Neurofibromatosis encompasses a set of distinct genetic disorders that cause tumors to grow along various types of nerves and, in addition, can affect the development of non-nervous tissues such as bones and skin. Neurofibromatosis causes tumors to grow anywhere on or in the body.
Types Of Neurofibromatosis
Neurofibromatosis (NF) has been classified into three distinct types: NF1, NF2 and Schwannomatosis.
Neurofibromatosis 1 (NF1): also known as von Recklinghausen NF or Peripheral NF. Occurring in 1:3,000 births, it is characterized by multiple cafe-au-lait spots and neurofibromas on or under the skin. Enlargement and deformation of bones and curvature of the spine (scoliosis) may also occur. Occasionally, tumors may develop in the brain, on cranial nerves, or on the spinal cord. About 50% of people with NF1 also have learning disabilities.
Neurofibromatosis 2 (NF2): also known as Bilateral Acoustic NF (BAN), is much rarer and occurs in 1:25,000 births. NF2 is characterized by multiple tumors on the cranial and spinal nerves, and by other lesions of the brain and spinal cord. Tumors affecting both of the auditory nerves are the hallmark. Hearing loss beginning in the teens or early twenties is generally the first symptom.
Schwannomatosis: a rare form of NF that has only recently been recognized and appears to affect around 1:40,000 individuals. It is less well understood than NF1 and NF2, and its features may vary greatly between patients.
Unlike NF1 and NF2, the inheritance patterns of schwannomatosis are not understood due largely to lack of cases to study. However, it is estimated that 85% of cases are in fact sporadic (no previous family history) and 15% are inherited.
Genetics of NF1 and NF2
NF1 and NF2 are called autosomal dominant genetic disorders. Half of all cases are inherited from a parent who has NF1 or NF2; half of all cases are not inherited but the result of a new or spontaneous mutation (change) in the sperm or egg cell. Each child of a parent with NF1 or NF2 has a 50% chance of inheriting the gene and developing NF1 or NF2. The type of NF inherited by the child is always the same as that of the affected parent (i.e. if the parent has NF1, each child is at 50% risk for NF1. If the parent has NF2, each child has a 50% chance to inherit NF2). However, the severity and the kind of manifestations may differ from person to person within a family.
When a parent has NF1 or NF2, there is a 50% chance with each pregnancy for the child to receive the NF1 or NF2 gene, and a 50% chance for the child to receive two unaffected genes and to be free of NF1 or NF2. The child with NF1 or NF2, as a result of a new mutation, does have the 50-50 chance of passing the NF1 or NF2 gene on to his or her children.
Unaffected parents who have a child born with NF1 or NF2 because of a spontaneous mutation do not have a 50-50 risk in future pregnancies. Their chance for another child with NF1 is about the same as that of any couple in the general population, that is, one chance in 7,000.
One additional birth in every 7,000 results in a child who has inherited NF1 from a parent with the disorder. Thus, a total of 2 children in 7,000 or 1 in 3,500 are born with NF1.
What Is Genetic Counseling?
Genetic counseling can help couples affected by NF to work through the decision-making processes as they plan to have a baby. Genetic counselors do not tell couples what to do. Instead, they provide information, clarify issues, and can also explain possible alternatives, such as adoption or artificial insemination. In this way, the couple is encouraged, with the support of the counselor, to arrive at a decision that is right for them. Most university-based medical centers and major hospitals offer genetic counseling services.
Other medical terms you may hear:
Von Recklinghausen's Disease: Neurofibromatosis was first reported by Dr. Friedrich von Recklinghausen in 1882. As a result, Neurofibromatosis was known as Von Recklinghausen's disease for many years. This term is rarely used today, but refers to Neurofibromatosis type I (see below).
Phakomatoses: (from the Greek word "phakos", meaning birthmark) Refers to several disorders, including Neurofibromatosis, characterized by benign skin lesions and neurological disorders.
Neurocutaneous Disorder: Refers to several disorders, of which NF is the most common, which affect the skin and the nervous system.
Genetics: A Primer
Below, we present some genetics terms and principles to help you understand how NF is inherited.
What is a Gene?
Our body is made up of millions of cells. Each cell contains a set of chemical structures known as chromosomes. There are 46 chromosomes, arranged in 23 pairs, in each cell in the body. One chromosome of each pair was contributed by the father, and the other by the mother. A gene is a small section of a chromosome. Genes also come in pairs. About 100,000 genes are arranged in a very specific order on the 23 chromosome pairs. One of these pairs, called the sex chromosomes, differs in males and females; the other 22 pairs, called autosomes, are the same in both sexes.
What Do Genes Do?
Genes direct cell behavior. When a gene is activated, a variety of events can occur in the cell, depending on the particular function of that gene. Some genes are responsible for obvious traits such as eye color; others control the production of substances essential to chemical processes inside our bodies. Certain genes simply act as on-off switches for other genes. These reactions are like orders to the cell. They are all the instructions needed for the first cell to develop into a human being and for the body to carry on all the functions of life.
What Is A Gene Mutation?
A mutation is a change. Gene mutations have occurred since the beginning of time and continue to do so. Most mutations are not detectable, and some are not harmful. When a "mutagen" (an agent that causes a mutation) alters the structure of a gene, the gene's "instructions" to the cell are changed or even stopped completely. An alteration of this kind can have serious effects, and may result in a genetic disorder.
NF is the result of such a changed gene. NF is an "autosomal dominant" disorder. "Autosomal" means that the NF gene is located on one of the 22 pairs of chromosomes called "autosomes." (NF1 is located on chromosome 17; NF2 on chromosome 22.) Since these chromosomes are the same in males and females, the gene can be present in either sex, and it can be passed on from either a mother or a father to a son or a daughter. The term "dominant" means that the presence of only one changed or affected gene causes the disorder to appear; the action of the unaffected gene which is paired with the dominant gene cannot prevent the disorder. Because one gene is enough to cause the disorder, NF can be passed from one generation to the next when only one parent has the gene. "Recessive" disorders, on the other hand, generally occur only in the presence of a pair of affected genes, each inherited from one of the affected individual's parents.
Why are the odds always 50-50 for a child to inherit NF from an affected parent?
The explanation for this lies in the process that brings egg cells and sperm cells to maturity. These cells carry our genetic heritage from one generation to the next. Before reaching maturity each of these cells contains 23 pairs of chromosomes, the full complement of genetic material just like any other body cell. As they approach maturity, however, these cells go through a special process (called "meiosis") that results in each egg or sperm having a single chromosome from each pair half of its original genetic material.
It happens this way:
When an egg and sperm, each with 23 single chromosomes, unite, a new cell is formed which contains the 23 pairs of chromosomes required for normal human development.
What does this have to do with the 50-50 chance of inheriting the NF gene? This diagram shows the only pair of chromosomes, which include the NF gene (representing NF1 or NF2 gene) and its unaffected partner:
Thus, a person who has NF1 or NF2 makes two different kinds of reproductive cells, one which will (if it happens to be used in conception) cause a child to have NF, and the other which will produce an unaffected child if it is the one that happens to be used. When a person with NF mates with an unaffected individual, there are four possible combinations of cells. Two will yield a child with NF1 or NF2; two will yield an unaffected child. This is how that it happens: