Expressions of CMN

Genetic cause of CMN

CMN is a rare disease, affecting 1 in 10-20,000 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. The effects of the mutation depend on lots of different things. The most important ones are when it occurs and whereabouts it occurs in the body. In general, the earlier the mutation happens, the more serious the disease will be. As a result of the variability, each child with a mosaic disorder is unique in their disease and needs to be assessed uniquely. Mosaic disorders affecting the skin are currently the best known because it is possible to see the effects on the skin as birthmarks. As a result, although they often affect many body systems as well as the skin, mosaic disorders affecting the skin are looked after by Paediatric Dermatologists and Dermatologists. This Rare Disease Collaborative Network (RDCN) focuses on the severe end of the spectrum of these diseases.

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 definitive treatment 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, the causes of CMN have started to be understood by the CMN research team studying the genes in CMN cells through skin biopsies, donated by people with CMN.  These studies have found that changes (known as mutations) in a gene called NRAS  are the most common cause of CMN of any size and any number. Overall, in one big cohort it causes 67% of cases. 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. Most of the fusions found have been the same with the BRAF and were responsible for the CMN being very itchy and forming lumps or ridges. 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. Our vision is to live in a world where no one suffers from CMN through providing tailored support for every expression of CMN, educating the healthcare profession about CMN, changing negative perceptions of CMN as a visible difference, and developing effective treatments for all expressions of 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.

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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