Kinsler, VA

Polubothu, S

UCL Discovery

Research letterThe ethnic profile of patients with birthmarksreveals interaction of germline and postzygoticgeneticsDOI: 10.1111/bjd.15260DEAR EDITOR, GNA11 and GNAQ are highly homologous genesencoding different Ga subunits of heterotrimeric G-proteins.We recently described postzygotic activating mutations inGNA11 or GNAQ as causes of phakomatosis pigmentovascularis(PPV), and GNAQ mosaicism as a cause of extensive dermalmelanocytosis (EDM).1 GNAQ mosaicism has previously beenfound to cause Sturge–Weber syndrome (SWS) and isolatednonsyndromic port-wine stain-type capillary malformations.2In all of these clinical phenotypes the mutations almost exclu-sively affect codons 183 of the protein products Gaq and Ga11.What is not yet understood is how the same mutations canlead to such differing skin phenotypes, either vascular alone(SWS), pigmentary alone (EDM) or a combination of both(PPV). The existence of a common precursor cell leading toboth the vascular and pigmentary birthmarks is likely, as thesame mutation has been identified in both types of lesion inpatients with PPV. In mosaic disorders we would usuallytherefore invoke the issue of the timing of the mutation as thecause of differing phenotypes, or in other words that themutation leading to PPV would be expected to occur earlier inembryogenesis than that for SWS or EDM. If this were the casewe would expect the multiorgan phenotype in PPV to bemore severe than in SWS, owing to an earlier embryologicalmutation. This was suggested in one case series of PPV;3 how-ever, owing to the well-known phenomenon of dermalmelanocytosis being overlooked as a normal finding by exam-ining doctors,4 it is likely that PPV is currently underdiag-nosed in comparison with SWS, and publications relating toPPV may therefore be biased towards severe cases. Even if tim-ing of the mutation proves to be important once largercohorts are collected, germline genetic factors could also con-tribute to the differences in phenotype observed from thesame mutations.Looking at our patient cohorts we hypothesized that ethnic-ity may be associated with a phenotype-modifying effect inthis spectrum of diseases. Although ethnicity is a looselydefined classification, it is already known to be clearly associ-ated with self-resolving dermal melanocytosis (Mongolian bluespots), which is far more common in Afro-Caribbean thanwhite populations.4 A bias towards nonwhite ethnicity wassuggested in one previous study of PPV,3 but it was not sys-tematically studied against control populations.Ethnicity data are collected routinely upon attendance at ourhospital, where patients and families choose their own(a) (b) (c)Fig 1. Cutaneous phenotypic spectrum of mosaic G-protein disorders. Patients with identical mosaic mutations in GNAQ (codon 183), presentingphenotypically with (a) Sturge–Weber syndrome, (b) phakomatosis pigmentovascularis and (c) extensive dermal melanocytosis.© 2017 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of DermatologistsBritish Journal of Dermatology (2017) 176, pp1385–1387 1385This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.ethnicity from a standard list. We have assumed that thereshould be no inherent bias in this choice relating to the typeof birthmark with which the child presents. Ethnicity datawere extracted for all patients seen in our department over a2-year period, between March 2011 and March 2013, with adiagnosis of SWS, isolated facial port-wine stain, congenitalmelanocytic naevi, congenital epidermal naevi and infantilehaemangioma. For the rarer conditions PPV and EDM, wherepatient numbers were small, we obtained information relatingto all patients with the condition rather than restricting ourobservations to this time period, to maximize the size of thiscohort.A review of the clinical records was used to complete miss-ing data where possible. To ensure that the common occur-rence of self-resolving Mongolian blue spots did not bias ourdata collection, dermal melanocytosis was considered to berelevant only where it was ‘atypical’. On the basis of observa-tional studies of normal Mongolian blue spots4,5 we havedefined this as fulfilling any two of the following criteria: (i)involvement of sites other than only the lumbosacral area, (ii)persistence beyond the first 2 years of life, (iii) areas > 10 cmin diameter at birth and (iv) some areas of accentuated deeppigmentation with clearly defined borders. Examples of theclinical phenotypes for PPV and EDM are shown in Figure 1.(a)(b)Fig 2. (a) Ethnicity of patients with different birthmarks attending Great Ormond Street Hospital paediatric dermatology department. CMN,congenital melanocytic naevus; PWS, isolated port-wine stain; SWS, Sturge–Weber syndrome; EDM, extensive dermal melanocytosis; PPV,phakomatosis pigmentovascularis. Patients who self-reported in the ‘other’ ethnicity cohort were predominantly of Middle Eastern descent. This isnot currently offered as an ethnic category in our hospital’s admission documentation, which uses standardized National Health Service ethniccategory codes derived from the classification used by the Office of National Statistics for the 2001 census. (b) Ethnicity profile of differentbirthmarks comparing white vs. nonwhite ethnicity. *P < 0001 using Fisher’s exact test.© 2017 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of DermatologistsBritish Journal of Dermatology (2017) 176, pp1385–13871386 Research letterThe percentages of different ethnicities in our whole referralcohort revealed a substantial preponderance of white ethnicityin all birthmark groups, as would be expected for our geo-graphical referral population, except for PPV and EDM(Fig. 2a). In these birthmark groupings there were signifi-cantly fewer white patients; there were none in the EDMcohort and only three out of 18 in the PPV cohort. Althoughthe numbers in these groups are relatively low, they are com-parable with the numbers of nonwhite patients in all otherbirthmark groupings. Furthermore, statistical comparison ofPPV or EDM and all other birthmark groupings revealed a sig-nificant difference in white vs. nonwhite ethnicity (P < 0001,Fig. 2b). When only the port-wine stain, SWS, PPV or EDMbirthmarks were analysed (restricting the analysis to these, aswe know they can be caused by GNAQ or GNA11 mosaicism)the same pattern is in evidence; logistic regression modellingof having a pigmentary component to the cutaneous pheno-type produced an odds ratio for white ethnicity of 0017(95% confidence interval 0005–0060, P < 0001). There wasno effect of sex.The mechanism of this association between cutaneous phe-notype within this diagnostic spectrum and ethnicity is notyet clear. However, we hypothesize that germline ethnicity-associated variants in pigment genes could be involved, per-haps including the melanocortin-1 receptor gene MC1R, whichencodes a G-protein-coupled receptor. Variants in MC1R arealready known to modify the phenotype of congenital pig-mentary disorders such as oculocutaneous albinism and con-genital melanocytic naevi.6,7 Furthermore, although thecanonical signalling pathway from MC1R is via cyclic AMP,there is some evidence that signalling via calcium release canoccur,8,9 which could support this hypothesis of coupling ofMC1R to Gaq and Ga11.In conclusion, postzygotic mosaicism for GNA11 and GNAQmutations causes an overlapping phenotypic spectrum of vascu-lar and melanocytic birthmarks, with associated ophthalmologi-cal, neurological, overgrowth and malignant complications.Ethnicity appears to be associated with congenital phenotypicvariation in the cutaneous component of this spectrum ofmosaic disease.S . POLUBOTHU1,2V .A . K IN S L E R 1,21Genetics and Genomic Medicine, UCLInstitute of Child Health, London, U.K.2Paediatric Dermatology, Great Ormond StHospital for Children, London, U.K.E-mail: s.polubothu@ucl.ac.ukiD http://orcid.org/0000-0001-7195-5670References1 Thomas AC, Zeng Z, Riviere JB et al. Mosaic activating mutations inGNA11 and GNAQ are associated with phakomatosis pigmentovascu-laris and extensive dermal melanocytosis. J Invest Dermatol 2016;136:770–8.2 Shirley MD, Tang H, Gallione CJ et al. Sturge-Weber syndrome andport-wine stains caused by somatic mutation in GNAQ. N Engl J Med2013; 368:1971–9.3 Hall BD, Cadle RG, Morrill-Cornelius SM et al. Phakomatosis pig-mentovascularis: implications for severity with special reference toMongolian spots associated with Sturge–Weber and Klippel–Trenau-nay syndromes. Am J Med Genet A 2007; 143a:3047–53.4 Cordova A. The Mongolian spot: a study of ethnic differences and aliterature review. Clin Pediatr 1981; 20:714–19.5 Gupta D, Thappa DM. Mongolian spots – a prospective study. PediatrDermatol 2013; 30:683–8.6 King RA, Willaert RK, Schmidt RM et al. MC1R mutations modifythe classic phenotype of oculocutaneous albinism type 2 (OCA2).Am J Hum Genet 2003; 73:638–45.7 Kinsler VA, Abu-Amero S, Budd P et al. Germline melanocortin-1-receptor genotype is associated with severity of cutaneous pheno-type in congenital melanocytic nevi: a role for MC1R in humanfetal development. J Invest Dermatol 2012; 132:2026–32.8 Tsatmali M, Yukitake J, Thody AJ. ACTH1–17 is a more potent ago-nist at the human MC1 receptor than alpha-MSH. Cell Mol Biol 1999;45:1029–34.9 Mountjoy KG, Kong PL, Taylor JA et al. Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells.Physiol Genom 2001; 5:11–19.Funding sources: V.A.K. is funded by the Wellcome Trust U.K., awardnumber WT104076MA.Conflicts of interest: none declared.© 2017 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of DermatologistsBritish Journal of Dermatology (2017) 176, pp1385–1387Research letter 1387

The ethnic profile of patients with birthmarks reveals interaction of germline and postzygotic genetics

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The ethnic profile of patients with birthmarks reveals interaction of germline and postzygotic genetics

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