Keratosis pilaris: an update and approach to management.

Keratosis pilaris (KP) is a common, hyperkeratotic skin condition characterized by small, folliculocentric papules with variable perifollicular erythema. We provide an updated review on the pathogenesis, clinical manifestations, and management of this common, and often annoying, finding. KP represents a family of follicular disorders, of which KP simplex is by far the most common. Other variants and rare subtypes include keratosis pilaris rubra, erythromelanosis follicularis faciei et colli, and the spectrum of keratosis pilaris atrophicans. Inherited mutations of the FLG gene and ABCA12 gene have been implicated etiologically. KP may be associated with ichthyosis vulgaris and palmar hyperlinearity, but less likely atopic dermatitis. Some potential differential diagnoses for KP include lichen spinulosus, phrynoderma, ichthyosis vulgaris, and trichostasis spinulosa. General cutaneous measures such as hydrating skin, avoiding long baths or showers, and using mild soaps or cleansers should be recommended. Topical keratolytic agents are first-line therapy, followed by topical retinoids and corticosteroids. Recent options include a variety of lasers and microdermabrasion if the patient is refractory to topical therapy.

Filaggrin expression via immunohistochemistry in basal cell carcinoma and squamous cell carcinoma.

BACKGROUND: Filaggrin is a protein integral to the structure and function of the epidermis. Filaggrin (FLG) loss-of-function (LOF) mutations are common and increase the risk of developing atopic dermatitis (AD) and ichthyosis vulgaris (IV). Epidemiologic data suggest a link between skin cancer and AD. We examined if FLG staining pattern can be used to characterize cutaneous squamous cell carcinomas (SCC), basal cell carcinomas (BCC), and reactive squamous epithelium. METHODS: Tissue microarrays (TMAs) were created from 196 cases of formalin-fixed paraffin-embedded (FFPE) SCC and 144 BCC cases. TMAs and sections of reactive squamous epithelium were stained with optimized anti-FLG antibody and evaluated for FLG expression (normal, abnormal, or negative). RESULTS: FLG was absent in poorly differentiated (PD) compared to well-differentiated (WD) SCC (P < .0001) and moderately-differentiated (MD) (P = .0231) SCC, and in MD compared to WD SCC (P = .0099). Abnormal staining was significantly increased in PD compared to WD cases (P = .0039) and in MD compared to WD cases (P = .0006). Most BCC did not exhibit FLG expression (P < .05). Reactive squamous epithelium demonstrated normal, but exaggerated FLG expression. CONCLUSIONS: Our findings demonstrate the differences in FLG expression patterns in types of keratinocyte carcinomas and their mimickers.

3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris.

Atopic dermatitis (AD) is characterized by dry and itchy skin evolving into disseminated skin lesions. AD is believed to result from a primary acquired or a genetically-induced epidermal barrier defect leading to immune hyper-responsiveness. Filaggrin (FLG) is a protein found in the cornified envelope of fully differentiated keratinocytes, referred to as corneocytes. Although FLG null mutations are strongly associated with AD, they are not sufficient to induce the disease. Moreover, most patients with ichthyosis vulgaris (IV), a monogenetic skin disease characterized by FLG homozygous, heterozygous, or compound heterozygous null mutations, display non-inflamed dry and scaly skin. Thus, all causes of epidermal barrier impairment in AD have not yet been identified, including those leading to the Th2-predominant inflammation observed in AD. Three dimensional organotypic cultures have emerged as valuable tools in skin research, replacing animal experimentation in many cases and precluding the need for repeated patient biopsies. Here, we review the results on IV and AD obtained with epidermal or skin equivalents and consider these findings in the context of human in vivo data. Further research utilizing complex models including immune cells and cutaneous innervation will enable finer dissection of the pathogenesis of AD and deepen our knowledge of epidermal biology.

Enhanced Expression of Genes Related to Xenobiotic Metabolism in the Skin of Patients with Atopic Dermatitis but Not with Ichthyosis Vulgaris.

Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down-regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to xenobiotic metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and α-linolenic acid metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to xenobiotic metabolism.

Symmetrical acrokeratoderma: A peculiar entity in China? Clinicopathologic and immunopathologic study of 34 new cases.

BACKGROUND: Symmetrical acrokeratoderma seems to be a new disorder in China, and 138 cases have been reported in the Chinese literature. OBJECTIVE: We sought to summarize the clinicopathologic features and immunophenotyping of inflammatory cells in 34 new cases. METHODS: Clinical data of 34 patients were prospectively collected over 4 years. Histopathology and immunostaining of infiltrated cells were performed in 27 and 9 patients, respectively. RESULTS: Brown to black hyperkeratotic patches were symmetrically distributed over the acral regions in 33 cases and on the scalp in 1 case, with a whitish change after water contact or sweating. The condition was aggravated in summer and alleviated in winter in 33 patients. History of ichthyosis vulgaris was seen in 23 cases. The typical histopathology included epidermal hyperkeratosis, acanthosis, and papillary dermal perivascular infiltrate of lymphohistiocytes. Number of CD3(+), CD4(+), and CD8(+) cells increased in lesional and perilesional skin compared with normal-appearing skin. The skin lesions developed slowly but were confined to the acral predilection sites after the mean follow-up of 25.4 ± 13.8 months. LIMITATIONS: The follow-up time was short. CONCLUSION: This disorder may represent a peculiar dermatosis that is frequently associated with ichthyosis vulgaris. No specific therapy is available for the disorder.

Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B).

BACKGROUND: Atopic dermatitis (AD), Netherton syndrome (NS) and peeling skin syndrome type B (PSS) may show some clinical phenotypic overlap. Corneodesmosomes are crucial for maintaining stratum corneum integrity and the components' localization can be visualized by immunostaining tape-stripped corneocytes. In normal skin, they are detected at the cell periphery. OBJECTIVE: To determine whether AD, NS, PSS and ichthyosis vulgaris (IV) have differences in the corneodesmosomal components' distribution and corneocytes surface areas. METHODS: Corneocytes were tape-stripped from a control group (n=12) and a disease group (37 AD cases, 3 IV cases, 4 NS cases, and 3 PSS cases), and analyzed with immunofluorescent microscopy. The distribution patterns of corneodesmosomal components: desmoglein 1, corneodesmosin, and desmocollin 1 were classified into four types: peripheral, sparse diffuse, dense diffuse and partial diffuse. Corneocyte surface areas were also measured. RESULTS: The corneodesmosome staining patterns were abnormal in the disease group. Other than in the 3 PSS cases, all three components showed similar patterns in each category. In lesional AD skin, the dense diffuse pattern was prominent. A high rate of the partial diffuse pattern, loss of linear cell-cell contacts, and irregular stripping manners were unique to NS. Only in PSS was corneodesmosin staining virtually absent. The corneocyte surface areas correlated significantly with the rate of combined sparse and dense diffuse patterns of desmoglein 1. CONCLUSION: This method may be used to assess abnormally differentiated corneocytes in AD and other diseases tested. In PSS samples, tape stripping analysis may serve as a non-invasive diagnostic test.

Spontaneous atopic dermatitis-like symptoms in a/a ma ft/ma ft/J flaky tail mice appear early after birth.

Loss-of-function mutations in human profilaggrin gene have been identified as the cause of ichthyosis vulgaris (IV), and as a major predisposition factor for atopic dermatitis (AD). Similarly, flaky tail (a/a ma ft/ma ft/J) mice were described as a model for IV, and shown to be predisposed to eczema. The aim of this study was to correlate the flaky tail mouse phenotype with human IV and AD, in order to dissect early molecular events leading to atopic dermatitis in mice and men, suffering from filaggrin deficiency. Thus, 5-days old flaky tail pups were analyzed histologically, expression of cytokines was measured in skin and signaling pathways were investigated by protein analysis. Human biopsies of IV and AD patients were analyzed histologically and by real time PCR assays. Our data show acanthosis and hyperproliferation in flaky tail epidermis, associated with increased IL1ß and thymic stromal lymphopoietin (TSLP) expression, and Th2-polarization. Consequently, NFκB and Stat pathways were activated, and IL6 mRNA levels were increased. Further, quantitative analysis of late epidermal differentiation markers revealed increased Small proline-rich protein 2A (Sprr2a) synthesis. Th2-polarization and Sprr2a increase may result from high TSLP expression, as shown after analysis of 5-days old K14-TSLP tg mouse skin biopsies. Our findings in the flaky tail mouse correlate with data obtained from patient biopsies of AD, but not IV. We propose that proinflammatory cytokines are responsible for acanthosis in flaky tail epidermis, and together with the Th2-derived cytokines lead to morphological changes. Accordingly, the a/a ma ft/ma ft/J mouse model can be used as an appropriate model to study early AD onset associated with profilaggrin deficiency.

Common FLG mutation K4671X not associated with atopic dermatitis in Han Chinese in a family association study.

BACKGROUND: Filaggrin gene (FLG) mutations have been identified as the cause of ichthyosis vulgaris (IV) and major predisposing factors for atopic dermatitis (AD). The relationship among AD, IV and FLG mutations has not been clarified yet. Mutations 3321delA and K4671X, two of the most common mutations in Chinese patients, were both statistically associated with AD in case-control studies. MATERIALS AND METHODS: A group of 100 family trios (a total of 300 members with one affected AD proband and both parents) were recruited and screened for three filaggrin null mutations (3222del4, 3321delA and K4671X). The subjects' manifestations of AD and IV were assessed by two experienced dermatologists and recorded in detail. The relationship of common mutations to AD were assessed using both case-control and family-based tests of association. Filaggrin expression was measured in skin of 3 subjects with K4671X heterozygote and the normal control using quantitative real-time RT-PCR and immunohistochemistry. RESULTS: Of 100 probands for AD, 22 were carriers for common FLG mutations and only 2 of them were from 40 none-IV family trios (5.00%), consistent with that of the healthy control group (3.99%, P>0.05). Significant statistical associations were revealed between AD and 3321delA (P<0.001, odds ratio 12.28, 95% confidence interval 3.35-44.98) as well as K4671X (P = 0.002, odds ratio 4.53, 95% confidence interval 1.77-11.60). The family-based approach revealed that 3321delA was over-transmitted to AD offspring from parents (T:U = 12∶1, P = 0.003) but failed to demonstrate transmission disequilibrium between K4671X and AD (T:U = 10∶8, P = 0.815). Moreover, compared to the normal control, filaggrin expression at both mRNA and protein levels in epidermis of subjects with K4671X(heter) was not reduced. CONCLUSIONS: AD patients from none-IV family trios have low probability of carrying FLG mutations. The present family samples confirmed the susceptibility of mutation 3321delA to AD in Han Chinese. K4671X was not a pathogenic mutation.

Novel FLG mutations associated with ichthyosis vulgaris in the Chinese population.

Loss-of-function mutations in the gene encoding filaggrin (FLG) can cause the semidominant keratinizing disorder ichthyosis vulgaris (OMIM 146700). To identify FLG mutations in three Chinese pedigrees with ichthyosis vulgaris, we sequenced the entire coding region of FLG in the proband of each pedigree. We found two novel FLG null mutations (c.477-478insA and c.6218-6219delAA) and a known mutation (c.3321delA). Both novel mutations were identified in the proband of pedigree 1; c.477-478insA was inherited from the proband's father, and the other was a de novo mutation. Neither of these two mutations was found in 200 unrelated controls. These findings extend the spectrum of functional FLG variants possibly causing ichthyosis vulgaris. Interestingly, the proband of pedigree 1 was compound heterozygous for these mutations, but had a mild phenotype, suggesting that an incomplete penetrance factor and perhaps other unknown factors may be involved in the pathogenesis of ichthyosis vulgaris.

Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris.

BACKGROUND: Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes. OBJECTIVE: The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected. METHODS AND FINDINGS: Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression. CONCLUSIONS: We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction.

Efficacy of topical 10% urea-based lotion in patients with ichthyosis vulgaris: a two-center, randomized, controlled, single-blind, right-vs.-left study in comparison with standard glycerol-based emollient cream.

BACKGROUND: Ichthyoses are genetic disorders of keratinization which are uncomfortable due to their conspicuous scaling, itching and cosmetic problems. Ichthyoses can lead to social discrimination and psychological problems. Ichthyosis vulgaris (IV) is the most common form of these geno-dermatoses. IV is a chronic disorder that often requires continuous therapy. Emollient and keratolytic products are the mainstay treatments of IV. It is important that efficient, safe and well tolerated therapies should be available. Direct comparative data regarding efficacy of different emollient products in IV patients are very few. OBJECTIVE: The aim of the study was to investigate the keratolytic and moisturizing properties as well as the tolerance of a new urea topical formulation (Ureadin Rx10) when applied to hyperkeratotic and dry skin in patients with (IV) in comparison with a standard emollient cream. METHODS: The study was conducted as a two-center, randomized, controlled, single-blind, intra-patient (right-vs.-left) trial design. A total of 30 patients with IV between 8 and 65 (mean age: 25 years) treated with a 10% urea-based lotion, Ureadin Rx 10 * *Ureadin RX 10 is a registered trade name of ISDIN, Spain. (URx), for 4 weeks or a glycerol-based emollient cream, Dexeryl † †Dexeryl is a registered trade name of Pierre Fabre Dermatologie. (DC), in a right-vs.-left study design. Primary outcome was a 5-point SRRC Index score (evaluating scaling roughness, redness and cracks) evaluated at baseline and after 2 and 4 weeks of treatment. As secondary endpoints patients evaluated also the global efficacy (GE) and global tolerability (GT) scores with the help of a 10 cm visual analogue scale (0 = no efficacy at all/very bad tolerability; 10: excellent efficacy/excellent tolerability). RESULTS: At baseline the mean (SD) SRRC score was 9.5 (1.9) in the URx treated sites and 9.5 (1.9) in the DC treated sites. A total of 27 patients (90%) concluded the study period. Three patients were withdrawn prematurely because of itching and burning sensation after DC application (1 patient) or URx application (2 patients). At week 4, in comparison with baseline values, both treatments were shown to be clinically effective: SRRC significantly (p = 0.0001) decreased to 3.3 (1.8) after URx (a 65% relative reduction) and to 5.7 (2.5) after DC (a 40% relative reduction). SRRC was significantly lower in URx treated regions in comparison with DC both after 2 and 4 weeks of treatment (p = 0.0005). Mean GE score in areas treated with URx was significantly (p = 0.0001) higher than in the areas treated with the DC (8.9 vs.7.3). Both treatments were in general well tolerated. GT score was 8.1 (range 10 to 3) with URx and 8.4 (range 10 to 3) with DC application (p = ns). The two main limitations of this trial are the study design (single blind), and the small sample size which is not adequate for an evaluation of safety. CONCLUSION: Ureadin Rx 10 lotion has shown a greater efficacy on ichthyosis vulgaris in term of reduction of scaling, roughness, redness and cracking in comparison with a glycerol-based emollient cream. Tolerability of the two topical treatments was comparable. Further studies with larger sample sizes are needed for the evaluation of safety and tolerability of urea 10% lotion in this clinical setting.

A pilot trial of dermoscopy as a rapid assessment tool in pediatric dermatoses.

Dermoscopy is a noninvasive technique to assess skin architecture. A pilot study was conducted using polarized dermoscopy as a tool to monitor the pediatric skin barrier. Ten pediatric patients (age range, 1-14 years) with mild to moderate atopic dermatitis (AD), ichthyosis vulgaris (IV), and/or keratosis pilaris (KP) participated in a 4-week clinical trial. After a week of emollient usage alone, a mid-potency topical corticosteroid cream was added twice daily if necessary to treat erythema, dermatitis, or pruritus. The participants were assessed at weeks 0, 1, and 4 using the eczema area and severity index (EASI) for atopic dermatitis, investigator global assessment for atopic dermatitis, children dermatology life quality index (CDLQI), and clinical and dermoscopic photography. Dermoscopic appearance demonstrated dermal vascular ectasia in AD and KP, hyperkeratosis and prominence of the interkeratinocyte space in AD and IV and widening of the follicular orifice in KP. Improvements in these dermoscopic abnormalities were noted after emollient usage, mirroring improvements in clinical appearance, EASI, and CDLQI. Dermoscopy is a promising tool to assess localized improvement in skin architecture in pediatric dermatoses. Further studies and development of scoring systems will be needed to apply this technology to clinical practice.

Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.

Although it is widely accepted that filaggrin (FLG) deficiency contributes to an abnormal barrier function in ichthyosis vulgaris and atopic dermatitis, the pathomechanism of how FLG deficiency provokes a barrier abnormality in humans is unknown. We report here that the presence of FLG mutations in Caucasians predicts dose-dependent alterations in epidermal permeability barrier function. Although FLG is an intracellular protein, the barrier abnormality occurred solely via a paracellular route in affected stratum corneum. Abnormal barrier function correlated with alterations in keratin filament organization (perinuclear retraction), impaired loading of lamellar body contents, followed by nonuniform extracellular distribution of secreted organelle contents, and abnormalities in lamellar bilayer architecture. In addition, we observed reductions in corneodesmosome density and tight junction protein expression. Thus, FLG deficiency provokes alterations in keratinocyte architecture that influence epidermal functions localizing to the extracellular matrix. These results clarify how FLG mutations impair epidermal permeability barrier function.

[Mutations in the gene encoding filaggrin cause ichthyosis vulgaris]. / Mutationer i filaggringenet som årsag til ichthyosis vulgaris.

Ichthyosis vulgaris is a common genetic skin disorder with an estimated prevalence of 1:250 caused by mutations in the gene encoding filaggrin. This disorder manifests itself within the first year of life and is clinically characterized by dry, scaly skin, keratosis pilaris, palmar hyperlinearity and atopic manifestations. Patients with a severe phenotype are homozygous or compound heterozygous for the mutations, whereas heterozygous patients show mild disease, suggesting semidominant inheritance with incomplete penetrance. We present a patient with classic severe ichthyosis vulgaris, atopic eczema and two loss-of-function mutations.

Overexpression of constitutively active BMP-receptor-IB in mouse skin causes an ichthyosis-vulgaris-like disease.

The skin is the outer layer of protection against the environment. The development and formation of the skin is regulated by several genetic cascades including the bone morphogenetic protein (BMP) signaling pathway, which has been suggested to play an important role during embryonic organ development. Several skin defects and diseases are caused by genetic mutations or disorders. Ichthyosis is a common genetic skin disorder characterized by dry scaly skin. Loss-of-function mutations in the filaggrin (FLG) gene have been identified as the cause of the ichthyosis vulgaris (IV) phenotype; however, the direct regulation of filaggrin expression in vivo is unknown. We present evidence that BMP signaling regulates filaggrin expression in the epidermis. Mice expressing a constitutively active form of BMP-receptor-IB in the developing epidermis exhibit a phenotype resembling IV in humans, including dry flaky skin, compact hyperkeratosis, and an attenuated granular layer associated with a significantly downregulated expression of filaggrin. Regulation of filaggrin expression by BMP signaling has been further confirmed by the application of exogenous BMP2 in skin explants and by a transgenic model overexpressing Noggin in the epidermis. Our results demonstrate that aberrant BMP signaling in the epidermis causes overproliferation and hyperkeratinization, leading to an IV-like skin disease.

Molecular studies of ichthyosis vulgaris in Pakistani families.

OBJECTIVE: To target and amplify a 1.5 kb FLG gene fragment known to carry R501X mutation responsible for causing ichthyosis vulgaris. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Centre for Molecular Genetics, University of Karachi and Dermatology Department, Jinnah Postgraduate Medical Centre (JPMC), Karachi, from October 2007 to December 2008. METHODOLOGY: Clinically examined seven ichthyosis vulgaris families were included in this study. The 1.5 kb FLG gene fragment was located in the genomic DNA of both the affected (patients) and unaffected (normal, controls) members of the families by PCR amplification using known primers FilF3 and RPTIP6. RESULTS: Amplification of 1.5 kb FLG gene fragment was successful in four families while one family showed amplification of the gene fragment in 3 members (one affected and two normal). Two families showed no amplification. CONCLUSION: The results obtained during this study suggested the possibility of the R501X mutation as being one of the major causes of ichthyosis vulgaris in Pakistan. In addition, the study also revealed the possibility of the presence of novel FLG gene mutations in our population.