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Neurofibromatosis

There are two types:

Type 1: This is the classic, more common type. It manifests mainly as skin spots and benign tumors.

Type 2: This is the less common type. The characteristic feature is the development of tumors in the vestibulocochlear (auditory) nerve.

Type 1

Clinical signs

This disease manifests mainly as many spots that appear on the skin from the age of 6 years, called cafe au lait spots. These have an elliptic form, and occur mainly on the skin of the abdomen, buttocks, rear thigh, etc. These spots may increase in diameter and proliferate over the years. From adolescence, benign tumors may appear on the skin - these constitute a cosmetic problem especially if they appear on the face. In addition, there may be benign tumors under the skin along nerves - these are often painful, in which case they should be excised.

Apart from these, there is a slightly increased risk for the development of benign tumors in internal organs, for example around the kidneys, in the meninges (the membranes surrounding the brain), on the optic nerves, etc. The patients may have short stature, particularly if the onset is in early adolescence. There is a slightly increased risk of problems at birth, and also of mental retardation, which mainly occurs in cases where complications such as brain tumors, epileptic seizures, etc. have been inadequately treated. There may be less common complications such as malignant tumors in the kidney region and various tumors in the brain tissue and other tissues.

A characteristic sign of the disease is Lisch nodules, which can be seen in an eye test. In most of these cases (about 90%), there are no severe medical complications.

Inheritance pattern

The disease is transmitted by autosomal dominant inheritance. The presence of other cases of neurofibromatosis in the family, such as in one of the parents or in other family members, supports this.

Penetrance

The penetrance is approximately 98% - i.e. carriers of the abnormal gene are usually affected, exhibiting characteristic signs of the disease.

This means that those family members who do not have the characteristic signs most probably (98% probability) do not carry the abnormal gene.

In order to establish that family members do not carry an abnormal gene for the disease, the skin must be examined thoroughly for cafe au lait spots, skin tumors and subcutaneous masses, etc, and such people should also be referred to an ophthalmologist in order to look for the common Lisch nodules.

Sometimes it only becomes apparent that an individual is affected after he or she has undergone a thorough examination in order to look for the signs of the disease. Without asking questions and making an in-depth investigation of the family, it is not a lways possible to know this, as some cases are expressed very mildly.

If the same condition is found in other family members, including in one of the parents, it can be assumed that this is isolated (non-syndromic) neurofibromatosis. This is important for the genetic and molecular investigation of the family.

Associated features that can be demonstrated by imagery:

Usually there are no defects that can be identified by ultrasound examination during pregnancy.

What is the risk of recurrence in a subsequent pregnancy?

In cases where the affected individual is the only one in the family: If this is the first case in the family, there is a high probability that the disease in the child is a result of a new mutation in the gene for neurofibromatosis - i.e. the hereditary transmission starts with the child, and there is a 50% chance in every pregnancy that he or she will transmit the abnormal gene to his or her offspring. On the other hand, in these cases, the parents and other family members who are not offspring of the patient apparently have only a small risk for having another affected child (approximately 2%).

In cases where there are many affected individuals in the family: The situation is different if there are already other cases in the family, because here one of the parents of each affected individual also carries the abnormal gene for neurofibromatosis, and the risk of transmitting this to the offspring is 50% in every pregnancy, although it may not always be expressed. Because the gene for this disease is not always expressed, one of the parents may carry it without having the disease him- or herself. In such situations, of course, there is a 50% risk of recurrence in every subsequent pregnancy, and the same risk of recurrence also applies to more distant relatives who carry this abnormal gene. The risk of transmitting the condition is less than 2% - 3% if the parents have undergone testing as above and have been found not to carry the abnormal gene, and if there are no other cases of affected family members in previous generations in either of the patient's parents - i.e. the disease in the child has been caused by a new mutation.

Molecular genetic information

The gene for the disease:

The gene causing neurofibromatosis has been found.

Location

On chromosome 17q11.2.

Genetic testing

Diagnostic testing

The direct test for identifying the mutation in the patient or suspected patient is relatively complex. The gene is long and establishing the entire sequence in order to identify the mutation is a complicated, time-consuming, expensive and currently impractical process, although it may well become simpler in the future. See the information sheet titled: Finding the gene (mutation) by establishing the gene sequence - autosomal dominant diseases.

In a family in which there are already a number of affected individuals, an indirect test as described below in the section on "fetal testing" can be performed. See the information sheet titled: Indirect testing for genetic markers in a family that has a number of patients - when there is only one gene that can cause the disease - autosomal dominant diseases.

Carrier testing

The test for detecting a carrier of an abnormal gene in an autosomal dominant disease where the condition is not clinically expressed is in fact the same as a diagnostic test.

Fetal testing

There are two possibilities:
  1. In a family in which there are at least 2 patients with neurofibromatosis, it is possible to perform linkage analysis. See the information sheet titled: Indirect testing for genetic markers in a family that has a number of patients - when there is only one gene that can cause the disease - autosomal dominant diseases. By this method it is possible to examine the offspring of patients at a young age and to perform prenatal diagnosis by chorionic villus sampling or amniocentesis.

  2. In a family in which there is only one patient, it is possible to perform prenatal testing for each subsequent pregnancy of that patient with approximately 90% reliability. This is done by an indirect genetic test called linkage analysis, which is based on the fact that in most cases a new mutation occurs in the paternal gene. See the information sheet titled: Indirect testing for genetic markers in a family that has a single patient - when there is only one gene that can cause the disease - autosomal dominant diseases.

Type 2

Clinical signs

This disease manifests mainly as tumors in the vestibulocochlear (auditory) nerve. The tumors can appear in childhood from the age of 6 years, and are sometimes bilateral. They are not malignant - they grow relatively slowly and do not produce metastases. However, they may cause hearing loss, tinnitus (ringing in the ears), and destruction of the auditory nerve due to the pressure they exert on it if the diagnosis has not been made before damage occurs.

There may be vestibulocochlear nerve tumors such as gliomas, which cause auditory damage if not treated in time, and other benign tumors of the meninges, etc. Sometimes there may also be caf? au lait spots or bright, elliptic spots on the skin, but only a few, and in this they differ from type 1 neurofibromatosis. Rarely, there may be a few subcutaneous neurofibroma type tumors. The Lisch nodule sign in the eye that is common in type 1 does not appear.

It is important to identify people affected by this disease because they can be monitored by MRI scans of the brain in order to identify the lesions and therefore excise them before the nerve is damaged.

Inheritance pattern

The disease is transmitted by autosomal dominant inheritance. The presence of other cases of neurofibromatosis in the family, such as in one of the parents or in other family members, supports this.

Penetrance

The penetrance is approximately 98% - i.e. carriers of the abnormal gene are usually affected, exhibiting characteristic signs of the disease. This means that those family members who do not have the characteristic signs most probably (98% probability) do not carry the abnormal gene. Sometimes the gene is expressed only at a later age. In order to establish that family members do not carry an abnormal gene for the disease, the skin must be examined thoroughly for cafe au lait spots, and such people should also be referred to an audiologist to look for signs of vestibulocochlear (auditory) nerve tumors. An auditory nerve conduction test and/or brain and auditory nerve MRI scan should also be performed.

If the same condition is found in other family members, including in one of the parents, this is important for the genetic and molecular investigation of the family.

Associated features that can be demonstrated by imagery

Usually there are no defects that can be identified by ultrasound examination during pregnancy.

What is the risk of recurrence in a subsequent pregnancy?

In cases where the affected individual is the only one in the family: If this is the first case in the family, there is a high probability that the disease in the child is the result of a new mutation in the gene for neurofibromatosis - i.e. the hereditary transmission starts with the child, and there is a 50% chance in every pregnancy that he or she will transmit the abnormal gene to his or her offspring. On the other hand, in these cases, the parents and other family members who are not offspring of the patient apparently have only a small risk for having another affected child (approximately 2%).

In cases where there are many affected individuals in the family: The situation is different if there are already other cases in the family, because here one of the parents of each affected individual also carries the abnormal gene for neurofibromatosis, and the risk of transmitting this to the offspring is 50% in every pregnancy, although it may not always be expressed. Because the gene for this disease is not always expressed, one of the parents may carry it without having the disease him- or herself. In such situations, of course, there is a 50% risk of recurrence in every subsequent pregnancy, and the same risk of recurrence also applies to more distant relatives who carry this abnormal gene. The risk of transmitting the condition is less than 2% - 3% if the parents have undergone testing as above and have been found not to carry the abnormal gene, and if there are no other cases of affected family members in previous generations in either of the patient's parents - i.e. the disease in the child has been caused by a new mutation.

Molecular genetic information

The gene for the disease:

The gene causing neurofibromatosis type 2 (Merlin) has been found.

Location:

On chromosome 22q12.

Genetic testing

Diagnostic testing

There are two possibilities:
  1. In a family with only one patient, the genetic test is usually complex. The gene is long and establishing the entire sequence in order to identify the mutation is a complicated, time-consuming and expensive process. However, because this is an important test for many couples and it has important preventive medical implications, in these cases it is worth examining the gene sequence, identifying the mutation in the patient, examining the children of the patient, and offering prenatal diagnosis in future pregnancies.

    If the offspring has not received the mutation found in the patient, it is not necessary to subject him or her to expensive and bothersome follow-up. See information sheet: Finding the defect (mutation) by establishing the gene sequence - autosomal dominant diseases.

  2. In a family that already has 2 patients with neurofibromatosis, it is possible to perform linkage analysis. See information sheet: indirect testing of genetic signs in a family in which there are a number of patients - when there is only one gene that can cause the disease - autosomal dominant diseases. By this method it is possible to examine the offspring of patients at a young age and to perform prenatal diagnosis by chorionic villus sampling or amniocentesis.



Carrier testing

The test for detecting a carrier of an abnormal gene in an autosomal dominant disease where the condition is not clinically expressed is in fact the same as a diagnostic test.

Fetal testing

In a family in which there are at least 2 patients with neurofibromatosis: It is possible in these families to perform linkage analysis. See information sheet: Indirect testing for genetic markers in a family that has a number of patients - when there is only one gene that can cause the disease - autosomal dominant diseases. By this method it is possible to examine the offspring of patients at a young age and to perform prenatal diagnosis by chorionic villus sampling or amniocentesis.

In a family in which there is only one patient: In this situation it is desirable to identify the mutation in the affected family member, thus allowing for precise prenatal diagnosis in each pregnancy. See information sheet: Finding the defect (mutation) by establishing the gene sequence - autosomal recessive diseases.

In a family in which one of the partners has an affected non-first degree relative, who is the only affected person in their family: If the mutation in the affected family member is known, it can be established with certainty whether the mutation is present in the partner in question. The risk is low if the partner is healthy; however, if it is present in the partner, precise prenatal diagnosis can be offered in each pregnancy. See information sheet: Finding the defect (mutation) by establishing the gene sequence - autosomal dominant diseases.
 
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