Multiple melanomas in ichthyosis with confetti: One more piece of evidence

frequency of revertant mosaicism and melanoma prone-ness in IWC. 3,6 In conclusion


Multiple melanomas in ichthyosis with confetti: One more piece of evidence
Dear Editor, Basal and squamous cell skin cancers have been described in patients with congenital ichthyoses, 1 whereas an increased incidence of melanoma in these diseases is not well established.
We describe the case of a 48-year-old Italian woman who referred to our dermatological department for ichthyosis with confetti (IWC).At birth, she presented a collodion phenotype with scaly erythroderma, while at the age of 10 years, she started developing isles of whitish nonichthyotic skin spots (Figure 1a).During adolescence, a generalized hypertrichosis and brown-greyish macules at the dorsum of hands and feet occurred.Through the years, these hyperpigmented macules spreaded to the rest of the body, particularly localizing at the borders of healthy white spots, showing a benign melanocytic proliferation at histological examination.
A de novo heterozygous 2-base pair deletion NM_000421.5:c.1506_1507del (p.Ser503fs) in exon 7 of KRT10 gene was identified from blood genomic DNA.No other causative variants were found in either lesional tissue or blood samples.
Our patient underwent acitretin at the dosage of 25 mg/ day for the last 30 years, with moderate benefits.
In May 2018, at the age of 46 years, she showed an atypical melanocytic lesion on the right knee, developing from a healthy skin spot, that was excised and histologically confirmed as melanoma (pT2a) (Figure 1b,c).In the following 3 years, a new melanoma was excised on the left thigh (pT2b) (Figure 1d) and two new melanomas were excised on the right leg (pT3b and pT1a).The patient, in the absence of family history of both melanoma and non-melanoma skin cancers (NMSC), had never suffered from NMSC and, due to her underlying condition, she had been exposed to sun since childhood, as confirmed by histological examinations.
In addition to our case just described two other cases of multiple melanomas in IWC, caused by KRT10 gene mutations, have been recently described. 2,3WC is an autosomal dominant congenital ichthyosis caused by heterozygous pathogenic variants in the KRT10 or KRT1 genes, in which healthy skin confetti-like spots represent 'repaired' skin due to a revertant mosaicism of keratin gene mutations via mitotic recombination. 4 To explain skin carcinogenesis in congenital ichthyoses, mechanisms including incomplete cellular maturation due to a genetic defect, chronic inflammation caused by keratinocyte barrier deficiency and increased susceptibility to irritation caused by external agents have been hypothesized. 5n the context of IWC, moreover, it has been hypothesized that mutant KRT10 promotes carcinogenesis by increasing the frequency of revertant clones with the ability to cause coding errors and exerts a direct carcinogenic effect, 6 since the wild-type allele inhibits proteins involved in cell cycle regulation. 7It has been in fact demonstrated that KRT10 acts as a negative modulator of cell cycle progression through sequestration of protein kinase B and zeta isotype of protein kinase C in the cytoskeleton. 7All IWC pathogenic variants reported so far in KRT10 result in a C-terminal (where its ability to suppress cell proliferation resides) frameshift into the same alternative reading frame, replacing a polyglycine tail with a polyarginine tail that redirects KRT10 from the cytoplasmic intermediate filament network to the nucleus. 8The mitotic spindle instability caused by this mis-localisation may induce carcinogenesis and confer high frequency of revertant clones in IWC via mitotic recombination. 3 The specific absence of reversion of other dominant mutations in KRT10 implicates KRT10 C-terminal frameshift peptide in the high This 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.© 2023 The Authors.Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.

F
I G U R E 1 (a) Small patches of pale skin over the underlying scaling erythema in an Italian 48-year-old woman affected by ichthyosis with confetti (IWC), slowly enlarging during years.(b) Histopathology of melanoma (pT2a) with haematoxylin-eosin staining and (c) detail magnification.(d) Melanoma on the left hip (pT2b): the surrounding skin shows typical features of IWC.