Expressions of CMN
As a rare disease, Congenital Melanocytic Naevi (CMN) has many expressions. For some CMN expresses itself solely on the skin as a dark brown birthmark covering up to 80% of the body and in varying forms, such as flat, raised, lumpy, hairy, itchy and fragile. Raised and lumpy CMN can be limiting for our members, affecting mobility, and often affecting sleep due to itch. There is also a small increase in the risk of developing melanoma when CMN is present on the skin.
CMN can also express itself beyond the skin, causing neurological complications and medical complexities, which in the worst cases can be fatal. These expressions are not exclusive to one another e.g. someone with raised, lumpy CMN could also experience neurological complications. What is key to remember, as a mosaic disorder, CMN must be present on the skin if it is to be present internally.
Different expressions of CMN have different risks of melanoma; the overall absolute risk for all expressions of CMN is low. However, when melanoma does develop in CMN it is highly aggressive.
Dependent upon the CMN expression, surgery may be required. As a charity, we are here to support our members, whatever their experience and expression of CMN is. This article hopes to further explain the broad range of expressions caused by CMN.
Genetic cause of CMN
CMN is a rare disease, affecting 1 in 20,000 births. CMN is not “just a birthmark” rather, it is now understood as a Mosaic Disorder because CMN is caused by a genetic mutation (change or ‘spelling mistake’) in a single cell as the baby develops during pregnancy. This leads to the baby being born with a mixture of normal cells (not carrying the mutation) and disease cells (carrying the mutation), which is referred to as mosaicism. This event can happen to any child, and importantly is not inherited from either parent. Mosaic disorders affecting the skin are most known because it is possible to see the effects on the skin as birthmarks.
An MRI scan is recommended for all children born with multiple CMN to determine the presence of any pigment in the brain or nervous system. An earlier MRI allows for a clearer scan. MRI results can be used as a framework for the child’s development and expression of CMN, as it will determine whether the CMN is internal.
Currently, there is no cure for CMN. As a charity we partner with Professor Kinsler and her research team at Great Ormond Street Institute of Child Health and The Francis Crick Institute to fund the CMN research taking place. In recent years, Professor Kinsler’s team have found the CAUSE of CMN and now they are working towards finding a CURE. To do this the research team use skin biopsies, donated by our members, to study the behaviour of CMN cells. Through biopsies their study found that the NRAS gene is the most common cause of CMN of any size and any number. The BRAF gene has been found as a cause for 7% of CMN, which is much less common than the NRAS mutation. In some patients, there are no spelling mistakes, but two genes get stuck together, which shouldn’t happen. This phenomenon stops the gene from doing its normal function causing the skin problems associated with CMN, this is known as a BRAF Fusion. Research has shown that adverse outcomes did not differ between genotypes of people with CMN. It did not matter if the person with CMN had BRAF or NRAS ‘spelling mistake’.
Raised and itchy CMN
CMN can develop nodules that can cause uncertainty. The BRAF gene can be responsible for making the CMN very itchy and very prone to growing firm lumps and ridges.
Skin cells containing BRAF gene fusions have been found to grow much faster than cells containing NRAS/BRAF spelling mistakes or no mistakes at all. This could explain why some members develop lumps, as the cells with the fusions divide excessively.
Risk of melanoma
Histology (the study of cells under a microscope) of CMN is difficult and often requires specialist review. A review should be carried out by at least two experts in the field. A genetic analysis of an individual’s CMN can help to differentiate melanoma from benign nodules in the skin, or from stable congenital disease in the Central Nervous System.
Small single CMN are common birthmarks with very low risk of melanoma, and do not require routine resection for this reason. Multiple CMN have a higher risk of melanoma due to larger area of skin covered. Different expressions of CMN have different risks of malignancy; however, the overall absolute risk for all types of CMN taken together is low. Where melanoma does arise in children with multiple CMN, a primary melanoma in the Central Nervous System is as common as in the skin. Melanoma can arise either in the skin or in the brain, the latter being more common in a study of affected children. The strongest statistical risk factor for all‐site melanoma in childhood is an abnormal screening MRI of the Central Nervous System (CNS) in the first months of life. When melanoma does develop in CMN it is highly aggressive. Central Nervous System melanoma currently has 100% mortality. We continue to fund pioneering research to find the cure for CMN through our partnership with Professor Kinsler and her research team. We have a vision of a world where no one suffers from CMN.
CMN syndrome
A syndrome is a collection of findings in one individual that can potentially be explained by the same genetic change. We believe the term CMN syndrome is useful to alert healthcare professionals to aspects other than the skin.
Neurological problems associated with CMN used to be called Neurocutaneous melanosis. This term is no longer used for two important reasons. The first reason is that some of the problems are not actually “melanosis”, in other words they are not a problem of pigment cells. The second reason is that in the medical literature neurocutaneous melanosis is often actually melanoma of the brain or spinal cord, and this has caused big problems with trying to advise families on diagnosis. We now prefer to call the neurological problems by their actual names – so if it is benign intraparenchymal melanosis (e.g. moles in the brain) we say so, and if it is melanoma of the brain or spine we say so. This allows us to give better information to parents and patients and has allowed us to divide the causes into serious and less serious.
Overall, problems in the brain or spinal cord are the most common complication seen in children with CMN. The most common problem is pigment-containing cells (like a CMN) in the substance of the brain. This is called intraparenchymal melanosis. Other rarer problems include benign brain or spinal tumours, too much fluid in the brain, or abnormal brain structure. All of these neurological problems are more common with larger and more numerous CMN. Our current recommendations are that any child born with two or more CMN should have a routine MRI scan of the brain and spine, preferably by the age of 6 months.
The overall chance of finding an abnormality on an MRI scan in children with multiple CMN (two or more at birth) is around 20%, but only around half of these children will have any actual problems. If they do have problems these can be fits (convulsions), developmental delay, or problems with their limbs. It is possible to have problems in development even when the scan is normal, but these tend to be milder. The reason for doing the scan is to pick up the rare cases of tumours and extra fluid on the brain that require an operation, and to allow us to monitor development more carefully in children with MRI findings. In addition, some of the findings alert us to monitor the children more carefully for the development of melanoma, by having more MRIs. Most children however will only have one scan.
Not only do we recommend this single screening scan, but anyone with multiple CMN who develops new problems with development or fits or limbs, or persistent headaches over a long period, or any problems which could be due to brain or spine disease should have a repeat MRI to look for the development of melanoma.
Click here to view our Medical Booklet online or to order your free copy.
Support available
If you or your child has been diagnosed with any of the above medical complexities due to CMN, there is dedicated support available. Please contact the charity’s support helpline 0300 373 3422 or email support@caringmattersnow.co.uk
