DISEASE CARD

Definition

Epidermolytic Ichthyosis (EI) is a rare keratinization disorder with blistering at birth, first described by Brocq in 1902.¹ It is inherited in an autosomal dominant fashion, but autosomal recessive cases have also been reported as well as cases of postzygotic mosaicism^.2-5 EI is usually caused by mutations in the genes coding for KRT1 (12q13.13) or KRT10 (17q21.2).⁶ Due to mutations in keratin genes, EI belongs to the keratinopathic ichthyoses, that include superficial epidermolytic ichthyosis (SEI, OMIM #146800, KRT2 mutations) and congenital reticular ichthyosiform erythroderma (CRIE, OMIM #609165, KRT1 or KRT10 mutations).⁷

Clinical Description

Infants with EI are born with varying degree of erythroderma, blistering and superficial erosions at sites of minor trauma. Infections, sepsis and dehydration can complicate the clinical course in the neonatal / early infancy period. Hyperkeratosis becomes manifest in late infancy / early childhood. Yellow-brown, waxy and ridged scales build up preferentially in skin creases, sometimes forming linear, spiny (hystrix) outgrowths. With increasing age, blister formation decreases and ichthyosis worsens, commonly associated with pruritus, anhidrosis and painful fissuring. Skin involvement is most often generalized but some patients have patchy or very limited skin lesions. Mutations in KRT1 can cause palmoplantar keratoderma of varying severity (in severe forms with digital contractures affecting joint mobility) that rarely occurs in patients with KRT10 mutations.^8,9

Pathogenesis

Keratins 1 (type II) and 10 (type I) are co-expressed in the suprabasal layers of the epidermis during differentiation of keratinocytes. Both are major constituents of the intermediate filament cytoskeleton. Mutations in KRT1/KRT10 impair keratin filaments formation and weaken the structural stability of the keratinocyte cytoskeleton causing easy blistering, hyperproliferation, and hyperkeratosis. Mutations at the beginning or end of the 1A rod domain of KRT1/10 are associated with a severe phenotype. Approximately 50% of cases of EI occur de novo due to spontaneous mutations.¹⁰

Diagnosis

Histopathologic signs are different from other ichthyosis types. Typical features are hypergranulosis with orthokeratosis, thickened stratum corneum, and cytolysis in the upper stratum spinosum and granular layers (epidermolytic hyperkeratosis). Electon microscopy shows tonofilament clumping in the supra basal layers of the epidermis. Molecular diagnosis can be established by screening of the KRT1 and KRT10 genes (disease-related mutations are frequently mapped to the HIP and HTP region, two highly conserved amino acid sequences, of the central rod domain).¹¹

The differential diagnosis between EI, CRIE and SEI can be difficult, since the phenotypes can vary in severity. Therefore, in patients with suspected EI, in which no mutation in the corresponding genes can be found, analysis of other keratin genes could be useful.​​​​

Treatment

Treatment is symptomatic. In infants, skin trauma should be prevented to avoid new blister formation. Appropriate wound care and prevention of infection as well as adequate pain management is further important. Nutritional monitoring is frequently necessary to prevent electrolyte imbalances due to increased fluid losses and metabolic demands. Systemic antibiotics should be initiated, when skin infections are suspected or identified. Hyperkeratosis in children and adults can be treated with keratolytics (e.g. urea, lactic acid, glycerin - however, efficacy of emollients alone is limited) as well as mechanical debridement for localized hyperkeratotic lesions. In children, the use of higher concentration salicylic acid topical preparations should not be used because of the risk of systemic salicylism.

Oral retinoids are effective against hyperkeratosis, but they can worsen skin fragility, exacerbate blistering and thus should not be given in the early phase of this disease. Bathing 2-3 times a week, with salt or sodium bicarbonate added to the bath as well as antiseptic agents (e.g. antibacterial soaps, chlorhexidine, dilute sodium hypochlorite), may help to descale and reduce bacterial colonization. 

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