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Background: Spontaneous lightening of congenital melanocytic naevi (CMN) has not been studied systematically. Final colour is considered an important outcome after superficial removal techniques such as curettage, dermabrasion or laser ablation, and is often compared with colour at birth., Objectives: To quantify the natural history of CMN lightening over time, and explore phenotypic and genotypic predictors of colour change., Methods: A longitudinal cohort study was undertaken of 110 patients with CMN (mean follow-up 5·3 years). Accurate colour-space measurements were taken from professional serial photographs of CMN and normal skin. Changes in colour over time were modelled using multiple logistic regression, against phenotypic and genotypic variables., Results: Lightening of CMN was significantly associated with lighter normal skin colour (P < 0·001) and with MC1R variant alleles (red/blonde hair gene) (P < 0·001), but not with CMN colour in the first 3 months of life, NRAS genotype or projected adult size of CMN. Importantly, the final colours of adjacent treated and untreated areas of CMN were indistinguishable., Conclusions: Final CMN colour in childhood is related to the genetically determined skin colour of the individual, is unrelated to the colour of CMN at birth, and is unaffected by superficial removal. What's already known about this topic? Final colour of congenital melanocytic naevi (CMN) is considered an important outcome after superficial removal techniques such as curettage, dermabrasion or laser ablation, and is often compared with colour at birth. The phenomenon of spontaneous lightening in CMN, in which naevi lighten gradually and sometimes dramatically during childhood, has been described but not systematically studied. What does this study add? Final CMN colour in childhood is significantly associated with the individual's normal skin colour, and with MC1R genotype, and is therefore genetically determined. Final CMN colour is not predictable from CMN colour in the first 3 months of life. Superficial removal techniques do not alter the final colour of CMN., (© 2019 British Association of Dermatologists.)

Background: Genotype-phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management., Objectives: To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype-phenotype and genotype-outcome associations., Methods: We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high-sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]., Results: Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild-type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild-type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF-mutant multiple CMN, however, this genotype is rare., Conclusions: CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70-80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. There has been debate about genotypic association with different sizes of CMN, and no data on genotype-outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild-type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype. Adverse outcomes did not differ between genotypes on current numbers., (© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Congenital melanocytic naevi (CMN) are a known risk factor for melanoma, with the greatest risk currently thought to be in childhood. There has been controversy over the years about the incidence of melanoma, and therefore over the clinical management of CMN, due partly to the difficulties of histological diagnosis and partly to publishing bias towards cases of malignancy. Large cohort studies have demonstrated that melanoma risk in childhood is related to the severity of the congenital phenotype. New understanding of the genetics of CMN offers the possibility of improvement in diagnosis of melanoma, identification of those at highest risk, and new treatment options. We review the world literature and our centre's experience over the last 25 years, including the molecular characteristics of melanoma in these patients and new melanoma incidence and outcome data from our prospective cohort. Management strategies are proposed for presentation of suspected melanoma of the skin and the central nervous system in patients with CMN, including use of oral mitogen-activated protein kinase kinase inhibitors in NRAS-mutated tumours., (© 2017 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The formation of a nodule within a congenital melanocytic nevus (CMN) raises concerns about possible melanoma. Most new nodular growths that develop during childhood, however, are benign proliferative nodules (PN); melanoma is very rare. The distinction of melanoma from PN can at times be difficult clinically and histopathologically, requiring ancillary molecular tests for diagnosis. Although the application of molecular methods has revealed new insights into the mutational and genomic landscape of childhood melanomas, little is known about epigenetic events that may drive the growth of a melanoma or PN in a CMN. In this study we compared the expression of H3K27me3, a key regulator in chromatin remodelling-controlled transcription, in PNs and pediatric nodular melanomas arising within medium-sized to large CMN by immunohistochemistry. Significant loss of H3K27me3 expression was seen in 4 of 5 melanomas, but not in any of the 20 PNs. This observation suggests that epigenetic events likely play a role in the pathogenesis of melanoma developing in the dermis or subcutis of CMN. Furthermore, assessing for H3K27me3 expression by immunohistochemistry may be diagnostically useful for problematic cases.

Background: The spectrum of central nervous system (CNS) abnormalities described in association with congenital melanocytic naevi (CMN) includes congenital, acquired, melanotic and nonmelanotic pathology. Historically, symptomatic CNS abnormalities were considered to carry a poor prognosis, although studies from large centres have suggested a much wider variation in outcome., Objectives: To establish whether routine MRI of the CNS is a clinically relevant investigation in children with multiple CMN (more than one at birth), and to subclassify radiological abnormalities., Methods: Of 376 patients seen between 1991 and 2013, 289 fulfilled our criterion for a single screening CNS MRI, which since 2008 has been more than one CMN at birth, independent of size and site of the largest naevus. Cutaneous phenotyping and radiological variables were combined in a multiple regression model of long-term outcome measures (abnormal neurodevelopment, seizures, requirement for neurosurgery)., Results: Twenty-one per cent of children with multiple CMN had an abnormal MRI. Abnormal MRI was the most significant predictor of all outcome measures. Abnormalities were subclassified into group 1 'intraparenchymal melanosis alone' (n = 28) and group 2 'all other pathology' (n = 18). Group 1 was not associated with malignancy or death during the study period, even when symptomatic with seizures or developmental delay, whereas group 2 showed a much more complex picture, requiring individual assessment., Conclusions: For screening for congenital neurological lesions a single MRI in multiple CMN is a clinically relevant strategy. Any child with a stepwise change in neurological/developmental symptoms or signs should have an MRI with contrast of the brain and spine to look for new CNS melanoma., (© 2015 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Multiple congenital melanocytic naevi (CMN) in one individual are caused by somatic mosaicism for NRAS mutations; however, the lineage of the mutated cells remains uncertain., Objectives: To test the hypothesis that CMN may be derived from cutaneous stem cells., Methods: Sixty-six CMN samples from 44 patients were stained for immunohistochemical (IHC) markers of melanocytic differentiation (TYR, TRP1, TRP2, LEF1, MITF, cKit), pluripotency (nestin, fascin, CD133, CD20, CD34), monocyte/macrophage lineage (CD68, CD163, CD14), proliferation (Ki67) and MTOR/Wnt-signalling pathway activation (pS6, β-catenin). Semiquantitative scoring compared samples with naevus cell nesting (group 1) with those with only diffuse dermal infiltration (group 2). Transmission electron microscopy (TEM) was performed on 10 samples., Results: A normal melanocyte population was seen overlying many dermal CMN. Group 1 samples were significantly more likely to express melanocytic differentiation markers than group 2, and expression decreased significantly with depth. Expression of these markers was correlated with each other, and with nestin and fascin. CD20 staining was positive in a substantial proportion and was stronger superficially. Expression of β-catenin and pS6 was almost universal. Some samples expressed monocyte/macrophage markers. TEM revealed variable naevus cell morphology, striking macromelanosomes, double cilia and microvilli., Conclusions: Congenital melanocytic naevi development frequently coexists with normal overlying melanocyte development, leading us to hypothesize that in these cases CMN are likely to develop from a cell present in the skin independent of, or remaining after, normal melanocytic migration. IHC and TEM findings are compatible with CMN cells being of cutaneous stem-cell origin, capable of some degree of melanocytic differentiation superficially., (© 2013 The Authors BJD © 2013 British Association of Dermatologists.)

The term "satellite lesions" is used in many conditions in dermatology, generally to describe smaller lesions near the edges of a principal lesion. An online medical dictionary gives the definition "a smaller lesion accompanying a main one and situated nearby," and this can apply both macroscopically and microscopically. The implication is that the smaller lesions have spread from the parent lesion. Given this definition and usual understanding of the term its use is not apt in the case of congenital melanocytic nevi (CMN). In the vast majority of cases where the patient is said to have satellite lesions these are not restricted to the area around or near the edge of the principal lesion, and are not necessarily significantly smaller. It seems likely that the early use of the term in this condition is an adaptation of the established and correct use in the context of melanoma. Not only is the term not apt clinically but has no known etiological basis. This leaves us with the question of what to call these lesions in cases of CMN. This proposal is to categorize cases into single or multiple CMN, where multiple is 2 or more nevi of any size at birth. An accurate count or good estimate of the number of lesions at birth should also be recorded, and the largest lesion classified as usual with respect to projected adult size., (© 2011 Wiley Periodicals, Inc.)

Recent advances in research have prompted this review of the role of surgery in the management of congenital melanocytic naevi (CMNs). Good data on the incidence of neurological and malignant complications of CMNs have re-fuelled the debates on whether surgery decreases the risk of malignant melanoma and whether early surgery is advantageous. We conclude the following: 1) untreated CMNs can lighten spontaneously, sometimes dramatically, 2) routine surgery has not been demonstrated to reduce the risk of malignancy and is, therefore, for cosmetic reasons only, 3) early surgery has not been shown to be advantageous and carries increased anaesthetic risk and 4) there is some evidence that surgical intervention may adversely affect the behaviour of the CMN cells. Our current practice is based on the following guidelines: 1) patients are treated in a multidisciplinary-team setting which includes the specialties of paediatric dermatology, plastic surgery and neuroradiology with access to neurology, neurosurgery and oncology, 2) serial photographs are taken at yearly intervals to assess spontaneous lightening. 3) all routine surgery is delayed for at least the first year. 4) patients with facial CMNs (either the principal lesion or large satellites) are offered surgery for cosmetic reasons, 5) patients with a single, easily excisable CMN are offered surgery for cosmetic reasons and 6) all families are made aware of the possibility of spontaneous lightening and the possibility that surgery may have effects on the behaviour of naevus cells.

Background: The treatment of congenital melanocytic naevi (CMNs) has become controversial as better data on complications have been published., Objectives: To determine the longer-term risks and benefits of surgery in treatment of CMNs., Methods: In this 19-year prospective study, 301 families completed yearly questionnaires about treatments and CMN changes. Forty per cent of CMNs were > 20 cm projected adult size (PAS) or multiple CMNs., Results: Girls were more likely to have had surgical treatments. There were no significant effects of treatment on the incidence of adverse clinical outcomes, although the numbers for melanoma were small. The majority of untreated CMNs lightened spontaneously during the follow-up period. Surgical treatment and satellites at birth were independently significantly associated with reported darkening of the CMN over the follow-up period. However there was no absolute measurement of final colour. Surgical treatment was associated with decreasing hairiness of the CMN over the follow-up period. PAS was associated with increasing hairiness. Excision with tissue expanders and PAS were significantly associated with an increased incidence of new satellite lesions. A proportion of patients reported new pigmentation in previously unaffected skin at the edge of a treated area, the majority after complete excision. There was a high level of satisfaction with surgery in the < 20 cm group and in those with facial CMNs. This was significantly reduced with increasing PAS., Conclusions: There is no evidence here that surgery reduces the incidence of adverse clinical outcomes in childhood. The natural history of the majority of untreated CMNs is to lighten spontaneously, whereas some treatments may cause adverse effects.

Background: The aetiology of congenital melanocytic naevi (CMNs) is unknown., Objectives: To identify potential aetiological factors in families of children with CMNs, and to relate these to long-term outcome measures., Methods: Three hundred and forty-nine CMN families completed questionnaires about pregnancy and parental factors, and yearly questionnaires on the health of their child and details of the CMN. Seventy-nine control families completed one set of questionnaires, excluding CMN details., Results: The mean prospective follow-up of 301 CMN families was 9.2 years, median 8.9 years, total 2679 years. Forty per cent of patients had CMNs > 20 cm projected adult size (PAS) or multiple CMNs. Twenty per cent of patients had abnormal neurodevelopment and although this was positively associated with PAS it was seen across all size categories. The rate of malignant melanoma was 1.4%. This was strongly associated with PAS with all five cases in patients with CMNs > 60 cm PAS/multiple CMNs (rate in that group 14%). Twenty-five per cent of CMN patients had a positive family history of a CMN in a second-degree relative (FHCMN). This group had a significantly different gender ratio, suggesting a different underlying mutation. Maternal FHCMN was negatively associated with PAS and satellites at birth, and maternal freckling was negatively associated with PAS. Other factors found to be significantly increased in CMN families compared with controls were maternal smoking and ill health during pregnancy. Maternal smoking was positively associated with PAS., Conclusions: This study relies on data from families after they have had a child with a CMN, and therefore may be subject to recall bias. Despite this, it contributes significantly to the knowledge of epidemiology of CMNs, and provides some important clues to the genetic basis of the condition.

Background: Congenital melanocytic naevi (CMNs) can be associated with abnormalities of the cental nervous system (CNS) and/or with melanoma. Quoted incidences for these complications vary in the literature, as do recommendations for investigations and follow-up., Objectives: To determine the incidence of complications, and to identify phenotypic features associated with a higher risk of complications., Methods: We reviewed records of 224 patients with CMNs seen in Dermatology clinic between 1991 and 2007. Patients were excluded if they had a complication at the time of referral. Magnetic resonance imaging (MRI) of the CNS was offered on the basis of CMN phenotype. Follow up was in clinic and/or by postal questionnaires., Results: One hundred and twenty patients (54 boys and 66 girls) who had MRI of the CNS were included in the analysis. Mean age at MRI was 2.46 years (median 1.20). Mean follow up was 8.35 years (median 7.86). Sixty-five per cent had naevi > 20 cm projected adult size or multiple CMNs (40% > 40 cm), and 83% had satellite lesions at birth. Outcome measures were MRI abnormality, clinical neurological abnormality, any tumour, malignant melanoma, and death. No complications were seen in the 16 patients with no satellite lesions at birth. MRI and/or clinical neurological abnormalities were found in 22 patients (18%) and were significantly associated with projected adult size of the CMN (particularly > 40 cm), and independently with male gender. Tumours occurred in five patients, two of which were malignant melanoma (1.7%). Due to small numbers there was no significant association between phenotype and occurrence of tumours. Three patients (2.5%) died (one from neuromelanosis and two from melanoma in patients with normal MRI scans). Death was significantly associated with CMN size > 40 cm. Importantly, there was no significant association between CMN distribution (including posterior axial location) and adverse outcomes., Conclusions: This is the largest study of CNS imaging in patients with CMNs. We report a newly recognized association between male gender and neurological complications, dispute the previously reported association between CMN site and neurological complications, and quantify the associations between CMN size, satellite lesions and neurological complications. We make recommendations for the management of these patients.

Aim: To establish the prevalence of central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) in a population of children with congenital melanocytic naevi (CMN) over the head and/or spine, and to compare this with clinical findings., Methods: Forty three patients identified from outpatient clinics underwent MRI of the brain and/or spine. These were reported by a paediatric radiologist and findings compared with the clinical picture., Results: Nine patients had abnormal clinical neurology, seven had abnormal findings on MRI, and six had both abnormal clinical and radiological findings. Only three of the abnormal MRIs showed features of intracranial melanosis. Three others showed structural brain abnormalities: one choroid plexus papilloma, one cerebellar astrocytoma, and one posterior fossa arachnoid cyst; the first two of these have not previously been described in association with CMN. The last abnormal MRI showed equivocal changes requiring reimaging., Conclusions: The prevalence of radiological CNS abnormality in this group of children was 7/43. Six of these developed abnormal clinical neurological signs within the first 18 months of life, but two did not do so until after the MRI. Two of the CNS lesions were operable; for this reason we support the routine use of early MRI in this group.