Vitiligo is a common acquired hypopigmented disorder characterized by melanocyte damage and/or loss, primarily resulting from excessive oxidative stress and dysregulated immune responses targeting melanocytes. The initial guidelines for the diagnosis and treatment of vitiligo in Japan were published in Japanese in 2012 and in English in 2013 to provide clinical evidence for vitiligo management. Since then, there has been a substantial accumulation of pathological research and therapeutic evidence. The second guidelines for the diagnosis and treatment of vitiligo in Japan (2025) are presented as an updated resource for clinicians, incorporating worldwide expert recommendations and recent advances in basic and clinical research. These guidelines aim to provide updated knowledge for individuals with vitiligo, public health professionals, scientists, and dermatologists.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and systemic complications, including bleeding tendencies. While 11 genes associated with HPS have been identified, cases of HPS5 remain exceedingly rare, particularly in Japan. Here, we report two Japanese patients with novel pathological HPS5 variants, expanding the genetic spectrum of this disorder. Both patients exhibited typical features of mild skin and hair hypopigmentation, and significant ocular involvement. Genetic analysis revealed a heterozygous nonsense variant, NG_008877.1 (NM_181507.2): c.2275G>T, in both patients, inherited from their fathers. Additionally, maternal variants NG_008877.1 (NM_181507.2): c.2952-13G>A and NG_008877.1 (NM_181507.2): c.1128A>G were identified in patient 1 and patient 2, respectively. These variants, initially presumed non-pathogenic, were found to induce alternative splicing, leading to truncated protein production. Our findings highlight the functional importance of synonymous variants and their potential role in HPS. This report represents the first documented case of a synonymous pathogenic variant associated with HPS and underscores the need for comprehensive genetic and transcriptomic analyses in rare genetic disorders.

BACKGROUND:If skin cancer (SC) can be screened using saliva, it would be extremely important for improving the prognosis of skin cancer. However, there is currently no available data on salivary screening for SC. OBJECTIVE:This study aimed to identify salivary metabolomic biomarkers for SC screening by comparing tissue and saliva samples. METHODS:This single-center study involved SC patients from Yamagata University Hospital, enrolled between May 2017 and April 2020. For the healthy controls (HCs), our database comprising salivary metabolomics data of HCs was used. Whole unstimulated saliva samples were collected from patients with SC (n = 75) and HCs (n = 77). Paired tumor and control tissues after SC resection were obtained from the same patients who donated saliva. Hydrophilic metabolites in the tissue and saliva samples were comprehensively analyzed using capillary electrophoresis-mass spectrometry. Using these candidate metabolites, a multiple logistic regression (MLR) model was developed to differentiate SC from HCs RESULTS: Sixty-six and 12 metabolites showed significant differences in tissues and saliva, respectively. Of these, six metabolites were commonly different between SC and HCs. Spermidine, 2-aminobutyric acid, and isoleucine were selected to develop the MLR model. The model exhibited a large area under the receiver operating characteristic curve (0.802, 95 % confidence interval: 0.731-0.874, P < 0.0001). Additionally, no significant differences were shown in candidate salivary metabolites between stages in both malignant melanoma and squamous cell carcinoma. CONCLUSIONS:The salivary metabolomic profiles between SC and HCs differed clearly. This combination of salivary metabolites could serve as non-invasive biomarkers for screening SC.

Vitiligo, a complex autoimmune disorder characterized by melanocyte destruction, arises from an intricate interplay of genetic, epigenetic, immune, and environmental factors. Genome-wide association studies (GWAS) have identified over 50 susceptibility loci, including key genes within the MHC region and those involved in immunity, oxidative stress, and melanogenesis. Concurrently, epigenetic research has unraveled regulatory networks critical to vitiligo pathogenesis, with a focus on DNA methylation and non-coding RNAs (e.g., microRNAs, long non-coding RNAs, and circular RNAs). These advancements provide deeper insights into gene regulation, immune processes, and cellular dynamics. This review integrates findings from genetic and epigenetic studies to offer a comprehensive understanding of molecular mechanisms of vitiligo, paving the way for innovative, personalized therapeutic approaches.

Small interfering RNA (siRNA) therapeutics are a new class of drugs that is rapidly expanding to tackle various diseases. Extrahepatic delivery of siRNAs, especially to the parenchyma of solid tumors, is challenging with multiple strategies being explored such as lipid nanoparticle based delivery and ligand conjugation strategies. Here, we report that an albumin-binding dendritic siRNA (D-siRNA) boosts blood circulation time following systemic administration, leading to improved delivery and silencing activity in a melanoma tumor model, in comparison to non-albumin binding lipophilic siRNAs. D-siRNAs increased the tumor-to-liver delivery ratio, including both immune and non-immune cell types within the tumor parenchyma. Using D-siRNAs to target JAK1 expression as an adjuvant to immune checkpoint inhibitors, we found that D-siRNAs was able to enhance PD1 antibody treatment and slow tumor progression of melanoma. Thus, this work demonstrates the utility of D-siRNAs as a systemically administered tumor delivery strategy, enabling the use of siRNAs as chemotherapeutic agents. Further mechanistic studies into the role of JAK1 in melanoma pathology and progression may expand this into additional targets as potential treatments.

Genetic pigmentary disorders represent a diverse group of genetic conditions characterized by alterations in melanin production and transport and melanocyte development, resulting from single-gene pathological variants. These disorders encompass both hypopigmentary and hyperpigmentary phenotypes, affecting not only skin pigmentation but also ocular, auditory, and systemic manifestations. This review examines the molecular mechanisms underlying major genetic pigmentary disorders, including hypopigmentary (e.g., oculocutaneous albinism, piebaldism, and Waardenburg syndrome) and hyperpigmentary (e.g., dyschromatosis symmetrica hereditaria, dyschromatosis universalis hereditaria, reticulate acropigmentation of Kitamura, and Dowling-Degos disease) disorders. Additionally, we discuss RASopathies, in which pigmentary abnormalities occur alongside multisystem developmental anomalies. Comprehensive understanding of these conditions can provide crucial insights into melanocyte biology and guide future clinical management strategies for affected patients.

PURPOSE:Newborn screening using dried blood spot (DBS) samples for the targeted measurement of metabolites and nucleic acids has made a substantial contribution to public healthcare by facilitating the detection of neonates with genetic disorders. Here, we investigated the applicability of non-targeted quantitative proteomics analysis to newborn screening for inborn errors of immunity (IEIs). METHODS:DBS samples from 40 healthy newborns and eight healthy adults were subjected to non-targeted proteomics analysis using liquid chromatography-mass spectrometry after removal of the hydrophilic fraction. Subsequently, DBS samples from 43 IEI patients were analyzed to determine whether patients can be identified by reduced expression of disease-associated proteins. RESULTS:DBS protein profiling allowed monitoring of levels of proteins encoded by 2912 genes, including 1110 listed in the Online Mendelian Inheritance in Man database, in healthy newborn samples, and was useful in identifying patients with IEIs by detecting reduced levels of disease causative proteins and their interacting proteins, as well as cell-phenotypical alterations. CONCLUSION:Our results indicate that non-targeted quantitative protein profiling of DBS samples can be used to identify patients with IEIs and develop a novel newborn screening platform for genetic disorders.

Vitiligo is an autoimmune disease that targets melanocytes, and preclinical models of the disease can strongly promote the development of new treatments. This study introduces a vitiligo model using hairless hk14-SCF Tg mice, whose melanocyte distribution closely mimics that of human skin, enabling comprehensive therapeutic evaluation. Two methods were used to induce vitiligo: (i) hairless hk14-SCF Tg mice received bone marrow-derived dendritic cells pulsed with the melanocyte-specific peptide gp100 and CD8+ T cells targeting gp100 (PMEL CD8+ T cells), and (ii) hk14-SCF Tg mice were crossbred with PMEL TCR transgenic mice without additional treatment. Skin samples were subsequently analyzed using immunohistochemistry, flow cytometry, bulk RNA sequencing, and cytokine assays, confirming that the mechanisms that drive vitiligo in this model closely resemble those of prior mouse models and patients with vitiligo. Various treatments, including UV irradiation, topical corticosteroids, and a Jak inhibitor, were tested, and all significantly reduced vitiligo-affected areas, as verified through objective ImageJ analysis. In conclusion, this model addresses key limitations of previous models, offering a robust platform for preclinical treatment evaluation and potentially accelerating clinical translation.

We present an updated analysis of albinism in Japan, encompassing both oculocutaneous albinism (OCA) and ocular albinism (OA), based on 290 families, which expands our previous study by 100 additional families. The overall frequency distribution of major subtypes remained consistent with our previous findings: OCA4 remains the most prevalent subtype (67 patients, 23.1%), followed by OCA1 (57 patients, 19.7%), Hermansky-Pudlak syndrome (HPS) 1 (35 patients, 12.1%), and OCA2 (30 patients, 10.3%). Notably, our expanded analysis identified patients with rare subtypes, including OCA3, OCA6, HPS2, HPS3, HPS5, and HPS6, as well as OA, further demonstrating the genetic diversity of albinism in the Japanese population. Through comprehensive genetic screening of the additional 100 families, we identified 17 patients harboring previously unreported pathological variants across multiple albinism subtypes. These findings expand the variant spectrum of albinism in Japan, provide valuable insights for genetic counseling, and underscore the critical importance of comprehensive clinical evaluation and long-term multidisciplinary follow-up for patients with albinism, particularly those with HPS subtypes.

The Journal of DermatologyEarly View LETTER TO THE EDITOR Post-COVID-19 vaccination diffuse cutaneous sarcoidosis Ami Hemmi, Corresponding Author Ami Hemmi [email protected] orcid.org/0000-0002-4092-6129 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan Correspondence Ami Hemmi, Department of Dermatology, Faculty of Medicine, Yamagata University, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan. Email: [email protected]Search for more papers by this authorKen Okamura, Ken Okamura orcid.org/0000-0001-7366-3233 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorMariko Nikaido, Mariko Nikaido Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorToru Saito, Toru Saito orcid.org/0000-0003-3769-8361 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorYosuke Arai, Yosuke Arai orcid.org/0009-0002-5143-4661 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorTamio Suzuki, Tamio Suzuki Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this author Ami Hemmi, Corresponding Author Ami Hemmi [email protected] orcid.org/0000-0002-4092-6129 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan Correspondence Ami Hemmi, Department of Dermatology, Faculty of Medicine, Yamagata University, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan. Email: [email protected]Search for more papers by this authorKen Okamura, Ken Okamura orcid.org/0000-0001-7366-3233 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorMariko Nikaido, Mariko Nikaido Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorToru Saito, Toru Saito orcid.org/0000-0003-3769-8361 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorYosuke Arai, Yosuke Arai orcid.org/0009-0002-5143-4661 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this authorTamio Suzuki, Tamio Suzuki Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, JapanSearch for more papers by this author First published: 14 March 2024 https://doi.org/10.1111/1346-8138.17194Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Potestio L, Megna M, Villani A, Cacciapuoti S, Scalvenzi M, Martora F. Herpes zoster and COVID-19 vaccination: a narrative review. Clin Cosmet Investig Dermatol. 2023; 16: 3323–3331. 10.2147/CCID.S441898 CASPubMedWeb of Science®Google Scholar 2Yamauchi K, Oiso N, Iwanaga T, Tatsumi Y, Matsumura I, Tohda Y, et al. Post-herpes zoster sarcoidosis as a recurrence. J Dermatol. 2018; 45: e150–1. 10.1111/1346-8138.14211 PubMedWeb of Science®Google Scholar 3Sahin U, Muik A, Vogler I, Derhovanessian E, Kranz LM, Vormehr M, et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature. 2021; 595: 572–577. 10.1038/s41586-021-03653-6 CASPubMedWeb of Science®Google Scholar 4Numakura T, Murakami K, Tamada T, Yamaguchi C, Inoue C, Ohkouchi S, et al. A novel development of sarcoidosis following COVID-19 vaccination and a literature review. Intern Med. 2022; 61: 3101–3106. 10.2169/internalmedicine.0104-22 PubMedWeb of Science®Google Scholar 5Tchernev G, Kordeva S, Kirilova H, Broshtilova V. The first reported case of erythrodermic sarcoidosis with systemic involvement during COVID-19 vaccination. Dermatol Reports. 2023; 15: 9636. PubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Newborn screening using dried blood spot (DBS) samples has made a substantial contribution to public healthcare by detecting patients with genetic disorders as neonates. Targeted measurements of nucleic acids and metabolites have played major roles in newborn screening to date, while the feasibility of new non-targeted approaches, including genome-wide DNA sequencing, has been explored. Here, we investigated the applicability of non-targeted quantitative proteomics analysis to newborn screening for genetic diseases. DBS protein profiling allowed monitoring of levels of proteins encoded by 2912 genes, including 1106 listed in the Online Mendelian Inheritance in Man database, in healthy newborn samples, and was useful in identifying patients with inborn errors of immunity by detecting reduced levels of disease causative proteins and cell-phenotypical alterations. Our results indicate that application of non-targeted quantitative protein profiling of DBS samples can forge a new path in screening for genetic disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JSPS KAKENHI under Grant Numbers 19K17328 and 21K07795; by AMED under Grant Number JP23ek0109586; and by the Research on Measures for Intractable Diseases project from the Japanese Ministry of Health, Labor, and Welfare. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Kyoto University Hospital gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All of the data used to generate the figures are available in the published article and its online supplemental material. * CHS : Chédiak-Higashi syndrome DBS : dried blood spot DEPs : differentially expressed proteins DIA : data-independent acquisition FHL : familial hemophagocytic lymphohistiocytosis GO : Gene Ontology HPS : Hermansky-Pudlak syndrome IEIs : inborn errors of immunity IEMs : inborn errors of metabolism KRECs : kappa-deleting element recombination circles LC-MS/MS : liquid chromatography-assisted mass spectrometry NBS : newborn screening OMIM : Online Mendelian Inheritance in Man TRECs : T cell receptor excision circles WAS : Wiskott-Aldrich syndrome XLA : X-linked agammaglobulinemia

Tietz albinism-deafness syndrome (TADS) is a rare and severe manifestation of Waardenburg syndrome that is primarily linked to mutations in MITF. In this report, we present a case of TADS resulting from a novel c.637G>C mutation in MITF (p.Glu213Gln; GenBank Accession number: NM_000248). A 3-year-old girl presented with congenital generalized hypopigmentation of the hair, skin, and irides along with complete sensorineural hearing loss. Histopathological and electron microscopy investigations indicated that this variant did not alter the number of melanocytes in the skin but significantly impaired melanosome maturation within melanocytes. Comprehensive melanin analysis revealed marked reductions in both eumelanin (EM) and pheomelanin (PM) rather than changes in the EM-to-PM ratio observed in oculocutaneous albinism. We conducted an electrophoretic mobility shift assay to investigate the binding capability of the identified variant to DNA sequences containing the E-box motif along with other known variants (p.Arg217del and p.Glu213Asp). Remarkably, all three variants exhibited dominant-negative effects, thus providing novel insights into the pathogenesis of TADS. This study sheds light on the genetic mechanisms underlying TADS and offers a deeper understanding of this rare condition and its associated mutations in MITF.

The Journal of DermatologyEarly View LETTER TO THE EDITOR Successful treatment of recurrent subcutaneous abscesses using granulocyte and monocyte adsorptive apheresis Ken Okamura, Corresponding Author Ken Okamura [email protected] orcid.org/0000-0001-7366-3233 Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, Japan Correspondence Ken Okamura, Department of Dermatology, Faculty of Medicine, Yamagata University, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan. Email: [email protected]Search for more papers by this authorMariko Nikaido, Mariko Nikaido Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorToru Saito, Toru Saito orcid.org/0000-0003-3769-8361 Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorYosuke Arai, Yosuke Arai orcid.org/0009-0002-5143-4661 Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorChiharu Yoshioka, Chiharu Yoshioka Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorMakoto Yagi, Makoto Yagi Division of Endoscopy, Yamagata University Hospital, Yamagata, JapanSearch for more papers by this authorHitomi Komoriya, Hitomi Komoriya Department of Psychiatry, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorNana Takahashi, Nana Takahashi Department of Psychiatry, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorYutaka Hozumi, Yutaka Hozumi Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorTamio Suzuki, Tamio Suzuki Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this author Ken Okamura, Corresponding Author Ken Okamura [email protected] orcid.org/0000-0001-7366-3233 Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, Japan Correspondence Ken Okamura, Department of Dermatology, Faculty of Medicine, Yamagata University, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan. Email: [email protected]Search for more papers by this authorMariko Nikaido, Mariko Nikaido Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorToru Saito, Toru Saito orcid.org/0000-0003-3769-8361 Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorYosuke Arai, Yosuke Arai orcid.org/0009-0002-5143-4661 Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorChiharu Yoshioka, Chiharu Yoshioka Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorMakoto Yagi, Makoto Yagi Division of Endoscopy, Yamagata University Hospital, Yamagata, JapanSearch for more papers by this authorHitomi Komoriya, Hitomi Komoriya Department of Psychiatry, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorNana Takahashi, Nana Takahashi Department of Psychiatry, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorYutaka Hozumi, Yutaka Hozumi Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this authorTamio Suzuki, Tamio Suzuki Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, JapanSearch for more papers by this author First published: 20 March 2024 https://doi.org/10.1111/1346-8138.17198Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Szalat R, Monsel G, Le Goff W, Battistella M, Bengouffa D, Schlageter M-H, et al. The spectrum of neutrophilic dermatoses associated with monoclonal gammopathy: association with IgA isotype and inflammatory profile. J Am Acad Dermatol. 2015; 73: 809–820. 10.1016/j.jaad.2015.07.031 CASPubMedWeb of Science®Google Scholar 2André MFJ, Piette JC, Kémény JL, Ninet J, Jego P, Delèvaux I, et al. Aseptic abscesses: a study of 30 patients with or without inflammatory bowel disease and review of the literature. Medicine (Baltimore). 2007; 86: 145–161. 10.1097/md.0b013e18064f9f3 PubMedWeb of Science®Google Scholar 3Kennis B, Ali A, Lasoff D, Sweeney DA, Wardi G. The diagnostic utility of procalcitonin is limited in the setting of methamphetamine toxicity. Am J Emerg Med. 2022; 54: 36–40. 10.1016/j.ajem.2022.01.049 PubMedWeb of Science®Google Scholar 4Marzano AV, Ortega-Loayza AG, Ceccherini I, Cugno M. LPIN2 gene mutation in a patient with overlapping neutrophilic disease (pyoderma gangrenosum and aseptic abscess syndrome). JAAD Case Rep. 2018; 4: 120–122. 10.1016/j.jdcr.2017.08.020 PubMedGoogle Scholar 5Kato S, Hosomi E, Amano F, Kobayashi T, Kani K, Yamamoto R, et al. The efficacy of intensive granulocyte and monocyte adsorption apheresis in a patient with Crohn's disease complicated by extensive subcutaneous aseptic neutrophilic abscesses. J Crohns Colitis. 2012; 6: 787–791. 10.1016/j.crohns.2012.02.005 PubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation