Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen’s disease, is a multi-organ disease of genetic origin with an autosomal dominant inheritance. It is one of the most common genetic diseases affecting between 1 in 3,000 and 6,000 births.
In this page, we cover the definitions of the terms used in the vocabulary of medical genetics and in connection with NF1. We also help in understanding the patient's genetic journey through genetic counselling, genetic consultation, Pre-Implantation Diagnosis (PGD,) and Prenatal Diagnosis (PND).
NF1 results from the dysfunction of the neurofibromin protein, which is encoded by the NF1 gene "MIM 162200" and located in the "17q11.2" position. This link between the disease and an altered single gene defines NF1 as a monogenic disease.
NF1 is an autosomal dominant inheritance disease. The mutated gene in question is then carried by an autosome (autosomes are all chromosomes except sex chromosomes: X and Y), which implies that both men and women can be affected to the same extent.
The presence of a single mutated allele is sufficient for the disease to manifest. The term heterozygous mutation means that only one copy of the NF1 gene is mutated. Heterozygosity is defined as the two copies of the same gene being different.
In the figure below, "A" represents the mutated allele and "a" represents the wild or non-mutated allele. The mode of transmission is reflected through the family tree, a valuable tool for consultation.
NF1 can result from a mutation of the NF1 gene not inherited by one of the two parents and therefore appeared spontaneously in the embryo. In this case, the form of NF1 is referred to as sporadic. These cases account for almost half of patients' mutations. It can sometimes happen that a recent mutation, de novo mutation, or neo-mutation, occurs in a sex cell of one of the two parents. If this mutation causes a dominant pathological allele, although neither parent is affected, one or more of their children may be ill and pass the mutation on to their offspring. This risk is then assessed by the medical genetic teams.
On the contrary, NF1 can be part of a so-called familial form. In this other half of cases, the mutation of the NF1 gene is inherited from one of the two parents, who himself has NF1.
Finally, the NF1 can be expressed in a so-called "mosaic" mode. Mosaicism is the fact of having two different types of cells, both from the same egg-cell. When the genetic mutation occurs in one of the cells of the embryo at a very early stage of development, the individual has two types of cells: cells in which the mutation is present and cells in which it is not. The patient then clinically presents segmental mosaicism, i.e., one part of his body expresses certain features of the disease, while other parts of the body are perfectly unharmed.
The diagnostic management of these mosaic forms is sometimes more complex and may require additional molecular analyses from other than blood samples, for instance, samples of hair, urine, skin, sperm, etc. The risk of transmission to the offspring of genuine NF1 is sometimes difficult to assess and analysing such biological samples may be useful.
The molecular analysis consists of the study of the NF1 gene and is performed from a blood sample from which lymphocytes (white blood cells containing the necessary genetic material) are extracted. This is also called genetic testing.
For more information about medical genetics, you can log on to the website of the Biomedicine Agency.
Figures made from an Orphanet document.
OrphaSchool – Transmission of genetic diseases
Because of the risk of transmission of NF1 to the patient's offspring, we offer genetic consultations, sometimes necessary as part of the diagnostic process, as well as genetic counselling interviews, offered to all patients in the referral centre.
The geneticist, or genetic counsellor, receives you in a genetic counselling interview to provide you with appropriate information on the genetic nature of your disease.
Genetic counselling is often offered in the following 3 situations:
- Following the announcement of the diagnosis concerning you or your child.
- Prior to the prescription of the genetic test. You are given clear and appropriate information about the disease, the purpose of the genetic test, the personal and family consequences of the result, and the right not to use genetic testing. The result of the genetic analysis is given in the context of an individual consultation.
- Upstream of a parental project to inform you about the possibilities of using a Prenatal Diagnosis (PND), a Pre-Implantation Diagnosis (PGD), or a Non-Invasive Prenatal Diagnosis (NIPT), under certain conditions.
Genetic counselling allows patients to make an autonomous and informed choice about whether or not to use one of these diagnoses.
Genetic consultations are provided by a medical geneticist at the request of your doctor. They can also include the intervention of a genetic counsellor, working under the responsibility of the doctor.
The geneticist works in collaboration with doctors at the neurofibromatosis referral centre to identify the genetic cause of your disease.
The geneticist prescribes genetic tests and sees you again in consultation to explain the results. A clinical examination can occur during the consultation, and photographs may be taken in case they are useful for the diagnosis.
The geneticist and the genetic counsellor are always interested in your family history. It is not necessary to prepare a family tree, but they will ask questions about the health of your loved ones (parents, uncles and aunts, brothers, sisters, and their children, cousins) including a disability, a genetic disease, malformations, etc. Any questions that will clarify genetic counselling, particularly when deciding to become a parent.
If you have already had a sample for a genetic analysis, it is necessary to come with the result of the genetic analysis or the date of the collection as well as the name of the prescribing doctor of the genetic analysis.
The risk of transmission of the disease to offspring is 50%. However, since the expression of the disease varies within the family, it is impossible to anticipate the severity of the phenotype.
Prenatal Diagnosis (PND) or Pre-Implantation Diagnosis (PGD) techniques are currently possible, whether it is a familial form (several affected people in the same family) or a sporadic form of the disease (only one person affected), provided that the molecular abnormality responsible for NF1 has been identified beforehand.
Non-Invasive Prenatal Diagnosis (NIPT) can now be proposed when the molecular abnormality sought in the foetus is of paternal origin and is a point mutation.