Melanoma pp 365-394 | Cite as

Congenital Melanocytic Naevi

  • Veronica A. KinslerEmail author
  • Miguel Reyes-Mugica
  • Ashfaq Marghoob
Reference work entry


The term congenital melanocytic naevi (CMN) covers a broad spectrum of clinical presentations, ranging from the common occurrence of small single CMN, to the rare occurrence of extensive and very numerous CMN accompanied by extra-cutaneous abnormalities. The study of these diseases is relevant to the wider understanding of naevogenesis and melanoma development and provides potentially powerful insights due to the lack of influence of ultraviolet radiation on the prenatal genetic events. Recent improved understanding of the pathogenesis of CMN, and of the relatively rare progression to melanoma, is contributing to the management of individuals affected by these conditions. In this chapter, current knowledge in this field and the authors’ approach to management of this multifaceted disease will be reviewed.


Congenital melanocytic naevus CMN NRAS BRAF Genetics Pathogenesis Management Proliferative nodule Melanoma CNS 


  1. Alper JC, Holmes LB (1983) The incidence and significance of birthmarks in a cohort of 4,641 newborns. Pediatr Dermatol 1:58–68CrossRefGoogle Scholar
  2. Barkovich AJ, Frieden IJ, Williams ML (1994) MR of neurocutaneous melanosis. AJNR Am J Neuroradiol 15:859–867PubMedGoogle Scholar
  3. Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, Pinkel D, Leboit PE (2002) Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol 161:1163–1169CrossRefGoogle Scholar
  4. Bauer J, Curtin JA, Pinkel D, Bastian BC (2007) Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 127:179–182CrossRefGoogle Scholar
  5. Bett BJ (2005) Large or multiple congenital melanocytic nevi: occurrence of cutaneous melanoma in 1008 persons. J Am Acad Dermatol 52:793–797CrossRefGoogle Scholar
  6. Bittencourt FV, Marghoob AA, Kopf AW, Koenig KL, Bart RS (2000) Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 106:736–741CrossRefGoogle Scholar
  7. Botton T, Yeh I, Nelson T, Vemula SS, Sparatta A, Garrido MC, Allegra M, Rocchi S, Bahadoran P, Mccalmont TH et al (2013) Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy. Pigment Cell Melanoma Res 26:845–851CrossRefGoogle Scholar
  8. Castilla EE, Da Graca Dutra M, Orioli-Parreiras IM (1981) Epidemiology of congenital pigmented naevi: I. Incidence rates and relative frequencies. Br J Dermatol 104:307–315CrossRefGoogle Scholar
  9. Chaithirayanon S, Chunharas A (2013) A survey of birthmarks and cutaneous skin lesions in newborns. J Med Assoc Thail 96. Suppl 1:S49–S53Google Scholar
  10. Charbel C, Fontaine RH, Malouf GG, Picard A, Kadlub N, El-Murr N, How-Kit A, Su X, Coulomb-L’hermine A, Tost J et al (2014) NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi. J Invest Dermatol 134:1067–1074CrossRefGoogle Scholar
  11. Cohen MC, Kaschula RO, Sinclair-Smith C, Emms M, Drut R (1996) Pluripotential melanoblastoma, a unifying concept on malignancies arising in congenital melanocytic nevi: report of two cases. Pediatr Pathol Lab Med 16:801–812CrossRefGoogle Scholar
  12. Cramer SF, Salgado CM, Reyes-Múgica M (2016) The high multiplicity of prenatal (congenital type) nevi in adolescents and adults. Pediatr Dev Pathol 19:409–416CrossRefGoogle Scholar
  13. Dessars B, De Raeve LE, El Housni H, Debouck CJ, Sidon PJ, Morandini R, Roseeuw D, Ghanem GE, Vassart G, Heimann P (2007) Chromosomal translocations as a mechanism of BRAF activation in two cases of large congenital melanocytic nevi. J Invest Dermatol 127:1468–1470CrossRefGoogle Scholar
  14. Dessars B, De Raeve LE, Morandini R, Lefort A, El Housni H, Ghanem GE, Van Den Eynde BJ, Ma W, Roseeuw D, Vassart G et al (2009) Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis. J Invest Dermatol 129:139–147CrossRefGoogle Scholar
  15. Etchevers HC, Rose C, Kahle B, Vorbringer H, Fina F, Heux P, Berger I, Schwarz B, Zaffran S, Macagno N, Krengel S (2018) Giant congenital melanocytic nevus with vascular malformation and epidermal cysts associated with a somatic activating mutation in BRAF. Pigment Cell Melanoma Res 31(3):437–441. Epub 2018 Jan 29CrossRefGoogle Scholar
  16. Feng J, Sethi A, Reyes-Mugica M, Antaya R (2005) Life-threatening blood loss from scratching provoked by pruritus in the bulky perineal nevocytoma variant of giant congenital melanocytic nevus in a child. J Am Acad Dermatol 53:S139–S142CrossRefGoogle Scholar
  17. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, Ding M, Bamford S, Cole C, Ward S et al (2015) COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res 43:D805–D811CrossRefGoogle Scholar
  18. Frieden IJ, Williams ML, Barkovich AJ (1994) Giant congenital melanocytic nevi: brain magnetic resonance findings in neurologically asymptomatic children. J Am Acad Dermatol 31:423–429CrossRefGoogle Scholar
  19. Frigon C, Desparmet J (2006) Ondansetron treatment in a child presenting with chronic intractable pruritus. Pain Res Manag 11:245–247CrossRefGoogle Scholar
  20. Hale EK, Stein J, Ben-Porat L, Panageas KS, Eichenbaum MS, Marghoob AA, Osman I, Kopf AW, Polsky D (2005) Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi – results from the NYU-LCMN registry. Br J Dermatol 152:512–517CrossRefGoogle Scholar
  21. Hendrickson MR, Ross JC (1981) Neoplasms arising in congenital giant nevi: morphologic study of seven cases and a review of the literature. Am J Surg Pathol 5:109–135CrossRefGoogle Scholar
  22. Hoang MP, Sinkre P, Albores-Saavedra J (2002) Rhabdomyosarcoma arising in a congenital melanocytic nevus. Am J Dermatopathol 24:26–29CrossRefGoogle Scholar
  23. Ichii-Nakato N, Takata M, Takayanagi S, Takashima S, Lin J, Murata H, Fujimoto A, Hatta N, Saida T (2006) High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J Invest Dermatol 126:2111–2118CrossRefGoogle Scholar
  24. Ilyas EN, Goldsmith K, Lintner R, Manders SM (2004) Rhabdomyosarcoma arising in a giant congenital melanocytic nevus. Cutis 73:39–43PubMedGoogle Scholar
  25. Jacobs AH, Walton RG (1976) The incidence of birthmarks in the neonate. Pediatrics 58:218–222PubMedGoogle Scholar
  26. Kadonaga JN, Barkovich AJ, Edwards MS, Frieden IJ (1992) Neurocutaneous melanosis in association with the Dandy-Walker complex. Pediatr Dermatol 9:37–43CrossRefGoogle Scholar
  27. Kinsler V, Bulstrode N (2009) The role of surgery in the management of congenital melanocytic naevi in children: a perspective from Great Ormond Street Hospital. J Plast Reconstr Aesthet Surg 62:595–601CrossRefGoogle Scholar
  28. Kinsler VA, Larue L (2018) The patterns of birthmarks suggest a novel population of melanocyte precursors arising around the time of gastrulation. Pigment Cell Melanoma Res 31(1):95–109CrossRefGoogle Scholar
  29. Kinsler VA, Sebire NJ (2016) Congenital naevi and other developmental abnormalities affecting the skin. In: Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D (eds) Rook’s textbook of dermatology. Wiley, Oxford, UKGoogle Scholar
  30. Kinsler VA, Chong WK, Aylett SE, Atherton DJ (2008) Complications of congenital melanocytic naevi in children: analysis of 16 years’ experience and clinical practice. Br J Dermatol 159:907–914CrossRefGoogle Scholar
  31. Kinsler VA, Birley J, Atherton DJ (2009) Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988–2007. Part 1 – epidemiology, phenotype and outcomes. Br J Dermatol 160:143–150CrossRefGoogle Scholar
  32. Kinsler V, Shaw AC, Merks JH, Hennekam RC (2012a) The face in congenital melanocytic nevus syndrome. Am J Med Genet A 158A:1014–1019CrossRefGoogle Scholar
  33. Kinsler VA, Abu-Amero S, Budd P, Jackson IJ, Ring SM, Northstone K, Atherton DJ, Bulstrode NW, Stanier P, Hennekam RC et al (2012b) Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development. J Invest Dermatol 132:2026–2032CrossRefGoogle Scholar
  34. Kinsler VA, Paine SM, Anderson GW, Wijesekara DS, Sebire NJ, Chong WK, Harkness W, Aylett SE, Jacques TS (2012c) Neuropathology of neurocutaneous melanosis: histological foci of melanotic neurones and glia may be undetectable on MRI. Acta Neuropathol 123:453CrossRefGoogle Scholar
  35. Kinsler VA, Thomas AC, Ishida M, Bulstrode NW, Loughlin S, Hing S, Chalker J, Mckenzie K, Abu-Amero S, Slater O et al (2013) Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Invest Dermatol 133:2229–2236CrossRefGoogle Scholar
  36. Kinsler VA, Krengel S, Riviere JB, Waelchli R, Chapusot C, Al-Olabi L, Faivre L, Haenssle HA, Weibel L, Jeudy G et al (2014) Next-generation sequencing of nevus spilus-type congenital melanocytic nevus: exquisite genotype-phenotype correlation in mosaic RASopathies. J Invest Dermatol 134:2658–2660CrossRefGoogle Scholar
  37. Kinsler VA, O’hare P, Bulstrode N, Calonje JE, Chong WK, Hargrave D, Jacques T, Lomas D, Sebire NJ, Slater O (2017a) Melanoma in congenital melanocytic naevi. Br J Dermatol 176:1131–1143CrossRefGoogle Scholar
  38. Kinsler VA, O’hare P, Jacques T, Hargrave D, Slater O (2017b) MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children. Br J Cancer 116:990–993CrossRefGoogle Scholar
  39. Kinsler VA, Boccara O, Fraitag S, Torrelo A, Vabres P, Diociauti A (2019) Mosaic abnormalities of the skin – review and guidelines from the European Reference Network for rare skin diseases (ERN-Skin). Br J Dermatol.
  40. Krengel S, Hauschild A, Schafer T (2006) Melanoma risk in congenital melanocytic naevi: a systematic review. Br J Dermatol 155:1–8CrossRefGoogle Scholar
  41. Krengel S, Scope A, Dusza SW, Vonthein R, Marghoob AA (2013) New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol 68(3):441–451. Epub 2012 Sep 13CrossRefGoogle Scholar
  42. Krengel S, Widmer DS, Kerl K, Levesque MP, Schiestl C, Weibel L (2016) Naevus spilus-type congenital melanocytic naevus associated with a novel NRAS codon 61 mutation. Br J Dermatol 174(3):642–644. Epub 2015 Nov 21CrossRefGoogle Scholar
  43. Kumar R, Angelini S, Snellman E, Hemminki K (2004) BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol 122:342–348CrossRefGoogle Scholar
  44. Lim YH, Ovejero D, Sugarman JS, Deklotz CM, Maruri A, Eichenfield LF, Kelley PK, Juppner H, Gottschalk M, Tifft CJ et al (2014) Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet 23:397–407CrossRefGoogle Scholar
  45. Marghoob AA, Dusza S, Oliveria S, Halpern AC (2004) Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients with large congenital melanocytic nevi. Arch Dermatol 140:171–175CrossRefGoogle Scholar
  46. Martins Da Silva VP, Marghoob A, Pigem R, Carrera C, Aguilera P, Puig-Butille JA, Puig S, Malvehy J (2017) Patterns of distribution of giant congenital melanocytic nevi (GCMN): the 6B rule. J Am Acad Dermatol 76:689–694CrossRefGoogle Scholar
  47. Martins Da Silva V, Martinez-Barrios E, Tell-Marti G, Dabad M, Carrera C, Aguilera P, Brualla D, Esteve-Codina A, Vicente A, Puig S et al (2019) Genetic abnormalities in large to giant congenital nevi: beyond NRAS mutations. J Invest Dermatol 139:900–908CrossRefGoogle Scholar
  48. Neuhold JC, Friesenhahn J, Gerdes N, Krengel S (2015) Case reports of fatal or metastasizing melanoma in children and adolescents: a systematic analysis of the literature. Pediatr Dermatol 32:13–22CrossRefGoogle Scholar
  49. Papp T, Pemsel H, Zimmermann R, Bastrop R, Weiss DG, Schiffmann D (1999) Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi. J Med Genet 36:610–614PubMedPubMedCentralGoogle Scholar
  50. Papp T, Schipper H, Kumar K, Schiffmann D, Zimmermann R (2005) Mutational analysis of the BRAF gene in human congenital and dysplastic melanocytic naevi. Melanoma Res 15:401–407CrossRefGoogle Scholar
  51. Phadke PA, Rakheja D, Le LP, Selim MA, Kapur P, Davis A, Mihm MC Jr, Hoang MP (2011) Proliferative nodules arising within congenital melanocytic nevi: a histologic, immunohistochemical, and molecular analyses of 43 cases. Am J Surg Pathol 35:656–669CrossRefGoogle Scholar
  52. Plumptre I, Stuart G, Cerullo A, Kinsler VA (2019) Sedation for screening MRI in patients with congenital melanocytic naevi under the age of one is a successful, safe and economical first-line approach. Br J Dermatol 180:668–669CrossRefGoogle Scholar
  53. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J et al (2003) High frequency of BRAF mutations in nevi. Nat Genet 33:19–20CrossRefGoogle Scholar
  54. Polubothu S, Kinsler VA (2019) Longitudinal study of congenital melanocytic naevi reveals that final colour is determined by normal skin colour, and is unaltered by superficial removal techniques. Br J Dermatol. [Epub ahead of print]
  55. Polubothu S, Mcguire N, Al-Olabi L, Baird W, Bulstrode N, Chalker J, Josifova D, Lomas D, Ong J, Rampling D, Sebire Nj, Stadnik P, Thomas A, Wedgeworth E, Kinsler VA (2019) Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi. Br J Dermatol [Epub ahead of print]
  56. Ramaswamy V, Delaney H, Haque S, Marghoob A, Khakoo Y (2012) Spectrum of central nervous system abnormalities in neurocutaneous melanocytosis. Dev Med Child Neurol 54:563–568CrossRefGoogle Scholar
  57. Rappaport BA, Suresh S, Hertz S, Evers AS, Orser BA (2015) Anesthetic neurotoxicity – clinical implications of animal models. N Engl J Med 372:796–797CrossRefGoogle Scholar
  58. Reyes-Mugica M, Chou P, Byrd S, Ray V, Castelli M, Gattuso P, Gonzalez-Crussi F (1993) Nevomelanocytic proliferations in the central nervous system of children. Cancer 72:2277–2285CrossRefGoogle Scholar
  59. Ruiz-Maldonado R, Tamayo L, Laterza AM, Duran C (1992) Giant pigmented nevi: clinical, histopathologic, and therapeutic considerations. J Pediatr 120:906–911CrossRefGoogle Scholar
  60. Salgado CM, Silver RB, Bauer BS, Basu D, Schmitt L, Khakoo Y, Reyes-Mugica M (2014) Skin of patients with large/giant congenital melanocytic nevi shows increased mast cells. Pediatr Dev Pathol 17:198–203CrossRefGoogle Scholar
  61. Salgado CM, Basu D, Nikiforova M, Bauer BS, Johnson D, Rundell V, Grunwaldt LJ, Reyes-Mugica M (2015a) BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi. Pediatr Dev Pathol 18:1–9CrossRefGoogle Scholar
  62. Salgado CM, Basu D, Nikiforova M, Hamilton RL, Gehris R, Jakacki R, Panigrahy A, Yatsenko S, Reyes-Mugica M (2015b) Amplification of mutated NRAS leading to congenital melanoma in neurocutaneous melanocytosis. Melanoma Res 25:453–460CrossRefGoogle Scholar
  63. Stratton MR, Fisher C, Gusterson BA, Cooper CS (1989) Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction. Cancer Res 49:6324–6327PubMedGoogle Scholar
  64. Strauss RM, Newton Bishop JA (2008) Spontaneous involution of congenital melanocytic nevi of the scalp. J Am Acad Dermatol 58:508–511CrossRefGoogle Scholar
  65. Waelchli R, Aylett SE, Atherton D, Thompson D, Chong WK, Kinsler VA (2015a) Classification of neurological abnormalities in children with congenital melanocytic naevus syndrome identifies MRI as the best predictor of clinical outcome. Br J Dermatol 173:739CrossRefGoogle Scholar
  66. Waelchli R, Williams J, Cole T, Dattani M, Hindmarsh P, Kennedy H, Martinez A, Khan S, Semple RK, White A et al (2015b) Growth and hormone profiling in children with congenital melanocytic naevi. Br J Dermatol 173:1471–1478CrossRefGoogle Scholar
  67. Wu D, Wang M, Wang X, Yin N, Song T, Li H, Yu J, Wang DM, Zhao Z (2011) Lack of BRAF(V600E) mutations in giant congenital melanocytic nevi in a Chinese population. Am J Dermatopathol 33:341–344CrossRefGoogle Scholar
  68. Zaal LH, Mooi WJ, Klip H, Van Der Horst CM (2005) Risk of malignant transformation of congenital melanocytic nevi: a retrospective nationwide study from The Netherlands. Plast Reconstr Surg 116:1902–1909CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Veronica A. Kinsler
    • 1
    Email author
  • Miguel Reyes-Mugica
    • 2
  • Ashfaq Marghoob
    • 3
  1. 1.Paediatric Dermatology DepartmentGreat Ormond Street Hospital for ChildrenLondonUK
  2. 2.Division of Pediatric PathologyChildren’s Hospital of Pittsburgh of UPMCPittsburghUSA
  3. 3.Hauppauge Dermatology SectionMemorial Sloan Kettering Cancer CenterNew YorkUSA

Section editors and affiliations

  • Boris C. Bastian
    • 1
  • Hensin Tsao
    • 2
    • 3
  1. 1.Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer CenterUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.AuburndaleUSA
  3. 3.Harvard-MIT Health Sciences and TechnologyCambridgeUSA

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