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. 2012 Aug;132(8):2026-32.
doi: 10.1038/jid.2012.95. Epub 2012 May 10.

Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development

Veronica A Kinsler  1 , Sayeda Abu-Amero, Peter Budd, Ian J Jackson, Susan M Ring, Kate Northstone, David J Atherton, Neil W Bulstrode, Philip Stanier, Raoul C Hennekam, Neil J Sebire, Gudrun E Moore, Eugene Healy
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Free PMC article

Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development

Veronica A Kinsler et al. J Invest Dermatol. 2012 Aug.
Free PMC article

Abstract

Congenital melanocytic nevi (CMN) are pigmented birthmarks that affect up to 80% of the skin surface area. The increased frequency of CMN in families of severely affected individuals is suggestive of a predisposing germline genotype. We noted a high prevalence of red hair in affected families, and considered a role for MC1R in this condition. A cohort of 166 CMN subjects underwent pigmentary phenotyping, with MC1R genotyping in 113. Results were compared with a local control group of 60 unrelated children and with 300 UK children without CMN. CMN subjects had higher prevalences of red hair and a red-haired parent than local controls and had a higher rate of compound heterozygosity and homozygosity for MC1R variants. The presence of a V92M or R allele (D84E, R151C, R160W, D294H) was associated with increasing size of the CMN, implying a growth-promoting effect of these alleles. Unexpectedly, the V92M and R151C alleles were also strongly associated with birth weight in the CMN cohort, a finding confirmed in the control group. The effect of germline MC1R genotype on development and severity of CMN led us to investigate potential broader effects on growth, revealing a role for MC1R in normal fetal development.

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Figures

Figure 1
Figure 1
Clinical images of children with congenital melanocytic nevi (CMN). Examples of (ai–v) red-haired children with CMN, and (b) different cutaneous phenotypes of CMN. (i) Projected adult size (PAS) 10–20 cm, (ii) PAS >60 cm with several other nevi also visible. Written, informed consent was obtained for publication in all cases.
Figure 2
Figure 2
Association between MC1R genotype and severity of cutaneous phenotype in congenital melanocytic nevi (CMN). Dot plot of proportions of V92M- or R allele–positive individuals with increasing projected adult size of largest CMN.
Figure 3
Figure 3
Association between MC1R genotype and birth weight. Effect of the presence of V92M or R151C alleles on birth-weight standard deviation score (SDS) in (a) the congenital melanocytic nevi (CMN) cohort, and (b) control group B. SDS includes the effects of gestation and sex, and a score of +1 is equivalent to an increase in one SD from the mean of the population. Error bars are 95% confidence intervals.
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