Missense Variant c.3301C>T (p.R1101W) in von Willebrand Factor A Sequence in a Patient with Recessive Dystrophic Epidermolysis Bullosa Pruriginosa with Compound Heterozygous COL7A1 Variants.

Dystrophic epidermolysis bullosa (DEB) pruriginosa is a rare subtype of DEB characterized by multiple, violaceous, and severe pruritic lichenified nodules along with blisters. Here, we report the case of a Korean male who, since the age of 3 years, had multiple pruritic nodules with blisters on both lower extremities. Genetic testing is required to diagnose DEB pruriginosa because its clinical and histologic features are inconclusive. We identified compound heterozygous COL7A1 variants of c.5797C>T (p.R1933*) and c.3301C>T (p.R1101W) in the patient, leading to a diagnosis of recessive DEB pruriginosa. Among the variants identified, c.3301C>T is a novel missense variant that has not been reported previously. This variant is in exon 26, which encodes von Willebrand factor A (vWFA) in collagen type VII. vWFA is known to preserve normal dermal structures by interacting with dermal collagens and basement membranes. Considering that this variant contradicts the general concept that autosomal dominant inheritance is more common and that variants typically occur in the triple helical collagenous domain of COL7A1 in DEB pruriginosa, we focus on the rarity of this case and the possible pathogenic role of the c.3301C>T (p.R1101W) variant.

Refractory Bullous Pemphigoid Successfully Treated with Reslizumab: A Possible Novel Therapeutic Modality.

Bullous pemphigoid (BP) is a chronic, autoimmune blistering disease that has concerning morbidity and mortality rates. Recently, several studies have focused on eosinophils due to their significant role in the pathogenesis of BP, considering that they are ubiquitous in the serum, tissue, and blister fluids of patients with BP. With this context, precision therapy that targets mediators of eosinophil activity could be a possible novel therapeutic strategy. Interleukin (IL)-5 is crucial for B-cell maturation, which consequently results in immunoglobulin production, and promotes eosinophil differentiation, proliferation, and activation. To our best knowledge, reslizumab has not yet been reported to treat BP. Herein, we report a case of steroid- and omalizumab-resistant BP treated successfully using reslizumab. Our data suggest that IL-5 could be a novel specific biologic target within the entire immunopathogenesis of BP, and reslizumab would be a novel therapeutic modality.

A postulated model for photoimmunopathogenesis of chronic actinic dermatitis around adaptive immunity, including Th17 cells, Tregs, TRMs, cytotoxic T cells, and/or common-γ chain receptor+ cells.

BACKGROUND/PURPOSE: The pathogenesis of chronic actinic dermatitis (CAD) is more complicated than other photodermatoses. However, the relationship between the clinical severity of CAD and the offending photocontact or contact allergens or both, and the correlations of CAD immunopathogenesis with the immunoregulatory molecules involved in adaptive immunity are yet to be investigated. METHODS: We performed phototesting with broad-spectrum ultraviolet (UV) B, UVA, and visible light to establish the presence of photosensitivity in 121 patients with CAD, together with photopatch and contact patch testing. Nine patients with CAD were selected according to their clinical severity score for CAD (CSS-CAD), and triple direct immunofluorescence analysis was performed with paraffin-embedded skin biopsy samples. RESULTS: As CSS-CAD was closely correlated with the multiplicity of photo(contact) allergens, particularly photoallergens, three or more photoallergens were detected in the severe CAD group (52.5%); less in the moderate group (32.8%); and only one in the mild group (14.8%; P = .025). In the groups showing greater severity of disease, the absolute numbers of IFN-γ+ , IL-17+ , CD4+, CD8+, common-γ chain receptor (common-γCR)+ , and CD69+ tissue-resident memory cells increased on average; there was also an increase in the CD4+/CD8+ cell ratio, with the more severely affected groups. However, the levels of TNF-α+ and FoxP3+ regulatory T (Treg) cells and the mean IL-17/IFN-γ cell ratio decreased in the more severely affected CSS-CAD subgroups. CONCLUSIONS: Based on the clinical analysis and immunopathogenic results, avoidance of excessive sun exposure, and topical and systemic blocking agents for photo(contact) allergens are recommended. Additionally, conventional immunomodulators and emerging agents including JAK-STAT inhibitors may be administered for CAD treatment in the future.

Impact of Pediatric Alopecia Areata on Quality of Life of Patients and Their Family Members: A Nationwide Multicenter Questionnaire Study.

BACKGROUND: Pediatric alopecia areata (AA) can affect the quality of life (QoL) of patients and their family members. Research on the QoL and burden on family members in pediatric AA is limited. OBJECTIVE: This nationwide multicenter questionnaire study described the QoL and burden of the family members of patients with pediatric AA. METHODS: This nationwide multicenter questionnaire study enrolled AA patients between the ages of 5 and 18 years from March 1, 2017 to February 28, 2018. Enrolled patients and their parents completed the modified Children's Dermatology Life Quality Index (CDLQI) and the modified Dermatitis Family Impact (mDFI). The disease severity was measured using the Severity of Alopecia Tool (SALT) survey scores. RESULTS: A total of 268 patients with AA from 22 hospitals participated in this study. Our study found that the efficacy and satisfaction of previous treatments of AA decreased as the severity of the disease increased. The use of home-based therapies and traditional medicines increased with the increasing severity of the disease, but the efficacy felt by patients was limited. CDLQI and mDFI scores were higher in patients with extensive AA than those with mild to moderate AA. The economic and time burden of the family members also increased as the severity of the disease increased. CONCLUSION: The severity of the AA is indirectly proportional to the QoL of patients and their family members and directly proportional to the burden. Physicians need to understand these characteristics of pediatric AA and provide appropriate intervention to patients and their family members.

Surgical Removal of a Thymoma without Myasthenia Gravis Can Have a Therapeutic Effect on Concurrent Alopecia Areata: A Case Report.

Alopecia areata is a chronic organ-specific autoimmune disease and it could be associated with other autoimmune diseases. We, herein, report a case of alopecia areata in a patient with a thymoma without myasthenia gravis. Multiple hairless patches rapidly developed 6 weeks before the first visit on the patient who had been newly diagnosed with thymoma 2 weeks before the hairless patches occurred, and thymectomy was done 2 weeks before visiting dermatologic department. She had no symptoms associated with myasthenia gravis, and there were no abnormal findings on neurologic exams and acetylcholine receptor autoantibody was not detected in serum. Scalp biopsy showed numerous lymphocytic inflammations around hair follicles and in immunohistochemical staining, the aggregation of CD4+ and CD8+ T cells was observed around hair follicles and FoxP3+ T lymphocytes were rarely observed around hair follicles. The patient refused any treatment and her hairless patches were completely recovered 3 months after thymectomy, without being recurred 3 years after thymectomy. On the basis of both clinical manifestations and histologic findings, we concluded that alopecia areata in the patient had developed in association with thymoma and was recovered rapidly after thymectomy.

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.

Suppression of Pax3-MITF-M Axis Protects from UVB-Induced Skin Pigmentation by Tetrahydroquinoline Carboxamide.

Paired box gene 3 (Pax3) and cAMP responsive element-binding protein (CREB) directly interact with the cis-acting elements on the promoter of microphthalmia-associated transcription factor isoform M (MITF-M) for transcriptional activation in the melanogenic process. Tyrosinase (Tyro) is a target gene of MITF-M, and functions as a key enzyme in melanin biosynthesis. Tetrahydroquinoline carboxamide (THQC) was previously screened as an antimelanogenic candidate. In the current study, we evaluated the antimelanogenic activity of THQC in vivo and elucidated a possible mechanism. Topical treatment with THQC mitigated ultraviolet B (UVB)-induced skin pigmentation in guinea pig with decreased messenger RNA (mRNA) and protein levels of melanogenic genes such as MITF-M and Tyro. Moreover, THQC inhibited cAMP-induced melanin production in α-melanocyte-stimulating hormone (α-MSH)- or histamine-activated B16-F0 cells, in which it suppressed the expression of the MITF-M gene at the promoter level. As a mechanism, THQC normalized the protein levels of Pax3, a transcriptional activator of the MITF-M gene, in UVB-exposed and pigmented skin, as well as in α-MSH-activated B16-F0 culture. However, THQC did not affect UVB- or α-MSH-induced phosphorylation (activation) of CREB. The results suggest that suppression of the Pax3-MITF-M axis might be a potential strategy in the treatment of skin pigmentary disorders that are at high risk under UVB radiation.

The expressions of MUM-1 and Bcl-6 in ALK-negative systemic anaplastic large cell lymphoma with skin involvement and primary cutaneous anaplastic large cell lymphoma.

BACKGROUND: It is important to differentiate between primary cutaneous anaplastic large cell lymphoma (PC-ALCL) and ALK-negative systemic ALCL with skin involvement, as the prognoses and treatments for these two diseases are considerably different. OBJECTIVE: This study aimed to compare the expressions of multiple myeloma oncogene 1 (MUM-1) and B-cell lymphoma 6 (Bcl-6) in PC-ALCL and ALK-negative systemic ALCL. METHODS: This retrospective qualitative study investigated the clinical features of 7 patients with ALK-negative PC-ALCL, 5 patients with ALK-negative systemic ALCL with skin involvement, and 6 patients with ALK-positive systemic ALCL with skin involvement. The MUM-1 and Bcl-6 expressions were evaluated using immunohistochemistry. RESULTS: The MUM-1 expression rates were 85.7% in the PC-ALCL cases and 100% in the ALK-negative systemic ALCL with skin involvement cases. The Bcl-6 expression rates were 28.5% in the PC-ALCL cases and 20% in the ALK-negative systemic ALCL cases with skin involvement. CONCLUSION: Although the cutaneous manifestations of ALK-negative systemic ALCL and PC-ALCL are similar, the prognoses and treatment approaches are considerably different. Our results indicate that MUM-1 expression is commonly expressed in both types of ALCL, but Bcl-6 is less commonly expressed in PC-ALCL cases and systemic ALCL with skin involvement cases.

Evaluation for Skin Cancer and Precancer in Patients With Vitiligo Treated With Long-term Narrowband UV-B Phototherapy.

Importance: Narrowband UV-B (NBUVB) phototherapy has been the mainstay in the treatment of vitiligo, but its long-term safety in terms of photocarcinogenesis has not been established. Objectives: To investigate the risks of skin cancer and precancerous lesions among patients with vitiligo undergoing NBUVB phototherapy, based on the number of NBUVB phototherapy sessions. Design, Setting, and Participants: This nationwide population-based retrospective cohort study enrolled 60 321 patients with vitiligo 20 years or older between January 1, 2007, and December 31, 2017. Patients and outcomes were identified through nationwide cohort data from the Korean national health insurance claims database, and frequency matching by age and sex was performed. Exposures: The number of phototherapy sessions each patient received between 2008 and 2017. Patients were classified into 5 groups according to the number of phototherapy sessions (0 sessions, 20 105 patients; 1-49 sessions, 20 106 patients; 50-99 sessions, 9702 patients; 100-199 sessions, 6226 patients; and ≥200 sessions, 4182 patients). We also identifed patients who underwent at least 500 phototherapy sessions (717 patients). Main Outcomes and Measures: Primary outcomes were the development of actinic keratosis, Bowen disease, nonmelanoma skin cancer, or melanoma after enrollment. Results: Among the 60 321 patients with vitiligo in this study (33 617 women; mean [SD] age, 50.2 [14.9] years), the risks of Bowen disease (<50 sessions of phototherapy: hazard ratio [HR], 0.289 [95% CI, 0.060-1.392]; 50-99 sessions: HR, 0.603 [95% CI, 0.125-2.904]; 100-199 sessions: HR, 1.273 [95% CI, 0.329-4.924]; ≥200 sessions: HR, 1.021 [95% CI, 0.212-4.919]), nonmelanoma skin cancer (<50 sessions: HR, 0.914 [95% CI, 0.533-1.567]; 50-99 sessions: HR, 0.765 [95% CI, 0.372-1.576]; 100-199 sessions: HR, 0.960 [95% CI, 0.453-2.034]; ≥200 sessions: HR, 0.905 [95% CI, 0.395-2.073]), and melanoma (<50 sessions: HR, 0.660 [95% CI, 0.286-1.526]; 50-99 sessions: HR, 0.907 [95% CI, 0.348-2.362]; 100-199 sessions: HR, 0.648 [95% CI, 0.186-2.255]; ≥200 sessions: HR, 0.539 [95% CI, 0.122-2.374]) did not increase after phototherapy. The risk of actinic keratosis increased significantly for those who had undergone 200 or more NBUVB phototherapy sessions (HR, 2.269 [95% CI, 1.530-3.365]). A total of 717 patients with vitiligo underwent at least 500 sessions of NBUVB phototherapy; their risks of nonmelanoma skin cancer and melanoma were no greater than those of the patients who did not undergo NBUVB phototherapy (nonmelanoma skin cancer: HR, 0.563 [95% CI, 0.076-4.142]; melanoma: HR, not applicable). Conclusions and Relevance: Our results suggest that long-term NBUVB phototherapy is not associated with an increased risk of skin cancer in patients with vitiligo and that NBUVB phototherapy may be considered a safe treatment.

BMP4-Induced Differentiation of Human Hair Follicle Neural Crest Stem Cells into Precursor Melanocytes from Hair Follicle Bulge.

Background: Vitiligo is a skin depigmentation disorder, for which, repigmentation treatment with combined follicular unit extraction (FUE) graft and narrowband ultraviolet B (NBUVB) is considered superior to micro-punch graft therapy. BMP4 can induce MITF expression in Neural crest stem cells (NCSCs), and α-MSH subsequently promotes the differentiation of MITF-expressing cells along the melanocyte lineage. Objective: To investigate why FUE grafting is superior to epidermal mini grafting in promoting hair follicles (HF) melanocyte cell survival and longevity, we planned the in vitro experiments HF bulge NCSCs differentiate into melanocyte precursors under the co-treatment of BMP4 and α-MSH. Methods: Cells that migrated from the HF bulge of scalp were cultured and assessed using immunofluorescence. Transcriptome analysis was performed on RNA sequencing results. Results: Basic fibroblast growth factor promotes the proliferation and survival of NCSCs, with spontaneous differentiation into SOX10+/SOX2+ glial progenitors, but not into SOX10+/MITF+ precursor melanocytes. Both BMP4 and α-MSH promoted the differentiation into MITF-expressing cells. RNA sequencing revealed a downregulation in neuregulin-1 (NRG1) and sermaphorin 3C (SEMA3C), and upregulation in WNT10A. Furthermore, FUE grafting had a source of reservoir melanocytes superior to mini- grafting in treatment for vitiligo. Conclusion: We obtained SOX10+/MITF+ precursor melanocytes through an induction of differentiation along the melanocyte lineage by BMP4 and α-MSH. According to the RNA sequencing results that NRG1 and SEMA3C were downregulated and WNT10A was upregulated, we postulated that HF NCSCs differentiated into melanocyte by co-treatment of BMP4 and α-MSH. Overall, FUE grafting is a more robust and substitutive treatment option for vitiligo.

Corrigendum: BMP4-Induced Differentiation of Human Hair Follicle Neural Crest Stem Cells into Precursor Melanocytes from Hair Follicle Bulge.

[This corrects the article on p. 409 in vol. 32.].

Association Between Lower Urinary Tract Symptoms and Falls in Adults Males: Based on the Korean Community Health Survey.

This study aimed to investigate the correlation between lower urinary tract symptoms (LUTSs) and falls considering places where falls can occur in adult males. We analyzed 101 862 males in the 2011 Korean Community Health Survey. LUTSs were assessed using the International Prostate Symptom Score system. The rate of total and indoor falls significantly increased with the LUTS severity, respectively. After adjusting for age and other confounding variables, the odds ratios (ORs) for total falls were significantly high for the mild (OR = 1.63, 95% confidence interval [CI] = 1.54-1.71), moderate (OR = 2.35, 95% CI = 2.16-2.56), and severe groups (OR = 2.83, 95% CI = 2.49-3.22), relative to the normal group. Indoor fall experience was the same for the mild (OR = 1.56, 95% CI = 1.36-1.79), moderate (OR = 2.37, 95% CI = 1.97-2.85), and severe groups (OR = 3.77, 95% CI = 3.00-4.72). Nocturia, hesitancy, and urgency were significantly associated with indoor falls. The association between falls and the degree of LUTS was observed in both the young and the elderly. Therefore, further studies are needed to determine the effects of treatment of LUTS on the risk of falls and the effectiveness of the fall prevention program.

Health-related quality of life in adult males with lower urinary tract symptoms.

PURPOSE: To assess the status and impact of lower urinary tract symptoms (LUTS) on health-related quality of life (HRQoL) in a community-based sample of Korean adult males. METHODS: We analyzed the data of 101,606 adult males aged ≥ 19 years of age obtained during the 2011 Korean Community Health Survey. Subject data were assessed for LUTS and HRQoL using international prostate symptom scores, and EuroQol-five-dimensions three-level version (EQ-5D-3L) and EuroQol-visual analogue scale (EQ-VAS) scores. RESULTS: Of the 101,606 subjects, 53,323 (52.5%) reported having at least one LUTS and 3116 (3.1%) had an IPSS of ≥ 20, indicating severe LUTS. In those aged 19-39 years, 28.7% (8343/29,072) reported they had mild to severe LUTS. The prevalence of LUTS was high among those aged 40-59 years (47.7%), 60-79 years (80.5%), and ≥ 80 years (91.2%). In addition, EQ-5D-3L and EQ-VAS scores decreased as LUTS severity and frequency increased. CONCLUSIONS: Adult men of all ages with mild to severe LUTS have poorer health statuses and quality of life. Even among young males, LUTS severity and was found to negatively affect HRQoL.

Application of acellular human dermis and skin grafts for lower extremity reconstruction.

OBJECTIVE: To use both acellular human dermis and skin grafting simultaneously for improved skin grafting without contracture. The study also aims to address the lack of research on the application of an acellular human dermis in diverse clinical cases. METHOD: The study examined patients who had received acellular human dermis (CGDerm, CGBio, Seoul, Korea) and split-thickness skin grafting (STSG) simultaneously for lower limb, full-thickness skin defects between September 2012 and June 2014. The researchers performed chart reviews retrospectively and examined the patients based on the following factors: gender, age, injury mechanism, size, exposed structure, pre-coverage dressing method, coverage method, post-operational engraftment and total healing period, contracture development, elasticity, and infection development. RESULTS: A sample of 27 patients with a total of 30 wounds took part in the study. Of these wounds, 29 showed successful engraftment without infection or contracture. In one case, continued seroma was observed and, following new coverage of both the acellular human dermis and STSG, engraftment was successful. CONCLUSION: Human dermis can play an important role in securing the availability of surrounding tissue and in contracture prevention, both of which are key to lower limb reconstruction. Of the types available, acellular human dermis showed lower infection rates than other human dermis types, and its engraftment rate was higher than in STSG-only cases. These findings suggest that acellular human dermis use in STSG is effective and safe in lower limb reconstruction.

Prostatic urethral length as a predictive factor for surgical treatment of benign prostatic hyperplasia: a prospective, multiinstitutional study.

BACKGROUND: We hypothesized that prostatic anatomical factors may affect the progression of benign prostatic hyperplasia (BPH) and analyzed whether prostatic anatomical factors could be predictive of the risk of surgery. MATERIALS AND METHODS: From February to October 2014, 679 men older than 40 years who had lower urinary tract symptoms and enlarged prostates were enrolled from five medical centers. Patients' medical characteristics, serum prostate-specific antigen levels, transrectal ultrasound (TRUS) results, and uroflowmetry were analyzed. Using TRUS in all patients, the total prostate volume, transitional zone volume, prostatic urethral length, transitional zone urethral length, intravesical prostatic protrusion, and prostatic urethral angle were measured. Logistic regression analysis was used to determine factors associated with the risk of surgery. Receiver operating characteristic curves were used to determine cutoff values for significant variables. RESULTS: Of 679 patients, 37 (5.4%) underwent BPH-related surgery. Prostatic urethral length and transitional zone urethral length were independently associated with the risk of surgery. Age, serum prostate-specific antigen levels, peak flow rate, postvoid residual urine, and other anatomical factors determined by TRUS were not statistically significant with respect to the risk of surgery. Using receiver operating characteristic curve-based predictions, the best cutoff values for prostatic and transitional zone urethral length were 4.53 cm (sensitivity: 83.3%, specificity: 61.6%) and 3.35 cm (sensitivity: 83.3%, specificity: 77.9%), respectively. CONCLUSIONS: This study showed that patients with BPH with longer prostatic and transitional zone urethral lengths had a higher risk of surgery. Prostatic and transitional zone urethral length may be useful predictive factors for medical treatment failure in patients with BPH.

The 308-nm excimer laser treatment does not increase the risk of skin cancer in patients with vitiligo: A population-based retrospective cohort study.

A 308-nm excimer laser (EL) has been widely used to treat patients with localized vitiligo. However, data are rare on the influence of EL treatment on the risks of skin cancer. To evaluate the skin cancer risks after long-term EL treatment, we performed a nationwide population-based retrospective cohort study using the Korean National Health Insurance Claims Database. A total of 5,052 patients with vitiligo were classified into three groups according to the EL treatment sessions between 2009 and 2016: no, 50-99, and 100 or more EL treatments after 2-year washout period (2007 and 2008). Using multivariable Cox proportional hazard models, we found that the risks of actinic keratosis, non-melanoma skin cancers, and melanoma did not significantly differ among the groups, respectively. In conclusion, EL treatment would not increase the risks of premalignant skin lesions and skin cancers in patients with vitiligo. Based on our results, EL is likely to be a safe treatment option for patients with localized vitiligo.

Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder.

Rationale: SOX10 (SRY-related HMG-box 10) and MITF-M (microphthalmia-associated transcription factor M) restrict the expression of melanogenic genes, such as TYR (tyrosinase), in melanocytes. DACE (diacetylcaffeic acid cyclohexyl ester) inhibits melanin production in α-MSH (α-melanocyte stimulating hormone)-activated B16-F0 melanoma cells. In this study, we evaluated the antimelanogenic activity of DACE in vivo and elucidated the molecular basis of its action. Methods: We employed melanocyte cultures and hyperpigmented skin samples for pigmentation assays, and applied chromatin immunoprecipitation, immunoblotting, RT-PCR or siRNA-based knockdown for mechanistic analyses. Results: Topical treatment with DACE mitigated UV-B-induced hyperpigmentation in the skin with attenuated expression of MITF-M and TYR. DACE also inhibited melanin production in α-MSH- or ET-1 (endothelin 1)-activated melanocyte cultures. As a mechanism, DACE blocked the nuclear import of CRTC1 (CREB-regulated co-activator 1) in melanocytes. DACE resultantly inhibited SOX10 induction, and suppressed the transcriptional abilities of CREB/CRTC1 heterodimer and SOX10 at MITF-M promoter, thereby ameliorating facultative melanogenesis. Furthermore, this study unveiled new issues in melanocyte biology that i) KPNA1 (Impα5) escorted CRTC1 as a cargo across the nuclear envelope, ii) SOX10 was inducible in the melanogenic process, and iii) CRTC1 could direct SOX10 induction at the transcription level. Conclusion: We propose the targeting of CRTC1 as a unique strategy in the treatment of acquired pigmentary disorders.