Neurofibromatosis type II

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Neurofibromatosis Type II is an inherited disease. The main symptom of the disease is the symmetrical apperance of non-malignant brain tumours in the region of the cranial nerve VIII. 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. There is no causal therapy due to the hereditary nature of the condition. Usually treatment is limited to neurosurgical interventions regarding the tumors and surgical treatment of the eye lesions.

Contents

Incidence, Mode of transmission, Epidemiology

NF II ia an inherited tumour with autosomal dominant mode of transmission. Patients develop certain tumours of the nervous system. Incidence of the disease is 1:35,000. There is a broad clinical spectrum known, but all patients suffer the same mutation. A gene on chromosome 22 is affected. In every second case a de novo mutation is suspected.

Pathogenesis, Molecular Biology and and pathophysiological relations

The NF II causing geneproduct is called "Merlin" or "Schwannomin" and the gene is located on chromosome 22 band q11-13.1. The Schwannomin-petide consists of 595 amino acids. Comparison of the Schwannomin with other proteins shows similarities to proteins, that connect the cyto-sceletton 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.

Pathology

The so called Acoustic neuroma of NF II is indeed a Schwannoma of the Nervus vestibularis. The wrong term is used despite better knowledge in the hole scientific and medical literature. The vestibular Schwannomas are growing slowly at the inner entrance of the Meatus acousticus internus. They derive from the nerve sheeds 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 acusticus, 1 cm from the brain stem.

Symptoms and Signs

The clinical spectrum of the disease is broad. The term "clinical spectrum" designates the appearance of symptoms, with have a causal correlation to the respective disorder.

  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 symptomatical. The spinal tumours in NF II are separeted in two groups. Intramedullar lesions are located within the spinal tissue and usually belong to the so called spinal Astrocytomas or Ependymomas. The extramedullar lesions are located within the small room between the surface of the spinal column and the bony wall of the spinal channel. 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).

The "clinical symptoms" (complaints which are regarded by the patient and referred to the doctor) of a lesion of the nervus vestibulocochlearis by 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).

The "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%).

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 gaolinium enhanced MRI scans, hearing loss in audiometric studies and perhaps pathological finds in Electronystagmography. Some times there are elevated levels of protein in liquor study.

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.

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-Phenotyp.

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 wich 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.

Diagnosis

The "cardinal symptom" of the disease is bilateral acoustic neurinoma. (By its cardinal symptom a disorder is defined.)

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:

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

Therapy

Early diagnosis is essential for planning of therapy in patient with NF II, because young people are affected. In many cases the hearing loss is present until 10 years before the correct diagnosis is established. The Acoustic neurinoma can be treated surgically in the early development of the disease to protect facial nerve function. This should be done despite the fact, that in only every second case the function of the facial nerve can be preserved.

Patients with the Wishard-Phenotype suffer multiple recidives (reoccurence of the tumour after surgical treatment). In the case of facial nerve palsy the so called "Lidloading" (implantation of small magnets in the lid) will help to prevent chronic conjunctivitis. Most patients with NF II suffer some sort of cataract, which need ophthalmological intervention (replacement of the lens). High risk patients (children of affected people) should have specialist examination every year. The preventive learning of sign-language is recommended for patients who will most probably suffer complete hearing loss.

Operative Therapy of Acoustic neurinoma

Surgical treatment have better results than radiation therapy. There are six different surgical techniques for the treatment of Acoustic neuroma. Three are only in rare cases used. The choice of approach is determined by size of the tumour, hearing capability and general clinical condition of the patient.

  • The suboccipital approach (SO) is preferred by Neurosurgeons. It offers better opportunity for the prevention of hearing, but is known to have more complications.
  • The translabyrinthine approach (TL) will destroy hearing of the respective side. There is a good chance to protect the facial nerve. There are more patients with post-OP CSF leaks.
  • The subtemporal approach is therapy of choice in the case of small tumours.

Tumours, greater than 4 cm diameter are treated with the suboccipital approach. Tumours with diameter 2-4 cm can be treated alternatively suboccipital or translabyrinthin. In this case the amount of hearing loss and the general condition of the patient determines which approach should be considered. In the case of severe hearing loss the TL-approach is selected. Patients with good general condition will be treated by the SO approach. Small tumours (< 2 cm diameter) in patients with severe hearing loss are treated by the TL approach. Small tumours in patients with good hearing and lateralized tumour should have MF approach. In cases where the tumour is more medial located the SO approach is considered.

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 Pubpishers 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

External links

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