Whole Exome Sequencing of a Patient with a Milder Phenotype of Xeroderma Pigmentosum Group C.

A 17-year-old female Korean patient (XP115KO) was previously diagnosed with Xeroderma pigmentosum group C (XPC) by Direct Sanger sequencing, which revealed a homozygous nonsense mutation in the XPC gene (rs121965088: c.1735C > T, p.Arg579Ter). While rs121965088 is associated with a poor prognosis, our patient presented with a milder phenotype. Hence, we conducted whole-exome sequencing in the patient and her family members to detect coexisting mutations that may have resulted in a milder phenotype of rs121965088 through genetic interaction. Materials and Methods: the whole-exome sequencing analysis of samples obtained from the patient and her family members (father, mother, and brother) was performed. To identify the underlying genetic cause of XPC, the extracted DNA was analyzed using Agilent's SureSelect XT Human All Exon v5. The functional effects of the resultant variants were predicted using the SNPinfo web server, and structural changes in the XPC protein using the 3D protein modeling program SWISS-MODEL. Results: Eight biallelic variants, homozygous in the patient and heterozygous in her parents, were detected. Four were found in the XPC gene: one nonsense variant (rs121965088: c.1735C > T, p.Arg579Ter) and three silent variants (rs2227998: c.2061G > A, p. Arg687Arg; rs2279017: c.2251-6A > C, intron; rs2607775: c.-27G > C, 5'UTR). The remaining four variants were found in non-XP genes, including one frameshift variant [rs72452004 of olfactory receptor family 2 subfamily T member 35 (OR2T35)], three missense variants [rs202089462 of ALF transcription elongation factor 3 (AFF3), rs138027161 of TCR gamma alternate reading frame protein (TARP), and rs3750575 of annexin A7 (ANXA7)]. Conclusions: potential candidates for genetic interactions with rs121965088 were found. The rs2279017 and rs2607775 of XPC involved mutations in the intron region, which affected RNA splicing and protein translation. The genetic variants of AFF3, TARP, and ANXA7 are all frameshift or missense mutations, inevitably disturbing the translation and function of the resultant proteins. Further research on their functions in DNA repair pathways may reveal undiscovered cellular relationships within xeroderma pigmentosum.

Serum 25-Hydroxy Vitamin D Levels and Association of Vitamin D Receptor Gene Polymorphisms in Vitiligo.

BACKGROUND: The role of vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms has been established in many autoimmune diseases, including vitiligo, but the result is still controversial. OBJECTIVES: The aim of this study was to investigate the serum vitamin D levels in vitiligo patients and to compare the association of VDR gene polymorphisms in vitiligo patients and healthy controls. METHODS: We collected the data of age, sex, serum 25-hydroxy vitamin D (25[OH]D) level, thyroid autoantibodies, disease duration, types of vitiligo, family history and the affected body surface area of vitiligo from 172 patients. And we analyzed the VDR gene polymorphisms in 130 vitiligo and 453 age-sex-matched control subjects. RESULTS: The mean serum level of 25(OH)D in 172 vitiligo patients was 18.75 ± 0.60 ng/mL, which had no significant difference with a mean serum value of 25(OH)D in the Korean population. However, there were significant differences according to the duration of the disease and family history. Also, there were no significant differences in the genotypic and allelic distributions of 37 examined SNPs of VDR gene between vitiligo patients and healthy controls. CONCLUSION: Serum level of 25(OH)D in vitiligo patients was not significantly different from the mean serum value of the Korean population. Also, there were no significant differences in the genotypic distributions of VDR gene between vitiligo patients and healthy controls.

The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo.

BACKGROUND: Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial. OBJECTIVE: To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy. METHODS: A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6 weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports. RESULTS: During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer. LIMITATIONS: Retrospective study, individual follow-up duration less than 4 years, and no adjustment for comorbidities and medication history. Not generalizable to other races. CONCLUSION: The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.

Development of evidence-based consensus on critical issues in the management of patients with vitiligo: A modified Delphi study.

BACKGROUND/PURPOSE: Vitiligo remains a major challenge in dermatology. However, much of the treatment remains unclear, because little evidence is available. We sought to answer some critical questions pertaining to management of vitiligo patients. METHODS: A modified Delphi process among 31 vitiligo experts was conducted. A total of 12 clinical vitiligo treatment questions without clear answers were collected via a vote. To address each question, two members performed systematic literature reviews and prepared draft statements along with the levels of evidence and strength of recommendation. After reviewing the draft, all expressed their extent of agreement from 1 (strong disagreement) to 9 (strong agreement) for each item. The drafts were revised to reflect suggested comments. Discussion continued until all members agreed with the ultimate decision. RESULTS: The consensus process was completed after five rounds. We identified the best answers to 12 key questions, including issues on long-term phototherapy, systemic and topical corticosteroids, topical calcineurin inhibitors, immunosuppressants, excimer laser treatment, and surgical interventions. CONCLUSION: This consensus would complement current guidelines and aid both physician and patient decision-making in the treatment of vitiligo.

Atypical maculopapular cutaneous mastocytosis showing a nevus spilus-like lesion.

A 13-year-old Korean girl presented with a 7-year history of a pruritic, light-brown patch containing multiple 0.2- to 0.5-cm brownish-to-reddish maculopapules on the left anterior chest. When her skin was rubbed, the lesion became itchy and red. Histopathologic evaluation demonstrated marked dense dermal infiltration of mast cells. We report a rare case of atypical maculopapular cutaneous mastocytosis with clinical features similar to those of nevus spilus.

A randomised comparative study of 1064 nm Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser and topical antifungal treatment of onychomycosis.

Conventional treatments for onychomycosis include oral and topical antifungal agents. Although Nd:YAG laser has been reported to be effective, controlled studies combined or compared with conventional treatments are needed. To evaluate the efficacy of 1064 nm Nd:YAG laser for onychomycosis and compare outcomes with those of topical antifungal treatment and combination therapy. Patients were randomly divided into three groups: Laser (L); laser with topical antifungal therapy (L + T); and topical antifungal treatment (T). Laser treatment consisted of three or four sessions at 4 week intervals. Outcomes were assessed clinically and mycologically. In 217 nails of 56 patients, 76% in the L group and 71.8% in the L + T group experienced clinical responses, and 15.2% and 22.5%, respectively, were cured at 24 weeks. The clinical and cure rates of both groups were significantly greater than those of the T group. Six patients of the L group developed new infections, as did one patient in the L + T group and two patients in the T group. 1064 nm Nd:YAG laser shows clinically good responses in onychomycosis. Addition of topical antifungal agent did not appear to improve efficacy, but may have protected against new infection.

Effectiveness of low-fluence and short-pulse intense pulsed light in the treatment of melasma: A randomized study.

BACKGROUND: Various treatment protocols for melasma have been suggested in the literature, but the efficacy and safety of treatment varies according to the report. OBJECTIVE: To investigate the selective photothermolytic effect of fluence-dependent intense pulsed light (IPL) in the treatment of melasma. METHODS: Twenty Korean adults with melasma were enrolled, randomly assigned to two groups and treated at fluences of 10 or 13 J/cm(2) of IPL weekly over 6 weeks. Subjects were evaluated at baseline and weekly during the 6 weeks of treatment and at 3 weeks following the final treatment. Melanin and erythema indices were scored using a spectrophotometer. RESULTS: The modified Melasma Area Severity Index (MASI) score of 20 patients at inclusion was 11.6 (± 0.9). Both 10J and 13J IPL treatment groups had decreased modified MASI scores from 2 weeks onward at statistically significant levels. Both 10J and 13J IPL treatment groups showed decreased melanin indices with statistically significant differences from 3 weeks onward. The effect of IPL on melasma was slightly greater in patients treated with 13J of IPL than in those treated with 10J over the entire duration of the study. The erythema index was transiently increased in weeks 1-3, but after 4 weeks it decreased to sub-baseline levels. CONCLUSION: We suggest that a low-fluence IPL protocol could provide more effective treatment for melasma with minimal side effects in Asian skin.

Histologic comparison of microscopic treatment zones induced by fractional lasers and radiofrequency.

INTRODUCTION: Fractional photothermolysis induces microscopic, localized thermal injury in the skin surrounded by undamaged viable tissue in order to promote wound healing. OBJECTIVE: This study evaluated acute histologic changes following each single pass of various fractional lasers and radiofrequency (RF). METHODS: Three male domestic swine were used. We used fractional Erbium:glass (Er:glass), Erbium:yttrium-aluminum-garnet (Er:YAG), CO2 lasers, and fractional ablative microplasma RF. We analyzed features and average values of the diameter, depth, and vertical sectional areas treated with each kind of laser and RF. RESULTS: The microscopic treatment zone (MTZ) of fractional Er:glass resulted in separation of dermoepidermal junction with no ablative zone. Fractional Er:YAG provided the most superficial and broad MTZ with little thermal collateral damage. Fractional CO2 resulted in a narrow and deep "cone"-like MTZ. Fractional RF resulted in a superficial and broad "crater"-like MTZ. CONCLUSIONS: This study provides the first comparison of MTZs induced by various fractional lasers and RF. These data provide basic information on proper laser and RF options. We think that these findings could be a good reference for information about fractional laser-assisted drug delivery.

Association study between nonsense polymorphism (rs2039381, Gln71Stop) of interferon-ε and susceptibility to vitiligo in Korean population.

Interferons (IFNs) are related to autoimmune responses. IFN-epsilon (IFNE) is included in IFN family, and may modulate immunological functions. Inflammation modulating functions of IFNE may be related with the pathophysiology of vitiligo. To investigate the association of nonsense polymorphism (rs2039381, Gln71Stop) of interferon-ε (IFNE) and susceptibility to vitiligo, we conducted a case-control association study in 265 non-segmental vitiligo (NSV) patients and 320 healthy controls. The nonsense single nucleotide polymorphism (SNP) (rs2039381, Gln71Stop) of IFNE was genotyped by direct sequencing. Multiple logistic regression models (log-additive, dominant, and recessive models) were applied to determine odds ratios (OR), 95% confidence interval (CI), and p values. The rs2039381 (Gln71Stop) of IFNE did not show significant differences between NSV patient group and control group. However, we found that in childhood onset NSV groups, the IFNE nonsense polymorphism (rs2039381, Gln71Stop) showed a significant association. There was significantly different distribution of nonsense polymorphism of rs2039381 (Gln71Stop) of IFNE between NSV patients (childhood <18 years) and control subjects. This study suggests that rs2039381 (Gln71Stop) polymorphism of IFNE may be related to onset time of vitiligo in NSV patients.

Analysis of the temporal change in biophysical parameters after fractional laser treatments using reflectance confocal microscopy.

BACKGROUND: Fractional photothermolysis is a popular treatment option for photorejuvenation. Previous literature studies have demonstrated the clinical effectiveness of fractional photothermolysis on cutaneous photoaging; however, the associated changes in biophysical properties of the skin following fractional photothermolysis have not been fully elucidated. This study was conducted to investigate the temporal changes in biophysical parameters after fractional laser treatment on Asian skin. MATERIALS AND METHODS: Eleven female subjects underwent a single treatment with an erbium glass fractional laser. Skin roughness, elasticity, transepidermal water loss (TEWL), dermal thickness were evaluated before and immediately after treatment and 3 days, 1 week, 2 weeks, and 4 weeks after treatment. The changes in the dermal papilla were analyzed using a reflectance confocal microscopy (RCM). RESULTS: Skin roughness showed the greatest improvement at the first week and net elasticity was most improved at the second week. TEWL and the percentage of melanized and active dermal papillae (DP) were mostly increased for 3 days. At 4 weeks after treatment, the number of total dermal papillae showed a significant increase compared with pretreatment. CONCLUSION: This is the first study of the characterization and quantification of dermal papilla reflecting the dermal repair process after fractional photothermolysis through an RCM.

Characterization of microthermal zones induced by fractional radiofrequency using reflectance confocal microscopy: a preliminary study.

BACKGROUND: The microthermal zone (MTZ) produced by fractional device have been mostly evaluated through histopathologic analysis. Study of ablative type MTZ created by fractional device and skin thermal interaction using in vivo reflectance confocal microscopy (RCM) has been rarely reported. OBJECTIVES: We evaluated the in vivo human RCM skin images of ablated fractional radiofrequency (RF) treatment to demonstrate the thermal interaction between RF and skin tissue. SUBJECTS AND METHOD: Three healthy male subjects underwent a single irradiation of fractional RF on the upper back area. The diameter, area, and depth of the MTZ was measured using RCM. Three female domestic swine were used for comparative histopathological study. RESULTS: After RF treatment, crusted holes surrounding pale edematous rings were visible in RCM images. The empty spaces correlated to the location of ablative channels, and the presence of thermal modification zones corresponded to areas with a whitish ring showing high reflectance. Ablation depth increased in proportion to the energy of fractional RF. However, the diameter of the thermal modified zone was relatively constant regardless of RF energy. CONCLUSIONS: RCM successfully identified in vivo acute thermal changes after fractional RF. The results obtained in this study provide a clearer picture of tissue-thermal interactions in the skin.

Tinea incognito in Korea and its risk factors: nine-year multicenter survey.

Tinea incognito (TI) is a dermatophytic infection which has lost its typical clinical appearance because of improper use of steroids or calcineurin inhibitors. The incidence of TI is increasing nowadays. We conducted retrospective review on 283 patients with TI from 25 dermatology training hospitals in Korea from 2002-2010 to investigate the demographical, clinical, and mycological characteristics of TI, and to determine the associated risk factors. More than half (59.3%) patients were previously treated by non-dermatologists or self-treated. The mean duration of TI was 15.0 ± 25.3 months. The most common clinical manifestations were eczema-like lesion, psoriasis-like, and lupus erythematosus-like lesion. The trunk and face were frequently involved, and 91 patients (32.2%) also had coexisting fungal infections. Among 67 isolated strains, Trichophyton rubrum was the most frequently detected (73.1%). This is the largest study of TI reported to date and the first investigational report concerning TI in Korea. We suggest that doctors should consider TI when a patient has intractable eczema-like lesions accompanied by tinea pedis/unguium. Furthermore, there should be a policy change, which would make over-the-counter high-potency topical steroids less accessible in some countries, including Korea.

Inhibitory effect of Gastrodia elata extract on melanogenesis in HM3KO melanoma cells.

Effective and safe antimelanogenic agents derived from natural products get interest continuously for both medical and cosmetic purposes. Melanin synthesis is regulated by melanogenic enzymes such as tyrosinase, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2) in mammals. Gastrodia elata (GE) has been shown to have multiple therapeutic actions related to antioxidation in many diseases. In this study, we investigate whether water extraction of GE has inhibitory effects on melanogenesis in vitro and on the expression of mRNA and protein of tyrosinase, TRP-1, and TRP-2 in HM3KO melanoma cells. To examine the inhibitory effect of GE on melanogenesis, mushroom tyrosinase inhibition assay; reverse transcription polymerase chain reaction; and western blotting of tyrosinase, TRP-1, and TRP-2 were performed using HM3KO melanoma cells. In this study, the GE extract was found to significantly inhibit mushroom tyrosinase activity (69.3 ± 7.2% of the control, p < 0.05), and the expression of mRNA and protein of tyrosinase, TRP-1, and TRP-2 was reduced significantly. These results suggest that the antimelanogenic effect of GE extract is mainly due to the decreased expression of mRNA and protein of tyrosinase, TRP-1, and TRP-2 in the process of melanin synthesis.

Association between exonic polymorphisms of human leukocyte antigen-G gene and non-segmental vitiligo in the Korean population.

Background Vitiligo is a pigmentary skin disorder characterised by a chronic and progressive loss of melanocytes. Although several theories have been suggested to the pathogenesis of vitiligo, an autoimmune process leading to melanocyte destruction appears most likely. Human leukocyte antigen-G is a non-classic, major histocompatibility complex Class I molecule that plays an important role in the suppression of the immune response. Several recent studies have provided evidences that polymorphisms in the human leukocyte antigen-G gene might be related with autoimmune diseases. Objectives The aim of this study was to decide whether exonic single nucleotide polymorphisms in human leukocyte antigen-G contribute to the risk of developing non-segmental vitiligo in the Korean population. Methods To evaluate the associations between exonic single nucleotide polymorphisms (rs1630223 [Ala5Ala] and rs12722477 [Leu134Ile]) of human leukocyte antigen-G and vitiligo, 244 patients with vitiligo and 398 healthy controls were recruited. Genotyping was performed using Fluidigm 192.24 Dynamic Array with EP1 (Fluidigm Corp., CA). The SNP type assay (Fluidigm Corp., CA), which employs allele-specifically designed fluorescences (FAM or VIC) primers and a common reverse primer was applied and the data were analysed using the EP1 single nucleotide polymorphisms genotyping analysis software to obtain genotype calls. Results Two exonic single nucleotide polymorphisms (rs1630223 and rs12722477) exhibited significant associations with susceptibility and remained a statistically significant association following Bonferroni correction. These two single nucleotide polymorphisms were located within a block of linkage disequilibrium. Haplotypes G-C and A-A comprising rs1630223 and rs12722477 demonstrated a significant association with non-segmental vitiligo. Limitations The protein expression level of patients with vitiligo and controls was not studied and a replication study of the genetic association in an independent group was not managed. Conclusion Our results suggest that exonic human leukocyte antigen-G polymorphisms (rs1630223 and rs12722477) are associated with the development of non-segmental vitiligo.

Effects of 15-deoxy-∆¹²,¹4-prostaglandin J2 on the production of IL-8 and the expression of Toll-like receptor 2 in human primary keratinocytes stimulated with lipopolysaccharide.

15-deoxy-∆(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an anti-inflammatory prostaglandin that plays a role in promoting the resolution of inflammation. We investigated the effects of 15d-PGJ(2) on the production of IL-8 and on the expression of Toll-like receptors (TLRs) 2 in human primary keratinocytes stimulated with lipopolysaccharide (LPS). Cell proliferation was analyzed using the MTT assay, TLR2 and -4 mRNA expression was detected by RT-PCR, and IL-8 production and NF-κB p65 activities were determined by ELISA. LPS and 15d-PGJ(2) did not influence the proliferation rate at low concentrations (0.5 and 2.0 µM) in keratinocytes, and showed toxicity at high concentrations (5.0 µM). LPS, compared with control, induced the expression of TLR2 mRNA, increased IL-8 production, and enhanced NF-κB activity. 15d-PGJ(2) decreased TLR2 mRNA, increased IL-8 production, and suppressed NF-κB activity. Costimulation with LPS and 15d-PGJ(2), compared with LPS stimulation alone, decreased TLR2 mRNA (1.8-fold), increased IL-8 production (1.8-fold at 0.5 µM and 3.7-fold at 2.0 µM), and inhibited NF-κB activity (3.3-fold at 0.5 µM and 5.1-fold at 2.0 µM). TLR4 mRNA was not expressed in primary keratinocytes. These results suggest that 15d-PGJ(2) suppresses TLR2 expression and that it up-regulates the production of IL-8 by inhibiting the NF-κB signaling pathway in primary keratinocytes. Thus, 15d-PGJ(2) can have both anti- and pro-inflammatory effects, and 15d-PGJ(2)-mediated IL-8 up-regulation is related to the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways.

Investigation of aging effects in human hair using atomic force microscopy.

BACKGROUND: A thorough characterization of the morphological structure and physical properties is essential for an understanding of human hair. A number of techniques such as scanning electron microscopy, transmission electron microscopy and confocal microscopy have been used to study hair surfaces. Recently, atomic force microscopy (AFM) has emerged as an ideal method for the non-invasive examination of hair surfaces. PURPOSE: To investigate the effects of aging on normal Korean hair diameter and surface features using AFM. METHODS: We enrolled 60 Korean volunteers of various ages who had no hair diseases. We analyzed hair diameter, AFM images of the hair surface, cuticular descriptors and micro-scale mechanical properties for their associations with aging. RESULTS: Hair diameter was found to increase for the first 20-30 years of life, after which it began to decrease. AFM images of most of the younger subjects showed typical step-like topographic properties with clear scale edges. The AFM images of most of the older subjects revealed dilapidated structures, poorly demarcated scale edges and undulated surfaces. Among the cuticular descriptors, surface roughness increased significantly with age. Force to distance analysis demonstrated a dependence on age. CONCLUSION: These results suggest that aging causes changes in hair diameter and surface structure.

Intense focused ultrasound tightening in Asian skin: clinical and pathologic results.

BACKGROUND: Laxity and wrinkles of the aging face are common cosmetic concerns. Intense focused ultrasound (IFUS), a novel treatment modality for skin laxity, produces thermal effects at various depths while sparing overlying epidermis. OBJECTIVE: To evaluate the safety and efficacy of IFUS in facial skin tightening. METHODS AND MATERIALS: Twenty-two Korean patients with facial laxity were analyzed after a single IFUS treatment. Patient assessments were recorded, and two blinded, experienced clinicians who assessed improvement of nasolabial folds and jaw tightening evaluated photographs of patients and rated skin laxity. Skin biopsies were taken from 11 patients before and 2 months after treatment. RESULTS: Objectively, nasolabial folds and jaw lines were improved in all patients. Subjectively, 77% of patients reported much improvement of nasolabial folds, and 73% of patients reported much improvement at the jaw line. Histologic evaluation of skin biopsy samples using hematoxylin and eosin and Victoria blue stains showed greater dermal collagen with thickening of the dermis and straightening of elastic fibers in the reticular dermis after treatment. CONCLUSION: IFUS is a safe, effective, noninvasive procedure to tighten the facial skin of Asian patients. Improvement is associated with greater production of dermal collagen and straightening of dermal elastic fibers.

Fusarium solani onychomycosis of the thumbnail coinfected with Pseudomonas aeruginosa: report of two cases.

Fusarium species are non-dermatophytic moulds, which are commonly known soil saprophytes and important plant pathogens, and have been frequently reported to be aetiological agents of opportunistic infections in humans. The prevalence of onychomycosis caused by Fusarium species varies in the literature because of geographical differences in mould distribution and diagnostic methods. Onychomycosis caused by Fusarium species is considered rare in Korea, and only four cases have been described to date. Pseudomonas aeruginosa also can infect nails and cause green nail syndrome, and recent research has shown that fungal infection may potentiate the colonisation or growth of P. aeruginosa within a nail. Furthermore, such coinfection with P. aeruginosa can prevent the isolation of the fungus because of bacterial overgrowth in culture. The authors report the cases of two immunocompetent patients with F. solani onychomycosis coinfected with P. aeruginosa. Both presented with a greenish/yellowish discolouration and thickening of a thumbnail, and were treated with systemic ciprofloxacin in combination with itraconazole or terbinafine.