Acquired ichthyosis, asteatotic dermatitis or xerosis? An update on pathoetiology and drug-induced associations.

Acquired ichthyosis (AI) is a relatively rare cutaneous entity characterized by transient, generalized scaling and pruritus in the absence of family history of ichthyosis or atopic disease. The hyperkeratosis in AI can range from the mild, white-to-brown scaling resembling that in ichthyosis vulgaris (IV) to the more prominent dark brown scaling phenotype, similar to that found in lamellar ichthyosis. The disease can wax and wane in relation to endogenous and/or exogenous factors. Histopathology of AI is similar to that found in IV. AI is usually of cosmetic concern to patients but can, in some cases, reflect the presence of more serious conditions, including malignancies, autoimmune diseases or metabolic disorders. In some cases, AI can be an adverse effect of a medication or the cutaneous symptom of a toxic exposure. Other conditions, such as severe xerosis or eczema, can present with clinical findings similar to AI, making diagnosis a challenge. Furthermore, cases of AI are sporadic throughout the literature and have been documented across a wide variety of medical settings distinct from dermatology, which often contribute to misdiagnosis of this disease. Definitive management requires prompt identification and treatment of the inciting factors combined with conservative therapies, which can include topical emollients, keratolytics, retinoids or corticosteroids, and in rare cases, oral retinoids.

Mood symptoms, neurodevelopmental traits, and their contributory factors in X-linked ichthyosis, ichthyosis vulgaris and psoriasis.

BACKGROUND: High rates of adverse mood/neurodevelopmental traits are seen in multiple dermatological conditions, and can significantly affect patient quality of life. Understanding the sex-specific nature, magnitude, impact and basis of such traits in lesser-studied conditions like ichthyosis, is important for developing effective interventions. AIM: To quantify and compare relevant psychological traits in men with X-linked ichthyosis (XLI, n = 54) or in XLI carrier women (n = 83) and in patients with ichthyosis vulgaris (IV, men n = 23, women n = 59) or psoriasis (men n = 30, women n = 122), and to identify factors self-reported to contribute most towards depressive, anxious and irritable phenotypes. METHODS: Participants recruited via relevant charities or social media completed an online survey of established questionnaires. Data were analysed by sex and skin condition, and compared with general population data. RESULTS: Compared with the general population, there was a higher rate of lifetime prevalence of mood disorder diagnoses across all groups and of neurodevelopmental disorder diagnoses in the XLI groups. The groups exhibited similarly significant elevations in recent mood symptoms (Cohen d statistic 0.95-1.28, P < 0.001) and neurodevelopmental traits (d = 0.31-0.91, P < 0.05) compared with general population controls, and self-reported moderate effects on quality of life and stigmatization. There were strong positive associations between neurodevelopmental traits and recent mood symptoms (r > 0.47, P < 0.01), and between feelings of stigmatization and quality of life, particularly in men. Numerous factors were identified as contributing significantly to mood symptoms in a condition or sex-specific, or condition or sex-independent, manner. CONCLUSION: We found that individuals with XLI, IV or psoriasis show higher levels of mood disorder diagnoses and symptoms than matched general population controls, and that the prevalence and severity of these is similar across conditions. We also identified a number of factors potentially conferring either general or condition-specific risk of adverse mood symptoms in the three skin conditions, which could be targeted clinically and/or through education programmes. In clinical practice, recognizing mood/neurodevelopmental problems in ichthyosis and psoriasis, and addressing the predisposing factors identified by this study should benefit the mental health of affected individuals.

Revisiting the Roles of Filaggrin in Atopic Dermatitis.

The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.

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.

Genetics of Inherited Ichthyoses and Related Diseases.

Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defined on the basis of clinical and genetic features and are mainly divided into non-syndromic and syndromic ichthyoses. Numerous genes, which encode for corresponding proteins, are involved in the normal differentiation of keratinocytes (cornification) and participate in the formation of a functional epidermal barrier. To date, mutations in more than 50 genes are known to result in various types of ichthyoses. Thanks to modern genetic diagnostic methods based on targeted next generation sequencing (NGS), approximately 80-90% of cases can be resolved at present. Further sequencing methods covering the whole exome (WES) or whole genome (WGS) will obviously elucidate another portion of the remaining unknown ichthyoses in the future.

Palmar hyperlinearity in early childhood atopic dermatitis is associated with filaggrin mutation and sensitization to egg.

BACKGROUND/OBJECTIVES: Palmar hyperlinearity is a typical clinical feature of Filaggrin gene (FLG) null mutations. There are reports of FLG mutations and allergic sensitization; however, reports on the relationship between palmar hyperlinearity to sensitization are limited. This study aimed to examine the association between palmar hyperlinearity and sensitization in atopic dermatitis (AD) children. METHODS: This cross-sectional, case-control study included children ˂ 6 years old with moderate-severe AD whose parents consented for mutation analysis and photographic documentation. Each child underwent genotyping to detect the eight most prevalent FLG mutations in the Japanese population: R501X, 3321delA, S1695X, Q1701X, S2554X, S2889X, S3296X, and K4022X. Clinical features and parameters including egg-specific IgE were examined, and palm photographs were evaluated by 12 trained dermatologists blinded to genotyping results. RESULTS: Of the 57 patients (age range, 2 months to 5 years; median, 22 months), 16 were heterozygotes and three were compound heterozygotes. Palmar hyperlinearity, as recognized by more than two-thirds of dermatologists, was significantly associated with FLG mutation (P = 0.002, OR = 6.98, 95% CI = 2.1-23.7), and this association was observed especially in children over 2 years. Cross-shaped crease of the thenar eminence, as known in previous reports, also demonstrated significant correlation with FLG mutation. When the children were divided according to the presence or absence of palmar hyperlinearity, the egg white-specific IgE was significantly higher in the hyperlinearity group (55.9 vs 18.3 IU/mL, P < 0.05). CONCLUSIONS: Palmar hyperlinearity indicates possible inherited barrier abnormalities of the skin in early childhood. Its identification may help to predict a more accurate prognosis, such as sensitization.

Exacerbation of ichthyosis vulgaris phenotype by co-inheritance of STS and FLG mutations in a Chinese family with ichthyosis: a case report.

BACKGROUND: X-linked ichthyosis (XLI) is a recessive keratinization condition caused by deficient activity of steroid-sulfatase due to mutations in steroid sulfatase (STS) gene located on the X chromosome. In contrast, ichthyosis vulgaris (IV) is caused by filaggrin deficiency due to semi-dominant loss-of-function mutations of filaggrin (FLG) gene. Filaggrin defects could synergize with XLI to exacerbate its phenotype. CASE PRESENTATION: We report a Chinese family with patients presenting diverse phenotype of Keratosis pilaris. A next-generation sequencing panel interrogating 25 ichthyosis related genes with sequencing coverage of the coding regions and splice site junctions, was applied to screen genetic mutations. A gross deletion encompassing the STS gene ranging from exon 1-10 and the FLG c.3321delA mutation were identified in a 31-year old male proband, one of his sister, and his mother, and all the three patients showed obvious symptom. The deletion of STS gene was confirmed by real-time quantitative PCR. The proband's another sister and his two nephews carried only FLG c.3321delA mutation. Patients carried both mutations presented more severe symptom, while those only carried FLG c.3321delA mutation showed slight or normal phenotype. CONCLUSIONS: In conclusion, we found that the IV phenotype was exacerbated by co-inheritance of STS and FLG mutations in a Chinese family with ichthyosis. Other genomic regions no included in the study might be also involved in phenotypic modifications.

Eyelash length for the diagnosis of atopic dermatitis and ichthyosis vulgaris in children-a case control study.

Eyelash trichomegaly (ET) is increased length (≥ 12 mm), curling, pigmentation, or thickness of eyelashes. Among acquired causes, allergic diseases and atopic dermatitis (AD) have been found to be associated with eyelash trichomegaly especially in children; however, to date, this claim has not been studied in detail. To compare the eyelash lengths of AD and ichthyosis vulgaris (IV) patients with those of age- and sex-matched patients with unrelated skin disorders, we measured (with a digital Vernier caliper) and compared the eyelash lengths of AD (n = 58) and IV (n = 31) patients to those of age- and sex-matched patients with unrelated skin disorders (n = 178). The eyelashes of the AD and male IV patients were found to be significantly longer than those of the controls (p < 0.05). The severity of atopic dermatitis, i.e., SCORAD of > 50, hyperlinearity of palms and soles, and high IgE levels significantly correlated with the long eyelashes. The limitations of study are single-center study and filaggrin gene mutation in patients of IV could not be studied. CONCLUSION: Thus, long eyelashes may act as surrogate marker of severe AD and serve as a cutaneous marker of IV patients. What is Known: • Among acquired causes, allergic diseases and atopic dermatitis have been found to be associated with eyelash trichomegaly especially in children. What is New: • The severity of atopic dermatitis, i.e., SCORAD of > 50, hyperlinearity of palms and soles, and high IgE levels significantly correlate with the long eyelashes; thus, long eyelashes may act as surrogate marker of severe atopic dermatitis. • It may also serve as a cutaneous marker of ichthyosis vulgaris especially in male patients and patients with palmoplantar hyperlinearity.

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.

Concurrent Chondrodysplasia Punctata Type 2 (Conradi-Hunermann-Happle Syndrome) and Ichthyosis Vulgaris in Teenaged Twin Girls.

We present concurrent X-linked chondrodysplasia punctata and ichthyosis vulgaris in adolescent fraternal twin girls, notable for initial presentation with dry skin in adolescence, characterized by dark-brown scale typical of ichthyosis vulgaris and blaschkolinear, atrophic, scaly plaques. This constellation of findings prompted further genetic investigation. Using a multigene approach to examine 39 genes associated with congenital ichthyosis, next-generation sequencing revealed a novel heterozygous missense mutation at a mutational hotspot in the EBP gene c.439C>T (p.R147C) in conjunction with a single nonsense mutation in the FLG gene (p.R501X) in both sisters. These individuals highlight the clinical variability of Conradi-Hunermann-Happle syndrome, illustrate the possibility of co-occurrence of rare and common forms of ichthyosis, and demonstrate the utility of multigene analysis.

[ANALYSIS OF ONE-CARBON METABOLISM GENES AND EPIDERMAL DIFFERENTIATION COMPLEX IN PATIENTS WITH ICHTHYOSIS VULGARIS].

The aim of the study was to evaluate the effects of allelic polymorphism of the FLG and MTHFR genes and their associations in gynecological patients with ichthyosis vulgaris. Gynecological disorders are observed in presence of some forms of ichtyosis. From the prospective of improving nation's healthcare, the greatest attention is drawn to reproductive disorders. Based on this, the research was also tasked with studying of the genetic nature of gynecological diseases, as well as the influence of geographical latitude on the frequencies of mutagenic alleles of the FLG gene and heterogeneous carriers of these mutations. The collection of clinical-gynecological 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. The diagnosis and form of dermatosis is established on the basis of the analysis of clinical and gynecological data and the results of laboratory tests in accordance with ICD-10: ichthyosis vulgaris (Q 80.1.0, OMIM 146700). The data on 18 women and 20 men from 3 families, aged 26 to 76 years old, suffering from ichthyosis, were analyzed. As a result of the study, a direct correlation was determined between the latitude and frequencies of mutant alleles of the FLG gene, as well as between the geographical latitude and frequency of heterozygous carriers of these mutations. The frequencies of the T allele and the CT genotype according to polymorphic variant C677T of the MTHFR gene demonstrate feedback with the latitude indicators. The frequency distributions of the 2282del4 allele and the CT genotype, the N/2282del4 and CT genotypes, the 2282del4 and T alleles, the N/2282del4 genotype and the T allele have opposite latitudinal zonation. The established connections made it possible to predict the development of gynecological pathologies in women with ichthyosis vulgaris. The prevalence of endometriosis and endometrial cancer in women with ichthyosis vulgaris in the Kharkiv region was 33.3%, while the average for the female population in the region was 0.29-0.35%. The number of children born to women with ichthyosis vulgaris did not differ from the regional index.

Clinical characteristics of Korean patients with filaggrin-related atopic dermatitis.

BACKGROUND: Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic dermatitis (AD). AIM: To investigative the clinical characteristics of patients with AD with FLG mutations and determine the differences between patients with AD with and without FLG mutations. METHODS: We identified FLG mutations in patients with AD by complete sequencing and SNaPshot methods, and then analysed the data on clinical characteristics from questionnaire responses. RESULTS: We found that earlier age of AD onset (P < 0.05), tendency to respiratory atopy (P = 0.03), more severe clinical characteristics of AD (higher Eczema Area and Severity Index, P = 0.02) and decrease in skin hydration (P = 0.04) were associated with FLG-related AD. CONCLUSION: Our data demonstrate that FLG mutations are indicators of a poor prognosis in AD, and are predisposing factors that exist in early infancy and persist into adulthood.

An Analysis of the Filaggrin Gene Polymorphism in Korean Atopic Dermatitis Patients.

Research of the FLG mutation in various ethnic groups revealed non-overlapping mutation patterns. In addition, Japanese and Chinese atopic patients showed somewhat different mutations. These ethnic differences make the research on Korean patients mandatory; however, no systematic research on Korean atopic dermatitis (AD) patients has been performed. This study aims to investigate the genetic polymorphism of FLG in Korean atopic dermatitis patients. The study was made up of three groups including 9 Ichthyosis vulgaris (IV) patients, 50 AD patients and 55 normal controls: the ichthyosis group was incorporated due to the reported association between the FLG mutation and IV. In comparison to other sequencing methods, the overlapping long-range PCR was used. We revealed the genetic polymorphism of filaggrin in Koreans, and at the same time, we discovered nonsense mutations in p.Y1767X and p.K4022X in Korean AD patients. By using FLG sequencing techniques confirmed in this study, new mutations or genetic polymorphisms with ethnic characteristics would be detected and further larger studies of repeat number polymorphisms could be performed.

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

[Novel missense mutations of the FLG gene identified in two Chinese families affected with ichthyosis vulgaris].

OBJECTIVE: To identify potential mutations of the FLG gene in two Chinese families affected with ichthyosis vulgaris. METHODS: All coding exons and exon-intron boundary of the FLG gene were amplified by polymerase chain reaction (PCR) and analyzed by direct sequencing. The results were compared with those of 100 unrelated healthy controls. RESULTS: Two novel missense mutations, c.1360A>G (p.T454A) and c.10363G>T (p.D3455Y), were detected in all affected individuals from family 1 and family 2 respectively but none of the controls. CONCLUSION: The c.1360A>G (p.T454A) and c.10363G>T (p.D3455Y) of the FLG gene may lead to alteration of the structure and function of the FLG protein and cause ichthyosis vulgaris in the two families.

Explant cultures of atopic dermatitis biopsies maintain their epidermal characteristics in vitro.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterised by various epidermal alterations. Filaggrin (FLG) mutations are a major predisposing factor for AD and much research has been focused on the FLG protein. Human skin equivalents (HSEs) might be useful tools for increasing our understanding of FLG in AD and to provide a tool for the screening of new therapies aimed at FLG replacement. Our aim is to establish an explant HSE (Ex-HSE) for AD by using non-lesional skin from AD patients wildtype for FLG or harbouring homozygous FLG mutations. These Ex-HSEs were evaluated as to whether they maintained their in vivo characteristics in vitro and whether FLG mutations affected the expression of various differentiation markers. FLG mutations did not affect the outgrowth from the biopsy for the establishment of Ex-HSEs. FLG expression was present in healthy skin and that of AD patients without FLG mutations and in their Ex-HSEs but was barely present in biopsies from patients with FLG mutations and their corresponding Ex-HSEs. AD Ex-HSEs and AD biopsies shared many similarities, i.e., proliferation and the expression of keratin 10 and loricrin, irrespective of FLG mutations. Neither KLK5 nor Lekti expression was affected by FLG mutations but was altered in the respective Ex-HSEs. Thus, Ex-HSEs established from biopsies taken from AD patients maintain their FLG genotype-phenotype in vitro and the expression of most proteins in vivo and in vitro remains similar. Our method is therefore promising as an alternative to genetic engineering approaches in the study of the role of FLG in AD.

Moisturizing treatment of patients with atopic dermatitis and ichthyosis vulgaris improves dry skin, but has a modest effect on gene expression regardless of FLG genotype.

BACKGROUND: Loss-of-function mutations in FLG (encoding filaggrin) are a predisposing factor for atopic dermatitis (AD) and cause ichthyosis vulgaris (IV). Patients with AD and IV display impaired skin barrier and dry skin, and altered epidermal expression of genes in pro-inflammatory and lipid metabolic pathways are often evident. OBJECTIVES: To evaluate the effect of three different moisturizers on skin barrier function and epidermal gene expression in patients with AD/IV in relation to FLG mutation status. METHODS: Patients (n = 43) were classified according to their FLG status: AD with FLG+/+ (n = 14), AD with FLG+/- (n = 14), and AD/IV with FLG-/- (n = 15). Dryness score and transepidermal water loss (TEWL) were monitored on volar forearms, and punch biopsies were taken for analysis of gene expression. Measurements were repeated after 4 weeks of treatment with either of two moisturizers on each forearm. RESULTS: Treatment with any of the three moisturizers significantly reduced dryness score and TEWL in the group as a whole. FLG-/- patients displayed the largest reduction in dryness score. Only minute changes occurred in the mRNA expression of 15 selected epidermal genes. CONCLUSIONS: Moisturizing treatment improves dry skin and certain aspects of abnormal skin barrier function, especially in patients with AD/IV and dual FLG mutations, but does not normalize the epidermal gene expression profile.

Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis.

BACKGROUND: The stratum corneum and tight junctions (TJs) form physical barriers in the epidermis. Dendrites of activated Langerhans cells (LCs) extend beyond the TJs to capture external antigens in mice. LCs and inflammatory dendritic epidermal cells (IDECs) are observed in the skin of patients with atopic dermatitis (AD). OBJECTIVE: We sought to investigate the characteristics of LCs and IDECs and the distribution of their antigen capture receptors in relation to TJs in normal and AD skin. METHODS: We characterized the interactions of LCs and IDECs with TJs and the expression patterns of langerin and FcεRI by using whole-mount epidermal sheets from healthy subjects and patients with AD, ichthyosis vulgaris, and psoriasis vulgaris. RESULTS: As in mouse skin, activated LCs penetrate TJs in human skin. The number of LCs with TJ penetration increased approximately 5-fold in erythematous lesional skin of patients with AD but not in nonlesional skin of patients with AD or lesions of patients with ichthyosis vulgaris or psoriasis. In contrast, IDECs localized in the lower part of the epidermis, and their dendrites extended horizontally without penetration through TJs. Although langerin accumulated on the tips of dendrites of activated LCs, FcεRI was expressed diffusely on the cell surfaces on LCs and IDECs in lesional skin from patients with AD. CONCLUSIONS: These findings highlight interesting differences between LCs and IDECs in epidermis of patients with AD, where LCs, but not IDECs, extend dendrites through the TJs, likely to capture antigens from outside the TJ barrier with a polarized distribution of langerin but not FcεRI. These behavioral differences between skin dendritic cells might reflect an important pathophysiology of AD.