gene. Genes Chromosomes Cancer 12:117-127.
• Parry DM et al. (1994) Neurofibromatosis 2: Clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. AM J Med Genet 52:450-461.
• Rouleau G et al. (1987) Genetic linkage of bilateral acoustic neurofibromatosis to DNA marker on Chromosome 22. Nature 329:246-248.
• Rouleau G et al. (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature 363:515-521.
• Sainz K et al. (1995) High freequenzy of nonsense mutations in the NF 2 gene caused by C to T transmission in five CGA codons. Hum Mol Genet 4:137-139.
• Trofatter JA et al. (1993) A novel moesin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791-800.

See also

• Acoustic neuroma
• CSF
• Ear
• Cerebellum
• Neurofibromatosis
• Mutation
• Gene

Acoustic neuroma (or Vestibular Schwannoma) is a benign tumor of the myelin forming cells called Schwann cells of the 8th cranial nerve, known as the acoustic nerve, (or more properly the vestibulocochlear nerve) just after it has left the brainstem, in the pontine angle; also at the point where the... CSF is an abbreviation of: Classical swine fever (also called hog cholera) Cerebrospinal fluid Complement Set Filtering Content Structure Format Critical Success Factor California Scholarship Federation Christian Special Forces Christian Student Fellowship Collège de la Sainte Famille, a Jesuit school in Cairo, Egypt Common Service Framework, a solution from... A human ear An ear is the organ used by a human or an animal to detect sound waves. ... Figure 1a: A human brain, with the cerebellum in purple. ... Neurofibromatosis is an autosomal dominant genetic disorder. ... In biology, mutations are changes to the genetic material (usually DNA or RNA). ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ...

External links

• General: http://www.neuroguide.com/
• Society for Neuroscience
• Online Mendelian Inheritance in Man
• Medline
• Description of surgical management: Acoustic Neuroma Patient Archive
• Support: NF2 Crew Website
• Support: NF2 Crew Mailing List
• Research/Advocacy: Advocure
• Information about auditory brainstem implants: House Ear Institute