Neurofibromatosis is a group of genetic conditions causing tumors to grow on nerves throughout the body, affecting the nervous system, skin, and bones. These non-contagious conditions can manifest with various symptoms, from mild skin changes to significant neurological issues. Understanding how they are inherited or arise without a family history is important.
Autosomal Dominant Inheritance
Neurofibromatosis follows an autosomal dominant inheritance pattern. This means only one altered copy of a specific gene is sufficient for an individual to develop the condition. If one parent has neurofibromatosis, they possess one normal and one altered gene copy.
With each pregnancy, there is a 50% chance a child will inherit the altered gene from the affected parent, and an equal 50% chance they will inherit the functioning gene and not develop the condition. This pattern applies equally to male and female offspring, as the genes are on non-sex chromosomes, called autosomes. A child who does not inherit the altered gene will not have neurofibromatosis and cannot pass it on.
Spontaneous Mutations
Neurofibromatosis can also occur in individuals with no family history. Approximately half of all cases arise from spontaneous, or de novo, mutations. These genetic alterations happen randomly in the sperm or egg cell that forms the child, or early in embryonic development.
Such mutations are not inherited from either parent and are not caused by environmental factors. Despite being a new mutation, an individual who develops neurofibromatosis this way can still pass the altered gene to their children. The chance of their children inheriting the condition remains 50% for each pregnancy.
How Different Types Are Inherited
The different types of neurofibromatosis are linked to specific gene mutations. Neurofibromatosis Type 1 (NF1) is the most common form, affecting approximately 1 in 2,500 to 5,000 people. It results from a mutation in the NF1 gene on chromosome 17.
This gene provides instructions for neurofibromin, a tumor suppressor protein regulating cell growth. An altered NF1 gene leads to nonfunctional neurofibromin, allowing cells to grow uncontrollably and form tumors. About half of NF1 cases are inherited, while the other half are due to spontaneous mutations.
Neurofibromatosis Type 2 (NF2) is less common, occurring in about 1 in 35,000 births, caused by a mutation in the NF2 gene on chromosome 22. This gene produces merlin (schwannomin), also a tumor suppressor. When the NF2 gene is altered, nonfunctional merlin allows Schwann cells to multiply excessively, leading to tumors like vestibular schwannomas. Similar to NF1, about 50% of NF2 cases are inherited, with the rest resulting from new mutations.
Schwannomatosis is a third type, often linked to mutations in the SMARCB1 or LZTR1 genes, both on chromosome 22. These genes play roles in cell regulation, and their alteration can lead to schwannomas on nerves, typically not on vestibular nerves, distinguishing it from NF2. Schwannomatosis also follows an autosomal dominant pattern.
Understanding Mosaicism
Mosaicism introduces another layer to understanding neurofibromatosis inheritance. This occurs when some cells in a person’s body have the genetic mutation, while other cells do not. This situation arises when the genetic change happens after conception, during early embryonic development.
Individuals with mosaic neurofibromatosis may experience a milder or atypical presentation, as not all their cells carry the altered gene. This also influences the chances of passing the condition to offspring. If the mutation is not present in all germline (sperm or egg) cells, the probability of passing the condition to a child may be lower than the typical 50% seen in autosomal dominant inheritance.