RESUMEN
Seborrheic keratosis (SK) is a common benign tumour, often associated with hyperpigmentation. To investigate the mechanism of melanin accumulation in SK, we have conducted comprehensive gene expression and histological analyses. We obtained five pairs of skin samples, including non-lesional and SK samples, from the backs of three male Japanese participants aged 40-59 years. To examine melanocytes and keratinocytes in SK, three pairs of skin samples were separated by laser capture microdissection into the basal layer and the other layer in the epidermis. We performed a comprehensive gene expression analysis to identify differentially expressed genes between non-lesional and SK skin, followed by gene ontology and pathway analysis. We found abnormal morphogenesis and cell proliferation in the basal layer, along with increased immune response and impaired cell differentiation and metabolism in the other layer of SK. We focused on cell proliferation and differentiation, as these are directly associated with melanin accumulation. Immunohistochemical analyses of Ki67, keratin 10, and keratin 14 demonstrated the decreases in the proliferation and early differentiation of the epidermis. Contrarily, no significant changes were observed in terminal differentiation markers, filaggrin and loricrin. Although the number of melanocytes was higher in SK than in non-lesional skin, melanogenic activity showed no difference. These results indicated that melanin accumulation in SK is caused by delayed melanin excretion due to reduced turnover around the basal and spinous layers of the epidermis and melanin production due to an increased number of melanocytes. Our findings provide new insights for therapeutic approaches in SK.
Asunto(s)
Diferenciación Celular , Proliferación Celular , Proteínas Filagrina , Queratinocitos , Queratosis Seborreica , Melaninas , Melanocitos , Humanos , Melanocitos/metabolismo , Melanocitos/patología , Queratosis Seborreica/metabolismo , Queratosis Seborreica/patología , Masculino , Melaninas/metabolismo , Persona de Mediana Edad , Queratinocitos/metabolismo , Adulto , Epidermis/metabolismo , Epidermis/patología , Proteínas de la MembranaRESUMEN
Oxidative metabolism of rhododendrol (RD), a skin-whitening ingredient, by tyrosinase has caused leukoderma in a certain population of Japanese consumers. Toxic RD metabolites and reactive oxygen species are proposed causes for the melanocyte death. However, the mechanism by which reactive oxygen species are produced during RD metabolism remains elusive. Some phenolic compounds are known to act as suicide substrates for tyrosinase, resulting in release of a copper atom and hydrogen peroxide during its inactivation. We hypothesized that RD may be a suicide substrate for tyrosinase and that the released copper atom may be responsible for the melanocyte death through hydroxyl radical production. In line with this hypothesis, human melanocytes incubated with RD showed an irreversible decrease in tyrosinase activity and underwent cell death. A copper chelator, d-penicillamine, markedly suppressed the RD-dependent cell death without significantly affecting the tyrosinase activity. Peroxide levels in RD-treated cells were not affected by d-penicillamine. Given the unique enzymatic properties of tyrosinase, we conclude that RD acted as a suicide substrate and resulted in release of a copper atom and hydrogen peroxide, which would collectively impair melanocyte viability. These observations further imply that copper chelation may alleviate chemical leukoderma caused by other compounds.
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Hipopigmentación , Monofenol Monooxigenasa , Humanos , Monofenol Monooxigenasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cobre/metabolismo , Penicilamina/efectos adversos , Penicilamina/metabolismo , Peróxido de Hidrógeno/metabolismo , Melanocitos/metabolismo , Hipopigmentación/inducido químicamente , Hipopigmentación/metabolismo , Quelantes/farmacologíaRESUMEN
BACKGROUND: The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed. OBJECTIVES: To reach an international consensus on the nomenclature and to develop a management algorithm for the diagnosis, assessment, and treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence of topics included in the algorithms. A survey was utilized to resolve remaining issues among a core group of eight experts. Subsequently, the unanimous recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The algorithms highlight the importance of shared decision-making. Dermatologists are encouraged to provide patients with detailed explanations of the prognosis and expected therapeutic outcomes based on clinical examination. The treatment goal should be discussed and clearly emphasized to patients given the different approaches for disease stabilization and repigmentation. The evaluation of disease activity remains a cornerstone in the tailor-made approach to vitiligo patients. CONCLUSIONS: These new treatment algorithms are intended to guide clinical decision-making in clinical practice. Promising novel therapies for vitiligo are on the horizon, further highlighting the need for reliable outcome measurement instruments and greater emphasis on shared decision-making.
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Vitíligo , Humanos , Vitíligo/diagnóstico , Vitíligo/terapia , Consenso , Algoritmos , Toma de Decisiones Clínicas , Encuestas y CuestionariosRESUMEN
BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.
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Fotoquimioterapia , Terapia Ultravioleta , Vitíligo , Humanos , Vitíligo/terapia , Vitíligo/tratamiento farmacológico , Fototerapia , Esteroides/uso terapéutico , Resultado del Tratamiento , Terapia CombinadaRESUMEN
Melanin in the epidermis is known to ultimately regulate human skin pigmentation. Recently, we exploited a phenotypic-based screening system composed of ex vivo human skin cultures to search for effective materials to regulate skin pigmentation. Since a previous study reported the potent inhibitory effect of metformin on melanogenesis, we evaluated several biguanide compounds. The unexpected effect of phenformin, once used as an oral anti-diabetic drug, on cutaneous darkening motivated us to investigate its underlying mechanism utilizing a chemical genetics approach, and especially to identify alternatives to phenformin because of its risk of severe lactic acidosis. Chemical pull-down assays with phenformin-immobilized beads were performed on lysates of human epidermal keratinocytes, and subsequent mass spectrometry identified 7-dehydrocholesterol reductase (DHCR7). Consistent with this, AY9944, an inhibitor of DHCR7, was found to decrease autophagic melanosome degradation in keratinocytes and to intensely darken skin in ex vivo cultures, suggesting the involvement of cholesterol biosynthesis in the metabolism of melanosomes. Thus, our results validated the combined utilization of the phenotypic screening system and chemical genetics as a new approach to develop promising materials for brightening/lightening and/or tanning technologies.
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Queratinocitos/metabolismo , Melanocitos/metabolismo , Melanosomas/metabolismo , Fenformina/farmacología , Pigmentación de la Piel/efectos de los fármacos , Colesterol/biosíntesis , Femenino , Humanos , Queratinocitos/citología , Masculino , Melanocitos/citología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Diclorhidrato de trans-1,4-Bis(2-clorobenzaminometil)ciclohexano/farmacologíaAsunto(s)
Psoriasis , Humanos , Enfermedad Aguda , Causalidad , Enfermedad Crónica , Psoriasis/epidemiología , Psoriasis/genética , Pirina/genéticaRESUMEN
BACKGROUND: Rhododendrol (rhododenol), an inhibitor of tyrosinase activity, is used as a skin-whitening component. Many cases of leukoderma after the application have been reported, termed rhododenol-induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo. METHODS: We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, six cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy. RESULTS: There were common findings in RIL and vitiligo at the light-microscopic level: (a) vacuolar changes in the dermo-epidermal junction, (b) melanophages in the papillary dermis, (c) perifollicular lymphocyte infiltration, (d) loss or decrease of basal melanin pigment and (e) decrease of melanocytes in the lesions. The ultrastructural observations showed specific findings of RIL: (a) remaining melanocytes in depigmented lesions, (b) inhomogeneous melanization in melanocytes and (c) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases. CONCLUSION: Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases.
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Butanoles/efectos adversos , Melanocitos , Nevo , Neoplasias Cutáneas , Vitíligo/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Butanoles/administración & dosificación , Femenino , Humanos , Melanocitos/metabolismo , Melanocitos/patología , Ratones , Persona de Mediana Edad , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Nevo/inducido químicamente , Nevo/metabolismo , Nevo/patología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Vitíligo/metabolismo , Vitíligo/patologíaAsunto(s)
Síndrome de Hermanski-Pudlak , Enfermedades Pulmonares Intersticiales , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Síndrome de Hermanski-Pudlak/genética , Humanos , Recién Nacido , Enfermedades Pulmonares Intersticiales/genética , MutaciónRESUMEN
Isolation of human metapneumovirus (HMPV) from clinical specimens is currently inefficient because of the lack of a cell culture system in which a distinct cytopathic effect (CPE) occurs. The cell lines LLC-MK2, Vero and Vero E6 are used for isolation of HMPV; however, the CPE in these cell lines is subtle and usually requires a long observation period and sometimes blind passages. Thus, a cell line in which an early and distinct CPE occurs following HMPV inoculation is highly desired by clinical virology laboratories. In this study, it was demonstrated that, in the human malignant melanoma cell line MNT-1, obvious syncytium formation occurs shortly after inoculation with HMPV-positive clinical specimens. In addition, the growth and efficiency of isolation of HMPV were greater using MNT-1 than using any other conventional cell line. Addition of this cell line to our routine viral isolation system for clinical specimens markedly enhanced isolation frequency, allowing isolation-based surveillance. MNT-1 has the potential to facilitate clinical and epidemiological studies of HMPV.
Asunto(s)
Melanoma/virología , Metapneumovirus/fisiología , Neoplasias Cutáneas/virología , Línea Celular Tumoral , Efecto Citopatogénico Viral , Humanos , Metapneumovirus/genética , Metapneumovirus/crecimiento & desarrollo , Metapneumovirus/aislamiento & purificación , Melanoma Cutáneo MalignoRESUMEN
To investigate the trends of antimicrobial resistance in pathogens isolated from skin and soft-tissue infections (SSTI) at dermatology departments in Japan, a Japanese surveillance committee conducted the first nationwide survey in 2013. Three main organisms were collected from SSTI at 30 dermatology departments in medical centers and 10 dermatology clinics. A total of 860 strains - 579 of Staphylococcus aureus, 240 of coagulase-negative Staphylococci, and 41 of Streptococcus pyogenes - were collected and shipped to a central laboratory for antimicrobial susceptibility testing. The patient profiles were also studied. Among all 579 strains of S. aureus, 141 (24.4%) were methicillin-resistant (MRSA). Among 97 Staphylococcus epidermidis strains, 54 (55.7%) were methicillin-resistant (MRSE). MRSA and MRSE were more frequently isolated from inpatients than from outpatients. Furthermore, these methicillin-resistant strains were also isolated more frequently from patients with histories of taking antibiotics within 4 weeks and hospitalization within 1 year compared to those without. However, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains between patients with a history of hospitalization within 1 year and those without. Therefore, most of the isolated MRSA cases at dermatology departments are not healthcare-acquired, but community-acquired MRSA. S. pyogenes strains were susceptible to most antibiotics except macrolides. The information in this study is not only important in terms of local public health but will also contribute to an understanding of epidemic clones of pathogens from SSTI.
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Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Infecciones de los Tejidos Blandos/microbiología , Infecciones Cutáneas Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/efectos de los fármacos , Estudios Transversales , Dermatología , Hospitalización/estadística & datos numéricos , Humanos , Japón/epidemiología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Infecciones de los Tejidos Blandos/epidemiología , Infecciones Cutáneas Estafilocócicas/epidemiología , Infecciones Estreptocócicas/epidemiologíaRESUMEN
Isolation of human parainfluenza virus (HPIV) serotypes 1 and 3 from clinical specimens is not very efficient because of the lack of a cell culture system capable of inducing CPE. In this study, the utility of a melanoma cell line, MNT-1, that allows HPIV growth and displays CPE was demonstrated. In particularly, the efficiency of isolating HPIV1 and HPIV3 using MNT-1 was greater than for cell lines conventionally used for HPIV isolation. Our demonstrated efficacy of HPIV1 and HPIV3 isolation with apparent CPE using the MNT-1 cell culture system has the potential to improve virus isolation from clinical specimens.
Asunto(s)
Virus de la Parainfluenza 1 Humana/aislamiento & purificación , Virus de la Parainfluenza 1 Humana/fisiología , Virus de la Parainfluenza 3 Humana/aislamiento & purificación , Virus de la Parainfluenza 3 Humana/fisiología , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Células Cultivadas , Efecto Citopatogénico Viral , Humanos , Melanoma/virología , Infecciones por Respirovirus/virologíaRESUMEN
Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation with an autosomal dominant pattern of inheritance and a high penetration rate. The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk. To identify mutations that cause RAK, we performed exome sequencing of four family members in a pedigree with RAK. Fifty-three SNV/Indels were considered as candidate mutations after some condition narrowing. We confirmed the mutation status in each candidate gene of four other members in the same pedigree to find the gene that matched the mutation status and phenotype of each member. A mutation in ADAM10 encoding a zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), was identified in the RAK family. ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin. Sanger sequencing of four additional unrelated RAK patients revealed four additional ADAM10 mutations. We identified a total of three truncating mutations, a splice site mutation and a missense mutation in ADAM10. We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation disorder Dowling-Degos disease (DDD), in all the patients and found no KRT5 mutation. These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from DDD.
Asunto(s)
Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Hiperpigmentación/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Papuloescamosas/genética , Proteína ADAM10 , Adulto , Anciano , Células Cultivadas , Exoma , Femenino , Humanos , Hiperpigmentación/fisiopatología , Mutación INDEL , Queratina-5/genética , Queratina-5/metabolismo , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Filogenia , Análisis de Secuencia de ADN , Análisis de Secuencia de Proteína , Enfermedades Cutáneas Genéticas/fisiopatología , Enfermedades Cutáneas Papuloescamosas/fisiopatología , Adulto JovenRESUMEN
Nephrogenic systemic fibrosis (NSF) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)-containing contrast agents used for magnetic resonance imaging trigger the development of NSF. However, the causative role of Gd and the mechanism of Gd-induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin-1 (ET-1)/ET receptor (ETR) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET-1/ETR signalling in Gd-induced fibrosis and calcification in NSF. First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue-derived mesenchymal stem cells (hMSC) in vitro. Next, we examined the expression of ET-1 and ETR-A in hMSC using proliferation or calcification assay. ET-1 and ETR-A expression in hMSC treated with Gd were elevated. ET-1/ETR signalling inhibitor, bosentan, inhibited Gd-induced proliferation and calcification of hMSC. In addition, bosentan inhibited Gd-induced phosphorylation of ERK and Akt in hMSC. Plasma ET-1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR-A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET-1/ETR signalling. Our results contribute to understand the pathogenesis of NSF.
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Endotelina-1/metabolismo , Dermopatía Fibrosante Nefrogénica/metabolismo , Receptor de Endotelina A/metabolismo , Adolescente , Bosentán , Calcinosis/etiología , Calcinosis/metabolismo , Calcinosis/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Medios de Contraste/efectos adversos , Antagonistas de los Receptores de Endotelina/farmacología , Endotelina-1/sangre , Gadolinio/efectos adversos , Humanos , Imagen por Resonancia Magnética/efectos adversos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Dermopatía Fibrosante Nefrogénica/etiología , Dermopatía Fibrosante Nefrogénica/patología , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacologíaAsunto(s)
Carcinoma Adenoide Quístico/patología , Epidermis/patología , Neoplasias Cutáneas/patología , Anciano , Biomarcadores de Tumor/análisis , Carcinoma Adenoide Quístico/química , Carcinoma Adenoide Quístico/cirugía , Epidermis/química , Epidermis/cirugía , Humanos , Masculino , Neoplasias Cutáneas/química , Neoplasias Cutáneas/cirugíaRESUMEN
Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids and tacrolimus have been used as topical treatments. Recently, novel topical agents targeting Janus kinase (JAK), a family of tyrosine kinases that regulates cytokine signaling, have emerged. Ruxolitinib is the first approved in vitiligo therapy. Furthermore, ritlecitinib is currently under clinical trials for oral treatment of active vitiligo. In this review, we discuss the possibility of topical JAK inhibitors as promising options for the treatment of vitiligo with regard to their mechanism of action, efficacy and safety.
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Inhibidores de las Cinasas Janus , Vitíligo , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Vitíligo/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas Janus , Administración TópicaRESUMEN
Ultraviolet (UV)-induced skin photoaging is caused by qualitative and quantitative degradation of dermal extracellular matrix components such as collagen and elastic fibers. Elastic fibers are important for maintaining cutaneous elasticity, despite their small amount in the skin. Previously, microfibril-associated protein 4 (MFAP-4), which is downregulated in photoaging dermis, has been found to be essential for elastic fiber formation by interaction with both fibrillin-1 and elastin, which are core components of elastic fiber. In addition, enhanced cutaneous MFAP-4 expression in a human skin-xenografted murine photoaging model protects against UV-induced photodamage accompanied by the prevention of elastic fiber degradation and aggravated elasticity. We therefore hypothesized that the upregulation of MFAP-4 in dermal fibroblasts may more efficiently accelerate elastic fiber formation. We screened botanical extracts for MFAP-4 expression-promoting activity in normal human dermal fibroblasts (NHDFs). We found that rosemary extract markedly promotes early microfibril formation and mature elastic fiber formation along with a significant upregulation of not only MFAP-4 but also fibrillin-1 and elastin in NHDFs. Furthermore, rosmarinic acid, which is abundant in rosemary extract, accelerated elastic fiber formation via upregulation of transforming growth factor ß-1. This was achieved by the induction of cAMP response element-binding protein phosphorylation, demonstrating that rosmarinic acid represents one of the active ingredients in rosemary extract. Based on the findings in this study, we conclude that rosemary extract and rosmarinic acid represent promising materials that exert a preventive or ameliorative effect on skin photoaging by accelerating elastic fiber formation.
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Cinamatos , Depsidos , Tejido Elástico , Elastina , Fibrilina-1 , Fibroblastos , Extractos Vegetales , Ácido Rosmarínico , Envejecimiento de la Piel , Humanos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Depsidos/farmacología , Fibrilina-1/metabolismo , Cinamatos/farmacología , Extractos Vegetales/farmacología , Elastina/metabolismo , Tejido Elástico/efectos de los fármacos , Tejido Elástico/metabolismo , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiación , Células Cultivadas , Rosmarinus/química , Regulación hacia Arriba/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Piel/efectos de los fármacos , Piel/efectos de la radiación , Piel/citología , Piel/patología , Piel/metabolismo , Dermis/citología , Dermis/efectos de los fármacos , Dermis/metabolismo , Rayos Ultravioleta/efectos adversos , Proteínas de la Matriz Extracelular/metabolismo , AdipoquinasRESUMEN
Woolly hair (WH) is a hair shaft anomaly characterized by tightly curled hair that typically stops growing at a few inches. Autosomal recessive WH (ARWH; OMIM no. 278150/604379/616760) has been reported to be caused by variants in genes coding lysophosphatidic acid receptor 6 (LPAR6), lipase H (LIPH), or keratin 25 (KRT25). In this study, we conducted a scanning electron microscopic (SEM) examination of the hair of a 3-year-old Japanese ARWH patient. The SEM revealed that her affected hair had an irregular and rough cuticle compared to her mother's hair. Many irregular small projections and longitudinal grooves were seen on the surface of the patient's hair shaft, and some free margins of the hair cortex were raised or serrated. Her hairs were oval-shaped on the cross-section. Mutation analysis revealed a homozygous pathogenic variant (c.736 T > A; Cys246Ser) in exon 6 in LIPH. In our clinic, we identified three additional cases with the homozygous Cys246Ser variant and one case with compound heterozygous variants in LIPH: Cys246Ser and c.671C > G (Pro224Arg). Consequently, genetic analyses, including genotype-phenotype correlation involving rare LIPH variants, have become more crucial in the Japanese population.
RESUMEN
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.
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Factor de Transcripción Asociado a Microftalmía , Mutación , Humanos , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Femenino , Preescolar , Mutación/genética , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/patología , Melaninas/metabolismo , Sordera/genética , Sordera/patología , Genes Dominantes , Melanosomas/metabolismo , Melanosomas/ultraestructura , Melanosomas/genética , Melanocitos/patología , Melanocitos/metabolismoRESUMEN
A PTEN deficiency leads to the activation of phospho-Akt at serine 473 (p-Akt) and promotes the tumorigenesis of melanomas by coupling with NUAK2 amplification. We tested the prognostic impact of p-Akt and/or NUAK2 expression on the relapse-free survival (RFS) and overall survival (OS) of melanoma patients. Primary tumors from patients with acral melanomas (112), Low-cumulative sun damage (CSD) melanomas (38), and High-CSD melanomas (18) were examined using immunohistochemistry and their prognostic significance was analyzed statistically. The expression of p-Akt was found in 32.1%, 68.4%, and 55.6% of acral, Low-CSD, and High-CSD melanomas, while NUAK2 expression was found in 46.4%, 76.3%, and 50.0%, respectively. Either p-Akt or NUAK2 expression was inversely correlated with the RFS of primary melanoma patients and acral melanoma patients (p-Akt: p < .0001, p < .0001; NUAK2; p = .0005, p < .0001, respectively). Strikingly, multivariate analyses revealed that p-Akt had a significant impact on RFS (Hazard ratio = 4.454; p < .0001), while NUAK2 did not. Further subset analyses revealed that p-Akt expression had an inferior RFS of patients with acral melanomas (Hazard ratio = 4.036; p = .0005). We conclude that the expression of p-Akt has a significant impact on RFS of patients with primary melanomas and can predict the relapse of patients with acral melanomas.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/patología , Proteínas Proto-Oncogénicas c-akt , Pronóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Enfermedad Crónica , Recurrencia , Proteínas Serina-Treonina QuinasasRESUMEN
BACKGROUND: Vitiligo is an acquired pigmentary disorder characterized by depigmented patches on the skin that majorly impact patients' quality of life. Although its etiology involves genetic and environmental factors, the role of microorganisms as environmental factors in vitiligo pathology remains under-researched. OBJECTIVES: Our study explored the presence of characteristic bacterial and fungal flora in vitiligo-affected skin and investigated their potential roles in vitiligo pathogenesis. METHODS: We sequenced bacterial 16S rRNA and the fungal ITS1 region from skin swabs collected at frequently affected sites, namely the forehead and back, of patients with vitiligo. We analyzed bacterial and fungal flora in lesional and non-lesional areas of patients with vitiligo compared with corresponding sites in age- and sex-matched healthy subjects. RESULTS: Our findings revealed elevated α-diversity in both bacterial and fungal flora within vitiligo lesions compared with healthy controls. Notably, bacterial flora exhibited a distinctive composition in patients with vitiligo, and the proportional representation of Enterococcus was inversely correlated with the degree of vitiligo progression. Gammaproteobacteria, Staphylococcus spp., and Corynebacterium spp. were more abundant in vitiligo patients, with notable Staphylococcus spp. prevalence during the stable phase on the forehead. Conversely, the proportion of Malassezia sympodialis was lower and that of Malassezia globosa was higher in the progressive phase on the back of vitiligo patients. CONCLUSION: Our study identified some characteristic bacterial and fungal groups associated with vitiligo activity and prognosis, highlighting the potential roles of microorganisms in pathogenesis and offering insights into personalized disease-management approaches.