DISEASE CARD

Definition

Superficial epidermolytic ichthyosis (SEI), formerly known as Ichthyosis bullosa of Siemens (IBS), is a rare autosomal dominant keratinization disorder with mild superficial peeling. Although hyperkeratotic, the skin is fragile. Mutations in KRT2 are causative for SEI.1, 2

Clinical Description

The clinical features of SEI are similar but milder to that of epidermolytic ichthyosis (EI) (formerly known as “bullous congenital ichthyosiform erythroderma of Brocq”). SEI infants are born with erythema (no erythroderma) and blistering which persists during infancy or early childhood in response to trauma, heat or excessive sweating. 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. Blistering improves with increasing age and becomes more localized to the acral extremities. Superficial peeling of the skin, described by Siemens in 1937 as "mauserung" or "moulting effect" is a typical feature.³ Grey or brown “flaky” hyperkeratosis develops on extremities. With age, hyperkeratosis and lichenification becomes limited to flexural areas as well as the umbilical skin and shins. Although skin erythema is a prominent feature in in infancy, erythroderma (involvement of the whole integument) is not typical.^{4, 5} A mosaic form of SEI has been reported.⁶

Pathogenesis

Mutations in the KRT2 gene at locus 12q13.13 are causative for SEI (according to HGCN, the abbreviation “KRT2E” should not be used any more).7 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. 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.^8-10

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.¹¹

With regard to SEI, the diagnosis is based upon the clinical features. SEI closely resembles EI and 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.⁵ Genetic analysis of the KRT2 gene is able to confirm the diagnosis.

Treatment

Treatment is symptomatic. Keratolytics and emollients can be used to treat hyperkeratosis. Low dose oral retinoids can be helpful (<0.5mg/kg), but should be used with caution.

References

^{1. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63(4):607-641.}

^{2. Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses - an update.JDDG 2014;12(2):109-121.}

^{3. Siemens HW. Dichtung und Wahrheit über die „Ichthyosis bullosa “, mit Bemerkungen zur Systematik der Epidermolysen. Archiv für Dermatologie und Syphilis. 1937;175(5):590-608.}

^{4. Steijlen PM, Perret CM, Schuurmans Stekhoven JH, Ruiter DJ, Happle R. Ichthyosis bullosa of Siemens: further delineation of the phenotype. Arch Dermatol Res. 1990;282(1):1-5.}

^{5. Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys. 2011;508(2):123-137.}

^{6. Li Y, Cheng R, Liang J, Yao Z, Li M. The first case of a mosaic superficial epidermolytic ichthyosis diagnosed by Ultra-Deep Sequence. 2020;8(11):e1457.}

^{7. Kremer H, Zeeuwen P, McLean WH, et al. Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene. J Invest Dermatol. 1994;103(3):286-289.}

^{8. Rothnagel JA, Traupe H, Wojcik S, et al. Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet. 1994;7(4):485-490.}

^{9. Akiyama M, Tsuji-Abe Y, Yanagihara M, et al. Ichthyosis bullosa of Siemens: its correct diagnosis facilitated by molecular genetic testing. Br J Dermatol. 2005;152(6):1353-1356.} 

^{10. Fischer H, Langbein L, Reichelt J, et al. Loss of keratin K2 expression causes aberrant aggregation of K10, hyperkeratosis, and inflammation. Journal of Investigative Dermatology. 2014;134(10):2579-2588.}

^{11. Schmuth M, Martinz V, Janecke AR, et al. Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013;21(2):123-133.}