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Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder characterized by skin fragility, chronic inflammation, malnutrition, and fibrosis. Metabolomics is an emerging investigative field that helps elucidate disease pathophysiology and identify biomarkers. However, previous metabolomic studies in RDEB are limited.To investigate the plasma metabolomic profiles in RDEB patients.We recruited 10 RDEB patients and 10 age-/gender-matched healthy controls. Peripheral blood samples were collected and plasma metabolomic profiling was performed by LC-MS/MS analysis. MS data processing and compound identification were executed by MS-DIAL. Enrichment analysis was performed by MetaboAnalyst 5.0.Metabolomic analyses demonstrated that most amino acid levels were downregulated in RDEB patients, and the extent of insufficiency correlated with clinical severity. Several metabolites were dysregulated in RDEB, including glutamine and glutamate metabolism, tryptophan-to-kynurenine ratio, phenylalanine-to-tyrosine ratio, and succinate accumulation.The study was limited by small case numbers and the unrepresentativeness of a single time-point blood sample.Our study demonstrated the altered metabolomic profiles in RDEB, reflecting the disease severity, the chronic inflammatory and malnourished status, while the fibrotic signatures were not evident.

Epidermolysis bullosa (EB) is a group of inherited skin and mucosal fragility disorders resulting from mutations in genes encoding basement membrane zone (BMZ) components or proteins that maintain the integrity of BMZ and adjacent keratinocytes. More than 30 years have passed since the first causative gene for EB was identified, and over 40 genes are now known to be responsible for the protean collection of mechanobullous diseases included under the umbrella term of EB. Through the elucidation of disease mechanisms using human skin samples, animal models, and cultured cells, we have now reached the stage of developing more effective therapeutics for EB. This review will initially focus on what is known about blister wound healing in EB, since recent and emerging basic science data are very relevant to clinical translation and therapeutic strategies for patients. We then place these studies in the context of the latest information on gene therapy, read-through therapy, and cell therapy that provide optimism for improved clinical management of people living with EB.

It is extremely rare for males with incontinentia pigmenti to survive. We summarize a diagnostic evaluation protocol for such individuals to provide an explanation for male survival.

Background Epidermolysis bullosa (EB) is a heterogeneous group of hereditary skin diseases characterized by skin fragility. Primary data on Taiwanese population remain scarce. Methods We gathered clinical information from EB patients at National Cheng Kung University Hospital from January, 2012, to June, 2021. Diagnostic tests including transmission electron microscopy, immunofluorescence studies, and whole-exome sequencing (WES) were performed. The pathogenicity of novel splice-site mutations was determined through reverse transcriptase-PCR of skin mRNA followed by Sanger and/or RNA sequencing. Results Seventy-seven EB patients from 45 families were included: 19 EB simplex, six junctional EB, and 52 dystrophic EB. Pathogenic variants were identified in 37 of 38 families (97.4%), in which WES was used as a first-line tool for mutational analysis; RNA sequencing determined pathogenic variants in the remaining one family. A total of 60 mutations in EB-related genes were identified, including 22 novel mutations. The mutations involved KRT5, KRT14, PLEC, COL17A1, LAMB3, LAMA3, ITGB4, and COL7A1. Over one-quarter of DEB patients had EB pruriginosa. Conclusions The distinct clinical presentation and molecular pathology of EB in Taiwan expand our understanding of this disorder. WES was an effective first-line diagnostic tool for identifying EB-associated variants. RNA sequencing complemented WES when multiple potentially pathogenic splice-site mutations were found.

Background Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole–induced SCAR remains unclear. Objective We aimed to investigate the genetic predisposition of co-trimoxazole–induced SCAR. Methods We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole–induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia. Results The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole–induced SCAR (P = 8.2 × 10−9; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole–related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole–induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10−21; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10−5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole–induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10−23; OR = 40.1). Conclusion This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole–induced SCAR in Asians.

In clinical settings, although Psoriasis Area and Severity Index (PASI) scoring system can provide a quick visual assessment of the severity of psoriasis vulgaris, there is still a strong demand for higher efficiency and accuracy in quantifying the inflammation status of psoriatic lesions. Currently, there are already commercial systems, such as the Courage + Khazaka Corneometer and Mexameter that measure skin capacitance and optical reflectance, for conveniently quantifying the status of skin barrier function and erythema of skin. Despite numerous comparisons of the Courage + Khazaka system with the PASI scoring system, they are rarely compared on parity with diffuse reflectance spectroscopy (DRS) based systems. In this study, we employed a custom-built DRS system shown to be able to determine the skin water-protein binding status and the hemoglobin concentration, and we performed cross-validation of the DRS measurement results with the readings derived from the Corneometer and Mexameter as well as a portion of the PASI scores. Our results revealed that the erythema readings from the Mexameter were a good representation of skin oxygenated hemoglobin but not the deoxygenated hemoglobin. On the other hand, the dermatologists recruited in this study were inclined to rate higher scores on the “erythema” category as skin’s deoxygenated hemoglobin level was higher. Thus, the Mexameter derived erythema readings may not be coherent with the PASI erythema scores. Further, the Corneometer derived skin capacitance readings were well correlated to the PASI “desquamation” and “thickness” scores, while the PASI “desquamation” evaluation was a dominating factor contributing to the DRS deduced water-protein binding status. We conclude that the DRS method could be a valuable addition to existing skin capacitance/reflectance measurement systems and the PASI scoring system toward achieving a more efficient and objective clinical psoriasis vulgaris severity evaluation.

An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient's gene, it is challenging to determine which two of the variants are responsible for the disease phenotype. Here, to decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5 ' and 3 ' variants was approximately 19 kb at the level of genomic DNA. nCATS successfully demonstrated that the most 5 ' and 3 ' variants were located in one allele while the variant in between was located in the other allele. Interestingly, the proband's mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study highlights the usefulness of nCATS as a tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can determine which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.

Psoriasis affects more than 125 million people worldwide, and the diagnosis and treatment efficacy evaluation of the disease mainly rely on clinical assessments that could be subjective. Our previous study showed that the skin erythema level could be quantified using diffuse reflectance spectroscopy (DRS), and the hemoglobin concentration of most psoriatic lesion was higher than that of its adjacent uninvolved skin. While the compromised epidermal barrier function has been taken as the major cause of clinical manifestation of skin dryness and inflammation of psoriasis, very few methods can be used to effectively evaluate this function. In this study, we investigate the near infrared spectroscopic features of psoriatic (n = 21) and normal (n = 21) skin that could link to the epidermal barrier function. From the DRS measurements, it was found that the water bonding status and light scattering properties of psoriasis are significantly different from those of uninvolved or normal skin. The connection between these parameters to the epidermal barrier function and morphology will be discussed. Our results suggest that objective evaluation of epidermal barrier function of psoriasis could be achieved using a simple DRS system.

Topical ivermectin is effective in treating papulopustular rosacea, but its effect on persistent facial erythema of rosacea with high Demodex densities has not been well documented. We retrospectively reviewed 39 rosacea patients with persistent facial erythema and high Demodex densities. Clinician's erythema assessment (CEA) and Demodex density were evaluated before and after topical ivermectin alone or combined with oral carvedilol. Three patients (all with papulopustular rosacea, in ivermectin group) dropped out due to early ivermectin-induced local flare of rosacea. In the remaining patients (ivermectin group n = 14; ivermectin-carvedilol group n = 22), the CEA grade and Demodex density were significantly reduced, both P < .01. There was no statistically significant difference between the two groups in CEA before and after treatment (P = .07 and P = .23, respectively), and in Demodex density (P = .82 and .10, respectively). Both regimens markedly improved the persistent facial erythema with response being excellent in 26 of 36 patients (72%), good in 2, fair in 4 and none in 4. There was a correlation between the reduction of CEA and Demodex density after treatment (rho = 0.50, P = .002). The results showed that topical ivermectin was effective in reducing persistent facial erythema of rosacea with Demodex overgrowth.

Background Real-world clinical data on psoriasis patients receiving different biological agents is needed, especially in Asian populations. Objectives Our aim is to compare and analyze the efficacy and safety profile of four biological agents (etanercept, adalimumab, ustekinumab and secukinumab) in a real-world setting in Taiwan. Methods We retrospectively analyzed the clinical data of all patients with moderate-to-severe plaque psoriasis (Psoriasis Area and Severity Index (PASI) ≥ 10) who received etanercept, adalimumab, ustekinumab or secukinumab between January 2011 and December 2018 in a tertiary hospital in Taiwan. Results A total of 119 treatment episodes in 75 patients were included in this study. Ustekinumab was used in 49 treatment episodes, followed by secukinumab in 46 treatment episodes, adalimumab in 14 treatment episodes and etanercept in 10 treatment episodes. The proportion of the biologic-naïve was highest in etanercept (100%) and lowest in secukinumab (23.9%). The PASI-75, -90 and -100 were the highest in secukinumab (91.3%, 82.6%, 41.3%, respectively), followed by ustekinumab (79.6%, 44.9%, 16.3%), adalimumab (64.3%, 28.6%, 7.1%) and etanercept (50.0%, 30.0%, 0%). The rate of adverse events that required treatment was highest for secukinumab (15.2%), followed by adalimumab (14.3%), ustekinumab (8.2%), and etanercept (0%), including 4 cases of infections, 2 cases of cardiovascular diseases and 4 cases of cancers. Conclusions This real world data showed differential efficacy and safety of the four biological agents.

Keloids are a fibrotic skin disorder caused by abnormal wound healing and featuring the activation and expansion of fibroblasts beyond the original wound margin. Signal transducer and activator of transcription 3 (STAT3) has been found to mediate the biological functions of keloid fibroblasts (KFs). Therefore, we aimed to demonstrate whether ASC-J9, an inhibitor of STAT3 phosphorylation, can suppress the activation of KFs. Western blotting results showed that ASC-J9 inhibited the levels of COL1A1 and FN1 proteins, which were upregulated in KFs, by decreasing the expression of pSTAT3 and STAT3. RNA sequencing and in vitro studies further demonstrated that ASC-J9 treatment of KFs reduced cell division, inflammation, and ROS generation, as well as extracellular matrix (ECM) synthesis. ELISA assays verified that ASC-J9 treatment significantly mitigated IL-6 protein secretion in KFs. Transmission electron microscopy images revealed that ASC-J9 induced the formation of multilamellar bodies in KFs, which is associated with autophagy-related signaling. These results suggested that inhibiting a vicious cycle of the ROS/STAT3/IL-6 axis by ASC-J9 may represent a potential therapeutic approach to suppress cell proliferation and ECM production in KFs.

Diagnosing cutaneous cytomegalovirus (CMV) is difficult due to its rarity and diverse manifestations, and early recognition is crucial as it may indicate disseminated disease and a poor prognosis. We examined a 71-year-old Taiwanese male presenting with a 1-week history of progressive, painful papulopustules associated with superficial ulcers and thick yellowish crusts on the scalp. He had been diagnosed with stage IVb lung adenocarcinoma 6 weeks earlier, and the epidermal growth factor receptor inhibitor (EGFRI) erlotinib and radiotherapy had been started to treat brain metastases 1 month before he came to our clinic. Histopathological examination of a scalp lesion and ELISA and PCR testing of blood samples were indicative of disseminated CMV infection. Unfortunately, the patient passed away the day after his scalp biopsy, before the investigations confirmed the infection. We would like to highlight the importance of remaining vigilant for cutaneous CMV in end-stage cancer patients receiving tyrosine kinase inhibitors (TKIs) and recognizing how this potentially life-threatening viral infection can masquerade as a possible side effect of erlotinib.

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Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, the treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation, and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and α4β1 integrins, more prominently for Lys679Met FXIII-A than the wild type. In addition, both the α4β1 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may lead to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provides insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

We report 2 generalized verrucosis (GV) patients homozygous for a novel mutation in the start codon of IL7. Unlike the previous report in which IL-7 deficiency accompanied CD4 T lymphocytopenia, circulating CD4 T cells were not depleted in one of our patients, suggesting a GV pathogenesis other than poor T-cell development.

Acne keloidalis (AK) is one of the primary cicatricial alopecias and predominantly affects men of African descent. Reports in Asians are scant. This study aimed to retrospectively review the clinical and histopathological features of AK patients in southern Taiwan and identify the pathognomonic features of AK. There were 15 patients with histopathologically confirmed AK in National Cheng Kung University Hospital between 1988 and 2018. The median onset age was 24 years (range, 14-71). The male : female ratio was 14:1. In the acute stage of AK, the lymphocytic and neutrophilic peri-infundibular inflammatory infiltrates with microabscess formation and edema corresponded to the clinical finding of isolated papules or pustules. Subsequently, the inflammatory infiltrates involved the mid-dermis and the isthmus of hair follicles. The "spade sign", a thin and dilated space resembling the shape of a balloon or spade symbol of playing cards at the level of lower isthmus, was identified in eight biopsies from five patients and may be a pathognomonic sign in the subacute stage of AK. At the chronic stage, the segments of hair shafts remained in the upper to mid-dermis and induced chronic inflammation and extensive fibrosis, resulting in the clinical keloid-like appearance. The restriction of inflammation and fibrosis in the upper to mid-dermis was another unique and pathognomonic feature of AK.

Background Paronychia is a common adverse event caused by epidermal growth factor receptor (EGFR) inhibitors. However, high rates of post-treatment discomfort, infection, recurrence, and increased time to return to work have been noted after nail plate avulsion for EGFR inhibitor-induced paronychia. Furthermore, poor wound healing and malnutrition were common conditions found in cancer patients. The aim of this study is to find an effective, pain-relieving, and noninvasive treatment for patients with severe paronychia induced by EGFR inhibitors. Methods Data from a series of 35 non-small cell lung cancer cases suffering from EGFR inhibitor-induced paronychia with pyogenic granuloma-like lesions of digits treated with betaxolol 0.25% ophthalmic solution once daily were collected and analyzed. Results Of the 35 patients suffering from grade 2 or 3 paronychia with pyogenic granuloma-like lesions induced by EGFR inhibitors, 34 (97.1%) demonstrated complete resolution and only one (2.9%) had partial resolution after 12 weeks of topical betaxolol treatment. The grading of paronychia according to the Common Terminology Criteria for Adverse Events decreased from an average of 2.29 to 0.63 after 4 weeks of treatment (P = 5.55 × 10-16 ). All the patients had significant improvement (50% pain reduction), as their pain visual analogue scale scores decreased from an average of 7.06 to 2.26 after one week of treatment (P = 6.11 × 10-25 ). Conclusion Betaxolol 0.25% ophthalmic solution is an effective, safe, and pain-relieving treatment for patients suffering from EGFR inhibitor-induced paronychia with pyogenic granuloma-like lesions and deep fissures.

Any cellular response leading to morphological changes is highly tuned to balance the force generated from structural reorganization, provided by actin cytoskeleton. Actin filaments serve as the backbone of intracellular force, and transduce external mechanical signal via focal adhesion complex into the cell. During migration, cells not only undergo molecular changes but also rapid mechanical modulation. Here we focus on determining, the role of spatial distribution of mechanical changes of actin filaments in epithelial, mesenchymal, fibrotic and cancer cells with non-migration, directional migration, and non-directional migration behaviors using the atomic force microscopy. We found 1) non-migratory cells only generated one type of filament elasticity, 2) cells generating spatially distributed two types of filament elasticity showed directional migration, and 3) pathologic cells that autonomously generated two types of filament elasticity without spatial distribution were actively migrating non-directionally. The demonstration of spatial regulation of filament elasticity of different cell types at the nano-scale highlights the coupling of cytoskeletal function with physical characters at the sub-cellular level, and provides new research directions for migration related disease.

Background Surgical excision with adjuvant radiotherapy has gained attention as an effective treatment of keloid. The Asian population is challenged with a high incidence of keloid occurrence with a specific genetic predominance. The annual reported incidence of new keloid cases in Taiwan is around 30,000, but the disease control rate and effectiveness by means of surgical excision with adjuvant radiotherapy is not yet clear. Methods A retrospective chart review of the included consecutive keloid patients receiving surgical excision and radiotherapy was performed from 2013 to 2016 in a single institute. The reported risk factors were collected to investigate according to the outcome analysis. The Vancouver Scar Scale and the Japan Scar Workshop (JSW) Scar Scale were used to evaluate the correlation with keloid recurrence. Results In this series, the overall recurrence rate was 32%, reported with an average follow-up of 28 months. Independent risk factors varied according to the different outcome variables. Only JSW classification score independently predicted the risk of keloid recurrence (odds ratio, 1.305; P = 0.02). Both the Vancouver Scar Scale and the JSW system showed a good correlation with keloid recurrence (correlation efficiency, 0.529 and 0.54; P = 0.0437 and 0.0165, respectively). Conclusions This preliminary report revealed convincing evidence of feasibility and effectiveness of applying adjuvant radiotherapy after keloid excision in the Taiwanese population. A more delicate biological equivalent dose of radiotherapy with an effective local control should be considered to improve the final outcome.

Deriving from the Greek word λειχήν for "tree moss" and the Latin word planus for "planar," lichen planus is a relatively uncommon and heterogeneous cutaneous disorder that typically develops in middle-aged adults. Despite the significant clinical burden associated with the disorder, little well-conducted molecular research has been undertaken, possibly because of heterogeneity impeding consistent and confident phenotyping. The multiple variants of lichenoid disease bear overlapping clinical and pathologic features despite manifesting as distinct clinical disorders. The first article in this 2-part continuing medical education series provides a comprehensive overview of the clinical and pathologic characteristics of cutaneous lichenoid dermatoses and links these manifestations to recent advances in our understanding of the underlying pathobiology of such diseases.

Having reviewed the diverse clinical subtypes of lichenoid disease and the postulated molecular basis thereof in the first article in this 2-part continuing medical education series, we discuss herein the existing and emerging treatment strategies in the most common clinical forms of lichenoid inflammation and provide an overview of their pharmacodynamics and evidence base. The scope of this review is not to exhaustively discuss treatment modalities for all lichenoid variants discussed in the previous article of this series. Instead, the focus will be on frequently encountered subtypes of lichen planus and on linking mechanisms of disease with mechanisms of drug action. Future directions and potential avenues for translational research will also be discussed.

Mechanical forces are known to regulate homeostasis of the skin and play a role in the pathogenesis of skin diseases. The epidermis consists of keratinocytes that are tightly adhered to each other by cell junctions. Defects in keratins or desmosomal/hemidesmosomal proteins lead to the attenuation of mechanical strength and formation of intraepidermal blisters in the case of epidermolysis bullosa simplex. The dermis is rich in extracellular matrix, especially collagen, and provides the majority of tensile force in the skin. Keloid and hypertrophic scar, which is the result of over-production of collagen by fibroblasts during the wound healing, are associated with extrinsic tensile forces and changes of intrinsic mechanical properties of the cell. Increasing evidences shows that stiffness of the skin environment determines the regenerative ability during wound healing process. Mechanotransduction pathways are also involved in the morphogenesis and cyclic growth of hair follicles. The development of androgenetic alopecia is correlated to tensile forces generated by the fibrous tissue underlying the scalp. Acral melanoma predominantly occurs in the weight-bearing area of the foot suggesting the role of mechanical stress. Increased dermal stiffness from fibrosis might be the cause of recessive dystrophic epidermolysis bullosa associated squamous cell carcinoma. Strategies to change the mechanical forces or modify the mechanotransduction signals may lead to a new way to treat skin diseases and promote skin regeneration.

One of the key features of keloid is its fibroblasts migrating beyond the original wound border. During migration, cells not only undergo molecular changes but also mechanical modulation. This process is led by actin filaments serving as the backbone of intra-cellular force and transduces external mechanical signal via focal adhesion complex into the cell. Here, we focus on determining the mechanical changes of actin filaments and the spatial distribution of forces in response to changing chemical stimulations and during cell migration. Atomic force microscopy and micropost array detector are used to determine and compare the magnitude and distribution of filament elasticity and force generation in fibroblasts and keloid fibroblasts. We found both filament elasticity and force generation show spatial distribution in a polarized and migrating cell. Such spatial distribution is disrupted when mechano-signalling is perturbed by focal adhesion kinase inhibitor and in keloid fibroblasts. The demonstration of keloid pathology at the nanoscale highlights the coupling of cytoskeletal function with physical characters at the subcellular level and provides new research directions for migration-related disease such as keloid.

Herpes simplex virus (HSV) ocular infection causes significant visual burden worldwide. Despite the fact that dendritic or geographic corneal ulcers are typical findings in HSV epithelial keratitis, conjunctival ulcer as a sign of HSV infection has rarely been reported. Although easily overlooked, this important sign could be enhanced by fluorescein staining. We report two cases of conjunctival geographic ulcers proven to be HSV infection by viral isolation and polymerase chain reaction (PCR). One patient had bilateral disease and blepharitis, and the other had unilateral involvement without skin lesions. With timely diagnosis and proper management, excellent visual outcome can be expected.

Summary The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders.

© 2016 The Authors. doi: 10.2340/00015555-2307 Journal Compilation © 2016 Acta Dermato-Venereologica. ISSN 0001-5555 Most cases of erythrokeratoderma variabilis (EKV, OMIM#133200) are inherited in an autosomal dominant manner, although autosomal recessive cases can occur. EKV is caused by mutations in GJB3 or GJB4, which encode connexin (Cx) 31 and Cx30.3, respectively. Clinically, there are 2 characteristic skin manifestations of EKV: localized, sharply circumscribed hyperkeratotic plaques; and migratory erythematous lesions (1, 2). Cxs are components of gap junctions, intercellular junctions that are expressed in several organs, including the skin and the cochlea. Individual Cxs are assembled in groups of 6 to form hemichannels in the plasma membrane, and then 2 hemichannels between adjacent cells combine to form a gap junction (2). To date, 21 Cx genes have been discovered that have essential roles in cell communication and free transfer of small molecules in many organs. In this report, we describe a recurrent mutation in GJB3, p.Gly45Glu, in a Japanese female with EKV. In addition, we review the literature and focus on genotype-phenotype correlations, notably for Cx mutations affecting the first glycine within the first extracellular domain of the protein.

Dissecting folliculitis (DF) or dissecting cellulitis of the scalp is regarded as a rare disease with disfiguring scarring alopecia. This study aimed to analyze the features of DF and to propose a classification to define its severity.A hospital-based retrospective study was conducted. Patients with a histopathological diagnosis or clinical features leading to diagnosis of DF were included and classified into three stages.Among the 66 patients recruited (63 men / 3 women, mean age 24.9 years), multiple interconnected alopecic nodules involving the vertex scalp were the main feature. Histopathology showed an extensive inflamed granulation abscess forming a dissection plane in the lower dermis/subcutis in the acute stage. Lymphocytic infiltration was predominant in seven of 21 histology specimens. Overweight and obesity were noted in 29 of 45 patients examined. No association with smoking was found. There was comorbidity with acne conglobata in 15 of 66 patients, two of whom had acne inversa. Longer disease duration and greater number of nodules were associated with higher severity of DF (p 0.05). A complete remission rate of 25 % was achieved by any treatment, and a rate of 37.5 % was achieved with oral isotretinoin alone.DF is not uncommon in Taiwan. An association with obesity needs to be clarified.

Summary The prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. By Fisher exact test, PDL1 expression and peritumoral FoxP3+ lymphocytes significantly correlated with less disease-specific death. By linear regression analysis, correlations between tumoral PDL1 expression with the density of tumoral CD8+ and peritumoral CD8+ lymphocytes, tumoral FoxP3+ with tumoral CD8+ lymphocytes, and peritumoral FoxP3+ with peritumoral CD8+ lymphocytes were observed. By univariate analyses, tumor thickness >4 mm predicted poorer progression-free survival, melanoma-specific survival, and overall survival. PDL1 expression >5% and peritumoral CD8+, peritumoral FoxP3+, and tumoral FoxP3+ lymphocytes correlated with better overall survival. By multivariate analyses, high peritumoral FoxP3+ lymphocytes independently predicted better melanoma-specific survival ( P = .023), and tumor thickness independently predicted poorer progression-free survival ( P = .05) and overall survival ( P = .039). In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy.

Following skin wounding, the healing outcome can be: regeneration, repair with normal scar tissue, repair with hypertrophic scar tissue or the formation of keloids. The role of chemical factors in wound healing has been extensively explored, and while there is evidence suggesting the role of mechanical forces, its influence is much less well defined. Here, we provide a brief review on the recent progress of the role of mechanical force in skin wound healing by comparing laboratory mice, African spiny mice, fetal wound healing and adult scar keloid formation. A comparison across different species may provide insight into key regulators. Interestingly, some findings suggest tension can induce an immune response, and this provides a new link between mechanical and chemical forces. Clinically, manipulating skin tension has been demonstrated to be effective for scar prevention and treatment, but not for tissue regeneration. Utilising this knowledge, specialists may modulate regulatory factors and develop therapeutic strategies to reduce scar formation and promote regeneration.

We report the clinical and pathological findings of two cases of Bowen's disease (BD) with features resembling myrmecia wart, and tried to find evidence of human papillomavirus (HPV) infection in such lesions by immunohistological staining, genotyping systems, polymerase chain reaction (PCR) and electron microscopy. Both cases manifested unique barnacle-like hyperkeratotic nodules or plaques clinically, and microscopically proliferation of atypical keratinocytes involving the entire thickness of the epidermis, hypergranulosis with eosinophilic and/or basophilic inclusion bodies, features that mimicked myrmecia wart. Electron microscopy revealed myrmecia inclusion-like large intranuclear and cytoplasmic electron-dense bodies. Immunohistological staining with anti-HPV antibody, genotyping systems for HPV infection and specific PCR designed to detect HPV-1 L1 sequences failed to detect evidence of HPV infection. P16(INK4a) was overexpressed in the atypical keratinocytes of both cases. This finding suggests that the pathogenesis of these two BD may involve certain unknown or undetectable HPV, or reflect disturbances of the Rb signaling pathway unrelated to HPV infection. The unique "myrmecioid" clinicopathological features in our cases suggest that this type of lesion may be a new variant of BD.