Disorders Of Keratinization Research Articles

Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families.

Autosomal recessive congenital ichthyosis (ARCI), a phenotypically heterogeneous group of non-syndromic Mendelian disorders of keratinization, is caused by mutations in as many as 13 distinct genes. We examined a cohort of 125 consanguineous families with ARCI for underlying genetic mutations. The patients' DNA was analyzed with a gene-targeted next generation sequencing panel comprising 38 ichthyosis associated genes. The interpretations of results of genomic data were assisted by genome-wide homozygosity mapping and transcriptome sequencing. Sequence data analysis identified biallelic mutations in 106 families out of a total of 125 (85%), most of them (102, 96.2%) being homozygous, reflecting consanguinity in these families. Among the 85 distinct mutations in 10 different genes, 45 (53%) were previously unreported. Phenotype-genotype correlations allowed assignment of specific genes in the majority of the families to a specific subtype of ARCI, lamellar ichthyosis (LI) versus congenital ichthyosiform erythroderma (CIE). Interestingly, mutations in several genes could give rise to an overlapping phenotype consistent with either LI or CIE. Also, this is the third report for SDR9C7 and SULT2B1, and fourth report for CERS3 mutations. Direct comparison of our results with previously published regional cohorts highlights the global mutation landscape of ARCI, however, population specific differences were noted.

Two Cases of Pediatric Keratosis Lichenoides Chronica with Review of the Clinical and Hitopathological Features of Pediatric versus Adult Presentation and Treatment with Acitretin

Keratosis Lichenoides Chronica (KLC) is a rare and chronic disorder of keratinization of unknown etiology. It is a progressive disease characterized by the linear and reticulate appearance of erythematous-to-violaceous keratotic and lichenoid papules over the trunk and limbs. KLC is uncommon in the pediatric population is uncommon and its clinical and histopathological presentation differs from the adult form. We report two cases in pediatric population, one of which has been treated successfully by acitretin. We also review the clinical and histopathologic features of the pediatric versus the adult form.

Coexistence of darier's disease and porokeratosis: A rare presentation

Darier's disease and porokeratosis are both autosomal dominant genodermatosis characterized by disorder of keratinization. Hereby, we report a case of co-existing Darier's disease and Porokeratosis in an elderly male.

Pachyonychia congenita: A case report

Pachyonychia congenita (PC) is a rare autosomal dominant disorder of keratinization. It is usually present at birth or develops within 1 year of birth. It is classified into four types, but type-1 (Jadassohn–Lewandowsky type) and type-2 (Jackson–Lawler type) are the most common. PC is characterized by dystrophic, thickened nails, and painful palmo–plantar keratoderma. The nails are dramatically affected in most patients, but oral lesions are seen in patients affected by the Jadassohn–Lewandowsky type. In literature, fewer than 500 cases have been reported about PC. We report a case of PC in an 18-year-old male patient who presented with subungual hyperkeratosis, palmar-plantar keratosis, and leukokeratosis.

Impairment of lipophagy by PNPLA1 mutations causes lipid droplet accumulation in primary fibroblasts of Autosomal Recessive Congenital Ichthyosis patients

BackgroundAutosomal Recessive Congenital Ichthyosis (ARCI) is a group of epidermal keratinization disorders. One of the disease-associated proteins, patatin-like phospholipase domain-containing protein-1 (PNPLA1), plays a key role in the epidermal omega-O-acylceramide synthesis and localizes on the surface of lipid droplets (LDs). ObjectivePreviously, routine clinical test results showed abnormal LD accumulation in blood smear samples of our ARCI patients with PNPLA1 mutations. To investigate the abnormal accumulation of LDs, we analyzed primary fibroblast cells of ARCI patients with PNPLA1 mutations (p.Y245del and p.D172N). We hypothesized that PNPLA1 mutations might affect lipophagy-mediated regulation of LDs and cause intracellular lipid accumulation in ARCI patients. MethodsLD accumulation was analyzed by fluorescence staining with BODIPY®493/503 in the fibroblasts of patient cells and PNPLA1 siRNA transfected control fibroblast cells. The expression of PNPLA1 and its effects on the lipophagy-mediated degradation of LDs were analyzed by immunocytochemistry and immunoblotting. ResultsOur results showed that mutant or downregulated PNPLA1 protein causes abnormal intracellular LD accumulation. We found that PNPLA1 mutations affect neither the cellular localization nor the expression levels of the protein in fibroblast cells. When we analyzed lipophagic degradation process, LC3 expression and the number of autophagosomes were significantly decreased in fibroblast cells of the patients. In addition, co-localization of LDs with autophagosomes and lysosomes were markedly less than that of the control group. ConclusionPNPLA1 mutations caused disturbances in both autophagosome formation and fusion of autophagosomes with lysosomes. Our results indicate a possible role for PNPLA1 protein in LD regulation via lipophagy-mediated degradation.

Hidradenitis suppurativa and associated diseases

Hidradenitis suppurativa is a chronic, inflammatory, recurrent, debilitating skin disease characterized by recurrent abscesses, draining sinuses, and scarring, affecting principally areas of body friction. Although the disease pathogenesis is not fully understood, recent advances suggest that hidradenitis suppurativa should be viewed as a systemic inflammatory disease. Moreover, recent studies have defined hidradenitis suppurativa as a systemic disease linked to several comorbidities. Metabolic disorders including obesity and metabolic syndrome are the most common associated conditions observed in patients with hidradenitis suppurativa. Autoimmune diseases, like inflammatory bowel diseases, autoinflammatory diseases, spondyloarthritis, some genetic keratin disorders and also the risk of skin tumor seems to occur more frequently in these patients. This disease can also have severe effects on self-esteem and quality of life and can be associated with psychiatric diseases. The link between hidradenitis suppurativa and systemic associations may be attributed to common genetic or environmental factors or shared inflammatory pathways. Due to these reasons it is mandatory that clinical intervention for hidradenitis suppurativa must include consideration and attention to these comorbidities and complications. In this article we have reviewed current available literature on diseases that can occur together with hidradenitis suppurativa.

Mutations in PERP Cause Dominant and Recessive Keratoderma

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.

Dermatological aspects of the S2k guidelines on Down syndrome in childhood and adolescence.

With an incidence of 1 in 700 births, Down syndrome (DS) is not an uncommon condition. It is associated with various disorders of different organ systems. Serious disorders include cardiac defects and leukemia. With an onset during the newborn period, the latter does not always progress to classic myeloid leukemia (transient myeloproliferative disorder). Skin manifestations in newborns include pustules/vesiculopustules. In individuals with DS, such lesions should not only prompt suspicion for typical neonatal rashes and infections but also for transient myeloproliferative disorder. However, most dermatoses are benign. They essentially comprise disorders of keratinization that present as xerosis, keratosis pilaris, lichenification, and ichthyosis vulgaris. Also typical but not specific is the four-finger palmar crease (simian crease). Patients frequently develop folliculitides, which - due to elastolysis - subsequently progress to anetoderma. The known immune disturbance in DS patients explains the occurrence of autoimmune diseases such as alopecia areata and vitiligo. Typical skin conditions associated with DS include elastosis perforans serpiginosa, syringomas, milia-like calcinosis cutis, and multiple eruptive dermatofibromas.

Study of prevalence of different forms of ichthyosis in Kharkiv region

Ichthyosis is genetically and clinically heterogenic group of epidermis keratinization disorders. Its prevalence is geographically different. Aim. The aim of this research was to evaluate ichthyosis prevalence in Kharkiv region. Methods. The collection of clinical-genealogical history was carried out by the method of single registration of the proband on the basis of the Regional Clinical Dermatological and Venereological Health Center No. 1 and the Dermatovenerological Health Centers of the Kharkiv Region in 2017. Results. The ichthyosis prevalence in Kharkiv region was 2.5·10–4 in 2017. The ichthyosis prevalence varied from 6.7∙10‑5 in Krasnohrad district to 1.0∙10‑3 in Dvorichna district. The least prevalence was in the population of Vovchansk city (1.1∙10‑4) and the highest one was in the population of Dvorichna city (10.7∙10‑4). The differences between the prevalence of ichthyosis vulgaris in Kharkiv region in 2008-2017 were established. Conclusions. It was found that the decrease of ichthyosis prevalence in Kharkiv region was 1.6 times during last 10 years. This index for ichthyosis vulgaris was decreased 1.9 times at the same period. Monogenic dermatoses, as an example of ichthyosis, can be used both to monitor the burden of genetic disorders in the region and to solve the problems of general and personal genetic safety in the population.
 Keywords: ichthyosis vulgaris, X-linked recessive ichthyosis, prevalence.

Ichthyosis Vulgaris

Ichthyosis Vulgaris

Mutation update for CYP4F22 variants associated with autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare disorders of keratinization characterized by generalized abnormal scaling of the skin. Ten genes are currently known to be associated with ARCI: TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, CYP4F22, PNPLA1, CERS3, SDR9C7, and SULT2B1. Over a period of 22 years, we have studied a large patient cohort from 770 families with a clinical diagnosis of ARCI. Since the first report that mutations in the gene CYP4F22 are causative for ARCI in 2006, we have identified 54 families with pathogenic mutations in CYP4F22 including 23 previously unreported mutations. In this report, we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing.

Keratins and epidermolysis bullosa simplex

Keratin intermediate filaments play an important role in maintaining the integrity of the skin structure. Understanding the importance of this subject is possible with the investigation of keratin defects in epidermolysis bullosa simplex (EBS). Nowadays, in addition to clinical criteria, new molecular diagnostic methods, such as next generation sequencing, can help to distinguish the subgroups of EBS more precisely. Becausethe most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14), comprehending the nature structure of these proteins and their involved processes can be very effective in understandingthe pathophysiology of this disease and providing new and effective therapeutic platforms to treat it. Here, we summarized the various aspects of the presence of KRT5 and KRT14 in the epidermis, their relation to the incidence and severity of EBS phenotypes, and the processes with which these proteins can affect them.

Prevalence of paediatric dermatoses among patients attending Dermatology outpatient department in a tertiary care hospital in Puducherry

<p class="abstract"><strong>Background:</strong> Skin diseases are a major health problem in the paediatric age group and are associated with significant morbidity. Dermatoses in children are more influenced by socioeconomic status, dietary habits, climatic exposure and external environment as compared to adults. The present study was undertaken to know the prevalence of paediatric dermatoses among patients attending Dermatology outpatient department in a tertiary care hospital in Puducherry.</p><p class="abstract"><strong>Methods:</strong> All newly diagnosed, untreated male and female paediatric patients (from neonates to adolescents ≤19 years of age) attending Dermatology OPD, from October 2015 to September 2017 were evaluated to study the prevalence and patterns of paediatric dermatoses. The skin disorders were classified into groups like infections, infestations, eczemas, acne, hypersensitivity disorders, sweat gland disorders, pigmentary disorders, nevi, keratinisation disorders, hair and scalp disorders, papulosquamous disorders, bullous disorders, nail disorders, drug reactions, other dermatoses.<strong></strong></p><p class="abstract"><strong>Results:</strong> The prevalence of pediatric dermatoses in our OPD is 25.21%. Incidence of pediatric dermatoses was found to be more in males 237 (59.39%) than in females 162 (40.60%) and the majority of the patients were in adolescent age group (217; 54.38%). Present study showed that majority of cases belonged to the lower socioeconomic group 186(46.6 %). In our study, majority (58.98%) of dermatoses belonged to infections and infestations group. Of the infective dermatoses, fungal infections (27.88%) were the most common.</p><p><strong>Conclusions:</strong> Infectious dermatoses were commonly seen in this study that may be due to poverty, overcrowding, poor hygiene. There is an increasing trend of fungal infections which might be related to hygiene and environment. </p>

Recent advances in understanding inherited disorders of keratinization.

The ichthyoses are a heterogeneous group of skin diseases characterized by localized or generalized scaling or both. Other common manifestations include palmoplantar keratoderma, erythroderma, recurrent infections, and hypohidrosis. Abnormal barrier function is a cardinal feature of the ichthyoses, which results in compensatory hyperproliferation and transepidermal water loss. Barrier function is maintained primarily by the stratum corneum, which is composed of cornified cells surrounded by a corneocyte lipid envelope and intercellular lipid layers. The lipid components are composed primarily of ceramides. Human genetics has advanced our understanding of the role of the epidermal lipid barrier, and a series of discoveries in animals and humans revealed mutations in novel genes causing disorders of keratinization. Recently, next-generation sequencing has further expanded our knowledge, identifying novel mutations that disrupt the ceramide pathway and result in disorders of keratinization. This review focuses on new findings in ichthyoses caused by mutations involving lipid synthesis or function or both.

Avian keratin disorder of Alaska black-capped chickadees is associated with Poecivirus infection

BackgroundAvian keratin disorder (AKD) is an epizootic of debilitating beak deformities, first documented in black-capped chickadees (Poecile atricapillus) in Alaska during the late 1990s. Similar deformities have now been recorded in dozens of species of birds across multiple continents. Despite this, the etiology of AKD has remained elusive, making it difficult to assess the impacts of this disease on wild populations. We previously identified an association between infection with a novel picornavirus, Poecivirus, and AKD in a small cohort of black-capped chickadees.MethodsTo test if the association between Poecivirus and AKD holds in a larger study population, we used targeted PCR followed by Sanger sequencing to screen 124 symptomatic and asymptomatic black-capped chickadees for Poecivirus infection. We further compared the efficacy of multiple non-terminal field sampling methods (buccal swabs, cloacal swabs, fecal samples, and blood samples) for Poecivirus screening. Finally, we used both in situ hybridization and a strand-specific expression assay to localize Poecivirus to beak tissue of AKD-positive individuals and to determine if virus is actively replicating in beak tissue.ResultsPoecivirus was detected in 28/28 (100%) individuals with AKD, but only 9/96 (9.4%) asymptomatic individuals with apparently normal beaks (p < 0.0001). We found that cloacal swabs are the most sensitive of these sample types for detecting Poecivirus in birds with AKD, but that buccal swabs should be combined with cloacal swabs in evaluating the infection status of asymptomatic birds. Finally, we used both in situ hybridization and a strand-specific expression assay to localize Poecivirus to beak tissue of AKD-positive individuals and to provide evidence of active viral replication.ConclusionThe data presented here show a strong, statistically significant relationship between Poecivirus infection and AKD, and provide evidence that Poecivirus is indeed an avian virus, infecting and actively replicating in beak tissue of AKD-affected BCCH. Taken together, these data corroborate and extend the evidence for a potential causal association between Poecivirus and AKD in the black-capped chickadee. Poecivirus continues to warrant further investigation as a candidate agent of AKD.

CRISPR/Cas9-Mediated Treatment Ameliorates the Phenotype of the Epidermolytic Palmoplantar Keratoderma-like Mouse

CRISPR/Cas9 has been confirmed as a distinctly efficient, simple-to-configure, highly specific genome-editing tool that has been used to treat monogenetic disorders. Epidermolytic palmoplantar keratoderma (EPPK) is a common autosomal dominant keratin disease resulting from dominant-negative mutation of the KRT9 gene, and it has no effective therapy. We performed CRISPR/Cas9-mediated treatment on a knockin (KI) transgenic mouse model that carried a small indel heterozygous mutation of Krt9, c.434delAinsGGCT (p.Tyr144delinsTrpLeu), which caused a humanized EPPK-like phenotype. The mutation within exon 1 of Krt9 generated a novel protospacer adjacent motif site, TGG, for Cas9 recognition and cutting. By delivering lentivirus vectors (LVs) encoding single-guide RNAs (sgRNAs) and Cas9 that targeted Krt9 sequence into HeLa cells engineered to constitutively express wild-type and mutant keratin 9 (K9), we found the sgRNA was highly effective in reducing expression of the mutant K9 protein in vitro. We injected the LV into the fore-paws of adult KI-Krt9 mice three times every 8 days and found that the expression of K9 decreased ∼14.6%. The phenotypic mitigation was revealed by restoration of the abnormal differentiation and aberrant proliferation of the epidermis. Our data are the first to show that CRISPR/Cas9 is a potentially powerful therapeutic option for EPPK and other PPK subtypes.

Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis.

Porokeratosis comprises heterogeneous keratinization disorders that are characterized by one or more atrophic patches surrounded by a ridge-like cornoid lamella. In this study, we evaluated seven families affected by porokeratosis and five sporadic patients of the disease in a Chinese population. We performed Sanger sequencing of exons and flanking intron-exon boundaries of mevalonate pathway genes (MVD, MVK, PMVK and FDPS) and of SLC17A9. In five familial and three sporadic patients, we detected six variations, including four novel mutations (MVD c.1A>G; p.Met1?, c.916G>A; p.Ala306Thr, c.1013+1G>A, and PMVK c.65A>G; p.Lys22Arg) and two recurrent mutations (MVD c.746T>C; p.Phe249Ser, and MVK c.1028T>C; p.Leu343Pro). We then applied I-TASSER and iGEMDOCK to assess these variants for probable functional impacts. The findings of this study extend the mutation spectrum of porokeratosis and provide further evidence for the genetic basis of this disease.

Genitogluteal porokeratosis: a clinical review.

Porokeratosis is an uncommon disorder of keratinization that presents with keratotic papules or annular plaques that expand centrifugally with a thread-like elevated border. A distinctive histologic structure, the cornoid lamella, is diagnostic of this disorder and consists of a column of parakeratosis with the absence of the granular layer and dyskeratotic cells in the upper spinous zone. Porokeratosis confined to the genitogluteal region is rare and may be subclassified into three types, namely, classical porokeratosis on the genital region, ptychotropic porokeratosis most often seen in the natal cleft and buttocks and penoscrotal porokeratosis that is seen on the penis and adjacent scrotal skin in young men in their third decade of life. Genitogluteal porokeratosis is usually pruritic and may be undiagnosed for several years as it does not resemble classical porokeratosis in many cases; however, a biopsy is diagnostic. In general, response of genital porokeratosis to any modality of treatment is disappointing. No malignant changes have hereto been reported in porokeratosis restricted to the genitogluteal region.

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas - Diagnostic algorithm and principles of therapy.

Hereditary palmoplantar keratodermas (PPKs) comprise a large and heterogeneous group of disorders characterized by persistent thickening of the epidermis at palmar and plantar surfaces. Clinical and genetic features of isolated and complex PPKs have been reviewed in part I of this 2-part review. Here we focus on clinical and molecular classification of syndromic PPKs which are recognized by additional extracutaneous manifestations, in particular deafness, specific mucosal lesions, cardiomyopathy, inborn errors of metabolism, involvement of internal organs or disorders of sexual development. Other genetic diseases, which may show palmoplantar involvement, such as selected subtypes of hereditary epidermolysis bullosa, various hereditary ichthyoses and other keratinization disorders, several ectodermal dysplasias and some multisystem genetic disorders, are also briefly summarized. PPK diagnosis is based on inheritance pattern, age at onset, morphology, distribution and severity of hyperkeratosis, pattern of additional dermatological and systemic manifestations and laboratory findings. Molecular analysis is at present the gold standard to confirm the diagnosis in PPK forms due to mutations in known causative genes. No specific and curative therapy is currently available for PPKs which highly impair patients' quality of life. Topical treatments are symptomatic and offer only temporary relief. Among systemic treatments, retinoids improve disease symptoms in the majority of patients.

CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris

Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors. We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14. Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed. We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab. Relatively small sample size. Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.