Before beginning this month’s blog topic, I want to mention a couple of developments related to our UAB NF Program.  First, one of the adult neuro-oncologists who worked with patients in our NF Clinic, Mina Lobbous, MD, recently left UAB for a position at another medical center.  I know that many of our patients benefitted greatly from Dr. Lobbous’s expertise, and we wish him well in his new role.  However, adult NF patients in our clinic still have the same access to specialists in the UAB neuro-oncology group, which assists NF patients with the management and treatment of NF-related neuro-oncological issues, including brain and spinal tumors and complex plexiform neurofibromas. In another development, we are planning a virtual UAB NF Symposium Family Day, scheduled to occur on Saturday, April 30. As we have for the past two years, we are holding this important event virtually this year to limit the spread of COVID-19. This free, half-day event, co-sponsored by the UAB Department of Genetics and the Children’s Tumor Foundation (CTF), gives patients and families the opportunity to hear a series of presentations on a range of NF-related topics from clinical experts. The agenda will be posted shortly on our UAB NF Program website (link) and Facebook page (link).

Previously, I have discussed the fact that NF is a highly variable condition that can express differently among affected individuals. For example, two people within the same family can have very different symptoms of the condition. In this post, I’ll briefly review the genetics and inheritance patterns of all forms of NF and discuss the primary reasons for variability in expression among people with NF.

Genetics and Inheritance of NF

All individuals have two copies of every gene, one copy inherited from each parent.  NF1, NF2, and schwannomatosis are each transmitted as autosomal dominant traits, which means that a parent with NF has a 50% chance of passing the altered gene copy to a child. For NF1 and NF2, anyone who inherits the altered gene will show signs of the condition, as the disorder does not skip generations.  Geneticists describe this as “complete penetrance.”

Penetrance refers to the proportion of people with a particular genetic change who show signs and/or symptoms related to the change. Both NF1 and N2 have complete penetrance, which means that at least some signs or symptoms are always present in a person who has a disease-causing genetic variant, though the onset and severity of symptoms can vary greatly. Schwannomatosis, however, has incomplete penetrance, which means that not everyone who inherits the genetic variant will develop signs or symptoms. Also, in familial cases of schwannomatosis, symptoms of the disorder may skip generations, although every individual with the genetic alteration has a 50% chance of passing the altered gene copy to a child.

Due to complete penetrance of NF1 and NF2, if a child diagnosed with NF1 or NF2 has parents who are free of signs of the disorder, it is assumed the child has a new, or spontaneous, mutation. In these cases, the genetic alteration, or mutation, occurred in the sperm or egg cell that formed the child. As with an inherited mutation, a person with a spontaneous mutation of the NF gene has a 50% chance of passing the altered gene copy to a child.

If a child with NF1 or NF2 has a distant relative with NF but the parents do not have signs of the disorder, the mutation in the child is assumed to be new, and the NF in the distant relative is likely due to a coincidental different genetic change. Also, if a sibling of an individual with NF does not have NF, the condition will not be passed through to the sibling’s offspring.

Sources of Variable Expressivity Among People with NF

Expressivity is the degree and manner in which a genetic trait is expressed. As discussed previously, NF is a highly variable condition that can express differently among people who are affected. Even within the same family, some people can have mild symptoms while others experience more severe symptoms. While it is not completely known why such a high degree of variability exists within NF, we have a general understanding of at least four probable sources of variability.

1. There is a random nature to some of the physical expressions of NF. In people with NF1, one copy of the NF1 gene is altered due to either inheriting the altered gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation in NF1. In a neurofibroma or most other tissues affected by NF1, the second copy of the NF1 gene is also altered due to a random genetic mutation that represents the “second-hit” mutation. The location in the body where this happens is unpredictable. For example, if the “second-hit” mutation occurs in an embryo in a developing nerve, it may result in a plexiform neurofibroma. Much the same mechanism applies to NF2 in the formation of tumors such as vestibular schwannomas or meningiomas. In schwannomatosis, the process is more complicated, requiring at least three separate genetic events (one of which is the inherited genetic variant).  This may be why schwannomatosis displays incomplete penetrance: a series of genetic events is required to produce a tumor, making it less probable that any at-risk cell will develop into a tumor.
2. Genetic background may be a mechanism for variable expression.There are probably genes other than NF that modify the phenotype (expression) to make the condition milder or more severe. This might explain how NF can manifest differently between two siblings, for example. Research is ongoing trying to find these modifying genes, since recognizing them might help predict who is at risk of specific complications and could eventually reveal potential new targets for therapy.
3. Some variants in the NF gene are associated with specific phenotypes.More than 3,000 pathogenic variants have been identified in the NF1 Most of these lead to loss of function of the NF1 gene product, and do not produce specific, distinct NF features. There are, however, a few examples in which a specific variant can be correlated to certain NF symptoms. For example, whole gene deletion, which accounts for 3% - 5% of all NF1 mutations, causes a form of NF that results in tall stature and increased risk of malignancy.  Those with whole gene deletions often develop a larger than the usual number of cutaneous and internal neurofibromas and may have significant learning problems.  There are a few other NF1 variants that are associated with distinctive features, in some cases a large number of neurofibromas and in at least one other case the opposite – café-au-lait spots and skin fold freckles, but no tumors.  There is also a general correlation of age of onset and severity of NF2 according to certain types of NF2 genetic variants.
4. Some affected individuals are mosaics for an NF1 pathogenic variant.Mosaicism results from a mutation occurring during early development rather than being present at the time of conception. Individuals with mosaicism therefore have a mixture of cells in their bodies, some with and some without the NF1  Sometimes this leads to only one region of the body being affected, referred to as “segmental NF;” other times it might affect the entire body, but symptoms might be milder since not all cells are affected.  If a person with mosaicism transmits an NF1 mutation to a child, however, the child will not be mosaic like the parent, because the mutation would be present from the time of conception.

There may be additional explanations for variable expression yet to be discovered.  It is important to recognize this variability, though, since it means that we generally can’t predict the specific ways in which NF might affect a child based on how it has affected other members of the family.  This is an important point to consider in genetic counseling.