Stunning observation leads to medical discovery

Categories: CMN Research
Veronica Kinsler

Veronica Kinsler from Great Ormond Street Hospital in London presents her findings to the special Congenital Melanocytic Nevus meeting held at the 2011 International Pigment Cell Conference in Bordeaux, France

Pediatric dermatologist Veronica Kinsler, MD, PhD, has been involved with caring for children with congenital melanocytic nevi (CMN) at Great Ormond Street Hospital (GOSH) in London since 1997.  But it wasn’t until about 2005, when she attended a Family Day at the CMN support group Caring Matters Now, that something curious caught her eye for the first time.  

Many British families affected by a nevus had red hair!

A CMN is a pigmented birthmark that may cover a significant part of the body.  So rare, this birthmark affects only about one child in every 20,000 births.  Scientists had long considered it to be sporadic in occurrence, with no family link whatever.  Now Kinsler wondered:  Could the melanocortin-1-receptor gene (MC1R) — known to result in red hair, freckles, and pale skin, — be associated with CMN?  She needed to know.

Kinsler recruited 166 boys and girls with CMN from the GOSH clinic.  These children had their blood checked for MC1R and had their hair and eye color recorded.  Results were compared with two control groups.  One group of 60 sex-matched children without CMN was from the same school or geographical area as the children with CMN.  Another group of 300 children without CMN was from the Avon Longitudinal Study of Parents and Children in the UK.  Comparisons between all these boys and girls were restricted to white-skinned children with four Northern European grandparents.  

Kinsler and her colleagues found a clear association between the MC1R gene and CMN.  They published their findings in the May 10, 2012 issue of the Journal ofInvestigative Dermatology.  

The MC1R gene has more than 100 known variants, each with a slightly different DNA spelling.  Children inherit one copy of the gene from each parent.  In this study, a third of children with CMN had a first- or second-degree family history of any size of CMN.  Small CMN are very common, occurring in one in every 100 babies.  These children had a higher instance of at least one MC1R allele than children without a family history of CMN.

Kinsler was especially surprised to learn that two specific variants — V92M and R151C  — are strongly associated with increased birth weight, suggesting a previously unknown role for MC1R in normal fetal development.  In children with CMN, the presence of these and a few other alleles appear also to correlate with increased size of the CMN.  

 “The finding that variants in MC1R are associated with CMN is important, because it is the first finding in this condition that explains why certain families may be more likely to have CMN than others,” says Kinsler.  She cautions “Large CMN are very rare, and having red hair in the family is very common, so people should not think that having red hair will lead to a CMN.”

These genetic studies in the future may also help to identify children most at risk for complications from CMN, such as skin cancer (melanoma).  
“It is already known that some changes in MC1R are associated with a higher risk of skin cancer, and that this is not only because of having paler skin.  It may be that having certain changes in this gene make skin cancer a little more likely in certain patients with CMN.  However, changes in MC1R are unlikely to be the only reason for the chance of skin cancer being raised in CMN.”

This study is significant, Kinsler says, because it has allowed researchers a glimpse of the underlying mechanisms behind this condition on a genetic and molecular level.

In addition to the research funded by Nevus Outreach and others, this finding may guide scientists toward treatments for large congenital melanocytic nevi.

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