Neurofibromatosis type II

The neurofibromatosis type II ( NF II), also known as central neurofibromatosis, is a hereditary tumor disease. Their main feature is the occurrence of benign brain tumors that develop symmetrically in the field of both hearing and balance nerve. Most patients with this disorder also suffer from changes in the eyes. Cause of NF II is caused by mutations of a gene that probably has an influence on the form and migration behavior of certain cell types. Since the NF II is genetic, a cure is not possible. The treatment consists in the removal of tumors of the brain and spinal cord, as well as surgical interventions in the area of the eyes and the affected cranial nerves.

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

History

The first description of the disease dates from the 20s and 30s of the 20th century. 1933 described Gardner and Frazie a family in which there was a numbness over five generations in 38 cases that were caused by bilateral tumors of the auditory nerve. In addition, 15 blind patients described. More cases of illness were reported by Worster - Drought in 1937, of Feiling and Ward in 1920 and Moyes in 1968. In the work of Forster- Drought, the authors pointed to a description of Wishart in 1822. This described the disease for the first time. Wishart was president of the Royal College of Surgeons of Edinburgh. He described a 21- year-old man (Michael Blair) who suffered from a double-sided deafness. He showed a special head shape and went blind on the right side since the fourth month of life. After the death of the patients showed at autopsy tumors of the brain and meninges. Remarkably, Wishart described a " tumor the size of a small walnut, which was very hard and had to find both sides of the auditory nerve, at the exact spot of the internal acoustic meatus ."

Incidence, Inheritance, epidemiology

The NF II is a hereditary tumor disease with autosomal dominant inheritance. The affected people develop certain tumors of the nervous system. The incidence ( new cases ) of 1:35.000. The clinical presentation is varied, but all people with this disease have mutations at the same locus. This affects a gene on chromosome 22 in about half of the patients is a new mutation ago.

Pathogenesis, molecular and pathophysiological mechanisms

The changes in NF2 gene codes for a protein called Merlin. It is believed that on the one hand Merlin, inhibits due to its structural similarity to signals of cell proliferation at or around the plasma membrane. In 2010 it was shown that Merlin but also accumulates in the nucleus and inhibits the E3 ubiquitin ligase CRL4 and thus triggers a signaling pathway that is directed against the mitosis of the cell. NF2 is present in a mutation of the gene which abolishes the antimitotic effect.

Pathology

The so-called acoustic neuromas in neurofibromatosis type II is in reality a schwannoma of the vestibular nerve ( vestibulocochlear nerve ). At the wrong term is retained despite better knowledge throughout the scientific literature. The vestibular schwannomas grow slowly on the inner input ( skull base side) of the internal acoustic meatus. They arise from the nerve sheath of the upper portion of the vestibular nerve at the junction of the central to the peripheral myelin (so-called Redlich -Oberstein zone) in the area of the internal acoustic meatus, approximately 1 cm from the brain stem.

Disease

The clinical spectrum of disease is wide. The term clinical spectrum we mean the appearance of symptoms that are in causal relationship with the disease.

  • Auditory nerve: As already mentioned are found in 90 % of patients with an MRI scan of the skull a two-sided acoustic neuroma.
  • Spinal cord: Just as often, there are spinal ( spinal cord in question ) masses ( in medicine, the term mass in many cases, a tissue proliferation ). In the patients with NF type II are the cranial ( skull in question ) lesions are almost always symptomatic (eg. Hearing loss ). The spinal lesions are symptomatic but only in about 40 % of cases. Spinal tumors are divided into two groups. Once you find intramedullary lesions. Thus, tumors are meant that are found in the tissue substance of the spinal cord. Here you will find mainly astrocytomas and ependymomas. On the other hand, there are extramedullary masses. This means you tumors or tissue changes that are located in the spinal canal but outside the spinal cord. The extramedullary area the gap between the surface of the spinal column and the bone wall of the spinal canal in the spinal column. In these cases occur primarily schwannomas and meningiomas.
  • Other lesions of the central nervous system: the Meningeoangiomatose is a lesion of the central nervous system with plaque- like growth of cells to individual containers, which may also occur with multifocal NF II. Glial Hamartien are circumscribed atypical cell clusters of the brain parenchyma. Intracranial calcifications are frequently observed NF II.
  • Other cranial nerves and meninges: Approximately 50 % of patients have tumors of the cranial nerves or meningiomas. Schwannosen are small cell proliferations nerve sheath tumor without full training. They are found in the NF II preferentially at the exit for the spinal nerves.
  • Skin: In children, the occurrence of neurofibromas can be an indication II for the presence of neurofibromatosis type
  • Eyes: Systematic studies of patients with NF type II revealed that more than 90 % of patients have ocular abnormalities. By far the most common eye change in NF II is the so-called juvenile ( occurring in adolescence ) subcapsuläre cataract (a form of lens opacity ).

The clinical features ( complaints, notice the patients themselves and the physician report ) a lesion of the vestibulocochlear nerve (hearing and balance nerve ) by a space-occupying lesion in the cerebellopontine angle are the following: hearing loss (98%), tinnitus ( ear noise ) ( 70%), vertigo ( 67%), cerebellar ataxia ( unsteadiness ), headache (32%) and numbness ( 32%) and paralysis (10%) in the facial nerve.

The clinical signs ( changes that do not notice the patients themselves, but a doctor can determine during a physical exam ) a lesion of the vestibulocochlear nerve (hearing and balance nerve ) by a space-occupying lesion in the cerebellopontine angle are the following: disturbance of the corneal reflex (33%), nystagmus ( 26%), hypoesthesia in the area of the facial nerve ( 26%).

For technical investigations following findings arise: Besides the typical findings of imaging ( extension of the internal acoustic meatus ( opening of the ear canal ) in the bone window of unenhanced CCT, contrast enhancement of the tumors ), one finds a protein increase in the cerebrospinal fluid and pathological findings in the auditory evoked potentials. A nystagmus can be characterized also by a electronystagmography with caloric stimulation.

Course of the disease

Characteristic for the course of the disease is the fact that the acoustic neuromas in patients with NF type II occur even in young adulthood, whereas the sporadic forms (so says one occurrence of acoustic neuromas, regardless of the existence of a hereditary tumor disease ), the age of onset is much higher lies.

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

Genotype-phenotype correlation

Many patients with neurofibromatosis type II were treated in recent years in the context of scientific studies. The severity of the disease, its course and the type of mutation was examined in detail. Such studies are concerned, therefore, with the phenotype - genotype correlation. The purpose of such studies is to answer the question of whether certain types of mutations are closely associated with certain symptoms. You will want to have at an even clinically normal patients can predict with great certainty the disease process in order to optimize therapy. In these studies, we have found that:

  • Perform most mutated NF II genes in shortened NF II peptides ( Schwannominen ).
  • There is no accumulation point of the mutations ( hot spots ).
  • Patients with a frameshift mutation or nonsense mutation or mutations of exon 7 above have a severe course.
  • Patients with a Missensemutation or a somatic mosaic pattern have a mild course.
  • In patients with a mutation in the splice acceptor sequences, there is no preferred course type.
  • Minor mutations ( point mutations, etc.) may not have clinical implications.
  • There are cases in which patients with the same mutation show different curve shapes.

These findings suggest that the severity of the clinical picture of the NF type II other genes or environmental factors are still responsible.

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

Diagnosis

The core or cardinal symptom of the disease are the two-sided benign tumors of the auditory nerve (known as bilateral acoustic neuroma ). By this symptom, the disease is defined.

As diagnostic criteria for a disorder is referred to the symptoms, if they are present, the clinical diagnosis may be made. For the present a definitive NF II are:

  • The presence of bilateral acoustic neuromas with imaging techniques.
  • A first-degree relative with NF II and the detection of neurofibromas, meningiomas, gliomas, schwannomas.
  • A first-degree relative with NF II and proof of juvenile posterior subcapsular cataract ( clouding of the lens at a young age ).

The following criteria make the existence of NF II probably:

  • Sided acoustic neuroma before age 30 and a Meningom, schwannoma, glioma or clouding of the lens.
  • Multiple meningioma and glioma, schwannoma, or clouding of the lens before the age of 30.

Therapy

For therapy, the early detection of the disease is important because in the NF type II already ill adolescents. Frequently, symptoms such as hearing loss up to 10 years before the correct diagnosis on. The acoustic neuromas can be operated to maintain the function of the facial nerve at an early stage. However, this results in only half of the patients to be a success. Patients with the Wishart phenotype also frequently suffer recurrences ( recurrence of the tumor after surgery ). In paralysis of the facial nerve reconstructive procedures can be performed. The so-called Lidloading small magnets are implanted into the eyelid of the affected eye to prevent a chronic conjunctivitis due to an incomplete eyelid closure in facial nerve paralysis. Most patients with NF II are suffering under the disease to cataract ( clouding of the lens ). Ophthalmologic surgery to replace the clouded lens with an artificial lens. Thereby, the reduction of the vision can be improved. In patients at risk (children involved) you recommends annual checkups in specialized centers. For the treatment also includes preventive learning the sign language in patients who have a high risk for a complete deafness.

Surgical treatment of acoustic neuromas

In principle, that surgery gives better results than radiotherapy. There are six different operation methods for the removal of ACN. Three of them come only in exceptional cases. The surgical procedure is selected according to the size of the tumor and the hearing of the patient.

  • The suboccipital access (SO) is preferred by neurosurgeons and allowed the preservation of hearing. The disadvantage of this method is the higher post-operative complications with respect Facialisparesen.
  • The translabyrinthine access ( TL) is more preferred by ENT physicians. The hearing on the affected side is destroyed. This is taken into account, when the patient's residual hearing prior to surgery is very bad. The advantage of this method is the conservation of the facial nerve. The disadvantage is the increased rate of CSF leaks.
  • The subtemporale access or way through the middle cranial fossa (MF ) is chosen only for small tumors. The chance of hearing to get is good.

Large and medium-sized tumors ( 2-4 cm) can be alternatively operated suboccipital or translabyrinthär. This decides the extent of the hearing and the general condition of the patient ( in bad hearing: TL; in good general condition: SO). Small tumors (less than 2 cm in diameter ) in patients with poor hearing are operated by TL. Small tumors in patients with good hearing and a lateral lying ( from the cranial midline ) tumor to be operated by means of MF. If the tumor is more medially ( to the cranial midline ), to choose the SO access.

Swell

Dominance (genetics) Merlin (Protein) Redlich-Obersteiner's Zone BMJ Neurology (journal) Cell (journal) Phakomatosis
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