Causes of NF

Segmental NF (sometimes referred to as mosaic) is a form of NF1 or NF2 in which signs and symptoms are limited to only one area (segment) of the body.

For people with this diagnosis the chances of passing the condition onto their children is thought to be as low as it is for the general population, but this depends on which area of the body is affected. If the area includes the ovaries or testes, the chances of passing it on could be as high as 50%.

Our US counterparts have an excellent information sheet Segmental NF: A guide for patients.

Also referred to as 17q11 microdeletion syndrome, this can be a more severe form of NF1 impacting up to 5% of people with NF1. The characteristics of someone with their whole NF1 gene deleted may include, among others: 

• Coarser facial features 
• Developmental delay 
• Intellectual disability 
• An increased risk of cancers 
• Larger than average number of neurofibromas 
• Heart abnormalities 

It is also important to remember that, like NF1, everyone with this deletion will have different signs and symptoms and will not necessarily develop all of those listed above or other known symptoms of NF1. The features of NF1 will also be experienced across a varying degree as they are for everyone with NF1. 

For anyone with a copy of the NF1 gene deleted, it is important to remain under close surveillance for tumour burden and complications. However, it does not mean they will experience all the above symptoms.

Some people impacted by NF1 also show physical signs and symptoms like those of Noonan Syndrome, as well as some of the typical NF1 features. They are most likely to have: 

• Wide-set eyes (hypertelorism) 
• Enlarged and thickened heart muscle 
• Low-set ears 
• Multiple cafe-au-lait marks
• Drooping upper eyelid (ptosis) 
• Narrowing of the valve connecting the heart to the pulmonary artery (which takes blood to the lungs) 
• Short stature 
• Webbed neck 
• Specific learning disabilities 

They may also have other signs and symptoms seen in either NF1 or Noonan Syndrome.  

There are however some symptoms common in NF1 that are generally infrequently seen in people with this condition. These include: 

• Lisch nodules  
• Optic Pathway Glioma (OPG)
• Freckling 
• Plexiform neurofibromas 
• Scoliosis.

Research has shown that a change within the NF1 gene is responsible for this presentation of the condition rather than that which causes Noonan Syndrome. 

The doctor may send you for investigation by a cardiologist if these above clinical features are present.

There are only a handful of known links between changes to the NF1 gene and its presentation.  

Because the NF1 gene is a really long one, compared to many other genes in our bodies, it is more prone to faults (mutation). We know that there is a vast number of ways in which the gene can be changed and often the change identified when someone’s DNA is analysed has not been seen before. 

This means there is often only minimal information, if any, about how a gene fault may impact someone, and so advice on this basis is generally provided with caution. 

Your NF specialist or geneticist will be best placed to discuss your gene fault and whether it will affect your care.

People affected by this condition generally have café-au-lait marks, limited neurofibromas on the skin and neurofibromas along the spinal cord.

A few gene faults have now been linked to condition symptom severity aside from those indicated above. One such involves a small deletion of part of the gene which results in no dermal, sub-dermal or superficial plexiform neurofibromas developing, and therefore a milder form of the condition.

A number of NF2 gene faults have been detected and some relationship between the type of fault and condition severity has been made, however, as there is still considerable variability in severity between people affected by similar faults the literature advises caution in providing families with the details of the impact of these changes. 

Furthermore, the changes will not impact upon the way surveillance or management/treatment is undertaken other than to ensure that those people with a likelihood of more severe symptoms be followed closely over time.

A correlation between pain and a change in the LZTR1 gene has been proposed for this condition. However, no links have been established between gene faults and tumour burden that we are currently aware of.