What Is CMN

Genes are the instructions which make a person.  We inherit them from our parents.  However, once they are inside a new developing embryo in the womb, there can be changes in the genes.

CMN are caused by a change (mutation) in a gene, which occurs when the embryo is developing in the womb. Changes in genes happen spontaneously in all developing embryos and babies. Mostly the changes don’t appear to have much or any effect, and in fact they are important in making us different from our parents, and important in evolution. Sometimes, however, the gene change is very important, and can have a major effect on the developing baby, for example in this case leading to CMN. CMN therefore arise by chance, and are not due to something the parents did or didn’t do.  They are also not inherited from the parents, despite being to do with genes.  They are also not passed on to the children of the person with a CMN.  Some families are more prone to having CMN, but it is extremely unusual to have more than one person with very large or multiple CMN in the same family.

So far two genes have been definitely demonstrated to cause CMN when they have a change (mutation).  The commonest is a gene called NRAS, which accounts for about 70% of CMN cases, and is the commonest cause of any size of CMN.  The second gene is called BRAF, which is a much rarer cause of CMN, first described in one case recently, and accounting for about 7% of cases.  NRAS and BRAF are genes which control the signalling that goes on inside cells, telling them when to grow and divide, and when to stop.  When they have a mutation they promote extra growing and dividing, which leads to too many pigment cells.

There have also been cases described as having fusions of other genes (where two genes get stuck together), which is highly likely to be a new cause of CMN.  So far however these have only been described in single patients, or have only been demonstrated in one CMN from a patient with many CMN, which can make it difficult to be certain if it is the cause of the CMN or just an extra finding, so at the moment we are awaiting more details on this.  More news on genes will keep being published from lots of different scientific groups in the coming years.

CMN are currently still classified mainly according to the size they will be in adulthood (known as “projected adult size”). This is a difficult definition to understand because different parts of the body grow at different rates, but it is used to give doctors a way of comparing different CMN. Another feature which is usually noted are the total number of CMN (the small ones are sometimes called satellites, but they are all actually CMN). Where the numbers are small we tend to count them, but for large numbers we estimate.  Usually, but not always, these two measures go together – in other words very large CMN are usually accompanied by lots of other naevi.

There are different versions of this type of classification, with the latest published one in this reference¹.  Other features collected in this classification are hairiness, and changes in the surface of the skin including lumps (nodules).  We are learning more about the importance of different types of classification all the time.

¹ Krengel, S., Scope, A., Dusza, S.W., Vonthein, R. & Marghoob, A.A. New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol 68, 441-51 (2013).

In many children the CMN will lighten to some degree in the first few years of life, and sometimes it can be very pronounced, particularly on the scalp¹. This has recently been studied in detail using colour measurements.  It was found that more lightening happens in children with lighter coloured hair and lighter coloured skin,  than in those with darker hair and skin colour².  Importantly, the colour of the CMN itself at birth is not connected to the colour it will eventually end up on its own.  CMN at birth are often very dark or black, and this is thought to be related to maternal hormones from during the pregnancy, or other factors we don’t yet understand.  It can be compared to the fact that babies are often born with completely different hair colour than they will eventually have, and the same with eye colour. The same study demonstrated that superficial removal techniques (which are dermabrasion, curettage, and laser therapy) only temporarily cause lightening of the CMN.  When areas of treated CMN and untreated CMN in the same person where measured over time, it was found that the treated areas got darker again after the treatment, and the untreated areas gradually lightened to the person’s natural colour.  These treatments are therefore not recommended for lightening of CMN.

1. Strauss, R.M. & Newton Bishop, J.A. Spontaneous involution of congenital melanocytic nevi of the scalp. J Am Acad Dermatol 58, 508-11 (2008).
2. Polubothu, S., Kinsler, V.A. Longitudinal study of congenital melanocytic naevi reveals that final colour is determined by normal skin colour, and is unaltered by superficial removal techniques. British Journal of Dermatology (2019 (under review)).

A consensus note on terminology from the NI leader team

The term neurocutaneous melanosis is not a term we use any more.  There is a very simple reason for this, which is that it is not specific enough, and can therefore be misleading for doctors and patients and families.

This term was first suggested 60 years ago, and it was actually used to describe a different condition, not related to CMN.  Later on it came to be used for CMN instead, whenever CMN was associated with any type of problem in the brain.  People then started using the term to relate back to a case described more than 150 years ago, of a patient with CMN who had died of what we now know was melanoma affecting the brain and spinal cord.  And in fact, all the early cases of what was called neurocutaneous melanosis could only be reliably diagnosed when the patient died of the brain problems, in other words at post-mortem examination.  As a result the general feeling was that having neurocutaneous melanosis was very serious, and likely to kill you.  This was a common medical mistake in previous times.

Once MRI was invented, MRI scans started to be used to look at the brains of people with CMN, and it was discovered that there were quite commonly changes in the brain (see below) which weren’t causing any problems to the person at all.  This was then also called neurocutaneous melanosis.  So the medical literature has been using the same term of neurocutaneous melanosis to describe any change in the brain or spinal cord in a person with CMN.  This would be the same as if we wanted to use only one term for a CMN, or for a melanoma on the skin – which none of us would do.  You have to distinguish between something benign, and something malignant.  You cannot call them both the same thing.  An attempt to address this was made by adding “asymptomatic” and “symptomatic” to the term neurocutaneous melanosis, but we know now that this is not adequate either, as lots of people with benign brain disease can have symptoms, and it doesn’t mean they have a bad prognosis (life expectancy or outlook).  The term neurocutaneous melanosis is therefore not an adequate diagnosis – people or their parents should actually be told if they have congenital brain/spine problems which are benign (and can be thought of as equivalent to having CMN on the skin, and where the prognosis is excellent, even if they have symptoms), or if they have melanoma of the brain/spine (where the prognosis is poor).

So what do we use instead of the term neurocutaneous melanosis?

Here are the diagnoses we suggest are used:

1. Single CMN– one only at birth, any size or site
2. Multiple CMN – more than one at birth, any size or site
3. CMN syndrome – CMN on the skin with the addition of any other complication, most commonly benign congenital changes in the brain or spine
4. CMN with melanoma of the skin
5. CMN with melanoma of the brain or spine

This allows patients and doctors to know exactly what they have, what their prognosis (outcome) is likely to be, and what treatment they should have.

Details of the different things that can happen in the brain and spine in people with CMN

Differences in the brain or spinal cord are the most common complication seen in people with CMN, and can be detected on MRI scan. The commonest difference is to have abnormal pigment-containing cells within the substance of the brain^1-3 (not in the covering of the brain which is known as the meninges).  These have been called “intraparenchymal melanosis” – which means pigment areas within the brain substance (known as the parenchyma).   These can be thought of as a bit like a having moles within the substance of the brain, and they are benign. They are not malignant, and do not need a biopsy (sample) if the changes on MRI are typical^1,2 .  They also do not need to have neurosurgery (brain surgery).  In about half the cases they cause problems with neurodevelopment, or with seizures.  In the other half of cases they don’t cause any apparent problems at all^2,4.   In addition, they do not seem to increase the risk of melanoma in childhood at least.

Other much rarer problems include benign brain or spinal tumours, too much fluid in or around the brain (known as hydrocephalus), or abnormal brain structure (many references, but these recent papers lists many of the others)^2,3. All of these problems can be benign, but in these rare cases, and particularly in cases of problems around the spine or with excess fluid in or around the brain, it is very important for the doctors to consider each case separately and usually they will require repeat brain scanning and possibly a biopsy (taking a sample) from the brain or spine. Some of them will require neurosurgery to help correct the abnormalities.  Some people (but not all) with this sort of rare problem can be at increased risk of developing melanoma in the brain or spine.

All of these neurological problems are more common with larger and more numerous CMN, but there is no connection with the site of the CMN. In other words having a CMN overlying the brain or spine does not increase the chance of having neurological problems. Serious problems in the brain or spine have not so far been described in people with a single CMN, no matter where it is or how large.

MRI scanning of the brain and spine

Our current recommendation based on the whole of the published medical literature is that any child born with two or more CMN of any size or site should have a routine MRI scan of the brain and spine in the first year of life, preferably before the age of 6 months. It is not possible to say that MRI abnormalities could never occur in children with only one CMN at birth, but the risk is much less.  If the child is well at the age of two years and hasn’t had a scan, then a scan is not needed in retrospect as even if there is something there it is unlikely to require intervention.

The reasoning behind this recommendation is the following:

1. The MRI scan result can be divided into the following 3 categories:

• a. normal
• b. intraparenchymal melanosis only (see above)
• c. all other abnormalities on MRI scan (see above)

2. The MRI results are the best predictor of clinical problems

• a. Normal MRI – low chance of melanoma in childhood; low chance of seizures in childhood; low chance of neurodevelopmental problems (and where they do occur they are generally mild)
• b. Intraparenchymal melanosis only – low chance of melanoma in childhood; some risk of seizures(fits); some risk of neurodevelopmental problems
• c. All other abnormalities on MRI scan – this depends very much on each individual case which will be assessed by the individual medical team, but if the group is considered as a whole: some risk of melanoma; considerable risk of needing neurosurgery; considerable risk of seizures (fits); considerable risk of neurodevelopmental problems

3. The MRI results therefore guide clinical management

• a. Normal MRI – scan doesn’t need to be repeated routinely, no routine monitoring of child development
• b. Intraparenchymal melanosis only – scan doesn’t need to be repeated routinely, yearly monitoring of child development until school age, and if problems are detected, appropriate early intervention for developmental support, and institution of a plan for school support
• c. All other abnormalities on MRI scan – individual specialist management is recommended until the child is clearly stable – scan will likely need repeated to see if any changes, neurosurgery may be needed, and risk of melanoma needs to be monitored

Melanoma

• The most important message is that melanoma in people with CMN is rare.
• The second most important message is that you can always ask for someone for a check-up if you are worried you might have melanoma.

For a recent review which references many other papers about CMN in melanoma see this reference⁵.  Melanoma is a cancer of melanocytes, the skin cells which produce pigment and which make up CMN. It used to be thought that melanoma was very common in people with CMN, but we now know that it is rare, occurring in around 1-2% of all people with any size of CMN over their lifetime. However, the risk is higher in people with very large and numerous CMN, and particularly where there are (rare) complex neurological changes in the brain on MRI – in these people it is around 10%, and there is a peak of risk during childhood². When considering these risks, you need to bear in mind that every one of us has a risk of about 50% of developing some kind of cancer at some time in our lives.

Where can melanoma start, and how does it present?
Melanoma in children with CMN can occur anywhere, not just within the CMN. In childhood it seems to be commonest within the brain or spine, when it can present with persistent headaches with nausea/vomiting, or visual disturbances, balance problems or fits^5,6.  It can also occur in the skin, presenting as a lump or other change in the CMN, in another area of skin, or in the lymph nodes (which are throughout the body), or very rarely in other places. Unfortunately, most often it seems to be the case that when malignant melanoma occurs in a person with a CMN, it is aggressive and difficult to treat. Our recommendations are that any rapidly changing area of CMN that doesn’t start to go away again within a couple of weeks should be reviewed by a doctor. Do remember however, that nodules appear in CMN quite frequently, sometimes in response to minor trauma or skin infection, and the great majority are completely harmless. We also recommend that children who develop new neurological problems such as recurrent headaches, visual disturbance, fits, or developmental changes should be seen by a doctor.

How can melanoma be diagnosed?
Melanoma can only be diagnosed reliably by a biopsy (taking a sample), either of the skin, or of the brain/spine depending on where the suspected melanoma has started.  This biopsy will usually be tested by looking under the microscope by experts, and ideally it should also have genetic testing for something called copy number changes (changes in the numbers of chromosomes in the sample).  If melanoma is diagnosed, the same sample can be tested for NRAS and BRAF gene changes, which can help direct treatment.

Further investigations where melanoma is diagnosed might include other types of scans, Xrays, blood tests, and biopsies (samples).

Treatment of melanoma
Since the genetic findings surrounding CMN have been discovered (see “cause of CMN” section of the website), we understand more about why melanoma happens in people with CMN.  This is because the gene changes which cause CMN are also involved in melanoma in the normal population. These findings are helping doctors to try to direct treatments for CMN melanoma better.  Treatment of melanoma in a person with CMN is difficult, however new treatments are being developed all the time for melanoma in the general population, and some of these are likely to be helpful in the future.  The exact treatment will depend on the age of the patient, the site of the melanoma (skin, brain/spine, lymph node), the genetics of the CMN and melanoma (NRAS or BRAF or other changes) and whether the melanoma has spread to anywhere else in the body.  New treatments which are being tried include MEK inhibitor drugs for NRAS-CMN melanoma, and BRAF inhibitors for BRAF-CMN, but the numbers of patients so far is small and more work is needed in this area.

References

1. Barkovich, A.J., Frieden, I.J. & Williams, M.L. MR of neurocutaneous melanosis. AJNR Am J Neuroradiol 15, 859-67 (1994).
2. Waelchli, R. et al. Classification of neurological abnormalities in children with congenital melanocytic naevus syndrome identifies MRI as the best predictor of clinical outcome. Br J Dermatol (2015).
3. Ramaswamy, V., Delaney, H., Haque, S., Marghoob, A. & Khakoo, Y. Spectrum of central nervous system abnormalities in neurocutaneous melanocytosis. Dev Med Child Neurol 54, 563-8 (2012).
4. Frieden, I.J., Williams, M.L. & Barkovich, A.J. Giant congenital melanocytic nevi: brain magnetic resonance findings in neurologically asymptomatic children. J Am Acad Dermatol 31, 423-9 (1994).
5. Kinsler, V., A, O’Hare P, Bulstrode N, Chong WK, Sebire N,J, Hargrave D, Slater O. Melanoma in congenital melanocytic naevi. British Journal of Dermatology In press(2017).
6. Neuhold, J.C., Friesenhahn, J., Gerdes, N. & Krengel, S. Case reports of fatal or metastasizing melanoma in children and adolescents: a systematic analysis of the literature. Pediatr Dermatol 32, 13-22 (2015).
7. Kinsler, V.A., O’Hare, P., Jacques, T., Hargrave, D. & Slater, O. MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children. Br J Cancer 116, 990-993 (2017).

Children with CMN can and should enjoy a normal life. They should have good sun protection but the same as we would recommend for all children. In particular, it is important that they should not become sun burnt.

• As a general rule: sun avoidance, coupled with good clothing protection, are much more important than suncream.
• Sun avoidance: children should be kept out of direct sun as much as possible during the hottest hours of the day and in the hottest months of the year, for example, by staying in the shade. The hottest hours of the day are 10am-4pm, and the hottest months of the year are April to October. Outside these times there is usually no need for sun protection in the UK. This does not mean children should not go outside between 10am-4pm in the hot months, it just means they should stay in the shade where possible and wearing appropriate clothing.
• Good clothing protection: sun hats with a brim that covers ears and the back of the neck as well as the face are ideal, as are longer sleeved tops and longer shorts/skirt.
• Suncream is not a substitute for sun avoidance and good clothing protection: It should, however, be used as extra protection if the child has to be in direct sun during hot periods for areas that are not protected by clothes. The best sunscreens contain a reflectant barrier such as titanium dioxide; select a high protection factor (SPF), ideally 25 or more, and with high UVA protection (4 or 5 stars, usually on the back of the bottle). Sunscreen needs to be refreshed every 2 hours or so, more often when swimming or sweating.
• Other important points to remember
  • UV exposure is much higher when beside water or snow, so special care should be taken when swimming outside or skiing
  • The sun is more harmful at higher altitudes
  • The sun remains almost as harmful when it is cloudy, so even if the day is cloudy the child should wear appropriate clothing such as sunhat during the hottest times of the year
  • Shade provides less protection when near water or snow or when the weather is cloudy
  • The increased risk of skin cancer in children with CMN probably applies to their whole body, not just on their CMN.

We think that the decision to have surgery has to be made on an individual basis, and very much depends if the plastic surgeons think they can improve the appearance, or whether it would not improve. In cases of very large CMN surgery is often not possible. In other cases the following points should be considered:

1. Many CMN will lighten spontaneously to at least some degree over a period of years. This can be monitored with repeat photographs.
2. Surgery has not been shown to reduce the risk of melanoma in the child.
3. Early surgery has not been shown to be advantageous. We do not do any routine surgery before 1 year of age.
4. The site of the CMN is very important – for example the child may get more benefit if a CMN on the face is removed, compared to one hidden in the scalp
5. The size of the CMN is very important- we have found that children with larger CMNs were less pleased with the cosmetic result than those with small lesions which could be completely removed.
6. The number of naevi is important, in particular if the child has a tendency to develop lots of new ones as this may reduce the benefit from removing some.
7. Whether you want your child to take part in the decision, in which case it is better to decide later.
8. What is involve in the type of surgery being offered – this will depend on the individual case.

If a CMN can be removed, for example by excision or serial excision (more than one operation but relatively straight-forward), the cosmetic benefits may easily outweigh the small risks associated with any operation. However, if a CMN is in a difficult place for removal, or if it is too large ever to be removed completely then that balance changes. It is very important in these cases to take time to decide about surgery, particularly to see if the CMN is lightening over time.

Hairiness only needs to be treated if it is causing a problem (eg making an area difficult to clean) or the child or family feel it looks better without hair. An electric shaver is best, and clipping the hair short rather than completely shaving often avoids problems of itchiness with regrowth. Hair removal creams etc should not be used as they can irritate the skin. Shaving does not affect the amount or thickness of hairs that grow. Hair regrowth after shaving is generally slow and the new hairs will have exactly the same appearance and feel as the original ones. Most parents find that they do not need to shave an area more often than once every couple of weeks in order to maintain a satisfactory appearance. Laser hair removal is possible but needs to be done regularly over a relatively long period and needs a general anaesthetic in children under teenage years. Electrolysis is slow and painful and is therefore not suitable for large areas.

Children who grow up with a prominent CMN or many CMN can have psychological issues relating to their different skin, particularly during the teenage years. This, however, is a very individual thing, and varies depending on the child’s personality and on the support from family and friends.  In many cases, where adequate support from friends and family is available, people with CMN can become very confident, as was seen in this recent exhibition.  Some research has been done about whether this has changed other people’s perception of CMN, and this data will be available soon.

It would be ideal if we were able to offer all children at risk some degree of automatic counselling during their childhood, as well as a good support group (for a current list see our website).  That is why Naevus International is actively supporting the creation of new support groups in new countries around the world.  Other organisations can also be very helpful in dealing with visible difference – for example Changing Faces is a support group specialising which has some excellent guidelines and information (www.changingfaces.org.uk)