DISEASE CARD

Disease group Keratinization disorders
DISEASE NAME EPIDERMOLYTIC ICHTHYOSIS
Synonymous Epidermolytic, Hyperkeratosis, Bullous Ichthyosiform Erythorderma, Bullous Congenital Ichthyosiform Erythroderma,
Bullous Erythroderma Ichthyosiformis Congenita of Brocq
Estimated prevalence < 1 / 200 000 to < 1 / 300 000
OMIM 113800
Inheritance Autosomal dominant
Gene (s) KRT1 (139350), KRT10 (148040), KRT2

Definition

In a consensus conference in 2009, a new classification system and terminology has been established for ichthyoses [1]. Ichthyoses are determined as Mendelian disorders of cornification (MeDOC) that are characterized by universal scaling of the skin. In two main categories, non-syndromic forms (phenotype restricted to the skin) are distinguished from syndromic forms (involvement of other organs). A further distinction is made between common and rare forms. Within the non-syndromic forms the term keratinopathic ichthyosis is used as an umbrella term to describe all forms of ichthyosis that are based on mutations in keratin genes. The keratinopathic ichthyoses manifest at birth and sometimes involve blistering [2, 3].

Epidermolytic Ichthyosis (EI) is a rare keratinization disorder with blistering in its early phase, first described by Brocq in 1902 [4]. It is usually inherited in an autosomal dominant fashion, but autosomal recessive cases have also been reported [5, 6]. Cases of postzygotic mosaicism are also described [7, 8]. EI is caused by mutations in the genes coding for KRT1 (12q13.13) or KRT10 (17q21.2) [9].

Clinical Description

Infants are born with erythroderma, blistering and superficial erosions at sites of minor trauma. Hyperkeratosis most often develops later in early childhood . Yellow-brown, waxy and ridged scale builds up in skin creases, sometimes forming linear, spiny (hystrix) outgrowths. Over time, blister formation decreases and the ichthyosis worsens. Skin involvement is most often generalized, with palmoplantar involvement, but some patients have patchy or limited skin lesions. For neonates EI can be life threatening, due to secondary infections. EI persists in adulthood, with hyperkeratosis of variable intensity and extension [10].

Pathogenesis

Keratins 1 (type II) and 10 (type I) are co-expressed in the suprabasal layers of the epidermis during differentiation of keratinocytes. They are assembled together in specific pairs to form intermediate filaments. Mutations in the keratin 1 or 10 impair keratin filaments formation and weaken the structural stability of the keratinocyte cytoskeleton. This causes easy blistering, hyperproliferation, and hyperkeratosis [11].

Diagnosis

Histopathology shows 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 is performed by sequencing the HIP and the HTP regions of the KRT1 and KRT10 genes.

Treatment

Keratolytics (10% urea, 10% lactic acid) can improve localized hyperkeratotic lesions. Gentle debridement of scale is useful in palms and soles. The efficacy of emollients is limited. Oral retinoids are effective on hyperkeratosis [12], but they can worsen the skin fragiliy and must be used with caution because of their secondary effects. Low maintenance doses or intermittent treatments help preventing side effects. Antibiotic therapy is often required to treat secondary infection.

References

1
Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, Coudiere P, DiGiovanna JJ, Elias P, Fischer J, Fleckman P, Gina M, Harper J, Hashimoto T, Hausser I, Hennies HC, Hohl D, Hovnanian A, Ishida-Yamamoto A, Jacyk WK, Leachman S, Leigh I, Mazereeuw-Hautier J, Milstone L, Morice-Picard F, Paller AS, Richard G, Schmuth M, Shimizu H, Sprecher E, Van Steensel M, Taïeb A, Toro JR, Vabres P, Vahlquist A, Williams M, Traupe H. (2010) Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol 63:607-641.

2
Schmuth M, Martinz V, Janecke AR, Fauth C, Schossig A, Zschocke J, Gruber R. (2013) Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet 21:123-133.

3
Traupe H, Fischer J, Oji V. (2013) Nonsyndromic types of ichthyoses – an update. J Dtsch Dermatol Ges Oct 11. doi: 10.1111/ddg.12229. [Epub ahead of print]

4
Brocq LAJ. (1902) Erythrodermie congenitale ichtyosiforme avec hyperepidermotrophie.
Annales de dermatologie et de syphilographie, Paris. 1902, III: 1-31.

5
Muller FB, Huber M, Kinaciyan T, Hausser I, Schaffrath C, Krieg T, Hohl D, Korge BP, Arin MJ. (2006) A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis. Hum Molec Genet 15: 1133-1141.

6
Terheyden P, Grimberg G, Hausser I, Rose C, Korge BP, Krieg T, Arin MJ. (2009) Recessive epidermolytic hyperkeratosis caused by a previously unreported termination codon mutation in the keratin 10 gene. J Invest Derm 129: 2721-2723.

7
Happle R, Konig A. (1999) Dominant traits may give rise to paired patches of either excessive or absent involvement. Am J Med Genet 84: 176-177.

8
Kiritsi D, Nanda A, Kohlhase J, Bernhard C, Bruckner-Tuderman L, Happle R, Has C. (2013) Extensive Postzygotic Mosaicism for a Novel Keratin 10 Mutation in Epidermolytic Ichthyosis. Acta Derm Venereol doi: 10.2340/00015555-1695. [Epub ahead of print]

9
McLean WH, Eady RA, Dopping-Hepenstal PJ, McMillan JR, Leigh IM, Navsaria HA, Higgins C, Harper JI, Paige DG, Morley SM, et al. (1994) Mutations in the rod 1A domain of keratins 1 and 10 in bullous congenital ichthyosiform erythroderma (BCIE). J Invest Dermatol 102:24-30.

10
Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. (2011) Keratin Gene Mutations in Disorders of Human Skin and its Appendages. Arch Biochem Biophys 508:123-137.