Epidermolytic Hyperkeratosis Research Articles

Induction of p38, tumour necrosis factor-α and RANTES by mechanical stretching of keratinocytes expressing mutant keratin 10R156H

Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), characterized by ichthyotic, rippled hyperkeratosis, erythroderma and skin blistering, is a rare autosomal dominant disease caused by mutations in keratin 1 or keratin 10 (K10) genes. A severe phenotype is caused by a missense mutation in a highly conserved arginine residue at position 156 (R156) in K10. To analyse molecular pathomechanisms of hyperproliferation and hyperkeratosis, we investigated the defects in mechanosensation and mechanotransduction in keratinocytes carrying the K10(R156H) mutation. Differentiated primary human keratinocytes infected with lentiviral vectors carrying wild-type K10 (K10(wt)) or mutated K10(R156H) were subjected to 20% isoaxial stretch. Cellular fragility and mechanosensation were studied by analysis of mitogen-activated protein kinase activation and cytokine release. Cultured keratinocytes expressing K10(R156H) showed keratin aggregate formation at the cell periphery, whereas the filament network in K10(wt) cells was normal. Under stretching conditions K10(R156H) keratinocytes exhibited about a twofold higher level of filament collapse compared with steady state. In stretched K10(R156H) cells, higher p38 activation, higher release of tumour necrosis factor-α and RANTES but reduced interleukin-1β secretion compared with K10(wt) cells was observed. These results demonstrate that the R156H mutation in K10 destabilizes the keratin intermediate filament network and affects stress signalling and inflammatory responses to mechanical stretch in differentiated cultured keratinocytes.

A novel mutation of the keratin 9 gene in a Chinese family with epidermolytic palmoplantar keratoderma

A novel mutation of the keratin 9 gene in a Chinese family with epidermolytic palmoplantar keratoderma

A novel homozygous keratin 10 mutation in siblings with autosomal recessive epidermolytic ichthyosis

Epidermolytic hyperkeratosis (EHK; OMIM 113800), or epidermolytic ichthyosis (EI), is a rare autosomal dominant skin disorder characterized by erythroderma and blistering at birth, which is replaced by progressive hyperkeratosis. In most cases, EHK/EI is due to dominant mutations in the genes encoding keratin 1 or keratin 10. A recessive form of EHK/EI has been described caused by truncating mutations in the KRT10 gene. Here, we report two male siblings with EHK/EI in whom we have identified a novel homozygous mutation, KRT10 c.1A>T. We discuss the importance of establishing the mode of inheritance in EHK. We also discuss the varying presentation of a ‘collodion baby’, and the differential diagnosis to consider. The histopathological and ultrastructural changes in both forms of EHK/EI have subtle differences that are detailed, and the importance of identifying these key features to target molecular analysis is further explained. These cases highlight the value of a dedicated skin genetics clinic with high...

Mutations in the keratin 9 gene in Pakistani families with epidermolytic palmoplantar keratoderma

Keratins are heteropolymeric proteins that form the intermediate filament cytoskeleton in epithelial cells. The common basic structure of all keratins is organized in a central α-helical rod domain flanked by nonhelical, variable head and tail regions. Most mutations in keratins are found in the central α-helical rod domain. Keratin 9 (K9) is expressed only in the suprabasal layers of palmoplantar epidermis. Mutations in the keratin 9 gene (KRT9) have been shown to cause epidermolytic palmoplantar keratoderma (EPPK; OMIM 144200), an autosomal dominant genodermatosis characterized clinically by diffuse hyperkeratosis limited to the palms and soles, and histologically by epidermolysis in suprabasal layers of the epidermis. To elucidate the genetic basis of EPPK in five Pakistani families. Using microsatellite markers localized to the areas around the type I keratin gene cluster on chromosome 17q21, genotyping of these families was performed, followed by sequencing of the KRT9 gene. The analysis resulted in the identification of two novel (p.M157K and p.Y454H) and two recurrent (p.M157T and p.R163Q) mutations in the KRT9 of all five families. All mutations occurred within the highly conserved helix initiation or termination motif of K9. The affected members of all five families possess mutations in the KRT9 gene that severely affect heterodimer formation with the type II keratin partner. The results of our study further underscore the crucial role of K9 protein in the palmoplantar epidermis.

Lichenoid Inflammation in Cutaneous Cysts

To the Editors: We recently observed a case of a benign epidermoid cyst with a prominent lichenoid reaction. A 49-year-old man with a history of hyperlipidemia controlled on simvastatin presented with a “boil” on his back of 2 weeks duration. It was felt to be a carbuncle and treated with incision and drainage, iodoform gauze packing, and the cephalexin before excision. Histologic exam revealed a cyst lined by stratified squamous epithelium with a granular layer. The cyst cavity contained orthokeratin, foreign body giant cells, neutrophils, and early granulation tissue. Nearly the entire epithelial lining demonstrated a saw-toothed rete pattern, dense band-like lymphoplasmacytic inflammation, and prominent Civatte bodies (Figs. 1 and 2).FIGURE 1: Low power of ruptured cyst with lichenoid inflammation throughout the majority of the cyst lining.FIGURE 2: High power of the lichenoid inflammation.Typically, when an epidermoid cyst ruptures, a suppurative and granulomatous foreign-body response is seen. As discussed by Weedon, a number of histologic changes have been seen in the lining of epidermoid cysts: epidermal proliferation, basal hyperpigmentation, melanophagic proliferation, pilomatricoma-like changes, clear cell change, coronoid lamellation, epidermolytic hyperkeratosis, changes of Darier disease, pyogenic granuloma formation, and a number of tumors.1 We are unaware of previous reports of a lichenoid interface dermatitis found in the lining of an epidermoid cyst. A Medline search using the methodology “cyst AND (lichenoid OR interface AND dermatitis)” failed to reveal prior reports. However, an electronic search of our pathology database over the last 10 years revealed 9 additional cases of cutaneous cysts with a lichenoid inflammatory response. All cases involved epidermoid cysts, and in all cases the lichenoid pattern was only focal. In 2 cases, there was overlying lichenoid inflammation and lichen simplex chronicus-like epidermal changes (Table 1).TABLE 1: Retrieved Cases of Cutaneous Cysts With Lichenoid InflammationThe significance of these changes is not known. Lichenoid interface dermatitis is felt to be mediated by cytotoxic CD8+ T cells that are responding to an unknown stimulus causing destruction of the basal layer epidermal keratinocytes.2 Many lichenoid conditions are linked epidemiologically to autoimmune phenomena and autoantibody formation. Our patient was taking simvastatin, a known cause of lichenoid drug eruptions.3 However, we think the drug is an unlikely cause of the lichenoid tissue reaction in our patient. Eric W. Hossler, MD Morgan L. Wilson, MD Department of Dermatopathology Geisinger Medical Center Danville, PA MAJ Scott R. Dalton, DO, MC, USA Department of Dermatology Geisinger Medical Center Danville, PA Dirk M. Elston, MD Departments of Dermatology and Dermatopathology Geisinger Medical Center Danville, PA

Localised epidermolytic hyperkeratosis of the vulva: a case of mistaken identity

Sir,Simulacra are the bane of the unwary pathologist's life, sometimes with non-trivial clinical or ‘social’ consequences for the patient, from a wrong diagnosis. Epidermolytic hyperkeratosis (EHK)...

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification, typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Sorèze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. It was agreed that currently the nosology should remain clinically based. "Syndromic" versus "nonsyndromic" forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, "keratinopathic ichthyosis"-under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. "Autosomal recessive congenital ichthyosis" is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. As more becomes known about these diseases in the future, modifications will be needed. We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research.

Quality of life in Swedish children with congenital ichthyosis

Congenital ichthyosis encompasses a large group of keratinizing disorders with widespread scaling and a variable degree of erythema. Little is known about the quality of life in children with congenital ichthyosis and the impact of the disease on their family. Fifteen children aged 5–16 years with lamellar ichthyosis, Netherton’s syndrome, epidermolytic hyperkeratosis or Harlequin ichthyosis, were investigated concerning the effect of their ichthyosis on their quality of life. This was measured with the established Children’s Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact questionnaire (DFI) modified by substituting the word ichthyosis for eczema. The questionnaires covered the preceding seven days and each had a maximum score of 30: the higher the score, the greater the Quality of Life impairment. The median score was 9.0 (range 2–19) for the CDLQI and 9.0 (range 3–21) for DFI. There was a significant correlation between the DFI and the CDLQI scores. The item in the CDLQI questionnaire that showed the highest score was “itchy, scratchy, sore or painful skin” and the most highly scored item in the DFI questionnaire was effect on “housework, e.g. washing, cleaning”; both items related to the children’s symptoms. The results of the study clearly establish that congenital ichthyosis impairs the quality of life of the affected children and their families.

An atypical presentation of bullous congenital ichthyosiform erythroderma

The authors report the case of a male neonate, born at full term by uncomplicated spontaneous vaginal delivery to non-consanguineous parents, who was noted to have areas of desquamation over the elbows, lower abdomen and scrotum within an hour of birth. Over the subsequent 48 h, flaccid blisters developed on the trunk and limbs, followed by extensive erosions, on a background of subtle generalised erythema, resembling that seen in staphylococcal scalded skin syndrome and toxic epidermal necrolysis. Although the baby remained afebrile and fed well, he was treated empirically with flucloxacillin, and an infection screen proved negative. There was no relevant family history. The clinical impression was that these signs represented an inherited blistering disorder. In order to exclude severe forms of epidermolysis bullosa, sections of frozen perilesional skin were stained, on postnatal day 2, with two commercially available antibodies, GB3 (a marker of laminin 332) and LH7.2 (a marker of type VII collagen): their normal expression excluded potentially life-threatening forms of junctional and dystrophic epidermolysis bullosa, respectively. Formal histological examination of lesional skin revealed a cleavage plane in the upper epidermis associated with dyskeratosis and clumped tonofilaments (“epidermolytic hyperkeratosis”), entirely consistent with bullous ichthyosiform erythroderma (BIE). Over the next few months, the tendency to blistering diminished, and a generalised dryness developed, in association with areas of “corrugated hyperkeratosis” typical of BIE. This case is likely to represent a sporadic mutation in one of the genes encoding either keratin 1 or 10. This case illustrates two important aspects relating to babies that develop a blistering and scalded appearance (“enfant brule”) in the neonatal period. The first is that such an appearance may indicate an inherited bullous disorder rather than an infective or reactive process. The second is that the primary diagnosis can often be quickly reached using very basic procedures, including direct immunofluorescence and routine histology.

Compound Heterozygous Desmoplakin Mutations Result in a Phenotype with a Combination of Myocardial, Skin, Hair, and Enamel Abnormalities

Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.

Lethal autosomal recessive epidermolytic ichthyosis due to a novel donor splice-site mutation inKRT10

Epidermolytic ichthyosis (EI; MIM 113800), previously named bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases. EI is caused by dominant mutations in either KRT1 or KRT10, encoding keratin 1 (K1) and keratin 10 (K10), respectively. Usually, mutations are missense substitutions into the highly conserved α-helical rod domains of the proteins. However, three inbred pedigrees in which EI is transmitted as a recessive trait due to KRT10 null mutations have been described.

A novel mutation in the L12 domain of keratin 1 is associated with mild epidermolytic ichthyosis

Epidermolytic ichthyosis (EI), previously termed bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a clinically heterogeneous genodermatosis caused by mutations in the genes encoding the suprabasal keratins 1 and 10. Classical EI is clinically characterized by severe neonatal erythroderma, blistering and fragile skin in infancy, quickly subsiding with subsequent development of generalized scaling hyperkeratosis. We report three Dutch families with palmoplantar keratoderma and mild blistering, but without neonatal erythroderma and generalized scaling. A novel heterozygous missense mutation in the linker L12 domain of KRT1:c.1019A>G, p.Asp340Gly was found associated with this phenotype in these families. To investigate the effects of the novel KRT1:p.Asp340Gly and the one other previously reported KRT1:p.Asp340Val mutations on keratinocyte cytoskeleton formation and stress resistance. Wild-type and mutant pEGFP-KRT1 fusion constructs were transfected into HaCaT cells and exposed to hypo-osmotic shock. Haplotyping and genealogical studies were performed to investigate the possibility of a common founder for p.Asp340Gly. Cells transfected with either one of the keratin 1 L12 domain mutations showed significantly increased tonofilament aggregation. The haplotype around the KRT1 gene was shared in all affected family members of two families and a common founder was traced. Our study supports the pathogenicity of the keratin 1 L12 domain mutations in vitro. These mutations are associated with a milder EI phenotype with pronounced palmoplantar keratoderma, and without neonatal erythroderma and scaling. The KRT1:p.Asp340Gly mutation in the Dutch families is likely to have arisen from a common founder.

Linear epidermolytic acanthoma of vulva: An unusual presentation

Epidermolytic acanthoma (EA) is a rare benign tumor that shows epidermolytic hyperkeratosis (EH) on histopathology. It can occur in a solitary or disseminated form. This condition needs to be distinguished from other hereditary or acquired conditions that may show EH. We diagnosed an unusual case of EA of the vulva presenting in a linear pattern in a 50-year-old lady based on the clinical features and typical histopathological findings and stress the importance of considering epidermolytic acanthoma in the differential diagnosis of verrucous lesions of the genitalia.

Mutation analysis of a Uighur family with epidermolytic palmoplantar keratoderma

To map and identify the disease gene for the epidermolytic palmoplantar keratoderma (EPPK) in a Uighur family of China. Blood samples were collected and genomic DNA was extracted from 48 members of the Xinjiang Uighur family. Six microsatellite repeat sequences on chromosome region 17q12-q21 and 12q13 were selected based on the two known candidate genes KRT9 and KRT1. Two-point linkage analysis and haplotype analysis were performed. Exons and their flanking intronic sequence of the KRT9 gene were amplified by polymerase chain reaction (PCR) and sequenced. Data from the marker D17S1787 suggested linkage and yielded a Lod score of 8.65 at theta=0 by using MLINK software. Genotypes and haplotypes were acquired. The disease gene of the EPPK family is located between markers 17/TG/36620115 and D17S846. Chromosome 12q13 region was excluded with the negative Lod score obtained in marker D12S96 (Lod=-infinity at theta=0). No pathogenic mutation was detected in the KRT9 gene. The disease gene of the EPPK family is located on chromosome region 17q21.2. The keratin 9 gene might not be the disease gene.

Ichthyosis hystrix Curth–Macklin type in an African girl

Ichthyosis hystrix Curth-Macklin type is a rare autosomal dominant skin disorder characterized by extensive hyperkeratosis and palmo-plantar keratoderma. It results from heterozygous frameshift mutation in keratin 1 gene (KRT1). Histological features, showing perinuclear vacuolization and binucleated cells, are similar to those of epidermolytic hyperkeratosis except for the absence of epidermolysis. The present report describes the condition in a 16-year-old African girl where available treatment was disappointing.

Case of mistaken identity: Bullous congenital ichthyosiform erythroderma mistaken as epidermolysis bullosa simplex

Distinguishing clinically similar dermatologic disorders can be challenging and the differential diagnosis of a blistering eruption in the newborn period can be extensive. Several genodermatosis, such as bullous congenital ichthyosiform erythroderma (BCIE) and epidermolysis bullosa simplex (EBS), autoimmune bullous disorders, infectious diseases, sucking blisters, and bullous mastocytosis must be considered. We present a case of BCIE misdiagnosed as EBS and review characteristic clinical and histopathological features of each disorder as well as the basic approach to treatment.

Bullous Congenital Ichthyosiform Erythroderma: A Sporadic Case Produced by a New KRT10 Gene Mutation

Bullous congenital ichthyosiform erythroderma is an unusual type of inherited ichthyosis by mutations in the genes that encode K1 and K10. We report the case of a girl with typical clinical and histopathologic findings of bullous congenital ichthyosiform erythroderma, who was found to have a new mutation in KRT10 gene, Glu445Lys at position 445, affecting the 2B region of the KRT10 protein, the end of the rod domain, where many other keratin mutations associated with hereditary skin disease have been reported. This new mutation contributes to add to the catalog of bullous congenital ichthyosiform erythroderma mutations known.

Prenatal diagnosis of epidermolytic palmoplantar keratoderma caused by c.T470C (p.M157T) of the keratin 9 gene in a Chinese kindred

Prenatal diagnosis of epidermolytic palmoplantar keratoderma caused by c.T470C (p.M157T) of the keratin 9 gene in a Chinese kindred

Epidermolytic hyperkeratosis with palmoplantar keratoderma in a patient with KRT10 mutation

We report the case of a 12-year-old girl presenting at birth with erythroderma, erosions and blisters scattered over the integument. By the age of 3 she presented generalized hyperkeratotic plaques with a cobblestone pattern and a pungent odour, most prominently around flexures, scalp and palmoplantar areas. Clinical, histological and ultrastructural findings confirmed the diagnosis of epidermolytic hyperkeratosis (EHK). Molecular genetic analysis revealed a mutation in the KRT10 gene. Treatment with oral acitretin was attempted but it was discontinued due to hepatic dysfunction and marked desquamation and blistering. EHK is a rare autosomal dominant disorder of keratinization, caused by mutations in either the KRT1 or KRT10 genes. Although palmoplantar keratoderma is typically found in patients with KRT1 mutation, our patient presents EHK with palmoplantar involvement and KRT10 mutation. Moreover, a poor response to systemic retinoids was observed, contrary to what is expected in patients with KRT10 mutation. Even though management is usually unsatisfactory, some patients with this lifelong and serious condition may experience improvement with age.

Clear (pale) cell acanthosis as an incidental finding

Different patterns of epidermal change, including epidermolytic hyperkeratosis and acantholytic dyskeratosis, may represent the predominant histopathologic finding in several localized and generalized processes. Occasionally, minute foci of these reaction patterns are identified as an incidental finding in a biopsy taken because of the presence of some other lesion. Clear (pale) cell acanthosis may occur as the main histologic alteration in clear (pale) cell acanthoma or incidentally, such as may be seen within a seborrheic keratosis. Two cases of incidental minute foci of clear (pale) cell acanthosis are described and put into the broader context of other epidermal histologic reaction patterns.