RESUMO
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.
Assuntos
Diferenciação Celular , Proliferação de Células , Proteínas Filagrinas , Queratinócitos , Ceratose Seborreica , Melaninas , Melanócitos , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Ceratose Seborreica/metabolismo , Ceratose Seborreica/patologia , Masculino , Melaninas/metabolismo , Pessoa de Meia-Idade , Queratinócitos/metabolismo , Adulto , Epiderme/metabolismo , Epiderme/patologia , Proteínas de MembranaRESUMO
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.
Assuntos
Fator de Transcrição Associado à Microftalmia , Mutação , Humanos , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Feminino , Pré-Escolar , Mutação/genética , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/patologia , Melaninas/metabolismo , Surdez/genética , Surdez/patologia , Genes Dominantes , Melanossomas/metabolismo , Melanossomas/ultraestrutura , Melanossomas/genética , Melanócitos/patologia , Melanócitos/metabolismoAssuntos
Albinismo Oculocutâneo , Dermoscopia , Melanoma Amelanótico , Neoplasias Cutâneas , Humanos , Albinismo Oculocutâneo/complicações , Albinismo Oculocutâneo/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/complicações , Melanoma Amelanótico/patologia , Melanoma Amelanótico/diagnóstico , Melanoma Amelanótico/diagnóstico por imagem , Melanoma Amelanótico/complicações , Masculino , FemininoRESUMO
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.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Proteínas Proto-Oncogênicas c-akt , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Doença Crônica , Recidiva , Proteínas Serina-Treonina QuinasesRESUMO
A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos , Síndrome de Hermanski-Pudlak , Feminino , Humanos , Adulto , Síndrome de Hermanski-Pudlak/complicações , Síndrome de Hermanski-Pudlak/diagnóstico , Peroxidase , Inflamação , DiarreiaRESUMO
Oculocutaneous albinism (OCA) 6 is a non-syndromic type of OCA that has distinct ocular symptoms and variable cutaneous hypopigmentation. The causative gene of OCA6 is SLC24A5, which encodes NCKX5, a K+ -dependent Na+ /Ca2+ exchanger 5. NCKX5 is involved in the maturation of melanosomes, but its function is still unclear. In this study, we characterized a Japanese patient with OCA6. Genetic analysis revealed compound heterozygous variants in SLC24A5, c.590 + 1dupG, and c.598G>A (p.G200R). To clarify the functional significance of the missense variant, we generated a knock-in (KI) mouse model carrying the mouse homolog of the G200R variant using the CRISPR/Cas9 system. Chemical analysis showed decreased amounts of eumelanin in the hair and skin of KI mice, while levels of benzothiazine units in pheomelanin were significantly increased in their hair. Retinal pigment was also decreased in KI mice. Notably, a histopathologic study revealed a significant pigment loss in the retinal pigment epithelium (RPE) but not in the choroid. Immunohistochemically, the expression of NCKX5 in the RPE was decreased but was maintained in the choroid of KI mice. These findings could explain the difference in phenotypic severity between eye symptoms and hypopigmentation in the skin/hair.
Assuntos
Albinismo Oculocutâneo , Hipopigmentação , Epitélio Pigmentado da Retina , Trocador de Sódio e Cálcio , Albinismo Oculocutâneo/genética , Animais , Humanos , Hipopigmentação/genética , Japão , Camundongos , Epitélio Pigmentado da Retina/metabolismo , Trocador de Sódio e Cálcio/metabolismoRESUMO
Oculocutaneous albinism (OCA) is the most frequent presentation of albinism, a heterogeneous rare genetic condition generally associated with variable alterations in pigmentation and with a profound visual impairment. There are non-syndromic and syndromic types of OCA, depending on whether the gene product affected impairs essentially the function of melanosomes or, in addition, that of other lysosome-related organelles (LROs), respectively. Syndromic OCA can be more severe and associated with additional systemic consequences, beyond pigmentation and vision alterations. In addition to OCA, albinism can also be presented without obvious skin and hair pigmentation alterations, in ocular albinism (OA), and a related genetic condition known as foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA). In this review, we will focus only in the genetics of skin pigmentation in OCA, both in human and mouse, updating our current knowledge on this subject.
Assuntos
Albinismo Oculocutâneo/genética , Predisposição Genética para Doença , Animais , Modelos Animais de Doenças , Humanos , Melaninas/metabolismo , Camundongos , SíndromeRESUMO
Background: Orbital metastases from cancers of various organs can arise via the hematogenous route, and many originate from breast, prostate, and lung cancers. Such metastatic orbital tumors may be diagnosed before the primary tumor. We have encountered a case of breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and responded to chemotherapy, with improvement in visual function. Case Presentation: A woman in her fifties visited our ophthalmology department with a chief complaint of foreign body sensation and exophthalmos in her right eye. An elastic soft mass was palpated from the lateral orbit to the temporal region. A systemic examination revealed breast cancer and a metastatic orbital tumor. Excisional biopsy of the breast revealed a diagnosis of invasive ductal carcinoma with neuroendocrine differentiation, and immunohistochemical examination was negative for cytokeratin 7, making the case unusual. Chemotherapy was remarkably effective, and the tumor size decreased, resulting in improvement of visual function. Her general condition and quality of life are still good at present. We searched the PubMed English language literature focusing on metastatic orbital tumors from breast cancer in which ocular symptoms had been the initial presenting sign. No previous reports have documented neuroendocrine differentiation or cytokeratin 7 expression in isolated orbital metastases from breast cancer. Although it is not possible to be certain from this case alone, we speculated that some such cases might involve cytokeratin 7-negative invasive breast cancer with neuroendocrine differentiation. Conclusion: We have described our experience of a very rare case of cytokeratin 7 negative breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and formed a solitary giant tumor initially manifesting as ocular symptoms.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Exoftalmia/etiologia , Neoplasias Orbitárias/secundário , Neoplasias da Mama/complicações , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/complicações , Carcinoma Ductal de Mama/diagnóstico por imagem , Exoftalmia/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Neoplasias Orbitárias/complicações , Neoplasias Orbitárias/diagnóstico por imagemRESUMO
Post-inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly understood, at least in part, because an appropriate animal model for research has not been established. In order to analyze the pathomechanism of PIH, we successfully induced PIH in a hairless version of transgenic mice (hk14-SCF Tg/HRM) that have a human-type epidermis containing melanin by repeated hapten application of 2,4-dinitrofluorobenzene. Histopathologic observation showed epidermal hyperplasia, predominant infiltrations of inflammatory cells, and melanin-containing cells in the dermis just after elicitation of the atopic dermatitis-like condition. At week 2, the findings were similar to the characteristics of PIH, that is, an increase of melanin without spongiosis or liquid degeneration in the epidermis and an increase in dermal melanophages. Dynamic analysis of melanin showed that the melanin in the dermis remained for a longer duration than in the epidermis. Furthermore, immunohistochemical staining revealed that the majority of cells containing melanin were positive for the anti-CD68 antibody, but negative for the anti-F4/80 antibody. These data suggest that novel treatments of PIH should be targeted against macrophages and should eventually lead to the development of new treatment modalities.
Assuntos
Modelos Animais de Doenças , Epiderme/patologia , Hiperpigmentação/patologia , Inflamação/complicações , Melaninas/metabolismo , Animais , Epiderme/imunologia , Epiderme/metabolismo , Feminino , Humanos , Hiperpigmentação/etiologia , Hiperpigmentação/metabolismo , Masculino , Camundongos , Camundongos TransgênicosRESUMO
SASH1 has been reported as a causal gene of lentiginous phenotypes with and without heredity, including an autosomal dominant type characterized by lentigines predominantly on sun-exposed areas such as the face and limbs. Recently, cases of dyschromatosis with SASH1 mutations have been reported worldwide; however, only one case has been reported from Japan. Here, we analyzed six Japanese patients who characteristically showed many lentigines on sun-exposed areas, using next-generation sequencing. We identified five novel heterozygous mutations in SASH1 (p.I586M, p.S531Y, p.R644W, p.T525R, and p.S516I) in our patients and their families. The p.R644W substitution identified in two unrelated families was the first mutation located in the sterile alpha motif 1 (SAM1) domain. The degree and location of the lentigines were variable across individuals, even if they shared the same SASH1 mutation. All mutations were predicted to be deleterious by six different algorithms used to evaluate the functional impact of a variation. In addition, immunohistopathological findings and RNA sequencing results suggested that SASH1 mutations were associated with an increase in the number of melanocytes, acceleration of melanogenesis, and upregulated hair keratin expression.
Assuntos
Lentigo/patologia , Mutação de Sentido Incorreto , Fenótipo , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Humanos , Lentigo/genética , Masculino , Linhagem , PrognósticoRESUMO
Oculocutaneous albinism (OCA), which is roughly divided into non-syndromic and syndromic OCA, is a group of autosomal recessive disorders caused by mutations in genes associated with pigmentation. Patients with OCA have hypopigmentation and ocular manifestations such as photophobia, amblyopia, and nystagmus. Hermansky-Pudlak syndrome (HPS), the most common syndromic OCA, is characterized by the additional features of a bleeding tendency and other critical systemic comorbidities such as pulmonary fibrosis and immunodeficiency. NGS-based gene analyses have identified several new causative genes for OCA and have detected rare subtypes of OCA with high accuracy including Japanese patients. In our survey of 190 Japanese OCA patients/families, OCA4 is the most common subtype (25.3%) followed by OCA1 (20.0%), HPS1 (14.7%), and OCA2 (8.4%). Similar to the A481T variant in OCA2, which is associated with a mild form of OCA2 and skin color variation, the c.-492_489delAATG variant located in the promoter region of SLC45A2 has been uniquely identified in Japanese patients with a mild form of OCA4. Further, rare OCA subtypes, including OCA3, HPS2, HPS3, HPS4, HPS5, HPS6, and HPS9, have also been identified in Japanese patients. The clinical characteristics and underlying molecular mechanisms of each subtype of OCA are concisely summarized in this review.
Assuntos
Albinismo Oculocutâneo/epidemiologia , Albinismo Oculocutâneo/patologia , Proteínas de Membrana Transportadoras/genética , Mutação , Albinismo Oculocutâneo/genética , Humanos , Japão/epidemiologiaAssuntos
Butanóis/efeitos adversos , Pigmentação da Pele/efeitos dos fármacos , Pele/patologia , Vitiligo/induzido quimicamente , Administração Cutânea , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos CD/metabolismo , Butanóis/administração & dosagem , Caderinas/análise , Caderinas/metabolismo , Estudos de Casos e Controles , Feminino , Glutamato-Cisteína Ligase/análise , Glutamato-Cisteína Ligase/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Pessoa de Meia-Idade , Monofenol Mono-Oxigenase/análise , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Pele/citologia , Pele/efeitos dos fármacos , Vitiligo/patologia , Adulto JovemRESUMO
Racemic RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol; trade name: Rhododenol [RD]), which is used in topical skin-lightening cosmetics, was unexpectedly reported in Japan to induce leukoderma or vitiligo called RD-induced leukoderma (RIL) after repeated application. To our knowledge, no studies have investigated chemical-induced vitiligo pathogenesis on a genome-wide scale. Here, we conducted a genome-wide association study (GWAS) for 147 cases and 112 controls. CDH13, encoding a glycosylphosphatidylinositol-anchored protein called T-cadherin (T-cad), was identified as the strongest RIL susceptibility gene. RD sensitivity was remarkably increased by T-cad knockdown in cultured normal human melanocytes. Furthermore, we confirmed tyrosinase upregulation and downregulation of the anti-apoptotic molecules (BCL-2 and BCL-XL), suggesting that T-cad is associated with RD via tyrosinase or apoptotic pathway regulation. Finally, monobenzyl ether of hydroquinone sensitivity also tended to increase with T-cad knockdown, suggesting that the T-cad could be a candidate susceptibility gene for RIL and other chemical-induced vitiligo forms. This is the first GWAS for chemical-induced vitiligo, and it could be a useful model for studying the disease's genetic aspects.