Epidermolytic Hyperkeratosis Research Articles

086 Familial Tree of Epidermolytic Ichthyosis Suggesting a Novel Genetic Mutation

The ichthyoses encompass a heterogeneous group of genetic disorders identified by varying degrees of erythema, scale, hyperkeratosis, xerosis, and pruritus. Non-syndromic and syndromic forms of ichthyoses exist, but common among all inherited ichthyoses is alteration in keratin maturation and function. A 28-year-old African-American woman was referred to dermatology for a rash. Punch biopsy revealed psoriasiform epidermal change and epidermolytic hyperkeratosis. The patient was diagnosed with epidermolytic ichthyosis (EI) and started on cyclosporine, methotrexate, and later ustekinumab with symptom control.

Diffuse Geometric Erosions on the Skin of a Premature Infant, Fraternal Twin Unaffected

Diffuse Geometric Erosions on the Skin of a Premature Infant, Fraternal Twin Unaffected

Ichthyosis in Dogs—Congenital Dermatologic Disorder

Abstract The skin provides protective functions, such as thermoregulation, resorption, provision of immune responses, storage and sensory functions, which all play an important role in the internal stability of the organism. The skin has 3 major layers: the epidermis, the dermis and subcutis. The outermost protective layer of the epidermis, the stratum corneum, consists of 20 to 30 overlapping layers of anucleate cells, the corneocytes. Ichthyosis is an autosomal recessive congenital skin disease, in which the corneocytes form defects that appear like individual steps of the stratum corneum. Ichthyosis is characterized by excessive scaling over the entire body surface and is not curable; the symptoms can only be alleviated. Several genetic variants have been identified in specific dog breeds: PNPLA1 in the Golden Retrievers, SLC27A4 in the Great Danes, NIPAL4 in the American Bulldogs, TGM1 in the Jack Russel Terriers, ASPRV1 in the German Shepherds, which cause different forms of nonepidermolytic ichthyosis and KRT10 in the Norfolk Terriers, which causes epidermolytic ichthyosis. When classifying breeds of dogs predisposed to ichthyosis, it is necessary to determine the presence of defective genes in the genome of the individual animals involved in mating.

Epidermolytic ichthyosis in a child and systematized epidermolytic nevi in the mosaic parent associated with a KRT1 variant

Epidermolytic ichthyosis and epidermolytic nevi share the same histopathological features of epidermolytic hyperkeratosis, characterized by distinctive vacuolar degeneration and hypergranulosis of the superficial epidermis. Both are caused by pathogenic variants in either of two keratin genes KRT1or KRT10, with epidermolytic ichthyosis presenting as a generalized phenotype and epidermolytic nevi presenting as a mosaic phenotype. We report a boy who presented as epidermolytic ichthyosis, with diffuse erythema, superficial erosions and flaccid blisters at birth progressing to generalized ichthyosis. He was found to have inherited a novel KRT1 variant from his mother who presented with extensive epidermolytic nevi or mosaic form of epidermolytic ichthyosis, with extensive, linear and Blaschkoid verrucous, hyperkeratotic plaques over the trunk and limbs. This case highlights the importance of recognising post-zygotic mosaicism which might be transmitted to a child, and the different presentations for germline and mosaic carriers.

Recalibrated Scales: The Use of Low-dose Isotretinoin in a Case of Epidermolytic Ichthyosis-NPS1 in a Filipino Child

Epidermolytic Ichthyosis (EI) is a rare non-syndromic keratinopathic ichthyosis without definitive treatment. This is a case of EI in a 5-year-old Filipino female who presented with hyperkeratotic scales sparing the palms and soles. Histopathology revealed epidermolytic hyperkeratosis. A trial of treatment with isotretinoin 0.3 mg/kg/day, together with keratolytic agents, urea lotion and lactic acid lotion, resulted in a marked decrease in the thickness of the scales and odor. Interestingly, rebound effects were noted at 0.6 mg/kg/day. Taking into account that EI presents with more skin fragility compared to non-EHK ichthyosis, the authors surmise that there may be a smaller treatment window for patients with EI, which is notably lower than recommended for ichthyosis in general.

Ichthyosis (concept, pathohistology, clinical picture, treatment)

Ichthyosis is a skin disease that is hereditary, has pronounced symptoms in the form of a violation of the skin, and the presence of formations resembling fish scales. It is possible to distinguish different approaches to the definition of ichthyosis, based on the modern study of this issue. Ichthyosis is classified by type: congenital and acquired. Congenital ichthyosis has its own classification depending on the manifestation of changes in the skin, the course of the disease, concomitant pathologies. Congenital ichthyosis is divided into ordinary (vulgar autosomal dominant, simple) ichthyosis, lamellar ichthyosis (dry ichthyosiform erythroderma, "collodion child", lamellar ichthyosis), X-linked ichthyosis (ichthyosis associated with the X chromosome, blackening ichthyosis), congenital bullous ichthyosiform erythroderma (erythroderma Broca's disease, ichthyosiform epidermolytic hyperkeratosis), fetal ichthyosis (intrauterine ichthyosis, universal hyperkeratosis, "Harlequin fetus", congenital keratosis), other congenital ichthyosis. Ichthyosiform conditions (the so-called acquired ichthyosis) are divided into symptomatic, age-related (senile), discoid ichthyosis. The causes of acquired ichthyosis can be various diseases, taking medications, improper skin care, unbalanced nutrition. Each form of ichthyosis differs by the type of inheritance, prevalence in the population, clinical picture, verified by histological examination of skin biopsies and electron microscopic examination of the skin. It may be accompanied by seasonality of exacerbation of the clinical picture, association with other diseases (allergic, diseases of the gastrointestinal tract, congenital malformations). There is no specific treatment for ichthyosis. In systemic therapy, derivatives of vitamin A are used, keratolytics, as well as moisturizing and emollient agents are used for external treatment. The use of therapeutic baths, general ultraviolet irradiation is effective.

Ichthyoses-A Clinical and Pathological Spectrum from Heterogeneous Cornification Disorders to Inflammation.

Ichthyoses are inborn keratinization disorders affecting the skin only (non-syndromic) or are associated with diseases of internal organs (syndromic). In newborns, they can be life-threatening. The identification of the gene defects resulted in reclassification and a better understanding of the pathophysiology. Histopathologic patterns include orthohyperkeratosis with a reduced or well-developed stratum granulosum, hyperkeratosis with ortho- and parakeratosis with preserved or prominent stratum granulosum, and epidermolytic ichthyosis. Another pattern features “perinuclear vacuoles and binucleated keratinocytes”, which is associated with keratin mutations. Some ichthyoses are histologically defined by psoriasis-like features, and distinct subtypes show follicular hyperkeratosis. In addition to histological and immunohistochemical methods, these patterns allow a better histopathologic diagnosis.

Epidermolytic epidermal nevus caused by a somatic mutation in KRT2.

Superficial epidermolytic ichthyosis (formerly Ichthyosis bullosa of Siemens) is an uncommon condition caused by dominant mutations in KRT2 encoding keratin 2. Epidermolytic epidermal nevus due to somatic mutations in KRT2 is even rarer. Here, we report the third case of KRT2-associated epidermal nevus and review the literature.

Generalized epidermolytic ichthyosis with palmoplantar hyperkeratosis

Epidermolytic ichthyosis (EI, OMIM 113800) is a rare autosomal dominant keratinization disorder that is caused by keratin 1 or 10 gene mutation. It can be classified clinically based on the presence of palmoplantar hyperkeratosis involvement and extent of skin involvement. The diagnosis is made by clinical and histopathological examinations that can be confirmed by genetic testing. We present a 2-year-old girl who presented with erythematous and thick scaling skin. Her condition began at birth as multiple flaccid blisters that would easily break into erosions. There was no history of similar condition nor consanguinity within her family. Skin examination revealed diffuse erythematous skin covered with thick scales and erosion, predominantly on her face, extremities, palms, and soles. The skin histopathology examination showed diffuse parakeratosis with vacuolar and granular degeneration within granular and spinous layers along the epidermis. She was diagnosed with generalized EI with palmoplantar hyperkeratosis based on the clinical and histopathological examinations. Clinical improvement was observed after a one-month treatment with mupirocin cream, sodium bicarbonate bath, and moisturizer after bathing.

Epidermolytic hyperkeratosis of the vulva

Vulvar epidermolytic hyperkeratosis is a benign entity that mimics other malignant and inflammatory vulvar dermatoses clinically and histologically requiring careful clinical pathologic correlation for diagnosis.

First Case of KRT2 Epidermolytic Nevus and Novel Clinical and Genetic Findings in 26 Italian Patients with Keratinopathic Ichthyoses.

Keratinopathic ichthyoses (KI) are a clinically heterogeneous group of keratinization disorders due to mutations in KRT1, KTR10, or KRT2 genes encoding keratins of suprabasal epidermis. Characteristic clinical features include superficial blisters and erosions in infancy and progressive development of hyperkeratosis. Histopathology shows epidermolytic hyperkeratosis. We describe the clinical, histopathological, and molecular findings of a series of 26 Italian patients from 19 unrelated families affected with (i) epidermolytic ichthyosis due to KRT1 or KRT10 mutations (7 and 9 cases, respectively); (ii) KTR10-mutated ichthyosis with confetti (2 cases); (iii) KRT2-mutated superficial epidermolytic ichthyosis (5 cases); and (iv) KRT10-mutated epidermolytic nevus (2 cases). Of note, molecular genetic testing in a third case of extensive epidermolytic nevus revealed a somatic missense mutation (p.Asn186Asp) in the KRT2 gene, detected in DNA from lesional skin at an allelic frequency of 25% and, at very low frequency (1.5%), also in blood. Finally, we report three novel dominant mutations, including a frameshift mutation altering the C-terminal V2 domain of keratin 1 in three familiar cases presenting a mild phenotype. Overall, our findings expand the phenotypic and molecular spectrum of KI and show for the first time that epidermolytic nevus can be due to somatic KRT2 mutation.

VP04.17: Acitretin embryopathy due to acitretin intake during the first and second trimesters of pregnancy

Acitretin is an aromatic retinoid analog of vitamin A used to treat severe forms of psoriasis and disorders of keratinisation. It is contraindicated during pregnancy because of its teratogenic potential. Acitretin embryopathy is a rare teratogenic disorder due to acitretin exposure during the 1st trimester, with a risk of fetal malformations of nearly 20% involving the central nervous system, various craniofacial and ear abnormalities, as well as cardiac, upper and lower limbs defects. Only a few cases of newborns with exposure to acitretin in the 1st trimester and anomalies compatible with this syndrome are known. We describe the case of a 24-year-old woman with epidermolytic hyperkeratosis, taking daily acitretin 25mg for many years. Pregnancy was unplanned, discovered at 18 weeks of gestation and very poorly monitored. She missed several appointments and inadvertently maintained acitretin intake until 30 weeks of pregnancy. When referred to our consultation at 32 weeks a fetal scan was requested. Ultrasound at 34 and 36 weeks exposed craniofacial malformations including prominent frontal bone, abnormal ears, low-set ears, low nasal bridge and absent hand finger. Fetal echocardiogram was normal. A female neonate was delivered at term with 2,515g and an Apgar score of 9/10/10. Evaluation at birth confirmed craniofacial dysmorphism with microcephaly, craniosynostosis, sinking of metopic sutures with prominent frontal bone, low nasal bridge, microphthalmia, hypertelorism, low-set ears, high-arched palate and limb defects with elbow arthrogryposis, absent 1st finger in both hands and 4th and 5th finger foot syndactyly. Brain MRI showed no endocranial abnormalities. These findings are in accordance to the spectrum of defects described in the literature for acitretin embryopathy. This case emphasises the extreme precaution that is needed with the use of teratogenic drugs in women of childbearing age and the importance of mandatory use of an effective contraception.

Epidermolytic acanthoma in a young woman: a case letter

Epidermolytic acanthoma (EA) is a rare benign tumor that is characterized by epidermolytic hyperkeratosis on histopathology.It usually presents in adulthood as an asymptomatic tumor <1 cm in diameter with a verrucous surface. We report a very uncommon case of epidermolytic acanthoma. A 21-year-old woman came to our hospital with a pale black papule on the left lower eyelid near the Inner canthus for 2 months. Two months ago the patient noted a pale brown spot on the inside of the left lower eyelid, which gradually enlarged, forming a papule with a deepened color. There were no associated symptoms, such as itching or pain. There were no local injuries, scratches, or other incidents before the crash occurred. The patient was always healthy, with no history of chronic disease or other skin diseases, and no similar cases existed in the family. We diagnosed it as EA.

Клиническое наблюдение ребенка с эпидермолитическим ихтиозом и врожденным пороком развития легкого

Клиническое наблюдение ребенка с эпидермолитическим ихтиозом и врожденным пороком развития легкого

Transepidermal water loss in the orphan forms of ichthyosis.

As a surrogate measure of skin barrier dysfunction, we sought to determine differences in transepidermal water loss (TEWL) among ichthyosis subtypes and correlate TEWL with clinical severity. Subjects with Netherton syndrome had the highest TEWL values (increased water loss), while TEWL values were lowest in subjects with epidermolytic ichthyosis. TEWL correlated with severity only in lamellar ichthyosis and age was inversely correlated with TEWL (rs =-.213, P=.02). TEWL is an objective measure that complements disease severity in ichthyosis and may be used as an adjuvant to monitor treatment response.

Annular epidermolytic ichthyosis with palmoplantar keratosis: a unique phenotype associated with interfamilial phenotypic heterogeneity.

Annular epidermolytic ichthyosis (AEI) is a rare autosomal dominant ichthyosis that was recently described in 10 separate families in the English literature. There are no reports on the phenotypic heterogeneity of AEI. We investigated, for the first time, a large Chinese AEI pedigree exhibiting interfamilial phenotypic heterogeneity. We collected clinical data and DNA from the members of the family, and skin lesions were obtained from two patients with different phenotypes. Skin imaging examinations were performed. Whole-exome sequencing (WES) and Sanger sequencing were used to detect gene mutations. The characteristic features of granular layer degeneration in the two biopsies were verified via histological methods. The missense mutation c.1436T > C in KRT1 was detected in all nine patients. This study demonstrates that AEI may present with different clinical phenotypes and that mutation analysis for suspected cases is necessary to obtain a precise diagnosis.

Notice of withdrawal.

L. Frommherz, J. Küsel, A. Zimmer, J. Fischer, C. Has. Skin fragility caused by biallelic KRT10 mutations: an intriguing form of self-improving epidermolytic ichthyosis https://onlinelibrary.wiley.com/doi/10.1111/bjd.18325 The above article from the British Journal of Dermatology, published online on 6 July 2019 in Wiley Online Library (wileyonlinelibrary.com), and in print and online in issue 182:3 (cover date March 2020) has been withdrawn by agreement between the authors, the journal's Editor-in-Chief, John Ingram, the British Association of Dermatologists, and John Wiley & Sons Limited. The withdrawal has been agreed because consent to publish was not obtained in this case. The authors and the journal sincerely apologize for this oversight. The article is no longer available online in order to protect patient confidentiality.

Mutations in KRT10 in epidermolytic acanthoma.

Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA. Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis. DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10. Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.

Bullous Congenital Ichthyosiform Erythroderma: Management of Otological Manifestations

Bullous Congenital Ichthyosiform Erythroderma (BCIE) is a rare form of congenital ichthyosis which...

Bullous diseases caused by KRT1 gene mutations: from epidermolytic hyperkeratosis to a novel variant of epidermolysis bullosa simplex.

IntroductionMutations in the KRT1 gene encoding keratin 1 cause epidermolytic hyperkeratosis characterized by blistering in the neonatal period followed by ichthyotic hyperkeratosis in childhood and adolescent life. We observed a spectrum of clinical manifestations of blistering disorders caused by different mutations in the same KRT1 gene.AimTo analyse the phenotypic spectrum of blistering disorders caused by the KRT1 mutations.Material and methodsFour patients with an epidermal barrier defect manifesting as blistering with the KRT1 mutations were included to the study. The clinical course of the disease was analysed, histology, immunofluorescence and electron microscopic examinations were performed.ResultsAn adult patient with severe ichthyosis with p.Asn188Lys mutation in exon 1 of KRT1 who occasionally develops blisters in adolescence represents epidermolytic hyperkeratosis, a newborn child who died 4 days after birth due to disruption of the epidermal barrier (extensive blister and erosions) with mutation p.Ser193Pro in the KTR1 gene and two adult sisters harbouring heterozygous mutation c.591+1A>G in the KRT1 gene who present superficial blisters induced by mild trauma from the birth up to adolescent life without ichthyosis suggesting the diagnosis of epidermolysis bullosa simplex. Histopathology in all adult patients showed cytoplasm disruption in keratinocytes of the stratum spinosum with keratohyalin granule-like structures and, on the ultrastructural level, the presence of keratin clumping confirming the pathology of keratin intermediate filaments.ConclusionsThis study extends the knowledge of the clinical spectrum for the KRT1 gene mutations. This is the first description of familial dominant epidermolysis bullosa simplex linked to the KRT1 mutation.