Assuntos
Carcinoma , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Neoplasias Esofágicas , Estenose Esofágica , Carcinoma/complicações , Epidermólise Bolhosa/complicações , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/genética , Neoplasias Esofágicas/complicações , Estenose Esofágica/etiologia , Genes Recessivos , HumanosRESUMO
Carmi syndrome is a rare and severe disease defined by pyloric atresia and junctional epidermolysis bullosa. There are no clear recommendations when to consider a curative therapy, including surgical repair of pyloric atresia and when to transition to palliative care. We report the case of a female preterm infant suffering from Carmi syndrome. After definitive diagnosis and appropriate ethical counselling, we decided for surgical repair of the pyloric atresia. Nonetheless, there was no clinical improvement and our patient died after 35 days. Reviewing the literature, we found immunofluorescence microscopy to be most decisive examination to determine the prognosis of this severe disease.
Assuntos
Alphapapillomavirus , Carcinoma in Situ/etiologia , Carcinoma de Células Escamosas/etiologia , Neutropenia/complicações , Infecções por Papillomavirus/complicações , Anormalidades da Pele/complicações , Neoplasias Cutâneas/etiologia , Adulto , Carcinoma in Situ/virologia , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Neutropenia/patologia , Anormalidades da Pele/patologia , Neoplasias Cutâneas/virologia , Úlcera Cutânea/etiologia , Úlcera Cutânea/patologiaRESUMO
Background: Rare syndromic skin disorders may represent a diagnostic challenge. Aims: We report a unique case associating cutaneous manifestations and developmental delay. Materials & Methods: The affected 14 months old boy had poikiloderma, facial dysmorphism with deep-set eyes, atrichia, as well as nail dysplasia and non-descended testes. In addition, his psychomotor development was delayed. Exome sequencing and molecular karyotyping via array-CGH (oligo-array, 180k Agilent, design 22060) were performed. Results: Mutations in RECQL4 (found in patients with RTS2) were first excluded. In the ANAPC1 gene, a novel combination of a recurrent intronic mutation (c.2705-198C>T) and a deletion of the second ANAPC1 allele was detected, thus confirming the clinical diagnosis of RTS1. The deletion on chromosome 2q13 comprised further genes and spanned 1,7 megabases. Heterozygous deletions in this region are known as 2q13 microdeletion syndrome and are associated with developmental delay, autism and facial dysmorphism. Discussion: The genetic findings most probably explain both, the RTS1 features and the developmental delay. Genetic diagnosis in RTS is indispensable to confirm the specific subtype and its associated risks: juvenile cataracts are features of RTS1 (ANAPC1 gene), whereas a high risk of osteosarcoma is part of RTS2 (RECQL4 gene). Thus, the patient described here is at high risk for the development of juvenile cataracts and requires regular ophthalmologic examination. Conclusion: This case report underlines the necessity of thorough clinical diagnosis prior to genetic diagnosis of RTS1, since the recurrent intronic ANAPC1 mutation is otherwise missed.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Celecoxib/uso terapêutico , Cetuximab/uso terapêutico , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Genes Recessivos , Neoplasias Cutâneas/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Carcinoma de Células Escamosas/complicações , Celecoxib/administração & dosagem , Celecoxib/farmacologia , Proliferação de Células/efeitos dos fármacos , Cetuximab/administração & dosagem , Cetuximab/farmacologia , Relação Dose-Resposta a Droga , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/genética , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Cutâneas/complicações , Resultado do TratamentoAssuntos
Nevo/patologia , Neoplasias Cutâneas/patologia , Telangiectasia/patologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-IdadeAssuntos
Cor de Cabelo/genética , Doenças do Cabelo/genética , Transtornos da Pigmentação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Biópsia , Criança , Análise Mutacional de DNA , Doenças do Cabelo/congênito , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/patologia , Humanos , Masculino , Mosaicismo , Mutação , Transtornos da Pigmentação/congênito , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/patologia , Couro Cabeludo , Pele/patologiaAssuntos
Carcinoma Verrucoso/genética , Conexinas/genética , Perda Auditiva Neurossensorial/genética , Nevo/genética , Poroceratose/genética , Neoplasias Cutâneas/genética , Biópsia , Carcinoma Verrucoso/diagnóstico , Carcinoma Verrucoso/patologia , Conexina 26 , Análise Mutacional de DNA , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Masculino , Mosaicismo , Nevo/diagnóstico , Nevo/patologia , Poroceratose/diagnóstico , Poroceratose/patologia , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Síndrome , Adulto JovemAssuntos
Alitretinoína/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Ceratodermia Palmar e Plantar/tratamento farmacológico , Proteínas Adaptadoras de Transporte Vesicular/genética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Alitretinoína/efeitos adversos , Estudos de Coortes , Análise Mutacional de DNA , Fármacos Dermatológicos/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Masculino , Pessoa de Meia-Idade , Mutação , Resultado do TratamentoRESUMO
Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.
Assuntos
Códon sem Sentido/genética , Dermatite/genética , Desmogleína 1/genética , Hipersensibilidade/genética , Ceratodermia Palmar e Plantar/genética , Adolescente , Feminino , Homozigoto , Humanos , Síndrome de Emaciação/genéticaRESUMO
Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (â¼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity.
Assuntos
Vesícula/genética , Epidermólise Bolhosa/genética , Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias/genética , Doenças Periodontais/genética , Transtornos de Fotossensibilidade/genética , Regiões Promotoras Genéticas , Adolescente , Biomarcadores , Vesícula/diagnóstico , Pré-Escolar , Análise Mutacional de DNA , Epidermólise Bolhosa/diagnóstico , Humanos , Masculino , Doenças Periodontais/diagnóstico , Fenótipo , Transtornos de Fotossensibilidade/diagnóstico , Pele/patologia , Adulto JovemAssuntos
Anodontia/genética , Mama/anormalidades , Dermatite Esfoliativa/genética , Displasia Ectodérmica/genética , Obstrução dos Ductos Lacrimais/genética , Deformidades Congênitas dos Membros/genética , Mutação/genética , Unhas Malformadas/genética , Transtornos da Pigmentação/genética , Fatores de Transcrição/genética , Transglutaminases/genética , Proteínas Supressoras de Tumor/genética , Anodontia/diagnóstico , Criança , Dermatite Esfoliativa/diagnóstico , Displasia Ectodérmica/diagnóstico , Feminino , Heterozigoto , Humanos , Obstrução dos Ductos Lacrimais/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Masculino , Unhas Malformadas/diagnóstico , Transtornos da Pigmentação/diagnóstico , Dermatopatias/congênitoRESUMO
BACKGROUND: Integrin α6ß4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6ß4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). OBJECTIVES: To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. METHODS: DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. RESULTS: We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of ß4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. CONCLUSIONS: The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of ß4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype.
Assuntos
Epidermólise Bolhosa/genética , Integrina alfa6beta4/genética , Mutação/genética , Adolescente , Adulto , Criança , Pré-Escolar , DNA/análise , Epidermólise Bolhosa/patologia , Evolução Fatal , Feminino , Imunofluorescência , Genótipo , Humanos , Lactente , Integrina beta4/genética , Masculino , Microscopia Eletrônica , Fenótipo , Pele/ultraestruturaRESUMO
BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.
Assuntos
Vesícula/patologia , Senescência Celular/fisiologia , Epidermólise Bolhosa/patologia , Queratinócitos/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Doenças Periodontais/patologia , Transtornos de Fotossensibilidade/patologia , Adolescente , Adulto , Vesícula/genética , Proliferação de Células , Células Cultivadas , Criança , Epidermólise Bolhosa/genética , Humanos , Pessoa de Meia-Idade , Doenças Periodontais/genética , Transtornos de Fotossensibilidade/genéticaRESUMO
Epidermolysis bullosa simplex (EBS) is mainly caused by mutations in the KRT5 and KRT14 genes. Squamous cell carcinoma (SCC) represents the second most frequent skin neoplasia with complex aetiology. The molecular events disrupting the orchestrated interplay between the cytoskeleton, cell adhesion molecules and signalling proteins are ill understood in SCC. We describe the molecular background and the unusual course of the disease in a patient with EBS Dowling-Meara, severe keratoderma and a massive verrucous carcinoma. Skin and tumour samples from the patient were analysed using light microscopy, immunohistochemistry and immunofluorescence mapping. Mutation analysis of the KRT5 and KRT14 genes identified the novel KRT5 mutation p.E477D. Invasive tumour areas were characterized by downregulation of keratins 5 and 14, reduced and irregular desmocollin-2 expression and increased expression of keratins 6, 16 and 17. Levels of Ki-67 were increased and levels of E-cadherin strongly reduced in the tumour tissue. In this case a novel KRT5 mutation led to increased fragility of keratinocytes. Desmosome and adherens junctions were destabilized, which may trigger keratinocyte-mediated inflammation, possibly via p120-catenin-dependent signalling, suggesting a link between a keratin mutation and SCC, which adds weight to the hypothesis that disturbance of the cytoskeleton represents a major cause in the appearance of the malignant phenotype. Some individuals with EBS may be at risk of developing secondary SCC.
Assuntos
Carcinoma Verrucoso/complicações , Epidermólise Bolhosa Simples/complicações , Queratina-5/genética , Mutação/genética , Neoplasias Cutâneas/complicações , Adulto , Caderinas/metabolismo , Carcinoma Verrucoso/diagnóstico , Carcinoma Verrucoso/genética , Análise Mutacional de DNA , Regulação para Baixo , Epidermólise Bolhosa Simples/diagnóstico , Epidermólise Bolhosa Simples/genética , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imuno-Histoquímica , Queratina-14/genética , Queratinócitos/metabolismo , Queratinas/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: There is confusion in the literature concerning disorders caused by EBP (emopamil-binding protein) mutations in males. OBJECTIVES: To study the clinical and genetic differences in males affected either with Conradi-Hünermann-Happle (CHH) syndrome (X-linked dominant chondrodysplasia punctata, CDPX2) or with a nonmosaic, X-linked recessive disorder for which we propose the acronymic term MEND syndrome (male EBP disorder with neurological defects). METHODS: We report a 7-year-old boy with a history of transient scaly erythematous lesions on his limbs, trunk and scalp soon after birth. DNA was isolated from ethylenediamine tetraacetic acid-blood samples of the patient and the four coding exons of the EBP gene were amplified by polymerase chain reaction. We review all published cases of CHH syndrome in males in the literature and elaborate the clinical and genetic differences between CHH syndrome in males and MEND syndrome. RESULTS: We found at position 33 of the EBP gene the variant c.33C>A leading to the same nonsense mutation p.Y11X that had previously occurred de novo in a female with typical manifestations of CHH syndrome. When the known male cases with EBP mutations were reviewed, a striking nosological difference between the mosaic and nonmosaic phenotypes was evident. Clear-cut clinical criteria are elaborated to distinguish between CHH syndrome in males and MEND syndrome. CONCLUSIONS: Because the clinical outcome and prognosis are different it is important to distinguish between males with CHH syndrome that represents a mosaic phenotype, and those with MEND syndrome that is a nonmosaic trait.