RESUMO
PURPOSE: To describe a series of non-immediate drug hypersensitivity reactions after intravitreal anti-vascular endothelial growth factors (anti-VEGFs). PATIENTS AND METHODS: Retrospective report of 6 patients with cutaneous non-immediate drug hypersensitivity reactions following intravitreal anti-VEGF injections, 4 after ranibizumab, 1 after bevacizumab and 1 after aflibercept. RESULTS: Clinical manifestations ranged from mild maculopapular rash, purpura to severe generalized erythroderma, with or without systemic involvement such as microscopic hematuria and proteinuria or fever. In two out of the six patients, reintroduction of either the same or an alternative anti-VEGF drug did induce a recurrence of the drug hypersensitivity reaction, while 4 patients showed no recurrence. CONCLUSION: Cutaneous non-immediate drug hypersensitivity reactions secondary to intravitreal anti-VEGF may occur. Continuation of the same drug or switch to another anti-VEGF may either induce recurrence or be well supported by the patient. The decision of drug discontinuation should be guided by the severity of the disease.
Assuntos
Hipersensibilidade a Drogas , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/efeitos adversos , Bevacizumab/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/tratamento farmacológico , Hipersensibilidade a Drogas/etiologia , Humanos , Injeções Intravítreas , Ranibizumab/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão , Estudos RetrospectivosRESUMO
BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases, NBCCS presents with a late onset of BCC development. OBJECTIVE: To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40 years. Two other siblings did not show signs of NBCCS. RESULTS: We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763-6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss-of-function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations. CONCLUSIONS: Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS.
Assuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Neoplasias Cutâneas , Adulto , Síndrome do Nevo Basocelular/genética , Carcinoma Basocelular/genética , Genômica , Humanos , Masculino , Receptores Patched , Receptor Patched-1/genética , Irmãos , Neoplasias Cutâneas/genéticaRESUMO
These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.
Assuntos
Consenso , Dermatologia/normas , Eritrodermia Ictiosiforme Congênita/terapia , Ictiose/terapia , Doenças do Prematuro/terapia , Dermatologia/métodos , Europa (Continente) , Humanos , Eritrodermia Ictiosiforme Congênita/complicações , Ictiose/complicaçõesRESUMO
These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert-based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.
Assuntos
Terapia Comportamental/normas , Consenso , Fármacos Dermatológicos/uso terapêutico , Dermatologia/normas , Eritrodermia Ictiosiforme Congênita/terapia , Administração Oral , Administração Tópica , Terapia Comportamental/métodos , Dermatologia/métodos , Europa (Continente) , Aconselhamento Genético/normas , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/psicologia , Qualidade de Vida , Apoio Social , Revisões Sistemáticas como AssuntoAssuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Hamartoma , Neoplasias Cutâneas , Síndrome do Nevo Basocelular/complicações , Carcinoma Basocelular/complicações , Carcinoma Basocelular/patologia , Criança , Hamartoma/complicações , Hamartoma/patologia , Humanos , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is caused by autosomal recessive nonsense mutations in the corneodesmosin gene (CDSN). OBJECTIVES: To investigate a novel mutation in CDSN. METHODS: A 50-year-old white woman showed widespread peeling with erythema and elevated serum IgE. DNA sequencing, immunohistochemistry, Western blot and real-time polymerase chain reaction analyses of skin biopsies were performed in order to study the genetics and to characterize the molecular profile of the disease. RESULTS: Histology showed hyperkeratosis and acanthosis of the epidermis, and inflammatory infiltrates in the dermis. DNA sequencing revealed a homozygous mutation leading to a premature termination codon in CDSN: p.Gly142*. Protein analyses showed reduced expression of a 16-kDa corneodesmosin mutant in the upper epidermal layers, whereas the full-length protein was absent. CONCLUSIONS: These results are interesting regarding the genotype-phenotype correlations in diseases caused by CDSN mutations. The PSD-causing CDSN mutations identified heretofore result in total corneodesmosin loss, suggesting that PSD is due to full corneodesmosin deficiency. Here, we show for the first time that a mutant corneodesmosin can be stably expressed in some patients with PSD, and that this truncated protein is very probably nonfunctional.
Assuntos
Códon sem Sentido/genética , Dermatite Esfoliativa/genética , Glicoproteínas/genética , Dermatopatias Genéticas/genética , Feminino , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Pessoa de Meia-IdadeRESUMO
Large or giant cellular blue nevi are usually congenital and represent a challenge for the physician. Close anatomic structures may be altered by the size of the moles. In this article, we report the case of an uncommon large, agminated, cellular blue nevus of the 'plaque type' in a 42-year-old female. Due to the risks of malignant melanoma development on a large or giant blue nevus, we highlight the importance of proper histopathological diagnosis. Furthermore, because of the possibility that the nevus may invade the bone and cerebral tissues, we discuss the indication of a radiological diagnosis. The accurate correlation to clinical and histopathological findings and appropriate multidisciplinary management can save the lives of patients.
Assuntos
Neoplasias da Orelha/patologia , Nevo Azul/patologia , Neoplasias Cutâneas/patologia , Adulto , Neoplasias da Orelha/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Nevo Azul/cirurgia , Neoplasias Cutâneas/cirurgiaRESUMO
Ichthyosis bullosa of Siemens (IBS) is an autosomal dominant skin disorder that resembles epidermolytic hyperkeratosis (EHK). We have identified mutations in two families originally diagnosed with EHK and in four families diagnosed with IBS at the same codon in the highly conserved carboxy terminal of the rod domain of keratin 2e, thus revealing a mutational hot spot. Our results allow a differential diagnosis to be made between IBS and EHK at the genetic level and we suggest that patients diagnosed with EHK, but lacking keratin K1 or K10 mutations, should be re-examined for mutations in their K2e genes.
Assuntos
Hiperceratose Epidermolítica/genética , Ictiose/genética , Queratinas/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , DNA/genética , Primers do DNA/genética , Diagnóstico Diferencial , Feminino , Genes Dominantes , Humanos , Hiperceratose Epidermolítica/diagnóstico , Hiperceratose Epidermolítica/patologia , Ictiose/diagnóstico , Ictiose/patologia , Queratina-2 , Queratinas/química , Masculino , Dados de Sequência Molecular , Estrutura Molecular , Mutação , LinhagemRESUMO
Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.
Assuntos
Conexinas/genética , Eritema/genética , Mutação , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 1 , Feminino , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de AminoácidosRESUMO
The ichthyoses are a heterogeneous group of monogenetically inherited disorders of cornification, and characterized clinically by scaling or hyperkeratosis. Historically, they were classified by clinical features and inheritance patterns. As a result of the recent molecular biological revolution, the ichthyoses are now recognized as comprising many diverse entities. Importantly, identical phenotypes may be caused by mutations in multiple genes, while mutations in a single gene may result in multiple and sometimes widely divergent phenotypes. The considerable complexity of this clinically and genetically heterogeneous group of disorders has prompted the need for a new classification. A classification that uses terminology based on a combination of the clinical and molecular genetic details, for instance loricrin keratoderma, is desirable. In this chapter we will use in principle the nosology adopted recently by an international group of experts at the First Ichthyosis Consensus Conference in Sorèz, France.
Assuntos
Epiderme/fisiopatologia , Ictiose/diagnóstico , Ictiose/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/terapia , Humanos , Ictiose/terapiaAssuntos
Dermatite Esfoliativa/diagnóstico , Sequenciamento do Exoma/métodos , Imunidade Celular , Subunidade alfa de Receptor de Interleucina-7/genética , Mutação , Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/diagnóstico , DNA/genética , Análise Mutacional de DNA , Dermatite Esfoliativa/etiologia , Dermatite Esfoliativa/imunologia , Feminino , Humanos , Lactente , Recém-Nascido , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Linhagem , Fenótipo , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genéticaRESUMO
BACKGROUND: Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), characterized by ichthyotic, rippled hyperkeratosis, erythroderma and skin blistering, is a rare autosomal dominant disease caused by mutations in keratin 1 or keratin 10 (K10) genes. A severe phenotype is caused by a missense mutation in a highly conserved arginine residue at position 156 (R156) in K10. OBJECTIVES: To analyse molecular pathomechanisms of hyperproliferation and hyperkeratosis, we investigated the defects in mechanosensation and mechanotransduction in keratinocytes carrying the K10(R156H) mutation. METHODS: Differentiated primary human keratinocytes infected with lentiviral vectors carrying wild-type K10 (K10(wt)) or mutated K10(R156H) were subjected to 20% isoaxial stretch. Cellular fragility and mechanosensation were studied by analysis of mitogen-activated protein kinase activation and cytokine release. RESULTS: Cultured keratinocytes expressing K10(R156H) showed keratin aggregate formation at the cell periphery, whereas the filament network in K10(wt) cells was normal. Under stretching conditions K10(R156H) keratinocytes exhibited about a twofold higher level of filament collapse compared with steady state. In stretched K10(R156H) cells, higher p38 activation, higher release of tumour necrosis factor-α and RANTES but reduced interleukin-1ß secretion compared with K10(wt) cells was observed. CONCLUSIONS: These results demonstrate that the R156H mutation in K10 destabilizes the keratin intermediate filament network and affects stress signalling and inflammatory responses to mechanical stretch in differentiated cultured keratinocytes.
Assuntos
Quimiocina CCL5/metabolismo , Hiperceratose Epidermolítica , Queratina-10/metabolismo , Queratinócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Western Blotting , Células Cultivadas , Imunofluorescência , Humanos , Hiperceratose Epidermolítica/genética , Hiperceratose Epidermolítica/metabolismo , Interleucina-1beta/metabolismo , Queratina-10/genética , Queratina-10/ultraestrutura , Queratinócitos/fisiologia , Queratinócitos/ultraestrutura , Mutação , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/metabolismo , Estresse MecânicoRESUMO
The diagnosis of melanoma is accompanied by numerous informations delivered in a systematic and synoptic histopathological report. Next to the ulceration and the tumor thickness, the clinician must know the significance of the number of mitosis, of the inflammation or of the lymphovascular invasion. We detail here each of the prognostic factor and present the last 7th edition of the TNM classification of the AJCC valid from January 2010. In therapy, concrete progresses have been done in metastatic melanoma. The explanation of the pathways involved in melanoma is of particular interest because it facilitates the comprehension of the different biological effects of these therapies. We present here briefly their molecular basis.
Assuntos
Melanoma/patologia , Neoplasias Cutâneas/patologia , Humanos , Técnicas de Diagnóstico Molecular , Patologia/tendências , PrognósticoRESUMO
The epidermal cornified cell envelope (CE) is a complex protein-lipid composite that replaces the plasma membrane of terminally differentiated keratinocytes. This lamellar structure is essential for the barrier function of the skin and has the ability to prevent the loss of water and ions and to protect from environmental hazards. The major protein of the epidermal CE is loricrin, contributing approximately 70% by mass. We have generated mice that are deficient for this protein. These mice showed a delay in the formation of the skin barrier in embryonic development. At birth, homozygous mutant mice weighed less than control littermates and showed skin abnormalities, such as congenital erythroderma with a shiny, translucent skin. Tape stripping experiments suggested that the stratum corneum stability was reduced in newborn Lor(-/-) mice compared with wild-type controls. Isolated mutant CEs were more easily fragmented by sonication in vitro, indicating a greater susceptibility to mechanical stress. Nevertheless, we did not detect impaired epidermal barrier function in these mice. Surprisingly, the skin phenotype disappeared 4-5 d after birth. At least one of the compensatory mechanisms preventing a more severe skin phenotype in newborn Lor(-/-) mice is an increase in the expression of other CE components, such as SPRRP2D and SPRRP2H, members of the family of "small proline rich proteins", and repetin, a member of the "fused gene" subgroup of the S100 gene family.
Assuntos
Epiderme/fisiologia , Proteínas de Membrana/genética , Fenômenos Fisiológicos da Pele/genética , Adaptação Biológica , Sequência de Aminoácidos , Animais , Fenômenos Biomecânicos , Membrana Celular , Clonagem Molecular , Proteínas Ricas em Prolina do Estrato Córneo , Proteínas de Filamentos Intermediários/biossíntese , Proteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Permeabilidade , Proteínas S100/biossíntese , Regulação para CimaRESUMO
BACKGROUND: Bullous pemphigoid (BP), pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune bullous diseases characterized by the presence of tissue-bound and circulating autoantibodies directed against disease-specific target antigens of the skin. Although rare, these diseases run a chronic course and are associated with significant morbidity and mortality. There are few prospective data on gender- and age-specific incidence of these disorders. OBJECTIVES: Our aims were: (i) to evaluate the incidence of BP and PV/PF in Swiss patients, as the primary endpoint; and (ii) to assess the profile of the patients, particularly for comorbidities and medications, as the secondary endpoint. METHODS: The protocol of the study was distributed to all dermatology clinics, immunopathology laboratories and practising dermatologists in Switzerland. All newly diagnosed cases of BP and pemphigus occurring between 1 January 2001 and 31 December 2002 were collected. In total, 168 patients (73 men and 95 women) with these autoimmune bullous diseases, with a diagnosis based on clinical, histological and immunopathological criteria, were finally included. RESULTS: BP showed a mean incidence of 12.1 new cases per million people per year. Its incidence increased significantly after the age of 70 years, with a maximal value after the age of 90 years. The female/male ratio was 1.3. The age-standardized incidence of BP using the European population as reference was, however, lower, with 6.8 new cases per million people per year, reflecting the ageing of the Swiss population. In contrast, both PV and PF were less frequent. Their combined mean incidence was 0.6 new cases per million people per year. CONCLUSIONS; This is the first comprehensive prospective study analysing the incidence of autoimmune bullous diseases in an entire country. Our patient cohort is large enough to establish BP as the most frequent autoimmune bullous disease. Its incidence rate appears higher compared with other previous studies, most likely because of the demographic characteristics of the Swiss population. Nevertheless, based on its potentially misleading presentations, it is possible that the real incidence rate of BP is still underestimated. Based on its significant incidence in the elderly population, BP should deserve more public health concern.
Assuntos
Penfigoide Bolhoso/epidemiologia , Pênfigo/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/imunologia , Pênfigo/imunologia , Estudos Prospectivos , Suíça/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Congenital, nonepidermolytic cornification disorders phenotypically resembling human autosomal recessive ichthyosis have been described in purebred dog breeds, including Jack Russell terrier (JRT) dogs. One cause of gene mutation important to humans and dogs is transposon insertions. OBJECTIVES: To describe an autosomal recessive, severe nonepidermolytic ichthyosis resembling lamellar ichthyosis (LI) in JRT dogs due to insertion of a long interspersed nucleotide element (LINE-1) in the transglutaminase 1 (TGM1) gene. METHODS: Dogs were evaluated clinically, and skin samples were examined by light and electron microscopy. Phenotypic information and genotyping with a canine microsatellite marker suggested TGM1 to be a candidate gene. Genomic DNA samples and cDNA generated from epidermal RNA were examined. Consequences of the mutation were evaluated by Western blotting, quantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme activity from cultured keratinocytes. RESULTS: Affected dogs had generalized severe hyperkeratosis. Histological examination defined laminated to compact hyperkeratosis without epidermolysis; ultrastructurally, cornified envelopes were thin. Affected dogs were homozygous for a 1980-bp insertion within intron 9 of TGM1. The sequence of the insertion was that of a canine LINE-1 element. Quantitative RT-PCR indicated a significant decrease in TGM1 mRNA in affected dogs compared with wild-type. TGM1 protein was markedly decreased on immunoblotting, and membrane-associated enzyme activity was diminished in affected dogs. CONCLUSIONS: Based on morphological and molecular features, this disease is homologous with TGM1-deficient LI in humans, clinically models LI better than the genetically modified mouse and represents its first spontaneous animal model. This is the first reported form of LI due to transposon insertion.