Search

Competing Interests: Conflicts of interest: none reported.

Pustular psoriasis is a chronic inflammatory skin disease characterized by erythematous plaques with sterile pustules. It includes the distinct clinical entities generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH) and palmoplantar pustular psoriasis (PPPP). Recently clarified pathomechanisms of pustular psoriasis indicate that hyperactivation of the skin innate immunity, including of the IL-1/IL-36 axis, plays an important role in the pathogenesis of pustular psoriasis. Autoinflammatory keratinization disease (AiKD) is the umbrella clinical entity for inflammatory keratinization disorders with genetic autoinflammatory pathomechanisms, and pustular psoriasis is a representative AiKD. To date, mutations/variants in five genes-IL36RN, CARD14, AP1S3, MPO and SERPINA3-have been reported to be genetic causative or predisposing factors for pustular psoriasis. The pathogenic mechanisms induced by the mutations/variants in these genes are all closely related to the excessive activation of skin innate immunity and autoinflammation. A number of biologics (e.g., tumor necrosis factor inhibitors, IL-17/IL-17 receptor inhibitors and IL-23 inhibitors) and granulocyte and monocyte adsorption apheresis are used to treat pustular psoriasis. Recently, based on novel information on the pathomechanisms of pustular psoriasis, which are mainly associated with autoinflammation, inhibitors of several pathogenic pathways, including of the IL-1, IL-36, IL-8 and granulocyte colony-stimulating factor signaling pathways, have been studied as emerging treatments., Competing Interests: Declaration of Competing Interest The author declares that he has no competing interests., (Copyright © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

We describe an 11-year-old girl with PLACK Syndrome (peeling skin, leukonychia, acral punctate keratosis, cheilitis, and knuckle pads), who was found to have a novel homozygous variant in CAST, the pathogenicity of which was confirmed using blood-derived RNA. There is no established treatment for PLACK syndrome. However, we demonstrate for the first time that this condition is associated with low levels of vitamin A and essential fatty acids, which prompted us to consider a potential treatment strategy. Indeed, we initiated this patient on intravenous lipid infusion (Vitalipid®; an emulsion of fat-soluble vitamins and lipofundin-MCT/LCT 20%) and the response was dramatic. Following the fourth monthly course of treatment, pruritis disappeared and the skin lesions showed remarkable objective improvement. PLACK syndrome is a very rare genodermatosis and only six families have been described to date with pathogenic CAST variants. This is the first report of an objective response to a therapeutic agent, which suggests that PLACK is a potentially treatable condition. The remarkable response we report and the relative safety of the intervention should prompt healthcare providers who care for PLACK syndrome patients to explore this as a potential treatment strategy in future studies., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

p16 INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16 INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16 INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16 INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16 INK4a expression, and Wnt inhibition suppresses p16 INK4a -induced hyperplasia. Senolytic treatment reduces p16 INK4a -expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16 INK4a -expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16 INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.

The skin plays a critical role in maintenance of water homeostasis. Dysfunction of the skin barrier causes not only delayed wound healing and hypertrophic scarring, but it also contributes to the development of various skin diseases. Dermatitis is a chronic inflammatory skin disorder that has several different subtypes. Skin of contact dermatitis and atopic dermatitis (AD) show epidermal barrier dysfunction. Na x is a sodium channel that regulates inflammatory gene expression in response to perturbation of barrier function of the skin. We found that in vivo knockdown of Na x using RNAi reduced hyperkeratosis and keratinocyte hyperproliferation in rabbit ear dermatitic skin. Increased infiltration of inflammatory cells (mast cells, eosinophils, T cells, and macrophages), a characteristic of dermatitis, was reduced by Na x knockdown. Upregulation of PAR-2 and thymic stromal lymphopoietin (TSLP), which induce Th2-mediated allergic responses, was inhibited by Na x knockdown. In addition, expression of COX-2, IL-1β, IL-8, and S100A9, which are downstream genes of Na x and are involved in dermatitis pathogenesis, were also decreased by Na x knockdown. Our data show that knockdown of Na x relieved dermatitis symptoms in vivo and indicate that Na x is a novel therapeutic target for dermatitis, which currently has limited therapeutic options.

A single male Rottweiler dog with severe footpad hyperkeratosis starting at an age of eight weeks was investigated. The hyperkeratosis was initially restricted to the footpads. The footpad lesions caused severe discomfort to the dog and had to be trimmed under anesthesia every 8-10 weeks. Histologically, the epidermis showed papillated villous projections of dense keratin in the stratum corneum. Starting at eight months of age, the patient additionally developed signs consistent with atopic dermatitis and recurrent bacterial skin and ear infections. Crusted hyperkeratotic plaques developed at sites of infection. We sequenced the genome of the affected dog and compared the data to 655 control genomes. A search for variants in 32 candidate genes associated with human palmoplantar keratoderma (PPK) revealed a single private protein-changing variant in the affected dog. This was located in the DSG1 gene encoding desmoglein 1. Heterozygous monoallelic DSG1 variants have been reported in human patients with striate palmoplantar keratoderma I (SPPK1), while biallelic DSG1 loss of function variants in humans lead to a more pronounced condition termed severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome. The identified canine variant, DSG1 :c.2541_2545delGGGCT, leads to a frameshift and truncates about 20% of the coding sequence. The affected dog was homozygous for the mutant allele. The comparative data on desmoglein 1 function in humans suggest that the identified DSG1 variant may have caused the footpad hyperkeratosis and predisposition for allergies and skin infections in the affected dog.

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-β1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-β1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target., Competing Interests: The authors have declared that no competing interests exist.

Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could be more related to altered barrier function and consequently disorders that affect epithelial cells, such as psoriasis, atopic dermatitis (AD), erythrokeratoderma, loricrin keratoderma (LK) and periodontitis. The aim of this review is to summarize what is known about the association between loricrin downregulation and epithelial-related disorders (ERDs). A search was performed on the following databases: Medline, Cochrane Library, PubMed, EMBASE, Lilacs, Scopus and Google Scholar, resulting in 16 included articles. Loricrin keratoderma was the ERD most frequently associated with loricrin mutations (730insG, 709insC and 578insG; 5/7 cases - 71.44 %). Atopic dermatitis was the ERD most frequently associated with loricrin downregulation (2/7 cases - 28.6 %). Mutilating palmoplantar keratoderma, progressive symmetrical erythrokeratoderma and a new type of erythrokeratoderma were not associated with any mutations. At the gene level, periodontitis patients showed the highest decrease (-6.89x), followed by AD (-6.5x) and psoriasis patients (-0.5x). In summary, loricrin mutation and downregulation were associated with several ERDs. The diversity in disease presentation is likely related to whether there is a total loss of loricrin, mislocalization and/or if the mutant form of loricrin causes dysfunction of other proteins and/or changes in cornification., (© 2019 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Objective: The molecular mechanisms underlying the development of dysplasia in leukoplakia are unknown. We used RNA sequencing to examine the molecular and biological pathway differences in oral leukoplakia with and without oral epithelial dysplasia., Materials and Methods: Excisional biopsy specimens (25) were taken from 24 patients with oral leukoplakia diagnosed histopathologically as either oral epithelial dysplasia (13) or epithelial hyperplasia and keratosis without dysplasia (12). Transcriptome analysis used RNA sequencing, differential expression and hierarchical clustering. Biological signalling was examined by gene ontology, pathway and protein-protein interaction analysis., Results: Differential expression analysis showed distinction between the two groups identifying 47 genes as altered in leukoplakia with dysplasia, including SAA1, SAA2, KRT31, KRT37, KRT76, ROBO2, DNAJB5 and DNAJA4. Using hierarchical clustering, dysplastic leukoplakia readily segregated from leukoplakia without dysplasia. Pathway and ontology enrichment analysis provided evidence that downregulation of extracellular matrix (ECM) pathways was a feature of dysplastic lesions., Conclusion: Our results suggest that there are detectable changes in the molecular profile of oral leukoplakia exhibiting dysplasia including downregulated ECM as a distinguishing feature of dysplastic lesions. This suggests that reactive changes in stroma may be an early manifestation of dysplastic development. Our study also demonstrates the feasibility of detecting such molecular changes in oral leukoplakia, providing avenues for further investigation of molecular mechanisms of oral dysplasia., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Approximately 9000 different phenotypes are known in medicine. The definition phenotype includes both manifest diseases as well as features without any disease value and the pure genetic disposition to develop a disease (e.g. tumors or complex diseases); however, most phenotypes are rare monogenic hereditary diseases. Approximately 6400 of these phenotypes have so far been elucidated by molecular genetics and are caused by mutations in 4064 different genes. Of all genetic diseases, an estimated one third are associated with skin symptoms. Genodermatoses are the phenotypes predominantly related to the skin, of which approximately 600 are familiar to dermatologists. The syndromes with scaling and keratosis include cornification disorders where the symptoms are not limited to the skin. They are associated with skin symptoms such as ichthyosis, erythroderma and palmoplantar keratoderma but show additional symptoms from other organ groups. The typical combination of symptoms may be unique to a syndrome and therefore seminal for the diagnosis.

Rationale: Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes)., Objective: To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin., Methods and Results: Expression of CSPG4 (chondroitin sulfate proteoglycan 4) was detected in epidermal keratinocytes and the cardiac conduction system. CSPG4 pos cells constituted ≈5.6±3.3% of the nonmyocyte cells in the mouse heart. Inducible postnatal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibroadipocytes, as in human arrhythmogenic cardiomyopathy. The mice exhibited palmoplantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP ., Conclusions: Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in patients with arrhythmogenic cardiomyopathy and cardiocutaneous syndromes., (© 2017 American Heart Association, Inc.)

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: Oral lichen planus (OLP) is a chronic inflammatory disease of unknown etiology with antigen-specific and non-specific mechanisms. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel activated by noxious stimuli such as oxidative stress products evoking pain and release of proinflammatory mediators from sensory nerve endings culminating in neurogenic inflammation. Extraneuronal TRPA1s, for example, on immune cells possess yet unknown functions., Subjects and Methods: We studied the buccal mRNA expression (qPCR) and protein localization (immunohistochemistry) of TRPA1 receptors and key OLP mediator transcripts in oral mucosa samples of healthy volunteers (n = 9), OLP patients (n = 43), and OLP-like hyperkeratotic patients (n = 12)., Results: We measured 27.7- and 25.5-fold TRPA1 mRNA increase in OLP and OLP-like hyperkeratotic patients compared to healthy controls. TRPA1 transcripts elevated 2.4-fold in hypertensive OLP but not in hyperkeratotic patients compared to counterparts, reduced by 1.6-fold by angiotensin-convertase inhibitor intake. TRPA1 messenger RNA was more coexpressed with transcripts of tumor necrosis factor α than with interferon γ. Keratinocytes, macrophages but not T cells expressed TRPA1., Conclusions: We provided evidence for the extraneuronal presence and upregulation of the proinflammatory TRPA1 receptor in buccal samples of patients with OLP. This may implicate the ion channel in the pathomechanism of OLP., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report a Japanese pedigree with dominant dystrophic epidermolysis bullosa (DDEB) harboring the p.G2251E mutation of COL7A1. The proband of this pedigree presented with multiple milia as an isolated skin manifestation without a history of blistering and subsequently developed generalized intractable blisters, suggesting that multiple milia could be a primary manifestation of DDEB. Her mother exhibited nail dystrophy and pruritic nodules and her elder sister was unaffected, despite having the same COL7A1 mutation. Inter- and intrafamilial clinical variability are often observed in DDEB, so we should be aware of this factor to provide appropriate genetic counselling., (© 2016 Wiley Periodicals, Inc.)

The role of telomere biology in cancer has been studied for a wide variety of different cancers but the association with telomere length has been controversial. This is because some cancers have been found to be associated with longer telomeres in circulating white cells whilst other cancer types are more common in individuals with shorter telomeres. Hence, there has been some skepticism as to whether telomere length may be helpful in estimating cancer risk. For melanoma, however, results have been fairly consistent showing that longer telomeres are associated with an increased risk. This link was first discovered because of a link between longer telomeres and a high number of naevi. In contrast, for cutaneous squamous cell carcinomas, the relationship is reversed with higher risk in individuals with shorter telomeres. Differences in skin phenotypes with the presence of high number of naevi versus photoageing with solar elastosis and solar keratoses have already been valuable for dermatologists as the former phenotype is associated with melanoma whilst the latter is more common in patients with squamous cell carcinoma of the skin. The hypothesis is that the differences in cutaneous phenotypes already observed by dermatologists for skin cancers may, in fact, be useful as well for cancer prediction in general as it may reflect underlying telomere biology. This manuscript will address the evidence for links between telomere biology, skin phenotypes and cancer risk., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Non-cage systems provide laying hens with considerable space allowance, perches and access to litter, thereby offering opportunities for natural species-specific behaviors. Conversely, these typical characteristics of non-cage systems also increase the risk of keel bone and foot pad disorders. The aim of this study was twofold: 1) to investigate if providing ramps between perches (housing factor) reduces keel bone and foot pad disorders and 2) to test for genetic predisposition by comparing 2 different layer hybrids. In a 2 × 2 design, 16 pens were equipped either with or without ramps between perches and nest boxes (8 pens/treatment), and housed with either 25 ISA Brown or Dekalb White birds per pen (in total 200 birds/hybrid). Keel bone injuries and foot health were repeatedly measured via palpation and visual assessment between 17 and 52 wk of age and daily egg production was recorded. The relationships between the dependent response variables (keel bone and footpad disorders, egg production) and independent factors (age, ramps, hybrid) were analyzed using generalized linear mixed models and corrected for repeated measures. Ramps reduced keel bone fractures (F 1,950  = 45.80, P < 0.001), foot pad hyperkeratosis (F 1,889  = 10.40, P = 0.001), foot pad dermatitis (F 1,792  = 20.48, P < 0.001) and bumble foot (F 1,395  = 8.52, P < 0.001) compared to pens without ramps. ISA Brown birds sustained more keel bone fractures (F 1,950  = 33.26, P < 0.001), had more foot pad hyperkeratosis (F 1,889  = 44.69, P < 0.001) and laid more floor eggs (F 1,1883  = 438.80, P < 0.001), but had fewer keel bone deviations (F 1,1473  = 6.73, P < 0.001), fewer cases of foot pad dermatitis (F 1,792  = 19.84, P < 0.001) and no bumble foot as compared to Dekalb White birds. Age, housing and hybrid showed several interaction effects. Providing ramps proved to be very effective in both reducing keel bone and foot pad problems in non-cage systems. Keel bone and foot pad disorders are related to genetic predisposition. These results indicate that adaptation of the housing systems and hybrid selection may be effective measures in improving laying hen welfare., (© 2016 Poultry Science Association Inc.)

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Trichostasis spinulosa (TS) is a common, underdiagnosed cosmetic skin condition., Objectives: The main objectives of this study were to determine the occurrence of TS relative to age and gender, to analyze its cutaneous distribution, and to investigate any possible familial basis for this condition, its impact on patients, and the types and efficacy of previous treatments., Methods: All patients presenting to the outpatient dermatology clinic at the study institution and their relatives were examined for the presence of TS and were questioned about family history and previous treatment. Photographs and biopsies of suspected cases of TS were obtained., Results: Of 2400 patients seen between August and December 2013, 286 patients were diagnosed with TS (135 males, 151 females; prevalence: 11.9%). Women presented more frequently than men with complaints of TS (6.3 vs. 4.2%), and more women had received prior treatment for TS (10.5 vs. 2.8%). The most commonly affected sites were the face (100%), interscapular area (10.5%), and arms (3.1%). Lesions involved the nasal alae in 96.2%, the nasal tip in 90.9%, the chin in 55.9%, and the cheeks in 52.4% of patients. Only 15.7% of patients had forehead lesions, and only 4.5% had perioral lesions. Among the 38 previously treated patients, 65.8% reported temporary improvement., Conclusions: Trichostasis spinulosa is a common condition that predominantly affects the face in patients of all ages. Additional studies employing larger cohorts from multiple centers will be required to determine the prevalence of TS in the general population., (© 2015 The International Society of Dermatology.)

Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks--mutilating palmoplanter and periorificial keratoderma. However, there's a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease.

Background: K1 and K2 are the main type II keratins in the suprabasal epidermis where each of them heterodimerizes with the type I keratin K10 to form intermediate filaments. In regions of the ears, tail, and soles of the mouse, only K2 is co-expressed with K10, suggesting that these keratins suffice to form a mechanically resilient cytoskeleton., Objective: To determine the effects of the suppression of both main keratins, K2 and K10, in the suprabasal plantar epidermis of the mouse., Methods: Krt2(-/-) Krt10(-/-) mice were generated by crossing Krt2(-/-) and Krt10(-/-) mice. Epidermal morphology of soles of hind-paws was examined macroscopically and histologically. Immunofluorescence analysis and quantitative PCR analysis were performed to analyze the expression of keratins in sole skin of wildtype and Krt2(-/-) Krt10(-/-) mice. Highly abundant proteins of the sole stratum corneum were determined by electrophoretic and chromatographic separation and subsequent mass spectrometry., Results: K2 and K10 are the most prominent suprabasal keratins in normal mouse soles with the exception of the footpads where K1, K9 and K10 predominate. Mice lacking both K2 and K10 were viable and developed epidermal acanthosis and hyperkeratosis in inter-footpad epidermis of the soles. The expression of keratins K1, K9 and K16 was massively increased at the RNA and protein levels in the soles of Krt2(-/-) Krt10(-/-) mice., Conclusions: This study demonstrates that the loss of the main cytoskeletal components of plantar epidermis, i.e. K2 and K10, can be only partly compensated by the upregulation of other keratins. The thickening of the epidermis in the soles of Krt2(-/-) Krt10(-/-) mice may serve as a model for pathomechanistic aspects of palmoplantar keratoderma., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

In recent years, there has been increasing use of BRAF-inhibiting drugs for the treatment of various malignancies, including melanoma. However, these agents are associated with the development of other nonmelanoma skin lesions, in particular squamoproliferative lesions such as keratoacanthomas (KAs), squamous cell carcinomas, and BRAF inhibitor-associated verrucous keratoses. The molecular pathogenesis of these lesions is of interest, not only for therapeutic reasons, but also for the insight it might provide into the development of similar lesions in a sporadic setting. We used next-generation sequencing to compare the mutational profiles of lesions after treatment with a BRAF inhibitor, with similar lesions arising sporadically. HRAS mutations were common among the BRAF inhibitor-induced lesions, being identified in 56%, compared with 14% of lesions in the sporadic group (P = 0.002). Thus, despite similar histomorphological appearances, the underlying molecular mechanisms may be different. In addition, within the BRAF inhibitor-associated group, the lesions designated as KAs and BRAF inhibitor-associated verrucous keratoses had a similar mutational profile (mutations in PIK3CA, APC, and HRAS), which was distinct to that seen in squamous cell carcinomas (FGFR3, CDKN2A, and STK11). We have previously noted histological overlap between KAs and BRAF inhibitor-associated verrucous keratoses, and this finding supports the notion that they may represent morphological or temporal variants of a single lesion type., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Verrucous venous malformation (VVM), also called "verrucous hemangioma," is a non-hereditary, congenital, vascular anomaly comprised of aberrant clusters of malformed dermal venule-like channels underlying hyperkeratotic skin. We tested the hypothesis that VVM lesions arise as a consequence of a somatic mutation. We performed whole-exome sequencing (WES) on VVM tissue from six unrelated individuals and looked for somatic mutations affecting the same gene in specimens from multiple persons. We observed mosaicism for a missense mutation (NM&#95;002401.3, c.1323C>G; NP&#95;002392, p.Iso441Met) in mitogen-activated protein kinase kinase kinase 3 (MAP3K3) in three of six individuals. We confirmed the presence of this mutation via droplet digital PCR (ddPCR) in the three subjects and found the mutation in three additional specimens from another four participants. Mutant allele frequencies ranged from 6% to 19% in affected tissue. We did not observe this mutant allele in unaffected tissue or in affected tissue from individuals with other types of vascular anomalies. Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)