Song Ee Kim

Serum levels of anti-type VII collagen antibodies detected by enzyme-linked immunosorbent assay in patients with epidermolysis bullosa acquisita are correlated with the severity of skin lesions.

Backgroundu2002 Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal bullous disease characterized by circulating autoantibodies against type VII collagen. Detecting these autoantibodies is crucial for the diagnosis of this disease, and is also useful for measuring disease activity. Enzyme‐linked immunosorbent assay (ELISA), a quantitative method to measure anti‐type VII collagen antibody levels, is currently available to diagnose EBA.

Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1–high T cells

BACKGROUNDnPsoriasis is one of the most common chronic inflammatory diseases of the skin. Recently, IL-17-producing Txa0cells have been shown to play a critical role in psoriatic inflammation. Programmed cell death 1 (PD-1) is a coinhibitory receptor expressed on Txa0cells in various chronic inflammatory diseases; however, the expression and function of PD-1 during psoriatic inflammation have not previously been characterized.nnnOBJECTIVEnWe examined PD-1 expression on IL-17A-producing Txa0cells from imiquimod-treated mice and patients with psoriasis. Additionally, we investigated the therapeutic effect of recombinant programmed cell death ligand 1 (PD-L1) protein on imiquimod-induced psoriatic inflammation.nnnMETHODSnPD-1 expression on IL-17A-producing γδ Txa0cells from imiquimod-treated mice was examined by means of multicolor flow cytometric analysis. In the psoriatic skin of patients, PD-1 and IL-17A expression was analyzed by using immunofluorescence. The therapeutic effect of PD-L1-Fc fusion protein (PD-L1-Fc) was assessed in imiquimod-treated mice exxa0vivo and inxa0vivo.nnnRESULTSnDuring imiquimod-induced psoriatic inflammation, PD-1 is overexpressed on CD27(-)Vγ1(-) γδ Txa0cells. Furthermore, PD-1 expression on IL-17A(+) Txa0cells was confirmed in psoriatic skin tissues from patients and imiquimod-treated mice. In the CD27(-)Vγ1(-) γδ T-cell population, Vγ4(-) γδ Txa0cells with Vγ6 mRNA expression showed a high level of PD-1 expression. Furthermore, these PD-1(hi)Vγ4(-) (Vγ6(+)) γδ Txa0cells were specialized for anti-CD3-induced IL-17A production, which was inhibited by PD-L1-Fc treatment. In imiquimod-treated mice PD-L1-Fc reduced psoriatic inflammation when given alone and enhanced the therapeutic effect of anti-p40 when given in combination.nnnCONCLUSIONnPD-1 is overexpressed in IL-17A-producing Txa0cells in both imiquimod-treated mice and patients with psoriasis. Moreover, recombinant PD-L1-Fc alleviates psoriatic inflammation in imiquimod-treated mice.

Differential effects of topical corticosteroid and calcineurin inhibitor on the epidermal tight junction.

Tight junction (TJ) is one of the functional barriers present in the skin. Although topical corticosteroids and calcineurin inhibitors are used widely for atopic dermatitis, the effect of these agents on TJs has not been reported. We investigated the structural changes of TJs in mice skin after application of 0.05% clobetasol propionate or 0.1% tacrolimus ointment for 10 days. Clobetasol caused epidermal thinning and decreased collagen density. Basal transepidermal water loss was significantly increased in clobetasol‐treated versus vehicle‐ or tacrolimus‐treated skin. Confocal immunofluorescence showed that clobetasol altered the structure of claudin‐1,‐4 and occludin. Tacrolimus also caused morphological alteration of occludin. Western blot and real‐time PCR revealed that clobetasol significantly decreased claudin‐1,‐4 and occludin, whereas tacrolimus did not significantly affect claudin‐1 and ‐4 but downregulated occludin to a lesser extent compared to clobetasol. In conclusion, we suggest that downregulation of TJ proteins expression is another pathomechanism of corticosteroid‐induced permeability barrier disruption.

Filaggrin Mutation in Korean Patients with Atopic Dermatitis

Purpose Atopic dermatitis (AD) is a chronic, relapsing eczematous inflammatory skin disease. Mutations in the filaggrin gene (FLG) are major predisposing factors for AD. Ethnic differences exist between Asian and European populations in the frequency and spectrum of FLG mutations. Moreover, a distinct set of FLG mutations has been reported in Asian populations. The aim of this study was to examine the spectrum of FLG mutations in Koreans with AD. We also investigated the association of FLG mutations and clinical features of AD and compared the Korean FLG landscape with that of other East Asian countries. Materials and Methods Seventy Korean patients with AD were enrolled in this study. Fourteen FLG mutations previously detected in Korean, Japanese, and Chinese patients were screened by genotyping. Results Four FLG null mutations (3321delA, K4022X, S3296X, and S2889X) were identified in eleven patients (15.7%). The most commonly detected mutations in Korean patients with AD were 3321delA (n=6, 9.1%) and K4022X (n=3, 4.5%). FLG mutations were significantly associated with elevated IgE (≥200 KIU/L and/or MAST-CLA >3+, p=0.005), palmar hyperlinearity (p<0.001), and a family history of allergic disease (p=0.021). Conclusion This study expanded our understanding of the landscape of FLG mutations in Koreans and revealed an association between FLG mutations and AD phenotype.

Mild phenotype of epidermolytic hyperkeratosis mimicking ichthyosis bullosa of Siemens is related to specific mutation in 2B domain of KRT1.

Epidermolytic hyperkeratosis (EHK) is an autosomal dominant genodermatosis caused by a mutation in either the keratin 1 gene (KRT1) or keratin 10 gene [1]. Keratins consist of an a-helical rod domain that possesses a characteristic heptad structure. Previous studies suggest that a mutation that corresponds to a specific position of the heptad structure in the a-helical rod domain of keratin is related to disease severity [2–4]. An 18-year-old male patient visited our department with bullous eruptions on the trunk and legs and palmoplantar hyperkeratosis. Physical examination showed fine, scaly patches with superficial bullae limited to the lower trunk and both legs. Rippled hyperkeratosis on the axilla and palmoplantar keratoderma (PPK) were noted (Fig. 1). The blisters had been present

Olmsted Syndrome Caused by a Heterozygous p.Gly568Val Missense Mutation in TRPV3 Gene

Olmsted syndrome (OS) is a rare congenital skin disorder characterized by severe palmoplantar and periorificial keratoderma, alopecia, onychodystrophy, and severe pruritus. Recently, pathogenic ‘gain-of-function‘ mutations of the transient receptor potential vanilloid 3 gene (TRPV3), which encodes a cation channel involved in keratinocyte differentiation and proliferation, hair growth, inflammation, pain and pruritus, have been identified to cause OS. Due to the rarity, the pattern of inheritance of OS is still unclear. We report a case of OS in a 3-year-old Korean girl and its underlying gene mutation. The patient presented with a disabling, bilateral palmoplantar keratoderma with onychodystrophy. She also exhibited pruritic eczematous skin lesions around her eyes, ears and gluteal fold. Genetic analysis identified a heterozygous p.Gly568Val missense mutation in the exon 13 of TRPV3. To our knowledge, this is the first case of OS in the Korean population showing a missense mutation p.Gly573Ser.

Dermatofibrosarcoma Protuberans: A Study of Clinical, Pathologic, Genetic, and Therapeutic Features in Korean Patients

Purpose Dermatofibrosarcoma protuberans (DFSP) carries a translocation resulting in the collagen type I alpha 1 (COL1A1)-platelet-derived growth factor beta (PDGFB) fusion gene, which is responsible for PDGFB activation. The purpose of this study is to evaluate the clinicopathological, genetic, and therapeutic features of DFSP in Korean patients. Materials and Methods Clinicopathological features of 37 patients with DFSP were reviewed. Multiplex reverse transcriptase-polymerase chain reaction (PCR) was carried out in 16 patients using formalin-fixed, paraffin-embedded tissues and specific primers for COL1A1 and PDGFB. Results The mean age of 37 patients was 37.4 years old. The most common tumor location was the trunk. All patients were treated primarily with surgery: 34 (91.7%) cases with Mohs micrographic surgery (MMS) and 3 (8.3%) cases with wide local excision. The median follow-up time was 33.7 months. Two patients, one in each treatment group, demonstrated local recurrence during the follow-up period. The COL1A1-PDGFB fusion gene was expressed in 14 (87.5%) cases, demonstrated by reverse transcriptase PCR analysis. No association was found among the different COL1A1-PDGFB fusion transcripts, the various histological subtypes and clinical features. Conclusion Our results support the effectiveness of MMS in treating DFSP. The COL1A1-PDGFB fusion transcript was observed in 87.5% of patients. Therefore, COL1A1-PDGFB is a useful and accurate tool in diagnosing DFSP in Koreans.

Novel compound heterozygous mutation in LAMC2 genes (c.79G>A and 382insT) in Herlitz junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is a heritable blistering skin disease characterized by separation within the lamina lucida. It is caused by mutations in the LAMA3, LAMB3 and LAMC2 genes encoding the α3‐, β3‐ and γ2‐chains, respectively, of laminin‐332. JEB Herlitz type (JEB‐H) is a lethal blistering disease with severe cutaneous and extracutaneous involvements caused by null mutations in the gene encoding laminin‐332. Here, we report a proband with JEB‐H who is a compound heterozygote for two novel mutations in LAMC2; a missense mutation (c.79G>A) and an insertion mutation (382insT) leading to a premature termination codon.

Anovel deletion mutation in the 2B domain of KRT5 in epidermolysis bullosa simplex with childhood-onset migratory circinate erythema

123 (VACV) at 3,000 mg/day to treat herpes zoster on the left frontal and periorbital region. After three days of treatment, she noticed oliguria (urinary volume<400 mL/day), nausea, and loss of appetite. The related laboratory tests were performed one day before admission. Full blood count revealed a slight increase in neutrophils, with normal eosinophil counts and coagulation factors. Urinalysis revealed a decrease in pH value (pH = 5), a slight increase in white blood cells and red blood cells, and protein content. Renal function was more severely impaired (urea nitrogen: 19.1 mmol/L; creatinine: 418 mol/L), compared to before treatment with VACV (when creatinine was 98 mol/L). Abdominal and renal ultrasound showed no remarkable abnormalities. The patient had hypertension and coronary heart disease and had been treated with irbesartan and hydrochlorothiazide tablets, atorvastatin tablet, clopidogrel hydrogen sulphate tablet, and bisoprolol tablet for more than one year. Because the oliguria symptom was closely followed by VACV administration, VACV-induced acute renal injury (ARI) was suspected. VACV and irbesartan and hydrochlorothiazide tablets were discontinued. She was treated with hydration, alkalizing urine (sodium bicarbonate), and diuresis to promote the urine discharge of medication. Her urinary volume dramatically increased (>2 L/day) three days after admission. The serum level of creatinine returned to normal 14 days after cessation of VACV. VACV is converted to acyclovir (ACV) and L-valine by first-pass intestinal and/or hepatic metabolism, and 89% of ACV is excreted in the urine. The oral bioavailability of VACV is three to five-fold greater than that of ACV, and VACV achieves effect with less frequent administration [1]. In the management of herpes zoster, VACV is superior to ACV because it accelerates the resolution of herpes zoster-associated pain [2]. Although VACV is generally well tolerated in most circumstances, vigilance is required to avoid adverse events. Although a rare occurrence, ARI following VACV administration has been reported in several publications [3-6]. These reports suggest that VACV could impair renal function not only in elderly patients with [3] or without [4-6] pre-existing renal diseases, but also in young adults without pre-existing renal disorders [7]. Moreover, the oliguria symptom is likely to appear after about four days following VACV administration in patients without pre-existing renal disease, while this could occur as early as 24 hours in elderly patients with pre-existing renal disease. The dosage of VACV might play an important role in the development of ARI. According to published reports, VACV is prescribed to treat herpes zoster with a dosage of 2,000-3,000 mg/day, which is recommended by the manufacturer for patients without renal dysfunction. Stephen et al. reviewed the safety of VACV in the long-term suppression of herpes simplex virus (HSV) with a dosage of no more than 1,000 mg/day; no adverse events of ARI were reported in more than 3,000 patients [8]. The combined medications might be a contributory factor of ARI. Non-steroidal anti-inflammatory drugs (NSAIDs) and angiotensin II receptor antagonist (ARB), which are also known to disturb glomerular haemodynamics, were suspected in two previously reported cases [3, 5], as well as our case. Thus, the significant reduction in glomerular filtration rate might have occurred even with an appropriate oral dosage of VACV, resulting in ARI. These findings indicate that physicians should prescribe VACV cautiously when patients take ARB or NSAIDs. All reported ARI cases following VACV administration are expected to recover after no more than four days following the cessation of VACV. The serum level of creatinine in our case returned to normal within two weeks. The prompt reduction in plasma concentrations of acyclovir by haemodialysis may improve glomerular haemodynamics and oliguria in such cases and hasten the recovery of ARI [6]. Overall, this case alerts us to the fact that renal function should be closely monitored when VACV is prescribed to elderly patients who are on combinations of medications that may disturb glomerular haemodynamics, such as NSAIDs and ARB. Early detection will help prevent a worse outcome.

Homozygous Deletion Mutation of the FERMT1 Gene in a Chinese Patient with Kindler Syndrome.

Dear Editor: n nKindler syndrome (KS, OMIM173650) is a rare autosomal recessive genodermatosis characterized by trauma-induced skin blistering, cutaneous atrophy, progressive poikiloderma and photosensitivity1. KS is caused by mutation in the FERMT1 gene1. This gene encodes kindlin-1, which regulates not only keratinocyte adhesion through β1-class integrins but also proliferation and differentiation of cutaneous stem cells by promoting αvβ6 integrin–mediated transforming growth factor-β activation and inhibiting Wnt ligand expression2. n nA 12-year-old Chinese boy presented with recurrent blistering after mild trauma from the age of 1 year. There is no family history. Physical examination revealed generalized skin atrophy with some scattered resolving blisters on the extremities and poikiloderma on the face and neck (Fig. 1). He has also suffered from pruritus and photosensitivity. A skin biopsy from non-blistered area on his leg revealed hyperkeratosis and epidermal atrophy (Fig. 2A). Immunofluorescence (IF) mapping of a blister showed that keratins 5 and 14 were localized at the roof of the blister while laminin 5 and type IV collagen were localized at the base (Fig. 2B, C). Electron microscopic findings of non-blistered skin revealed widening of the lamina lucida and reduplication of the lamina densa (Fig. 2D). DNA extracted from the patients blood was processed for direct nucleotide sequencing and we detected a homozygous dinucleotide deletion mutation at c.994_995delCA in exon 8. The mutation causes frameshift and a premature stop codon (Fig. 2E). Based on these results, we diagnosed the patient with KS. n n n nFig. 1 n nClinical features of the patient. (A, B) Poikiloderma on the face and neck