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

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.

Keywords: KRT1; KRT10; KRT2; epidermal nevus; epidermolytic ichthyosis; histopathology; ichthyosis with confetti; keratin; superficial epidermolytic ichthyosis; ultrastructure.

Figure 1

Molecular findings in three familial and two sporadic cases of epidermolytic ichthyosis. Sequence electropherograms showing the three novel mutations identified: (A) c.1792dupA (p.Ser598Lysfs*56), (B) c.1319C > T (p.Ala440Val) in KRT1 (NM_006121) (patients n. 1–3 and 4 of Table 1, respectively), and (C) c.461A > G (p.Asn154Ser) in KRT10 (NM_000421) (n. 13 of Table 1).

Figure 2

Phenotypic spectrum of epidermolytic ichthyosis (EI). Mild EI phenotype in two siblings (patients n. 1 and 2 of Table 1): yellowish plantar keratoderma with erythematous halo, left hand dorsum hyperkeratosis and hypertrichosis on the upper left limb in the sister aged 19 years (n. 2 of Table 1) (A,D); yellowish verrucous hyperkeratosis of the left knee and mild linear hyperkeratosis in the left antecubital fossa in the brother aged 21 (n. 1 of Table 1) (B,E). Severe and diffuse erythroderma, with erosions, crusts, and yellowish thick hyperkeratosis in a 3-year-old child (C,F) (n. 13 of Table 1). Note leg hypertrichosis in F (arrow).

Figure 3

Clinical, histopathological, and ultrastructural findings in epidermolytic nevus (EN) due to KRT10 somatic mutation. Hypopigmented (arrowheads) and brownish hyperkeratotic linear lesions following a blaschkoid distribution (yellow lines) on the left upper and lower limbs (A,B) of a 7-year-old girl (n. 17 of Table 1). Focal vacuolar degeneration (arrows) of suprabasal epidermal layers with hypergranulosis and compact hyperkeratosis. Numerous eosinophilic cytoplasmic inclusions in suprabasal epidermal layers are also visible (C) and correspond to perinuclear tonofilament aggregation and clumping (asterisks) visualized by ultrastructural examination (D). Bar: 100 µm in (C) and 5.0 µm in (D).

Figure 4

Clinical, histopathological, and molecular genetic findings in the first case of epidermolytic nevus (EN) due to KRT2 somatic mutation. Extensive bilateral brownish hyperkeratosis and hypopigmentation, both following Blaschko lines, on the inguinal folds, gluteal and perineal regions, thighs, and left leg (A–C) in a boy aged 3 years (n. 26 of Table 1). Histopathology of a hypopigmented lesion shows vacuolar degeneration of suprabasal epidermal layers with irregular keratohyalin granules and eosinophilic cytoplasmic inclusions, in addition to hyperkeratosis (D); bar: 50 µm; similar findings accompanied by acanthosis and thicker hyperkeratosis were present in hyperkeratotic lesions (not shown). Mutant alleles with the KRT2 c.556A > G somatic mutation were detected by NGS sequencing both in DNA from blood (estimated frequency 1.5%) and affected skin (25%) (E). Sanger sequencing failed to detect the mutation in blood DNA but confirmed it in the DNA from affected skin, as demonstrated by the lower peak of nucleotide G under the wild-type A (F).

Figure 5

Clinical, histopathological, and ultrastructural findings in superficial epidermolytic ichthyosis (SEI). Brownish hyperkeratosis on the buttocks and infragluteal folds with linear hyperkeratosis on the right popliteal fossa in a 7-year-old boy (n. 23 of Table 1) (A,B). Note the two erythematous patches on the left calf, and polycyclic mildly erythematous and focally eroded areas with peripheral superficial lamellar desquamation on both calves (A). Leg hypertrichosis is also evident (A). Skin histopathology shows vacuolization of the granular and upper suprabasal epidermal layers, with numerous eosinophilic inclusions (C). Ultrastructural examination reveals initial cytoplasmic vacuolization in the granular layer (arrows) with extensive tonofilament clumps (filled circles) and keratohyalin granules of irregular size and shape (asterisks) (D). Bar: 100 µm in (C) and 5.0 µm in (D).