The speckles in a nevus spilus are a second genetic event, not a second naevus

Design

clinicopathological and molecular case series with compartment-separated sequencing

Population

three patients with nevus spilus-type congenital melanocytic naevus, multiple biopsies of background and superimposed components

Primary outcome

NRAS variant status and copy-neutral loss of heterozygosity by lesion component

Effect

postzygotic NRAS variants in 10/11 background and 16/16 superimposed dermal samples; copy-neutral loss of heterozygosity in 14/16 superimposed and 0 background samples

Nevus spilus-type congenital melanocytic naevus has an unmistakable appearance - a flat brown patch with darker macules and papules scattered across it - and no accepted explanation for why it looks that way. This study took three cases, sampled background and superimposed components separately, split epidermis from dermis before extracting DNA, and ran whole-exome sequencing, targeted Sanger sequencing of NRAS codons 13 and 61, and single-nucleotide polymorphism arrays. In one patient, melanocyte-lineage cells from each compartment were cultured and analysed separately.

Postzygotic NRAS variants were present in the dermis of both components: 10 of 11 samples from the background brown macule and 16 of 16 from the superimposed dark lesions. What distinguished the two was copy-neutral loss of heterozygosity spanning the NRAS locus, found in 14 of 16 dermal samples from the superimposed lesions and in none from the background. Histologically the background carried scattered spindle-shaped dermal melanocytes and the superimposed areas carried nests of naevus cells.

The model that follows is two-step mosaicism: one early postzygotic NRAS variant creates the whole patch, and independent later events duplicating the mutant allele create each speckle. It explains the clinical appearance precisely - the speckles are not separate naevi that happened to land inside a café-au-lait patch, they are clonal subpopulations of the same lesion. For counselling, that reframes the whole lesion as a single mosaic field, which is a more coherent way to describe it to a parent than the two-lesion account, and a reminder that new dark macules appearing within the patch over time are expected rather than alarming in themselves.

• Describe the lesion to families as one mosaic patch with clonal spots, not as separate naevi on a background patch
• Expect new speckles to appear over time - that is the model working, not necessarily a change requiring biopsy
• Keep the usual threshold for biopsy: asymmetric growth, ulceration, nodularity, colour change within a single spot
• Photograph and map the lesion at baseline so that a genuine change is distinguishable from another speckle
• Note this is three patients - the model is coherent but not established across the phenotype's full range

Why it matters

It turns a descriptive naevus pattern into a defined two-step mosaic lesion, which changes how it is explained and what a new spot means.

Don't overread it

Three patients - this explains the pattern's formation and says nothing about malignant potential or how these lesions should be followed.

The statistics, in plain English

Three patients with multiple biopsies each is a case-series depth of evidence, and the proportions quoted - 16 of 16, 14 of 16 - describe samples rather than people, so they cannot be read as a prevalence. What makes the finding convincing despite the tiny sample is the internal contrast: the loss of heterozygosity was present in the speckled areas and absent in the background of the same patient, which is a within-lesion comparison that does not depend on sample size in the usual way.

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