Summary
Background
Reticulate pigmentary disorders include the rare autosomal dominant Galli–Galli disease (GGD) and Dowling–Degos disease (DDD). Clinical diagnosis between some of the subtypes can ...be difficult due to a degree of overlap between clinical features, therefore analysis at the molecular level may be necessary to confirm the diagnosis.
Objectives
To identify the underlying genetic defect in a 48‐year‐old Asian‐American woman with a clinical diagnosis of GGD.
Methods
Histological analysis was performed on a skin biopsy using haematoxylin–eosin staining. KRT5 (the gene encoding keratin 5) was amplified from genomic DNA and directly sequenced.
Results
The patient had a history of pruritus and hyperpigmented erythematous macules and thin papules along the flexor surfaces of her arms, her upper back and neck, axillae and inframammary areas. Hypopigmented macules were seen among the hyperpigmentation. A heterozygous 1‐bp insertion mutation in KRT5 (c.38dupG; p.Ser14GlnfsTer3) was identified in the proband. This mutation occurs within the head domain of the keratin 5 protein leading to a frameshift and premature stop codon.
Conclusions
From the histological findings and mutation analysis the individual was identified as having GGD due to haploinsufficiency of keratin 5.
What's already known about this topic?
Mutations in keratin 5 have been identified as an underlying cause of Galli–Galli disease (GGD).
What does this study add?
Identification of a previously unreported frameshift mutation in keratin 5 resulting in a premature stop codon provides further evidence that GGD is caused by haploinsufficiency of keratin 5.
Summary
Background Mutations in the gene encoding filaggrin (FLG) have been shown to predispose to atopic eczema (AE).
Objectives Further to establish population genetics of FLG mutations in the ...Japanese population and to elucidate effects of FLG mutations to filaggrin biosynthesis in skin of patients with AE.
Methods We searched for FLG mutations in 19 newly recruited Japanese patients with AE. We then screened 137 Japanese patients with AE and 134 Japanese control individuals for a novel mutation identified in the present study. In addition, we evaluated FLG mRNA expression by real‐time reverse transcription–polymerase chain reaction and profilaggrin/filaggrin protein expression by immunohistochemical staining in the epidermis of the patients carrying the novel mutation.
Results We identified a novel FLG nonsense mutation c.12069A>T (p.Lys4021X) in one patient with AE. Upon further screening, p.Lys4021X was identified in four patients with AE (2·9% of all the patients with AE). In total, there are at least eight FLG variants in the Japanese population. Here we show that about 27% of patients in our Japanese AE case series carry one or more of these eight FLG mutations and these variants are also carried by 3·7% of Japanese general control individuals. There is a significant statistical association between the eight FLG mutations and AE (χ2P = 6·50 × 10−8). Interestingly, the present nonsense mutation is in the C‐terminal incomplete filaggrin repeat and is the mutation nearest the C‐terminal among previously reported FLG mutations. Immunohistochemical staining for filaggrin revealed that this nonsense mutation leads to remarkable reduction of filaggrin protein expression in the patients’ epidermis.
Conclusions We clearly demonstrated that FLG mutations are significantly associated with AE in the Japanese population. The present results further support the hypothesis that the C‐terminal region is essential for proper processing of profilaggrin to filaggrin.
Summary
Background
Biomarkers of atopic dermatitis (AD) are largely lacking, especially in infant AD. Those that have been examined to date have focused mostly on serum cytokines, with few on ...noninvasive biomarkers in the skin.
Objectives
We aimed to explore biomarkers obtainable from noninvasive sampling of infant skin. We compared these with plasma biomarkers and structural and functional measures of the skin barrier.
Methods
We recruited 100 infants at first presentation with AD, who were treatment naive to topical or systemic anti‐inflammatory therapies, and 20 healthy children. We sampled clinically unaffected skin by tape stripping the stratum corneum (SC). Multiple cytokines and chemokines and natural moisturizing factor were measured in the SC and plasma. We recorded disease severity and skin barrier function.
Results
Nineteen SC and 12 plasma biomarkers showed significant differences between healthy and AD skin. Some biomarkers were common to both the SC and plasma, and others were compartment specific. Identified biomarkers of AD severity included T helper 2‐skewed markers interleukin (IL)‐13, CCL17, CCL22, IL‐5; markers of innate activation (IL‐18, IL‐1α, IL1β, CXCL8) and angiogenesis (Flt‐1, vascular endothelial growth factor); and others (soluble intercellular adhesion molecule‐1, soluble vascular cell adhesion molecule‐1, IL‐16, IL‐17A).
Conclusions
We identified clinically relevant biomarkers of AD, including novel markers, easily sampled and typed in infants. These markers may provide objective assessment of disease severity and suggest new therapeutic targets, or response measurement targets for AD. Future studies will be required to determine whether these biomarkers, seen in very early AD, can predict disease outcomes or comorbidities.
What's already known about this topic?
Atopic dermatitis is a clinically heterogeneous condition with multiple clinical manifestations and a complex pathogenesis.
Systemic biomarkers of severity have been identified in adults, but are less well defined in children.
Biomarkers from the skin compartment have been based on biopsies to date.
What does this study add?
Noninvasive sampling can detect clinically relevant biomarkers in AD skin.
These biomarkers may be useful for disease stratification, and provide insights into the pathogenesis of infant AD.
Innate immune activation is important in the epidermis in infantile AD.
What is the translational message?
Noninvasive biomarkers can yield significant insights into infantile AD.
They identify innate activation, the T helper 2 pathway and angiogenesis as important pathways in this condition.
Respond to this article
Linked Comment: Hijnen. Br J Dermatol 2019; 180:455–456.
Plain language summary available online
Summary
Background Mutations in the gene encoding filaggrin (FLG) were identified to underlie ichthyosis vulgaris (IV) and also shown to predispose to atopic eczema. Until now, no FLG mutations have ...been described in the Taiwanese population.
Objectives To elucidate filaggrin mutations in the Taiwanese population and further to clarify the population genetics of filaggrin gene mutations in the Asian populations.
Methods In the present study, 12 individuals from four unrelated Taiwanese IV families were examined for FLG mutations. We carried out comprehensive sequencing of the entire FLG coding region using an overlapping polymerase chain reaction strategy.
Results We identified three FLG mutations in the Taiwanese IV families. One mutation E1795X was a previously unidentified FLG mutation, which might be specific to the Taiwanese. Interestingly, another FLG mutation 3321delA is prevalent in the Japanese population and the other mutation Q2417X was found in the Singaporean Chinese population. No FLG mutation identified in the white European population was found in the Taiwanese population.
Conclusions The present findings suggest that the Taiwanese population, as an East Asian group, share FLG mutations with both the Japanese and the Singaporean Chinese population. In addition, these results exemplify differences in the population genetics of filaggrin between Europe and Asia.
Summary
Background
Atopic dermatitis (AD) affects children of all skin types. Most research has focused on light skin types. Studies investigating biomarkers in people with AD with dark skin types ...are lacking.
Objectives
To explore skin barrier and immune response biomarkers in stratum corneum (SC) tape strips from children with AD with different skin types.
Methods
Tape strips were collected from lesional and nonlesional forearm skin of 53 children with AD and 50 controls. We analysed 28 immunomodulatory mediators, and natural moisturizing factors (NMF) and corneocyte morphology.
Results
Interleukin (IL)‐1β, IL‐18, C‐X‐C motif chemokine (CXCL) 8 (CXCL8), C‐C motif chemokine ligand (CCL) 22 (CCL22), CCL17, CXCL10 and CCL2 were significantly higher (P < 0·05) in lesional AD skin compared with nonlesional AD skin; the opposite trend was seen for IL‐1α. CXCL8, CCL2 and CCL17 showed an association with objective SCORing Atopic Dermatitis score. NMF levels showed a gradual decrease from healthy skin to nonlesional and lesional AD skin. This gradual decreasing pattern was observed in skin type II but not in skin type VI. Skin type VI showed higher NMF levels in both nonlesional and lesional AD skin than skin type II. Corneocyte morphology was significantly different in lesional AD skin compared with nonlesional AD and healthy skin.
Conclusions
Minimally invasive tape‐stripping is suitable for the determination of many inflammatory mediators and skin barrier biomarkers in children with AD. This study shows differences between children with AD with skin type II and skin type VI in NMF levels, suggesting that some aspects of pathophysiological mechanisms may differ in AD children with light versus dark skin types.
What's already known about this topic?
Atopic dermatitis (AD) affects children of all skin types, but most research is focused on white people with light skin types.
Studies investigating biomarkers in patients with AD with dark skin types are lacking.
Tape‐stripping can be used for analysis of skin barrier and immune response biomarkers in AD skin.
What does this study add?
Stratum corneum tape‐stripping is suitable to study a broad panel of biomarkers in children with AD.
We show differences in skin barrier and immune response biomarkers between lesional, nonlesional and control skin.
Immune response biomarkers are similar in light and dark skin types. However, natural moisturizing factor levels differ between skin types II and VI, suggesting a different pathogenesis in AD between light and dark skin types.
Respond to this article
Linked Comment: Furue. Br J Dermatol 2019; 180:457–458.
Plain language summary available online
The term 'keratin' is generally accepted to refer to the epithelial keratins of soft and hard epithelial tissues such as: skin, cornea, hair and nail. Since their initial characterization, the total ...number of mammalian keratins has increased to 54, including 28 type I and 26 type II keratins. Inherited defects that weaken the keratin load-bearing cytoskeleton produce phenotypes characterized by fragility of specific subsets of epithelial tissues. The vast majority of mutations are either missense or small in-frame in-del mutations and disease severity often relates to the position of the mutation in relation to the rod domain. The most complex epithelial structure in humans, the hair follicle, contains trichocyte ('hard') keratin filaments and approximately half of the 54 functional human keratin genes are trichocyte keratins. So far, only four of these have been linked to human genetic disorders: monilethrix, hair-nail ectodermal dysplasia, pseudofolliculitis barbae and woolly hair, while the majority of the hair keratins remain unlinked to human phenotypes. Keratin disorders are a classical group of dominant-negative genetic disorders, representing a large healthcare burden, especially within dermatology. Recent advances in RNA interference therapeutics, particularly in the form of small-interfering RNAs, represent a potential therapy route for keratin disorders through selectively silencing the mutant allele. To date, mutant-specific siRNAs for epidermolysis bullosa simplex, pachyonychia congenita and Messmann epithelial corneal dystrophy-causing missense mutations have been developed and proven to have unprecedented specificity and potency. This could herald the dawn of a new era in translational medical research applied to genetics.
Summary
Background Ichthyosis vulgaris (IV) is a genetic disorder with a prevalence of 1 : 250–1000 caused by filaggrin (FLG) mutations, which also predispose to atopic diseases.
Objectives To ...study the genotype/phenotype relationship in IV and to analyse whether the suggested skin barrier defect is associated with differences of epidermal dendritic cells.
Patients/methods We evaluated a cohort of 26 German patients with IV, established an IV severity score and analysed epidermal ultrastructure, histology, filaggrin and CD1a antigens. Mutations were screened by restriction enzyme analysis. Particular sequencing techniques allowed the complete FLG analysis to reveal novel mutations.
Results The combined null allele frequency of R501X and 2282del4 was 67·3%. Patients also showed the mutations S3247X and R2447X as well as five novel FLG mutations: 424del17 and 621del4 (profilaggrin S100 domain), 2974delGA (repeat 2), R3766X (repeat 101) and E4265X (repeat 102). Their combined allele frequency in controls was < 0·7%. No mutation was found in one IV patient, all in all ∼27% were heterozygous, and the majority (∼69%) showed two null alleles. The IV severity score and ultrastructure showed a significant correlation with genotypes. Interestingly, CD1a cell counts showed a significant difference between nonatopic and atopic IV patients both with eczema and without eczema.
Conclusions We confirm that the mutations R501X and 2282del4 represent the most frequent genetic cause in German IV patients. The novel mutations are probably population and family specific. The observed differences of CD1a cells support the hypothesis that there is a barrier defect that predisposes to atopic manifestations, possibly independent of atopic eczema.
Rotating mirror cameras represent a workhorse technology for high speed imaging in the MHz framing regime. The technique requires that the target image be swept across a series of juxtaposed CCD ...sensors, via reflection from a rapidly rotating mirror. Employing multiple sensors in this fashion can lead to spatial jitter in the resultant video file, due to component misalignments along the individual optical paths to each CCD. Here, we highlight that static and dynamic fiducials can be exploited as an effective software-borne countermeasure to jitter, suppressing the standard deviation of the corrected file relative to the raw data by up to 88.5% maximally, and 66.5% on average over the available range of framing rates. Direct comparison with industry-standard algorithms demonstrated that our fiducial-based strategy is as effective at jitter reduction, but typically also leads to an aesthetically superior final form in the post-processed video files.
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