First Case of KRT2 Epidermolytic Nevus and Novel Clinical and Genetic Findings in 26 Italian Patients with Keratinopathic Ichthyoses.

Andrea Diociaiuti,Angelo Giuseppe Condorelli,Elisa Pisaneschi,Sabrina Rossi,May El Hachem,Giovanna Zambruno,Claudia Cesario,Daniele Castiglia,Marialuisa Corbeddu,Roberta Rotunno

doi:10.3390/ijms21207707

Abstract

Keratinopathic ichthyoses (KI) are a clinically heterogeneous group of keratinization disorders due to mutations in KRT1, KTR10, or KRT2 genes encoding keratins of suprabasal epidermis. Characteristic clinical features include superficial blisters and erosions in infancy and progressive development of hyperkeratosis. Histopathology shows epidermolytic hyperkeratosis. We describe the clinical, histopathological, and molecular findings of a series of 26 Italian patients from 19 unrelated families affected with (i) epidermolytic ichthyosis due to KRT1 or KRT10 mutations (7 and 9 cases, respectively); (ii) KTR10-mutated ichthyosis with confetti (2 cases); (iii) KRT2-mutated superficial epidermolytic ichthyosis (5 cases); and (iv) KRT10-mutated epidermolytic nevus (2 cases). Of note, molecular genetic testing in a third case of extensive epidermolytic nevus revealed a somatic missense mutation (p.Asn186Asp) in the KRT2 gene, detected in DNA from lesional skin at an allelic frequency of 25% and, at very low frequency (1.5%), also in blood. Finally, we report three novel dominant mutations, including a frameshift mutation altering the C-terminal V2 domain of keratin 1 in three familiar cases presenting a mild phenotype. Overall, our findings expand the phenotypic and molecular spectrum of KI and show for the first time that epidermolytic nevus can be due to somatic KRT2 mutation.

Highlights

Keratinopathic ichthyoses (KI) are a group of genetic skin diseases due to mutations in keratin genes KRT1, KRT2, and KRT10 encoding keratins 1, 2 and 10 (K1, K2, K10), respectively, expressed in suprabasal epidermis [1]
The phenotype was quite mild in some patients, who had minimal (e.g., n. 4) or even overlooked (n. 1–3) skin fragility in infancy, followed by localized hyperkeratosis
palmoplantar keratoderma (PPK) was a typical but not exclusive feature of KRT1 mutated patients, as it was observed in one patient with KRT10 mutation (n. 14), and in patient n. 22 affected with SEI due to a KRT2 in-frame deletion [15]

Summary

Introduction

Keratinopathic ichthyoses (KI) are a group of genetic skin diseases due to mutations in keratin genes KRT1, KRT2, and KRT10 encoding keratins 1, 2 and 10 (K1, K2, K10), respectively, expressed in suprabasal epidermis [1]. They have been included in classifications of both ichthyoses and skin fragility disorders due to the presence of hyperkeratosis as well as of trauma-induced superficial blisters and erosions [1,2]. EI, previously known as epidermolytic hyperkeratosis or bullous congenital ichthyosiform erythroderma of Brocq, manifests at birth with widespread superficial erosions and blisters on erythrodermic skin. Very rare cases of recessively inherited EI due to homozygous mutations in KRT10 have been described [4,5,6,7]

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