A Case of Annular Epidermolytic Ichthyosis Resulting from a de Novo Mutation, p.I479T, in Keratin 1 Gene.

We report a case of annular epidermolytic ichthyosis (AEI) resulting from de novo keratin 1 gene mutation. AEI is a rare autosomal dominantly inherited cornification disorder and is a distinct phenotypic variant of bullous congenital ichthyosiform erythroderma. Blisters and erosions in AEI are widespread; hence, initially, it is sometimes mistaken with epidermolysis bullosa, acrodermatitis enteropathica, and staphylococcal scalded skin syndrome. Genetic tests including next-generation sequencing and Sanger sequencing are essential for AEI diagnosis. AEI is treated symptomatically by wound dressing, prevention of infection, and the use of emollients, humectants, and keratolytic products; topical or systemic retinoids may also prove helpful. Copyright:

Introduction

Annular epidermolytic ichthyosis (AEI) is a rare autosomal dominant cornification disease that results from keratin 1 or keratin 10 gene mutations.[1] It is a distinct phenotypic variant of bullous congenital ichthyosiform erythroderma and is characterized by intermittent episodes of polycyclic, erythematous, scaly plaques on the trunk and proximal extremities.[1] Here, we report a case of AEI that resulted from a de novo keratin 1 gene (KRT 1) mutation.

Case History

A 4-month-old girl was referred to the outpatient clinic due to intermittent episodes of erythema, blistering, and scaling [Figure 1a and b] since 2 days old, with each episode lasting for 2–4 weeks. The patient was initially diagnosed with staphylococcal scalded skin syndrome (SSSS), but no improvement was observed after systemic antibiotic therapy. Her blisters presented with positive Nikolsky's sign and have improved spontaneously for several months. However, polycyclic erythema and scaling developed on her trunk and extremities. During the interim periods, the lesions partially remitted. From 8 months old, she had palmoplantar hyperkeratosis and annular hyperkeratotic plaques on her trunk. None of her family members reported similar symptoms.

Figure 1

(a and b) Blisters, erosions, and peeling with erythema on the thighs; (c and d) intraepidermal vesicle and vacuolar degeneration of keratinocytes in superficial layer of epidermis (hematoxylin–eosin staining, original magnification c×100, d×400); (e) the arrow indicates the heterozygous mutation (the reverse strand A→G is shown in the upper panel) in the patient; this mutation predicts the amino acid substitution 1436T→C, in the KRT 1 gene, compared with her old brother's (lower panel)

A skin biopsy of a bullous lesion from the left thigh was done, and hematoxylin–eosin staining revealed an intraepidermal vesicle in the upper epidermis, intracellular vacuolation and irregular eosinophilic granules in the superficial layers of the epidermis [Figure 1c and d]. Direct immunofluorescence and indirect immunofluorescence staining for IgA, IgG, IgM, and C3 were negative. In addition, next-generation sequencing was performed and revealed a heterozygous transition mutation, 1436T→C, in the KRT 1, which was confirmed by Sanger sequencing [Figure 1e], indicating an isoleucine-to-threonine amino acid change in codon 479 (Ile479Thr). No mutation was detected in brother [Figure 1e] and her parents [Supplementary Figure 1]. Based on the clinical and genetic profile, the patient was diagnosed with AEI. Our patient was then given an emollient and diluted bleach baths with minimal improvement.

Discussion

AEI or cyclic ichthyosis with epidermolytic hyperkeratosis (CI-EH) was first reported by Sahn et al. in 1992[1] in eight families and two sporadic patients [Table 1]. AEI was characterized by blistering and scaling at birth and in the perinatal period, developing later in life into annular or polycyclic hyperkeratotic lesions. It was described as a relatively mild epidermolytic hyperkeratosis, and due to the widespread blisters and erosions, epidermolytic ichthyosis patients might be misdiagnosed with SSSS or epidermolysis bullosa simplex. Its typical histological features are vacuolar degeneration and coarse keratohyalin granules in the granular layer.

Table 1

Summary of previous reported cases of AEI

Author/Year of report	Age/Gender	Family or individual	Mutation	Clinical manifestation
				Blister	PPK	Ichthyosis	Annular erythema or hyperkeratotic plaques	Additional condition
Sahn et al., 1992	30/F (mother) 2/M (son)	1 family	N/A	At 8 mo (mother) and 6 mo (son), pressure on an erythematous papule resulted in a blister	No	After birth	On the trunk and extremities, intermittent	N/A
Joh et al., 1997	33/M (father) 2 mo/F (daughter)	1 family	Novel dinucleotide mutation within 2B segment of K10	At 2 mo (daughter)	No	After birth,	On the trunk and proximal extremities	N/A
Suga et al., 1998	11/M	1 individual	Novel mutation within at the end of the rod domain of K10	No	No	At the age of 7 mo, in the flexural areas and over the extensor surfaces	Intermittent episodes, on flexural areas and extensor surfaces	Misdiagnosed as atopic dermatitis
Sybert et al., 1999	5/M	1 individual, 1 family	Heterozygous mutations in the 2B domain of K1	At age 12h	Yes	N/A	On the trunk with intermittent episodes	Misdiagnosed as SSSS and EBS, one additional episode of explosive erythroderma
	18/M (son) NA/F (mother) NA/F (aunt)			N/A	Yes	No	Varied greatly	The aunt affected most severe, she was misdiagnosed with pityriasis rubra pilaris and pustular psoriasis
Yoneda K et al., 1999	48/F (mother) 18/M (son)	1 family	1A rod domain of K10	Severe extensive blistering immediately after birth	No	N/A	After 4 yo	N/A
Naik et al., 2003	21/F	1 family	N/A	No	Yes	No	Episodic flares	Misdiagnosed as psoriasis
Sheth N et al., 2007	42/F 16/M	1 family	2B domain of K10	Erythroderma at birth and blisters during early childhood	No	N/A	On the extremities and flexure after adulthood	Worsen during pregnancy
Jha et al., 2015	26/F (mother) NA/M (son)	1 family	N/A	No	No	N/A	Recurrent episodes of flare	Worsen during infancy
Abdul et al., 2016	25/F	1 family	Missense mutation in KRT10	No	No	Infancy	Over the trunk and extremities	Contraceptive pill may be the trigger, during the summer months or after sun exposure lesion improved

M: Male; F: Female; N/A: Not available; mo: Months old; yo: Years old; KRT: Keratin gene; K: Keratin; PPK: Palmoplantar hyperkeratosis; SSSS: Staphylococcal scalded skin syndrome; EBS: Epidermolysis bullosa simplex

Specific KRT 1 and KRT 10 mutations have been identified to cause AEI.[234] Keratin 1 (K1) is a member of the keratin family, and compared to keratin 10 (K10), K1 is specifically expressed in the spinous and granular layers of the epidermis. Keratins share a basic structural organization, with four helical or coiled-coil segments.[5] In our case, the mutation resides in the C-terminal aspect of helix 2B of K1, a highly conserved portion.[5] Ile479Thr eliminates stabilizing hydrophobic interactions from the isoleucine and adds hydrogen bonding from the threonine side chain.[5] Moreover, palmoplantar keratinocytes express K1 but not K10; hence, the palmoplantar hyperkeratosis that developed later in our case was consistent with KRT 1 mutation rather than KRT 10. Although skin manifestation and mutation were not observed in her parents and elder brother [Figure 1e and Supplementary Figure 1], we believe that our patient had a de novo mutation of KRT 1.

AEI treatment is symptomatic. When blistering is prominent, treatment is focused on wound dressing and infection prevention. Emollients, humectants, and keratolytic products are usually recommended as maintenance treatment, and topical or systemic retinoids may also be helpful.

In conclusion, we report a de novo heterozygous transition mutation of the KRT 1 gene in an infant, presenting a mild form of epidermolytic hyperkeratosis, which needs to be differentiated from other bullous diseases.

Patient's consent

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Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (81803134).

Conflicts of interest

There are no conflicts of interest.

The Sanger test of the mother (a) and father (b) revealed no mutation at the same site