Neurofibromatosis: Information & specialists for neurofibromatosis

Leading Medicine Guide Editors
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Leading Medicine Guide Editors

Neurofibromatoses are a group of genetic diseases that mainly affect the nervous system. Of particular clinical importance are neurofibromatosis type 1, type 2 and type 3, which can cause complex health problems. What they have in common is that different types of benign tumors can develop. Here you will find further information and selected neurofibromatosis specialists and centers.

ICD codes for this diseases: Q85.0

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Article overview

Definition: Neurofibromatoses

Neurofibromatoses are genetic diseases that are either

  • passed on to the offspring or
  • as a new mutation, usually during germ cell development.

Neurofibromatosis type 1, which is one of the most common genetic diseases, also belongs to this group. Around one in 3000 to 4000 people are affected.

However, the other types occur much less frequently. In Germany, around 40,000 people are affected by one of these diseases.

In around 50 percent of patients, the disease is caused by a genetic change during germ cell formation. In this case, a so-called germline mutation or new mutation leads to the disease. Compared to other genetic diseases, this is a very high proportion.

In the other half, the genetic disposition was passed on from parents to children.

Classification of neurofibromatosis

Neurofibromatosis includes several diseases. They differ

  • in the gene or chromosome that is altered by a mutation, and
  • in the symptoms.

Types 1, 2 and 3 are particularly clinically significant.

Neurofibromatosis type 1 (NF1)

Neurofibromatosis type 1 is also known as Recklinghausen's disease or Von Recklinghausen's disease. The disease is based on changes in the NF1 gene, which is located on chromosome 17.

This gene codes for a protein called neurofibromin, which influences regulatory processes in the cells. If cell regulation no longer functions correctly, tumors can develop, for example.

With a frequency of 1:3000 to 1:4000, NF1 is one of the most common genetic diseases.

Clinical manifestations of neurofibromatosis type 1 include

  • Skin spots,
  • neurofibromas (benign tumors of certain nerve and connective tissue cells) and
  • nodules in the iris.
DNA-Strang
Neurofibromatoses are caused by errors in the genome © Giovanni Cancemi | AdobeStock

    Neurofibromatosis type 2 (NF2)

    This form of the disease is much rarer and is also known as central neurofibromatosis or bilateral acoustic neuroma.

    Around one person per 50,000 inhabitants is affected by NF2. The ratio of patients with NF1 to patients with NF2 is therefore roughly 15 to 1.

    In type 2, a mutation in the NF2 gene, which is located on chromosome 22, is responsible for the development of the disease. The exact role of the gene product, which is called schwannomin or merlin, is not yet fully understood. It possibly appears to play a role in the signal transmission of growth factors and after cell adhesion (cell binding).

    Clinically, neurofibromatosis type 2 is characterized by tumours of the central and peripheral nervous system. Schwannomas are particularly common. These are benign tumors of the nerve sheath, which consists of Schwann cells.

    Neurofibromatosis type 3 (NF3) - Schwannomatosis

    This form of neurofibromatosis, also known as Schwannomatosis, is also a very rare disease. Depending on the study, the incidence of the disease is estimated at around 1:25,000 to 1:70,000.

    As schwannomatosis is clinically similar to NF2, there are sometimes problems with differentiation in practice. As a result, schwannomatosis is sometimes not diagnosed correctly.

    Mutations in the SMARCB1 gene, which is also located on chromosome 22 like the NF2 gene, have been found in around half of patients with schwannomatosis. However, very little is known about the function of the gene product.

    Symptoms of neurofibromatosis

    Symptoms of neurofibromatosis type 1

    In type 1, the first symptoms appear in infancy or early childhood. By the age of five, the disease has broken out in almost all people who have the altered gene. However, the severity of the symptoms can vary greatly.

    For example, pigment disorders can be visible at birth or shortly after birth. As these spots have a light brownish color, they are also known as café au lait spots . Initially, they are only a few millimetres in size, but can grow with increasing age. They can also appear on the skin and look very similar to freckles (so-called lentigines). The armpit or groin area in particular can be affected.

    If at least two so-called Lisch nodules are present, this is also a sign of type 1 neurofibromatosis. However, they do not impair vision. Lisch nodules are small nodules of a brownish color that appear on the iris (iris) of the eye and are also called iris hamartomas.

    Benign tumors of certain nerve and connective tissue cells can occur in this disease. They are known as neurofibromas and occur in or under the skin and in any part of the body.

    Neurofibromatose
    Connective tissue skin changes are a symptom of neurofibromatosis © SUWIWAT | AdobeStock

    These mostly nodular, sometimes also net-like growing tumors often only appear after puberty. They multiply over time or become larger. Although these are benign changes, they can also develop into malignant tumors in some cases.

    Tumors can also form on the optic nerve. These are called optic gliomas, which can then also cause visual impairment.

    Another indication of the disease are typical changes in the bones. These include a malformation of the bone behind the eye socket (so-called sphenoid dysplasia). This is often manifested by a protruding eye or, more rarely, a downwardly displaced eye.

    Thinning of the long tubular bones is also possible. For example, a malposition of the tibia, i.e. an excessive curvature of the lower leg. In addition, curvatures(scoliosis) can occur in the spinal column.

    Relatively frequent symptoms also include learning, performance and behavioral disorders as well as cardiovascular diseases. Slower body growth with faster growth of the head can also be observed. This is sometimes accompanied by headaches or vomiting.

    Symptoms of neurofibromatosis type 2

    The symptoms of type 2 usually only set in at a much later stage. The symptoms also differ largely from those of type 1. For example, the café-au-lait spots are either not present at all or are present in much smaller quantities.

    In contrast, tumors in the nervous system, particularly in the brain on the cranial nerves and in the spinal column, are very common. Almost all patients develop acoustic neuromas, which are tumors on the right and left auditory nerves.

    Type 2 patients typically experience the following symptoms due to the tumors:

    • initially problems with hearing, including tinnitus, or dizziness,
    • sometimes also neurological deficits (e.g. sensory disturbances, pain in the arms and legs, paralysis) or
    • visual disturbances.

    In addition, benign skin tumors and changes to the eyes (e.g. squinting or clouding of the lens) can occur.

    Symptoms of neurofibromatosis type 3 - schwannomatosis

    The first symptoms usually appear between the second and fourth decade of life. The most common symptom of NF3 is pain. It is related to the size, number and location of the tumors.

    The schwannomas are mainly found on the peripheral nerves and the spinal nerves, with meningiomas (tumors originating from the meninges) occurring in only around five percent of cases. Tissue growths and muscle weakness are also occasionally observed, but no skin changes or skin tumors.

    Diagnosis of neurofibromatosis

    Diagnosis of neurofibromatosis type 1

    The diagnosis of NF1 can usually be made on the basis of the typical symptoms.

    Skeletal changes can be assessed using an X-ray examination . In the case of headaches or vomiting with rapid head growth, a computer tomography (CT) or magnetic resonance imaging (MRI) should be performed. MRI is also used to diagnose tumors. The ophthalmologist should examine those affected at least once a year for visual disturbances.

    Computertomographie (CT)
    A CT scan is helpful for examining the brain if neurofibromatosis is suspected © Werner | AdobeStock

    The café-au-lait spots are often the first sign of NF1. As other features often only appear later, the final diagnosis can often only be confirmed years later. Regular monitoring is therefore very important.

    A diagnosis can only be made if at least two of the following seven characteristics are present:

    • Six or more café-au-lait spots
    • Freckle-like pigmentation of the armpits and/or groin area
    • Two or more neurofibromas
    • Two or more Lisch nodules
    • Skeletal changes
    • Optic glioma
    • A first-degree relative (parent or sibling) diagnosed with NF1 according to these criteria

    Diagnosis of neurofibromatosis type 2

    The diagnosis of NF2 can be confirmed by

    • physical,
    • audiological (such as hearing tests, recording of auditory evoked potentials, which are certain brain waves),
    • neurological (for example, determination of nerve conduction velocity) and
    • imaging examinations (MRT, CT)

    should be carried out. An ophthalmologic check-up should also be carried out every year.

    The following criteria can be used as a basis:

    • Tumor (schwannoma) on one or both auditory nerves
    • Other(brain) tumors, such as neurofibromas, gliomas, meningiomas
    • Neurological and other complications, such as bilateral hearing loss, paralysis of the facial nerve(facial nerve palsy), tumors under the skin, clouding of the lens(cataract)

    Diagnosis of neurofibromatosis type 3 - schwannomatosis

    As with the other two types, physical, audiological, neurological, ophthalmologic and imaging examinations are used. Differentiation from NF2 in particular is difficult due to the clinical features. The following criteria are taken into account in the diagnosis:

    • At least two schwannomas that are not located in the skin.
    • There is no acoustic neuroma .
    • First-degree relatives have schwannomatosis.

    For all forms of neurofibromatosis, those affected should see their doctor regularly. This is the only way to detect deterioration and the appearance of malignant tumors in good time.

    In certain situations, genetic testing may also be advisable.

    Treatment of neurofibromatosis

    Neurofibromatosis cannot be cured. Treatment can therefore only focus on alleviating the symptoms and preventing them from worsening.

    For example, the neurofibromas can be surgically removed. This is particularly appropriate if they cause pain or become malignant.

    Tumors in the brain are often not removed surgically. The doctor therefore decides, in consultation with the patient, whether to irradiate the affected area.

    In the case of an optic glioma, depending on the examination findings

    may be necessary. However, many optic nerve tumors do not cause any symptoms and therefore do not require treatment.

    Sphenoid dysplasia does not usually require therapy. However, the deformity can be improved by cosmetic surgery.

    Scoliosis can be treated with a corset in mild cases and surgically in severe cases.

    Special exercises can be used for physical and psychological developmental delays.

    No treatment required

    • Café-au-lait spots,
    • Lisch nodules and
    • freckle-like pigmentation.

    Tumors in the brain and on the nerves in neurofibromatosis type 2 are usually treated surgically, less frequently with radiotherapy. However, surgery is delayed for as long as medically justifiable, as nerve surgery is always associated with an increased risk. The benefits and risks must always be weighed up against each other.

    Nerve pain in neurofibromatosis type 3 is treated with drugs such as

    • gabapentin and pregabalin,
    • sometimes also with antidepressants

    treated. Substances for mood stabilization, such as lamotrigen or valproic acid, have also proven to be effective.

    An attempt can also be made to surgically remove the tumors pressing on the nerves. However, due to the increased risk, the surgeon must be very experienced.

    Prognosis for neurofibromatosis

    Patients with neurofibromatosis type 1 must be monitored regularly, as

    • the course of the disease cannot be predicted
    • the severity varies greatly and
    • there is an increased risk of malignant tumors.

    The development of severe complications, such as facial or leg changes, has only been observed in the first few years of life. Overall, they are very rare. It is also extremely unlikely that those affected will develop all complications.

    Overall, however, many patients with neurofibromatosis can lead a largely normal life. However, life expectancy is reduced in a certain proportion of patients.

    However, this mainly depends on the course of the disease and the success of the treatment of individual symptoms.

    References

    • Ardern-Holmes S et al. (2016) Neurofibromatosis Type 2: Presentation, Major Complications, and Management, With a Focus on the Pediatric Age Group. Journal of Child Neurology 32(1):9-22
    • Dhamija R et al. (2018) Schwannomatosis. GeneReviews
    • Evans DG (2018) Neurofibromatosis 2. GeneReviews
    • Friedman JM (2018) Neurofibromatosis 1. GeneReviews
    • Hirbe AC, Gutmann DH (2014) Neurofibromatosis type 1: a multidisciplinary approach to care. The Lancet 13(8): 834-843
    • Mautner V-F (2016) Neurofibromatose Typ 1. Patientenorientierte Krankheitsbeschreibung aus dem ACHSE Netzwerk. Bundesverband Neurofibromatose, Hamburg
    • Mautner V-F, Farschtschi S (2016) Schwannomatose. Patientenorientierte Krankheitsbeschreibung aus dem ACHSE Netzwerk. Bundesverband Neurofibromatose, Hamburg
    • Orphanet (2002) Artikel: Neurofibromatose Typ 1; Neurofibromatose Typ 2. Orphanet - Das Portal für seltene Krankheiten und Orphan Drugs
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