Shayan Cheraghlou1, Lihi Atzmony1, Simon F Roy2, Jennifer M McNiff1, Keith A Choate1,3,4. 1. Department of Dermatology, Yale School of Medicine, New Haven, Connecticut. 2. Department of Pathology, University of Montréal, Montréal, Quebec, Canada. 3. Department of Genetics, Yale School of Medicine, New Haven, Connecticut. 4. Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
Abstract
BACKGROUND: Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA. METHODS: Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis. RESULTS: DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10. CONCLUSIONS: Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.
BACKGROUND:Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA. METHODS: Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis. RESULTS: DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10. CONCLUSIONS: Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.
Authors: Lihi Atzmony; Habib M Khan; Young H Lim; Amy S Paller; Jonathan L Levinsohn; Kristen E Holland; Fatima Nadeem Mirza; Emily Yin; Christine J Ko; Jonathan S Leventhal; Keith A Choate Journal: JAMA Dermatol Date: 2019-05-01 Impact factor: 10.282
Authors: J A Rothnagel; M P Fisher; S M Axtell; M R Pittelkow; I Anton-Lamprecht; M Huber; D Hohl; D R Roop Journal: Hum Mol Genet Date: 1993-12 Impact factor: 6.150
Authors: J A Rothnagel; A M Dominey; L D Dempsey; M A Longley; D A Greenhalgh; T A Gagne; M Huber; E Frenk; D Hohl; D R Roop Journal: Science Date: 1992-08-21 Impact factor: 47.728