Ichthyosis Bullosa Of Siemens Research Articles

Superficial epidermolytic ichthyosis: A rare disorder with the unusual absence of blistering

Superficial epidermolytic ichthyosis (SEI), formerly known as ichthyosis bullosa of Siemens (IBS), is an extremely rare keratinization disorder with superficial peeling, with an estimated prevalence of 1:500,000, caused by a variety of mutations in the keratin 2E gene. The clinical features include hyperkeratosis and blistering, but these are milder than in epidermolytic hyperkeratosis. The treatment is symptomatic and involves keratolytics and emollients. Herein, we report a case of SEI with the unusual absence of spontaneous blistering.

Ichthyosis bullosa of Siemens

Ichthyosis bullosa of Siemens (IBS) is a rare hyperkeratotic blistering condition caused by mutations in keratin 2e gene. This is a case of a 18-year-old female with generalized blisters, erosions and thickened skin since she was 3 months old. As she aged, there was decrease in development of blisters and erosions, with accompanying increase in severity of hyperkeratosis. Skin punch biopsy showed overlying basket weave hyperkeratosis and acanthosis, prominent vacuolization of the granular cell layer, and intraepidermal blisters with the split at the granular layer. The patient was treated with emollients, with marked improvement. Mutations in the different keratin genes have been shown to underlie a wide range of disorders of keratinization. Epidermolytic hyperkeratosis and ichthyosis bullosa of Siemens are distinct disorders with mutations in different genes. Although molecular genetic testing should ideally be done for confirmation of diagnosis, ichthyosis bullosa of Siemens could be diagnosed in this patients based on key clinical characteristics.

Histopathologic characterization of epidermolytic hyperkeratosis: A systematic review of histology from the National Registry for Ichthyosis and Related Skin Disorders

The clinical condition generalized epidermolytic hyperkeratosis, also known as bullous congenital ichthyosiform erythroderma, is an autosomal dominant disorder and presents as a bullous disease of the newborn followed by an ichthyotic skin disorder throughout life. Clinical epidermolytic hyperkeratosis (cEHK) has characteristic histopathologic findings. Mosaic cEHK, which occurs without a family history, is a sporadic condition that clinically resembles epidermal nevi but demonstrates histopathologic findings similar to the generalized disorder; when a postzygotic mutation involves the germ line, the disease can occur in subsequent generations as generalized cEHK. Ichthyosis bullosa of Siemens (IBS) is similar histopathogically, but is clinically distinct from generalized cEHK, presenting with more superficial bullae. It is well established that the clinical diagnoses generalized cEHK, mosaic cEHK, and IBS have similar histopathologic findings of epidermolysis with hyperkeratosis. We sought (1) to characterize the spectrum of histopathologic features and (2) to assess whether there were histopathologic differences between these clinically distinct disorders. One hundred seventeen skin biopsy slides from the National Registry for Ichthyosis and Related Skin Disorders were reviewed, with those reviewers blinded to clinical information. All slides were systematically evaluated for a variety of features, including differences in the pattern of the epidermolysis and hyperkeratosis. Clinical predictions of whether the biopsy specimen was obtained from patients with generalized cEHK, mosaic cEHK, or IBS were made on the basis of histologic pattern of the epidermolysis and hyperkeratosis. Eighteen of the 117 slides revealed features sufficient to make a histologic diagnosis of epidermolytic hyperkeratosis (hEHK). One additional slide, for which a definitive histologic diagnosis was not possible, had features of both hEHK and acantholytic dyskeratosis. Two distinct patterns of the histopathologic changes were observed within the 18 slides diagnostic of hEHK: (1) continuous involvement of the entire horizontal epidermis and (2) focal involvement revealing skip areas of normal-appearing epidermis along the horizontal epidermis. Upon clinical correlation, all 12 of the slides with continuous involvement were from patients with generalized cEHK. One slide was from acral skin and had continuous involvement; this was from a patient with Vorner's palmoplantar keratoderma. Of the remaining 5 slides with focal involvement, two patterns were observed: focal involvement of both granular and spinous layers and focal involvement of only the granular layer. The 3 slides with focal involvement of the granular and spinous layers were from patients with mosaic cEHK. Of the two slides with focal involvement confined to the granular layer, one was from a patient with IBS and the other from a patient with generalized cEHK. The sample pool is biased by who was enrolled in the Registry and therefore may not represent the full spectrum of the disease. The pattern of histologic involvement may be a useful predictor of the clinical phenotype of cEHK.

A novel H1 domain mutation in the keratin 2 gene in a Japanese family with ichthyosis bullosa of Siemens

Conflicts of interest: none declared. Ichthyosis bullosa of Siemens (IBS) is a rare autosomal dominant skin disorder characterized by blister formation in the upper suprabasal layers of the epidermis. Clinical features of the disease, which include blistering after mechanical trauma, lichenified hyperkeratosis over the flexural areas of the limbs, and superficial peeling of the skin, are similar to those of epidermolytic hyperkeratosis/bullous congenital ichthyosiform erythroderma (EHK/BCIE). This clinical resemblance makes diagnosis difficult. Recent molecular studies have identified mutations in the keratin 2 (K2) gene (KRT2; this new designation is used throughout this report according to the current nomenclature for mammalian keratins1) in patients with IBS, in contrast to the keratin 1 or 10 mutations that have been detected in patients with EHK/BCIE, enabling us to differentiate between IBS and EHK/BCIE.2 Thus far, 29 missense mutations that result in amino acid substitutions in K2 have been identified in patients with IBS; all such mutations reside in the helix initiation or termination motifs of K2. Here, we describe a novel mutation in the H1 region of K2 in a Japanese family with IBS.

The keratins and their disorders.

Diseases caused by mutations in gene encoding keratin intermediate filaments (IF) are characterized by a loss of structural integrity in the cells expressing those keratins in vivo. This is manifested as cell fragility, compensatory epidermal hyperkeratosis, and keratin filament aggregation in some affected tissues. Keratin disorders are a novel molecular category including quite different phenotypes such as epidermolysis bullosa simplex (EBS), bullous congenital ichthyosiform erthroderma (BCIE), pachyonychia congenital (PC), steatocystoma multiplex, ichthyosis bullosa of Siemens (IBS), and white sponge nevus (WSN) of the orogenital mucosa.

Effect of topical tazarotene in the treatment of congenital ichthyoses.

The clinical efficacy and tolerability of the topical receptor-selective retinoid tazarotene in the treatment of congenital ichthyoses was investigated. Twelve consecutive patients with different forms of congenital ichthyosis were enrolled in an open, non-randomized, intraindividually controlled, half-side pilot study. Diagnoses were X-linked recessive ichthyosis, non-erythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant ichthyosis vulgaris and ichthyosis bullosa of Siemens (IBS). Tazarotene 0.05% gel was applied unilaterally daily on a defined body area measuring 10% of the body surface area. The contralateral side was treated with an ointment containing 10% urea. After 14 days, application frequency was reduced to three times a week, and stopped after another 2 weeks. The follow-up period was 3 months. Reduction in scaling and roughness was used to assess the clinical response in the tazarotene-treated area compared with the control area. Clinical and laboratory assessments were performed every 14 days during the trial. Unilateral improvement in favour of the tazarotene-treated side was observed in nine of 12 patients (75%). Four patients (33%) achieved an excellent response and four (33%) achieved a good response. No therapeutic effect was seen in patients with IBS. The remission persisted during the reduction phase and after discontinuation for up to 2 months. Local irritation in three patients was the only side-effect detectable. Short-term topical application of tazarotene 0.05% gel is a very effective and well-tolerated treatment modality in different forms of congenital ichthyoses and may be an alternative to systemic retinoid therapy.

Human keratin diseases: hereditary fragility of specific epithelial tissues.

Keratins are heteropolymeric proteins which form the intermediate filament cytoskeleton in epithelial cells. Since 1991, mutations in several keratin genes have been found to cause a variety of human diseases affecting the epidermis and other epithelial structures. Epidermolysis bullosa simplex (EBS) was the first mechanobullous disease for which the underlying genetic lesion was found, with mutations in both the K5 and K14 genes rendering basal epidermal keratinocytes less resilient to trauma, resulting in skin fragility. The site of mutation in the keratin protein correlates with phenotypic severity in this disorder. Since mutations were identified in the basal cell keratins, the total number of keratin genes associated with diseases has risen to eleven. The rod domains of suprabasal keratins K1 and K10 are mutated in bullous congenital ichthyosiform erythroderma (BCIE; also called epidermolytic hyperkeratosis, EH) and mosaicism for K1/K10 mutations results in a nevoid distribution of EH. An unusual mutation in the VI domain of K1 has also been found to cause diffuse non-epidermolytic palmoplantar keratoderma (DNEPPK). Mutations in palmoplantar specific keratin K9 cause epidermolytic palmoplantar keratoderma (EPPK) and mutations in the late differentiation suprabasal keratin K2e cause ichthyosis bullosa of Siemens (IBS). In the last year or so, mutations were discovered in differentiation specific keratins K6a and K16 causing pachyonychia congenita type 1 and K17 mutations occur in pachyonychia congenita type 2. K16 and K17 mutations have also been reported to produce phenotypes with little or no nail changes: K16 mutations can present as focal non-epidermolytic palmoplantar keratoderma (NEPPK) and K17 mutations can result in a phenotype resembling steatocystoma multiplex. Recently, mutation of mucosal keratin pair K4 and K13 has been shown to underlie white sponge nevus (WSN). This year, the first mutations in a keratin-associated protein, plectin, were shown to cause a variant of epidermolysis bullosa associated with late-onset muscular dystrophy (MD-EBS). An unusual mutation has been identified in K5 which is responsible for EBS with mottled pigmentation and genetic linkage analysis suggests that the hair disorder monilethrix is likely to be due to a mutation in a hair keratin. The study of keratin diseases has led to a better understanding of the importance of the intermediate filament cytoskeleton and associated connector molecules in maintaining the structural integrity of the epidermis and other high stress epithelial tissues, as well as allowing diagnosis at the molecular level thus facilitating prenatal testing for this heterogeneous group of genodermatoses.

Ichthyosis Bullosa of Siemens–A Disease Involving Keratin 2e

Ichthyosis bullosa of Siemens (IBS) is a congenital bullous ichthyosis without erythroderma. In contrast to bullous congenital ichthyosiform erythroderma (BCIE), there is a relatively mild involvement of the skin and epidermolytic hyperkeratosis (EHK) is restricted to the upper suprabasal layers of the epidermis. Tonofilament aggregation was observed by EM in suprabasal cells from affected patients in the two families under study, indicative of a keratin abnormality. Keratin 2e is a differentiation specific type II keratin expressed suprabasally in the epidermis. Part of the K2e gene was amplified by polymerase chain reaction using genomic DNA from affected and unaffected individuals from two IBS families. Direct sequencing of polymerase chain reaction products revealed a point mutation in the highly conserved helix termination motif, producing the protein sequence change LLEGEE-LLEGKE. This mutation was found in all affected members of a five-generation kindred and also in a sporadic case in a second unrelated family. No mutation was seen in unaffected individuals. The mutation destroys a MnlI restriction site, which allowed exclusion of the mutation from a population of 50 unaffected unrelated individuals by restriction fragment analysis of K2e PCR products. This is the sixth keratin gene found to be involved in an inherited epidermal disorder.

Ichthyosis bullosa of Siemens responds well to low-dosage oral retinoids

Two patients with ichthyosis bullosa of Siemens (IBS) and one patient with bullous ichthyosiform erythroderma of Brocq (BIE) were treated with etretinate. Two additional patients with IBS received acitretin. All the patients had a marked improvement when on retinoids and the maintenance dose required was for IBS 10-25 mg per day. The patient with BIE was on a maintenance dose of 40-60 mg per day.