Neurofibromatosis type 2

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Classification according to ICD-10
D33. 3 Acoustic neuroma
ICD-10 online (WHO version 2019)
NF-2 locus

The neurofibromatosis type II (NF II), also known as central neurofibromatosis referred to is a hereditary tumor. Its main feature is the occurrence of benign brain tumors that develop symmetrically in the area of ​​both auditory and equilibrium nerves. Most people with this condition also have changes in their eyes. NF II is caused by mutations in a gene that presumably influences the shape and migration behavior of certain cell types. Since NF II is genetic, a cure is not possible. Treatment consists of the removal of tumors in the area of ​​the brain and spinal cord, as well as surgery in the area of ​​the eyes and the affected cranial nerves.

NF II is about ten times rarer than the most common form of neurofibromatosis , peripheral neurofibromatosis type 1 (Recklinghausen's disease) .

history

The disease was first described in the 1920s and 1930s. In 1933, Gardner and Frazie described a family in which over five generations there were 38 cases of deafness caused by tumors of the auditory nerve on both sides. In addition, 15 of the patients described became blind. Other cases of illness were reported by Worster-Drought in 1937, by Feiling and Ward in 1920, and by Moyes in 1968. In the Forster-Drought paper, the authors referred to a description by Wishart from 1822. This first described the disease. Wishart was President of the Royal College of Surgeons of Edinburgh . He described a 21 year old man (Michael Blair) who suffered from bilateral deafness. He showed a special head shape and had been blind on his right side since he was four months old. After the death of the patient, the autopsy revealed tumors of the brain and meninges. Remarkably, Wishart described a "tumor the size of a small nut that was very hard and was to be found on both sides of the auditory nerve, exactly at the location of the internal acoustic meatus ".

Incidence, inheritance, epidemiology

Autosomal Dominant Pedigree Chart.svg

NF II is a hereditary tumor disease with an autosomal dominant inheritance. The affected people develop certain tumors of the nervous system. The incidence (new cases) is 1: 35,000. The clinical presentation is diverse, but all people with this disease have mutations in the same genetic locus. Affected is a gene on chromosome 22 . About half of the patients have a new mutation .

Pathogenesis, molecular biology and pathophysiological relationships

The gene changed in NF2 codes for a protein called Merlin . On the one hand, it is assumed that Merlin, due to its structural relationship, inhibits signals of cell reproduction on or around the plasma membrane. In 2010 it was shown that merlin also accumulates in the cell nucleus and inhibits E3 ubiquitin ligase CRL4 and thus triggers a signaling pathway that is directed against mitosis of the cell. In NF2 there is a mutation in the gene that removes the antimitotic effect.

pathology

Bilateral schwannomas

The so-called acoustic neuroma in neurofibromatosis type II is actually a schwannoma of the vestibular nerve (equilibrium nerve ). Despite better knowledge, the wrong term is retained in the entire scientific literature. The vestibular schwannomas grow slowly at the inner entrance (base of the skull) of the internal acoustic meatus . They arise from the nerve sheath of the upper section of the vestibular nerve at the transition from the central to the peripheral myelin (so-called Redlich-Obersteiner zone ) in the area of ​​the internal acoustic porus, around 1 cm away from the brain stem.

Clinical picture

Schwannoma of the vestibular nerve

The clinical spectrum of the disease is broad. The term clinical spectrum means the occurrence of symptoms that are causally related to the disease.

Intramedullary ependymomas
  • Spinal cord: Spinal masses (affecting the spinal cord) are just as common (in medicine, the term space mass refers in many cases to a tissue growth). In patients with NF type II, the cranial masses (affecting the skull) are almost always symptomatic (e.g. hearing loss). The spinal masses only become symptomatic in approx. 40% of cases. The spinal tumors are divided into two groups. One finds intramedullary masses. This means tumors that are found in the tissue of the spinal cord. Here you will mainly find astrocytomas and ependymomas . On the other hand, there are extramedullary masses. This means tumors or tissue changes that are located in the spinal canal but outside of the spinal cord substance. The extramedullary space is the gap between the surface of the spinal column and the bony wall of the spinal canal within the spine. Schwannomas and meningiomas are the most common in these cases .
Meningiomas in NF II
  • Other lesions of the central nervous system : Meningioangiomatosis is a lesion of the central nervous system with plaque-like growth of cells around individual vessels, which can also occur multifocally in NF II. Glial hamartia are circumscribed, atypical cell clusters in the brain parenchyma. Intracranial calcifications are more common in NF II.
  • Other cranial nerves and meninges: About 50% of patients have tumors around the cranial nerves or meningiomas . Schwannoses are small cell proliferation of the nerve sheaths without complete tumor formation. In NF II they are found primarily at the exit points of the spinal nerves.
  • Skin: In children, the appearance of neurofibromas can be an indication of the presence of type II neurofibromatosis.
  • Eyes: Systematic studies of patients with NF type II have shown that over 90% of those affected have eye changes. By far the most common eye change in NF II is the so-called juvenile (occurring in adolescence) subcapsular cataract (a form of lens opacity ).

The clinical symptoms (complaints that the patients themselves notice and report to the doctor) of a lesion of the vestibulocochlear nerve (auditory and equilibrium nerves ) due to a mass in the cerebellopontine angle are as follows: hearing loss (98%), tinnitus (noise in the ear) (70%), Balance disorder (67%), cerebellar ataxia (unsteady gait), headache (32%) and numbness (32%) and paralysis (10%) in the area of ​​the facial nerves .

The clinical signs (changes that the patient does not notice themselves, but which a doctor can determine during a physical examination) of a lesion of the vestibulocochlear nerve (auditory and equilibrium nerves ) caused by a mass in the cerebellopontine angle are as follows: Disturbance of the corneal reflex (33%) , Nystagmus (26%), hypoesthesia in the area of ​​the facial nerve (26%).

Technical examinations yield the following findings: In addition to the typical imaging findings (enlargement of the internal acoustic porus (opening of the auditory canal) in the bone window of the native CCT , contrast medium uptake of the tumors), there is an increase in protein in the liquor and pathological findings in the acoustically evoked potentials . A nystagmus can also be characterized with the help of an electronystagmography with caloric stimulation.

Course of disease

Characteristic of the course of the disease is the fact that acoustic neuromas in patients with NF type II already occur in young adulthood, while in the sporadic forms (this means the occurrence of acoustic neuromas regardless of the presence of a hereditary tumor disease) the age of onset is much higher lies.

Two forms of progression are described in NF II: The so-called Wishart phenotype is characterized by the occurrence of multiple cerebral and spinal masses before the age of 20 with rapid tumor progression. The Feiling-Gardner phenotype is characterized by an onset of disease after the age of 20 with singular central tumors and slow tumor progression.

Genotype-Phenotype Correlation

Many patients with type II neurofibromatosis have been treated as part of scientific studies in recent years. The severity of the disease, its course and the type of mutation were carefully examined. Such studies are therefore concerned with the phenotype-genotype correlation . The purpose of such studies is to answer the question of whether certain types of mutations are closely related to certain symptoms. One would like to be able to predict the course of the disease with great certainty in a clinically inconspicuous patient in order to optimize the therapy. These studies found that:

  • Most mutated NF II genes lead to shortened NF II peptides (schwannomines).
  • There is no accumulation of mutations (hot spots).
  • Patients with a frameshift mutation or nonsense mutation or mutations above exon 7 have a severe course.
  • Patients with a missemutation or a somatic mosaic pattern have a mild course.
  • There is no preferred type of course in patients with a mutation in the splice acceptor sequences .
  • Minor mutations (point mutations, etc.) may not have any clinical impact.
  • There are cases when patients with the same mutation show different forms of disease.

These findings suggest that other genes or environmental factors are responsible for the development of the disease pattern of NF type II.

  • Maternal inheritance of the disease and families with known occurrence can be associated with a more pronounced clinical picture.

diagnosis

The core or cardinal symptom of the disease are bilateral benign tumors of the auditory nerve (so-called bilateral acoustic neuromas). This symptom defines the disease.

Diagnostic criteria for a disease are the symptoms, if they are present the clinical diagnosis can be made. For a definitive NF II, these are:

  • The detection of bilateral acoustic neuromas by means of imaging procedures.
  • A first-degree relative with NF II and evidence of neurofibromas, meningiomas, gliomas, schwannomas.
  • A first-degree relative with NF II and evidence of juvenile posterior subcapsular cataract (lens opacification in adolescence).

The following criteria make the existence of a NF II likely:

  • Unilateral acoustic neuroma before the age of 30 and a meningioma, schwannoma, glioma or lens opacity.
  • Multiple meningiomas and one glioma, lens opacification, or schwannoma before age 30.

therapy

Early detection of the disease is important for therapy, since with NF type II, adolescents already become ill. Symptoms such as hearing loss often occur up to 10 years before the correct diagnosis is made. The acoustic neuromas can be operated on at an early stage in order to maintain the function of the facial nerve. However, this is only successful in half of the patients. Patients with the Wishart phenotype also often suffer from recurrences (recurrence of the tumor after surgery). If the facial nerve is paralyzed, reconstructive interventions can be performed. With so-called lid loading , small magnets are implanted in the lids of the affected eye in order to avoid chronic conjunctivitis caused by incomplete lid closure in facial nerve paralysis. Most patients with NF II suffer from a cataract (clouded lens) as part of the disease . Ophthalmological operations replace the clouded lens with an artificial lens. This improves the reduction in vision. For high-risk patients (children of those affected), we recommend annual check-ups in specialized centers. Treatment also includes preventative sign language learning in patients who are at high risk of complete deafness.

Surgical therapy of acoustic neuroma

In principle, an operation gives better results than radiation therapy. There are six different surgical techniques for removing an ACN. Three of them are only used in exceptional cases. The surgical procedure is selected based on the size of the tumor and the patient's hearing ability.

  • The suboccipital approach (SO) is preferred by neurosurgeons and allows hearing to be preserved. The disadvantage of this procedure is the higher postoperative complication rate with regard to facial paralysis .
  • The translabyrinthine approach (TL) is rather preferred by ENT doctors. The hearing of the affected side is destroyed. This is accepted if the patient's residual hearing is already very poor before the operation. The advantage of this procedure is that it protects the facial nerve. The increased rate of liquor fistulas is a disadvantage .
  • The subtemporal approach or path through the middle cranial fossa (MF) is only chosen for small tumors. The chance of maintaining hearing is good.

Large and medium-sized tumors (2 to 4 cm) can alternatively be operated suboccipitally or translabyrinthine. Here, the extent of the hearing ability and the general condition of the patient decide (with poor hearing ability: TL; with good general condition: SO). Small tumors (smaller than 2 cm in diameter) in patients with poor hearing are operated on using TL. Small tumors in patients with good hearing and a tumor lying laterally (away from the midline of the skull) are operated on with MF. If the tumor is more medial (towards the midline of the skull), the SO approach is chosen.

Individual evidence

  1. ^ WJ Gardner, CH Frazier: Hereditary bilateral acoustic tumors. In: J Hered. Vol. 22, 1933, pp. 7-8.
  2. ↑ C. Worster-Drought, WEC Dickson, WH McMenemey: Multiple meningeal and perineural tumors with analogous changes in the glia and ependyma (neurofibroblastomatosis). . In: Brain. Vol. 60, 1937, pp. 85-117.
  3. ↑ A. Feiling, E. Ward: A familial form of acoustic tumor. . In: Brit Med J . Vol. 1, 1920, pp. 496-497.
  4. ^ PD Moyes: Familial bilateral acoustic neuroma affecting 14 members from four generations. In: J Neurosurg . Vol. 29, 1968, pp. 78-82. PMID 5674095
  5. ^ JH Wishart: Case of tumors in the skull, dura mater, and brain. In: Edinburgh Med Surg J. Vol. 18, 1822, pp. 393-397.
  6. ↑ Wei Li, Liru You, Jonathan Cooper, Gaia Schiavon, Angela Pepe-Caprio and others: Merlin / NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4 in the Nucleus. In: Cell. Volume 140, Issue 4, pp. 477–490, February 19, 2010, abstract available as html; last accessed on March 1, 2010.

Books

  • R. Jackler, DE Brackman (Ed.): Neurotology. Mosby, Elsevier 2004, ISBN 0-323-01830-0 .
  • 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 .
  • Josef Dude (Ed.): Neurosciences. Springer, Berlin 1996, ISBN 3-540-61328-5 .
  • Mark S. Greenberg: Handbook of Neurosurgery. Lakeland 1997, ISBN 0-9626384-5-5 .
  • Wolfgang Hennig: Genetics. Springer, Berlin 2002, ISBN 3-540-42958-1 .
  • Thomas Herdegen (Ed.): Clinical Neurobiology. Spectrum, Heidelberg 1997, ISBN 3-8274-0069-4 .
  • Andrew H. Kaye, Edward R. Laws Jr (Eds): Brain Tumors. An Encyclopedic Approach. Churchill Livingston, Edinburgh 1995, ISBN 0-443-04840-1 .
  • John G. Nicholls (Ed.): From Neuron to Brain. Gustav Fischer, Stuttgart 1995, ISBN 3-437-20517-X .
  • Olaf Rieß, Ludger Schöls (Ed.): Neurogenetics. Molecular genetic diagnosis of neurological diseases. 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, AP Read (Ed.): Molecular Human Genetics. Spectrum, Heidelberg 1996, ISBN 3-8274-0039-2 .

Technical article

  • ME Baser et al .: Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. In: Am J Hum Genet. 2004 Aug; 75 (2), pp. 231-239. PMID 15190457
  • ME Baser et al.: Predictors of the risk of mortality in neurofibromatosis 2. In: Am J Hum Genet. 2002 Oct; 71 (4), pp. 715-723. Epub 2002 Aug 22. PMID 12235555
  • ME Baser ao: Presymptomatik diagnosis in neurofibromatosis 2 using genetic markers, neuroimaging and ocular examination. In: Neurology . 1996; 47, pp. 1269-1277. PMID 8909442
  • DGR Evans et al.: A genetic study of neurofibromatosis 2. In: J Med Gent. 1992; 29, pp. 841-846 and 847-852. PMID 1479598 and PMID 1479599
  • DGR Evans et al: A clinical study of neurofibromatosis 2. In: QJM . 1992; 304, pp. 603-218. PMID 1484939
  • MI Kaiser-Kupfer et al .: The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. In: Arch Ophthalmol. 1989 Apr; 107 (4), pp. 541-544. PMID 2705922
  • L. Kluwe et al: Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes. In: Hum Genet. 1996 Nov; 98 (5), pp. 534-538. Erratum in: Hum Genet. 1997 Feb; 99 (2), p. 292. PMID 8882871
  • VF Mautner et al: Neurofibromatosis 2 in the pediatric age group. In: Neurosurgery. 1993 Jul; 33 (1), pp. 92-96. PMID 8355853
  • VF Mautner et al .: Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. In: AJR Am J Roentgenol. 1995 Oct; 165 (4), pp. 951-955. Erratum in: AJR Am J Roentgenol. 1996 May; 166 (5), p. 1231. PMID 7676998
  • VF Mautner et al: The neuroimaging and clinical spectrum of neurofibromatosis 2. In: Neurosurgery. 1996 May; 38 (5), pp. 880-885; discussion 885-886. PMID 8727812
  • P. Merel et al .: Screening for germ-line mutations in the NF2 gene. In: Genes, Chromosomes & Cancer . 1995 Feb; 12 (2), pp. 117-127. PMID 7535084
  • DM Parry et al .: Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. In: Am J Med Genet. 1994 Oct 1; 52 (4), pp. 450-461. PMID 7747758
  • G. Rouleau et al.: Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. In: Nature . 1987 Sep 17-23; 329 (6136), pp. 246-248. PMID 2888021
  • G. Rouleau et al: Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. In: Nature. 1993; 363, pp. 515-521. PMID 8379998
  • J. Sainz et al .: High frequency of nonsense mutations in the NF2 gene caused by C to T transitions in five CGA codons. In: Hum Mol Genet . 1995 Jan; 4 (1), pp. 137-139. PMID 7711726
  • JA Trofatter ua: A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. In: Cell . 1993 Mar 12; 72 (5), pp. 791-800. Erratum in: Cell. 1993 Nov 19; 75 (4), p. 826. PMID 8453669
  • C. Warren et al .: Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridization. In: J Med Genet. 2003 Nov; 40 (11), pp. 802-806. PMID 14627667

See also

Acoustic neuroma , phacomatosis , neurofibromatosis , neurofibromatosis type 1 , neurocutaneous disease , cerebrospinal fluid , inner ear , cerebellum , gene mutation , mutation , gene , point mutation .

Web links

Commons : Neurofibromatosis Type 2  - Collection of pictures, videos and audio files