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Br J Dermatol. 2019 May 21. doi: 10.1111/bjd.18106. [Epub ahead of print]

Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi.

Author information

1
Genetics and Genomic Medicine, University College London Great Ormond Street Institute of Child Health, London, U.K.
2
Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, U.K.
3
Paediatric Plastic Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, U.K.
4
Paediatric Malignancy Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, U.K.
5
Clinical Genetics, Guy's and St Thomas' Hospital NHS Foundation Trust, U.K.
6
Paediatric Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, U.K.
7
Department of Dermatology, Guy's and St Thomas' Hospital NHS Foundation Trust, U.K.

Abstract

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.

PMID:
31111470
DOI:
10.1111/bjd.18106

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