DISEASE CARD

Disease group Keratinization disorder
DISEASE NAME SUPERFICIAL EPIDERMOLYTIC ICHTHYOSIS
Synonymous Ichthyosis Bullosa of Siemens, Ichthyosis exfoliativa
Estimated prevalence < 1 / 1 000 000
OMIM 146800
Inheritance Autosomal dominant
Gene (s) KRT2 (600194)

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 to describe all forms of ichthyosis that are based on mutations in keratin genes. They manifest at birth and sometimes involve blistering [2, 3].

Superficial epidermolytic ichthyosis (SEI), formerly know as Ichthyosis bullosa of Siemens (IBS), is a rare keratinization disorder with superficial peeling. Although hyperkeratotic, the skin is unusually fragile and has tendency to shed the outer layers of the epidermis, producing localized denuded areas.

Clinical Description

The clinical features of SEI are similar but milder to that of epidermolytic ichthyosis (EI) (formerly known as “Brocq). SEI infants are born with erythema and widespread blistering which persists during infancy or early childhood in response to trauma, heat or excessive sweating. Blistering improves with increasing age, becoming more localized to the acral extremities, leading to superficial erosions with peripheral scales. Superficial peeling of the skin, described by Siemens in 1937 as "mauserung" or "moulting effect" is characteristic [4]. Grey or brown hyperkeratosis appears on arms and legs, and when improving with age, hyperkeratosis and lichenification becomes limited to flexural areas. Although erythema are seen in infancy, erythroderma had never been observed in any of the affected patients. Skin lesions are localized especially at the extensor surfaces of the arms and legs (wrist, elbows, knee, ankle) as well as the periumbilical region, buttocks and palms and soles [5, 6].

Pathogenesis

Mutations in the KRT2 gene at locus 12q13.13 are made responsible for SEI [7, 8] (According to HGCN, the abbreviation “KRT2E” should not be used any more). The majority of mutations affect the helix termination motif of KRT2, and hot spot mutations in the 1A and 2B domain of KRT2 have been identified molecularly [8, 9]. Expression of KRT2 is restricted to the upper epidermis, more prominent in the skin of palms and soles and extensor surfaces, consistent with the clinical distribution of the disease. As with other keratin defects, the formation of the keratin cytoskeleton is impaired, resulting in structural fragility.

Diagnosis

In general, differential diagnosis of MeDOC should include the following clinical criteria: 1) the type of scaling and hyperkeratosis; 2) the onset and evolution of skin changes over time; 3) other dermatologic features and the involvement of other organ systems; 4) the family history/mode of inheritance [2].

In the case of SEI, the diagnosis is based on the association of hyperkeratosis with superficial blistering. Patients typically show dark, gray hyperkeratotic lesions with superficial denuded areas. SEI closely resembles EI. It should also be differentiated from ichthyosis hystrix of Curth-Macklin, in which hyperkeratosis is more verrucous and lacks epidermal fragility. Ultrastructural analysis in SEI shows aggregates of keratin filament bundles in the granular and the upper spinous layers [6].

Treatment

Treatment is symptomatic. Keratolytics and emollients can be used to treat hyperkeratosis. Low dose oral retinoids can be helpful, but should be used with caution.

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
Siemens HW. (1937) Dichtung und Wahrheit ueber die Ichthyosis bullosa, mit Bemerkungen zur Systematik der Epidermolysen. Arch Derm Syph 175: 590-608.

5
Steijlen PM, Perret CM, Schuurmans Stekhoven JH, Ruiter DJ, Happle R. (1990) Ichthyosis bullosa of Siemens: further delineation of the phenotype. Arch Dermatol Res 282:1-5.

6
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.

7
Kremer H, Zeeuwen P, McLean WH, Mariman EC, Lane EB, van de Kerkhof CM, Ropers HH, Steijlen PM. (1994) Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene. J Invest Dermatol 103:286-289.

8
Rothnagel JA, Traupe H, Wojcik S, Huber M, Hohl D, Pittelkow MR, Saeki H, Ishibashi Y, Roop DR. (1994) Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet 7:485-490.

9
Akiyama M, Tsuji-Abe Y, Yanagihara M, Nakajima K, Kodama H, Yaosaka M, Abe M, Sawamura D, Shimizu H. (2005) Ichthyosis bullosa of Siemens: its correct diagnosis facilitated by molecular genetic testing. Br J Dermatol 152:1353-1356.