RESUMO
Xeroderma Pigmentosum (XP) is a genetic disorder characterized by photosensitivity, dyschromia, and high risk of skin cancer. From a clinical and histologic view, it can be difficult to diagnose cutaneous melanoma (CM) in XP patients and to define its resection margins. We aimed to study the role of PRAME (PReferentially Expressed Antigen in MElanoma) in differentiating intraepidermal CM from superficial atypical melanocytic proliferation of uncertain significance (SAMPUS) and evaluating the histological margins of CMs. We included XP patients. melanocitic and nonmelanocytic lesions with adjacent skin, and, as control groups, sun-damaged skin from non-XP individuals. Melanocytic lesions with a consensus diagnosis were grouped into CM, SAMPUS, or benign. The selected samples were PRAME-immunoshistochemically stained, and the ratio between immuno-positive cells/mm was recorded, according to Olds and colleagues for intraepidermal lesions. Lezcano and colleagues' method was used for intradermal lesions. Clinical data from XP patients were reviewed. All 9 patients were alive and well at the study closure, even those who developed melanoma metastases. Positive/diffuse PRAME expression was found in 29% (7/24) of intraepidermal CMs and 20% (1/5) SAMPUS samples. All 103 XP control samples and 24 adjacent lesions skin of non-XP patients were PRAME negative. This was a single-center and retrospective study, using a relatively small sample, limiting our conclusions. In XP patients' lesions, PRAME expression could help in the setting of challenging melanocytic tumors and surgical margins evaluation. It is also possible that the method can avoid overdiagnosis and, consequently, more aggressive treatment recommendation in unequivocal CM cases.
Assuntos
Antígenos de Neoplasias , Melanoma Maligno Cutâneo , Melanoma , Neoplasias Cutâneas , Xeroderma Pigmentoso , Humanos , Melanoma/metabolismo , Melanoma/diagnóstico , Melanoma/patologia , Antígenos de Neoplasias/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/diagnóstico , Masculino , Feminino , Xeroderma Pigmentoso/patologia , Xeroderma Pigmentoso/metabolismo , Xeroderma Pigmentoso/diagnóstico , Adulto , Adolescente , Pessoa de Meia-Idade , Criança , Imuno-HistoquímicaRESUMO
PURPOSE: To describe cellular alterations detected by impression cytology of the ocular surface in patients with xeroderma pigmentosum. The secondary objective was to assess the reliability of impression cytology in diagnosing ocular surface squamous neoplasia. METHODS: Patients with xeroderma pigmentosum underwent a single-day complete ophthalmological examination and impression cytology for ocular surface evaluation using 13 mm diameter mixed cellulose esters membrane filters and combined staining with Periodic Acid Schiff, Hematoxylin and Eosin, and Papanicolaou stains followed by microscopic analysis. The cytological findings were correlated with the clinical diagnosis. The impression cytology findings at baseline and one-year follow-up were correlated with the clinical course (no tumor, treated tumor, residual tumor recurrent tumor, new tumor). RESULTS: Of the 42 patients examined, impression cytology was performed in 62 eyes of 34 participants (65% females). The mean age of patients was 29.6 ± 17 years (range 7-62). Fifteen eyes had a clinical diagnosis of ocular surface squamous neoplasia. Impression cytology showed goblet cells (47, 75%), inflammatory cells (12, 19%), keratinization (5, 8%), and squamous metaplasia (30, 48%). Impression cytology was positive for atypical cells in 18 patients (12 with and 6 without ocular surface squamous neoplasia). The sensitivity, specificity, positive predictive value, and negative predictive value of impression cytology (at baseline) for diagnosis of ocular surface squamous neoplasia were 80%, 87%, 67%, and 93%, respectively, using clinical diagnosis of ocular surface squamous neoplasia as the reference standard. CONCLUSION: Impression cytology has a moderate positive predictive value for the diagnosis of ocular surface squamous neoplasia in patients with xeroderma pigmentosum. However, the lack of detection of atypical cells on impression cytology has a high negative predictive value for ocular surface squamous neoplasia. Integration of impression cytology in the long-term management of high-risk patients, such as patients with xeroderma pigmentosum, can avoid unnecessary diagnostic biopsies.
Assuntos
Xeroderma Pigmentoso , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Carcinoma de Células Escamosas/patologia , Neoplasias da Túnica Conjuntiva/patologia , Citodiagnóstico/métodos , Técnicas Citológicas/métodos , Reprodutibilidade dos Testes , Xeroderma Pigmentoso/patologia , Xeroderma Pigmentoso/complicaçõesRESUMO
BACKGROUND: Xeroderma pigmentosum group E (XP-E) is one of the least common forms of XP, a rare syndrome where patients are prone to develop skin cancer in exposed sunlight areas. XP-E patients are generally not diagnosed until they are adults due to the mild phenotype. CASE PRESENTATION: two XP-E siblings, female, 23 years, and male, 25 years, from a Brazilian consanguineous family carrying the novel missense pathogenic variant in DDB2 gene, NM_000107.3:c.1027G > C, associated with skin cancer early-onset and severe phenotype, as nodular melanoma in the cornea and in the ear. CONCLUSION: The assessment of genomic variant pathogenicity was a challenge since this family belongs to an underrepresented population in genomic databases. Given the scarcity of literature documenting XP-E cases and the challenges encountered in achieving an early diagnosis, this report emphasizes the imperative of sun protection measures in XP-E patients. Additionally, it highlights the detrimental impact of the COVID-19 pandemic on cancer diagnosis, leading to the manifestation of a severe phenotype in affected individuals.
Assuntos
COVID-19 , Melanoma , Neoplasias Cutâneas , Xeroderma Pigmentoso , Masculino , Feminino , Humanos , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/epidemiologia , Xeroderma Pigmentoso/patologia , Brasil , Pandemias , Irmãos , COVID-19/epidemiologia , Melanoma/genética , Neoplasias Cutâneas/genética , Reparo do DNA , Proteínas de Ligação a DNA/genéticaRESUMO
BACKGROUND: Xeroderma pigmentosum (XP) is a rare, genetically heterogeneous, autosomal recessive disorder caused by defects in the genes involved in repairing DNA damaged by ultraviolet radiation. These defects lead to a propensity to develop skin cancer at early ages as a hallmark, and progressive neurological degeneration can be observed in around 25% of patients. Eight clinically heterogeneous groups have been identified so far (XPA to XPG and XPV). Xeroderma pigmentosum variant type (XPV) is associated with pathogenic variants in POLH on chromosome 6, and no neurological dysfunction has been seen in these cases. However, on the same chromosome, it has been shown that TREM2 is associated with some types of dementia, particularly in patients with a behavioral variant frontotemporal phenotype. METHODS: Gene mutational analysis was performed by whole-exome sequencing. RESULTS: We report a case of a Caucasian woman with XP that developed behavioral and cognitive impairment at age 37. Whole-exome sequencing identified novel homozygous variants in POLH c.638C>G (p.Ser213*) and TREM2 c.154C>T (p.Arg52Cys), classifying the patient as XPV and suggesting that her frontotemporal dementia phenotype could be related to the variant in TREM2. CONCLUSION: This paper describes a rare case of a patient with two novel variants in the same chromosome associated with XPV and early-onset dementia.
Assuntos
DNA Polimerase Dirigida por DNA/genética , Demência/genética , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Xeroderma Pigmentoso/genética , Adulto , Demência/patologia , Feminino , Homozigoto , Humanos , Mutação de Sentido Incorreto , Fenótipo , Xeroderma Pigmentoso/patologiaRESUMO
In central Brazil, in the municipality of Faina (state of Goiás), the small and isolated village of Araras comprises a genetic cluster of xeroderma pigmentosum (XP) patients. The high level of consanguinity and the geographical isolation gave rise to a high frequency of XP patients. Recently, two founder events were identified affecting that community, with two independent mutations at the POLH gene, c.764 + 1 G > A (intron 6) and c.907 C > T; p.Arg303* (exon 8). These deleterious mutations lead to the xeroderma pigmentosum variant syndrome (XP-V). Previous reports identified both mutations in other countries: the intron 6 mutation in six patients (four families) from Northern Spain (Basque Country and Cantabria) and the exon 8 mutation in two patients from different families in Europe, one of them from Kosovo. In order to investigate the ancestry of the XP patients and the age for these mutations at Araras, we generated genotyping information for 22 XP-V patients from Brazil (16), Spain (6) and Kosovo (1). The local genomic ancestry and the shared haplotype segments among the patients showed that the intron 6 mutation at Araras is associated with an Iberian genetic legacy. All patients from Goiás, homozygotes for intron 6 mutation, share with the Spanish patients identical-by-descent (IBD) genomic segments comprising the mutation. The entrance date for the Iberian haplotype at the village was calculated to be approximately 200 years old. This result is in agreement with the historical arrival of Iberian individuals at the Goiás state (BR). Patients from Goiás and the three families from Spain share 1.8 cM (family 14), 1.7 cM (family 15), and a more significant segment of 4.7 cM within family 13. On the other hand, the patients carrying the exon 8 mutation do not share any specific genetic segment, indicating an old genetic distance between them or even no common ancestry.
Assuntos
DNA Polimerase Dirigida por DNA/genética , Haplótipos , Padrões de Herança , Mutação , Isolamento Reprodutivo , Xeroderma Pigmentoso/genética , Brasil/epidemiologia , Consanguinidade , Europa (Continente)/epidemiologia , Éxons , Feminino , Genética Populacional , Heterozigoto , Homozigoto , Migração Humana , Humanos , Íntrons , Masculino , Fenótipo , Xeroderma Pigmentoso/epidemiologia , Xeroderma Pigmentoso/patologiaRESUMO
Os tumores malignos de glândula salivar (TMGS) são lesões raras, heterogêneas e de prognóstico variável. As células dos mamíferos estão sujeitas a milhares de modificações espontâneas na molécula de ácido desoxirribonucleico (DNA). A proteína endonuclease apúrica ou apirimídica 1 (APE1) e a proteína 1 de complementação cruzada de reparo de raios-x (XRCC1) são dois componentes importante da via de reparo por excisão de base (BER), e a proteína fator de complementação F do xeroderma pigmentoso (XPF), da via de reparo por excisão nucleotídeo (NER). Este estudo analisou a expressão imuno-histoquímica das proteínas APE1 e XRCC1 da via BER, e XPF da via NER, em amostra de tumores primários de carcinoma de células acinares (CCA), adenocarcinoma polimorfo (AcP), carcinoma adenoide cístico (CAC) e carcinoma mucoepidermoide (CME). Um total de 62 TMGS foram incluídos e submetidos à imuno-histoquímica contra os anticorpos selecionados, correspondendo a 14 CCA, 15 AcP, 16 CAC e 17 CME. As células do parênquima tumoral foram avaliadas quantitativamente, a partir de fotomicrografias de 5 campos (em aumento de 400x), por um único avaliador. Foram consideradas células imunorreativas aquelas com coloração acastanhada no núcleo e/ou núcleo/citoplasma, independente da intensidade. As células imunomarcadas e negativas foram contadas nos 5 campos, estabelecendo o porcentual de células positivas em relação ao número total de células contadas. Ademais, estabeleceu-se a razão núcleo ou núcleo/citoplasma, inferindo se a localização era predominantemente uni ou bicompartimental. Os testes estatísticos incluíram o exato de Fisher, Mann-Whitney, KruskalWallis, correlação de Spearman e log-rank para comparação das curvas de sobrevida global construídas pelo método Kaplan-Meier. O nível de significância foi estabelecido em 5%. Todos os TMGS selecionados marcaram para APE1, XRCC1 e XPF. Não houve diferença entre a expressão de APE1 e XPF entre os tumores estudados. Para XRCC1, contudo, observou-se diferença significativa entre AcP e CME (p=0.032). A marcação nuclear de APE1 foi estatisticamente maior nos TMGS selecionados (p<0.0001). Houve relação estatística de APE1 com tumores T1-T2 no CAC (p=0.006), bem como de aumento de XPF em pacientes com CME acima de 60 anos (p=0.015) e CAC em glândula salivar menor (p=0.012), embora tenha reduzido em pacientes tratados com cirurgia associado à terapia adjuvante no CCA e no CAC (p=0.036 e p=0.020, respectivamente). A baixa expressão de XRCC1 no núcleo (p=0.028) ou a expressão de XRCC1 concomitante no núcleo e no citoplasma (p=0.017) foram associadas com menor taxa de sobrevida global em 5 anos. Finalmente, o teste de correlação de Spearman demonstrou correlação positiva entre a APE e XRCC1 em todos os TMGS analisados, embora a correlação entre as três proteínas (APE1, XRCC1 e XPF) tenha sido observada apenas em CAC e CME (p<0.05). Este trabalho demonstrou alta expressão das proteínas de reparo APE1, XRCC1 e XPF em CCA, AcP, CAC e CME, o que pode sugerir atividade reguladora relacionada ao controle genotóxico dessas proteínas nos TMGS (AU).
Malignant salivary gland tumors (MSGT) are rare, heterogeneous lesions with a variable prognosis. Mammalian cells are subject to thousands of spontaneous changes in the deoxyribonucleic acid (DNA) molecule. The apuric or apyrimidic endonuclease protein 1 (APE1) and the X-ray crossover complementation protein 1 (XRCC1) are two important components of the base excision repair pathway (BER), and the complementation factor protein F of the xeroderma pigmentosum (XPF), the nucleotide excision repair pathway (NER). This study analyzed the immunohistochemical expression of APE1 and XRCC1 proteins of the BER pathway, and XPF of the NER pathway, in a sample of primary tumors of acinar cell carcinoma (ACC), polymorphic adenocarcinoma (PAC), adenoid cystic carcinoma (AdCC) and mucoepidermoid carcinoma (MEC). A total of 62 MSGT were included and submitted to immunohistochemistry against the selected antibodies, corresponding to 14 ACC, 15 PAC, 16 AdCC, and 17 MEC. The tissue sections were subjected to immunohistochemistry for APE1, XRCC1 and XPF. The cells of the tumor parenchyma were quantitatively evaluated, using photomicrographs of 5 fields (in 400x magnification), by a single evaluator. Immunoreactive cells were those with brownish color in the nucleus and/or nucleus/ cytoplasm, regardless of intensity. Immunomarked and negative cells were counted in the 5 fields, establishing the percentage of positive cells in relation to the total number of cells counted. In addition, it was established whether the nucleus or nucleus/cytoplasm ratio, inferring whether the location was predominantly uni or bicompartmental. Statistical tests included Fisher's exact, Mann-Whitney, Kruskal-Wallis, Spearman's correlation, as well as the log-rank for comparison of the overall survival built through Kaplan-Meier method. Significance was set at p<0.05. All selected MSGT scored for APE1, XRCC1 and XPF. There was no difference between the expression of APE1 and XPF among the studied tumors. For XRCC1, however, there was a significant difference between PAC and MEC (p=0.032). Nuclear labeling of APE1 was statistically higher in the selected MSGT (p<0.0001). There was a statistical relationship between APE1 and T1-T2 tumors in the AdCC (p=0.006), as well as an increase in XPF in patients with MEC over 60 years (p=0.015) and AdCC in a minor salivary gland (p=0.012), although reduced in patients treated with surgery associated with adjuvant therapy in ACC and AdCC (p=0.036 and p=0.020, respectively). The low expression of XRCC1 in the nucleus (p=0.028) or the expression of concomitant XRCC1 in the nucleus and cytoplasm (p=0.017) were associated with a lower overall 5-year survival rate. Finally, the Spearman correlation test demonstrated a positive correlation between APE and XRCC1 in all MSGT analyzed, although the correlation among the three proteins (APE1, XRCC1 and XPF) was observed only in AdCC and MEC (p<0.05). This study demonstrated high expression of the repair proteins APE1, XRCC1 and XPF in ACC, PAC, AdCC, and MEC, which may suggest regulatory activity related to the genotoxic control of these proteins in MSGT (AU).
Assuntos
Humanos , Xeroderma Pigmentoso/patologia , Neoplasias das Glândulas Salivares/patologia , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Reparo do DNA , Proteína 1 Complementadora Cruzada de Reparo de Raio-X , Imuno-Histoquímica/métodos , Adenocarcinoma , Análise de Sobrevida , Estatísticas não ParamétricasRESUMO
The UVA component of sunlight induces DNA damage, which are basically responsible for skin cancer formation. Xeroderma Pigmentosum Variant (XP-V) patients are defective in the DNA polymerase pol eta that promotes translesion synthesis after sunlight-induced DNA damage, implying in a clinical phenotype of increased frequency of skin cancer. However, the role of UVA-light in the carcinogenesis of these patients is not completely understood. The goal of this work was to characterize UVA-induced DNA damage and the consequences to XP-V cells, compared to complemented cells. DNA damage were induced in both cells by UVA, but lesion removal was particularly affected in XP-V cells, possibly due to the oxidation of DNA repair proteins, as indicated by the increase of carbonylated proteins. Moreover, UVA irradiation promoted replication fork stalling and cell cycle arrest in the S-phase for XP-V cells. Interestingly, when cells were treated with the antioxidant N-acetylcysteine, all these deleterious effects were consistently reverted, revealing the role of oxidative stress in these processes. Together, these results strongly indicate the crucial role of oxidative stress in UVA-induced cytotoxicity and are of interest for the protection of XP-V patients.
Assuntos
Reparo do DNA/efeitos da radiação , Fibroblastos/efeitos da radiação , Pontos de Checagem da Fase S do Ciclo Celular/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Acetilcisteína/farmacologia , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Replicação do DNA/efeitos da radiação , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Nocodazol/farmacologia , Oniocompostos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Carbonilação Proteica/efeitos dos fármacos , Carbonilação Proteica/efeitos da radiação , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/metabolismo , Xeroderma Pigmentoso/patologiaRESUMO
We conducted a case-control study to investigate the role of three common single nucleotide polymorphisms (SNPs) in the xeroderma pigmentosum complementation group G (XPG) gene (rs2094258, rs751402 and rs17655) in the development of gastric cancer in a Chinese population. Between January 2012 and December 2014, samples from a total of 177 patients with gastric cancer and 237 control subjects were collected from the Ankang City Central Hospital. XPG rs2094258, rs751402 and rs17655 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Using logistic regression analysis, we found that the CC genotype of rs17655 was associated with an elevated risk of gastric cancer, and the adjusted odds ratio (OR) and 95% confidence intervals (95%CI) were 1.91 and 1.07-3.41, respectively. Moreover, individuals carrying the GC + CC genotype of rs17655 had an increased susceptibility to gastric cancer (OR = 1.61, 95%CI = 1.03-2.54). However, we did not observe a significant association between XPG rs2094258 and rs751402 polymorphisms and development of gastric cancer. In conclusion, our study suggests that the rs17655 polymorphism in XPG is associated with an increased risk of gastric cancer. The results of our findings should be further validated by further large sample size studies.
Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Estudos de Associação Genética , Proteínas Nucleares/genética , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Xeroderma Pigmentoso/genética , Adulto , Idoso , China , Feminino , Predisposição Genética para Doença , Genótipo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias Gástricas/complicações , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/microbiologia , Xeroderma Pigmentoso/patologiaRESUMO
Xeroderma pigmentosum (XP) is a rare, autosomal recessive disease involving a defect in DNA repair leading to the premature development of numerous aggressive cutaneous malignancies. Although atypical fibroxanthoma (AFX) is a neoplasm typically found in the setting of extensive sun exposure or therapeutic radiation, AFXs are rarely associated with children with XP. We report the case of a 13-year-old Guatemalan girl with the XP type C variant who developed one of the largest AFXs reported on a child's finger.
Assuntos
Dedos/cirurgia , Lesões Pré-Cancerosas/patologia , Neoplasias Cutâneas/patologia , Xantogranuloma Juvenil/patologia , Xeroderma Pigmentoso/patologia , Adolescente , Amputação Cirúrgica/métodos , Biópsia por Agulha , Feminino , Dedos/patologia , Guatemala , Humanos , Imuno-Histoquímica , Doenças Raras , Medição de Risco , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento , Xantogranuloma Juvenil/complicações , Xantogranuloma Juvenil/cirurgia , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/cirurgiaRESUMO
Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.
Assuntos
DNA Glicosilases/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células Cultivadas , DNA Glicosilases/genética , Reparo do DNA/fisiologia , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Peróxido de Hidrogênio/farmacologia , Imunoprecipitação , Oxidantes/farmacologia , Estresse Oxidativo , RNA Mensageiro/metabolismo , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/patologiaRESUMO
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by clinical and cellular sensitivity, pigmentary changes, and early development of malignancies in sun-exposed mucocutaneous and ocular structures due to a defective ability to repair intracellular DNA damage. Individuals with XP also have a greater frequency of oral cancer, particularly squamous cell carcinoma of the anterior third of the tongue. The current study reports four cases of XP that exhibited a characteristic crescent-shaped, atrophic, telangiectatic area on the distal border of the tongue and correlates this lesion with the development of tumors at this site during follow-up. The tongue lesion was photographed and biopsied in the four patients. During routine follow-up visits, new biopsies were performed if additional tongue lesions were observed. The studied lesions were similar in the four patients. During follow-up, squamous cell carcinoma developed in one patient and pyogenic granuloma developed in three patients and was relapsing in one. The lesion remained stable in one patient during the study. The atrophic and telangiectatic patches probably occur because of chronic sun damage to the exposed portion of the tongue, and this area has a high predisposition for the development of benign and malignant tumors.
Assuntos
Telangiectasia/diagnóstico , Doenças da Língua/diagnóstico , Xeroderma Pigmentoso/diagnóstico , Adolescente , Biópsia , Criança , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Telangiectasia/patologia , Doenças da Língua/patologia , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/patologia , Xeroderma Pigmentoso/patologiaRESUMO
The De Sanctis-Cacchione Syndrome is the rarest and most severe kind of xeroderma pigmentosum, characterized by microcephaly, hypogonadism, neurological disorders, mental and growth retardation, with very few cases published. The clinical findings compatible with De Sanctis-Cacchione Syndrome and the therapeutic approach used to treat a one year and nine months old child, with previous diagnosis of xeroderma pigmentosum, are reported.
A síndrome de de Sanctis-Cacchione é a forma mais rara e grave do xeroderma pigmentoso e é caracterizada por microcefalia, hipogonadismo, alterações neurológicas e retardo mental e de crescimento, com poucos casos publicados. Relatam-se os achados clínicos compatíveis com essa síndrome e a terapêutica instituída em uma lactente de um ano e nove meses, com diagnóstico prévio de xeroderma pigmentoso.
Assuntos
Feminino , Humanos , Lactente , Nanismo/patologia , Hipogonadismo/patologia , Deficiência Intelectual/patologia , Doenças Raras/patologia , Neoplasias Cutâneas/patologia , Xeroderma Pigmentoso/patologia , Nanismo/terapia , Hipogonadismo/terapia , Deficiência Intelectual/terapia , Prognóstico , Doenças Raras/terapia , Neoplasias Cutâneas/terapia , Pele/patologia , Xeroderma Pigmentoso/terapiaRESUMO
DNA damage induced by ultraviolet (UV) radiation can be removed by nucleotide excision repair through two sub-pathways, one general (GGR) and the other specific for transcribed DNA (TCR), and the processing of unrepaired lesions trigger signals that may lead to cell death. These signals involve the tumor suppressor p53 protein, a central regulator of cell responses to DNA damage, and the E3 ubiquitin ligase Mdm2, that forms a feedback regulatory loop with p53. The involvement of cell cycle and transcription on the signaling to apoptosis was investigated in UVB-irradiated synchronized, DNA repair proficient, CS-B (TCR-deficient) and XP-C (GGR-deficient) primary human fibroblasts. Cells were irradiated in the G1 phase of the cell cycle, with two doses with equivalent levels of apoptosis (low and high), defined for each cell line. In the three cell lines, the low doses of UVB caused only a transient delay in progression to the S phase, whereas the high doses induced permanent cell cycle arrest. However, while accumulation of Mdm2 correlated well with the recovery from transcription inhibition at the low doses for normal and CS-B fibroblasts, for XP-C cells this protein was shown to be accumulated even at UVB doses that induced high levels of apoptosis. Thus, UVB-induced accumulation of Mdm2 is critical for counteracting p53 activation and apoptosis avoidance, but its effect is limited due to transcription inhibition. However, in the case of XP-C cells, an excess of unrepaired DNA damage would be sufficient to block S phase progression, which would signal to apoptosis, independent of Mdm2 accumulation. The data clearly discriminate DNA damage signals that lead to cell death, depending on the presence of UVB-induced DNA damage in replicating or transcribing regions.
Assuntos
Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Fase G1/efeitos da radiação , Fase S/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Transcrição Gênica/efeitos da radiação , Raios Ultravioleta , Western Blotting , Morte Celular/efeitos da radiação , Células Cultivadas , Síndrome de Cockayne/patologia , Dano ao DNA , Reparo do DNA/efeitos da radiação , Relação Dose-Resposta à Radiação , Fibroblastos/citologia , Humanos , Cinética , Proteínas Proto-Oncogênicas c-mdm2 , Proteína Supressora de Tumor p53/metabolismo , Xeroderma Pigmentoso/patologiaRESUMO
The De Sanctis-Cacchione Syndrome is the rarest and most severe kind of xeroderma pigmentosum, characterized by microcephaly, hypogonadism, neurological disorders, mental and growth retardation, with very few cases published. The clinical findings compatible with De Sanctis-Cacchione Syndrome and the therapeutic approach used to treat a one year and nine months old child, with previous diagnosis of xeroderma pigmentosum, are reported.
Assuntos
Nanismo/patologia , Hipogonadismo/patologia , Deficiência Intelectual/patologia , Doenças Raras/patologia , Neoplasias Cutâneas/patologia , Xeroderma Pigmentoso/patologia , Nanismo/terapia , Feminino , Humanos , Hipogonadismo/terapia , Lactente , Deficiência Intelectual/terapia , Prognóstico , Doenças Raras/terapia , Pele/patologia , Neoplasias Cutâneas/terapia , Xeroderma Pigmentoso/terapiaRESUMO
El xeroderma pigmentoso (XP) es una rara enfermedad, autosómica recesiva, causada por un defecto en la reparación del ADN. Se manifiesta en la niñez temprana. Los pacientes conXP tienen una extrema fotosensibilidad, lo que conduce a quemaduras solares, cambios pigmentarios y una elevada incidencia de tumores malignos de piel. Una minoría de pacientes presenta anomalías neurológicas progresivas. El diagnóstico es clínico y puede ser confirmado con estudios genéticos. El tratamiento consiste en una rigurosa fotoprotección y la extirpación precoz de lesiones precancerosas. Presentamos el caso de un niño de 2 años de edad con compromiso cutáneo y ocular, sinalteraciones neurológicas...
Assuntos
Humanos , Reparo do DNA/genética , Xeroderma Pigmentoso/diagnóstico , Xeroderma Pigmentoso/patologia , DermatopatiasRESUMO
Recombinant adenoviral vectors provide efficient means for gene transduction in mammalian cells in vitro and in vivo. We are currently using these vectors to transduce DNA repair genes into repair deficient cells, derived from xeroderma pigmentosum (XP) patients. XP is an autosomal syndrome characterized by a high frequency of skin tumors, especially in areas exposed to sunlight, and, occasionally, developmental and neurological abnormalities. XP cells are deficient in nucleotide excision repair (affecting one of the seven known XP genes, xpa to xpg) or in DNA replication of DNA lesions (affecting DNA polymerase eta, xpv). The adenovirus approach allows the investigation of different consequences of DNA lesions in cell genomes. Adenoviral vectors carrying several xp and photolyases genes have been constructed and successfully tested in cell culture systems and in vivo directly in the skin of knockout model mice. This review summarizes these recent data and proposes the use of recombinant adenoviruses as tools to investigate the mechanisms that provide protection against DNA damage in human cells, as well as to better understand the higher predisposition of XP patients to cancer.
Assuntos
Adenovírus Humanos/genética , Dano ao DNA , Vetores Genéticos/genética , Animais , Células Cultivadas , Reparo do DNA , Distúrbios no Reparo do DNA/genética , Inativação Gênica , Terapia Genética , Humanos , Camundongos , Camundongos Knockout , Recombinação Genética , Pele/patologia , Pele/efeitos da radiação , Transdução Genética/métodos , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/patologia , Xeroderma Pigmentoso/terapiaRESUMO
UV radiation is the most common risk factor for skin cancer. Patients with the autosomal recessive DNA repair disorder xeroderma pigmentosum (XP) suffer high incidence of skin cancer after sunlight exposure. XP-mutant mice are attractive models to study this syndrome, as they, too, develop UV radiation-induced skin tumors, mimicking the human phenotype. Recombinant adenovirus carrying the human XPA gene was used for in vivo gene therapy in UVB-irradiated skin of such mice. Virus s.c. injection led to the expression of the XPA protein in basal keratinocytes and prevented deleterious effects in the skin, including late development of squamous cell carcinoma. Thus, efficient adenovirus gene delivery to the skin is a promising tool for reconstitution of specific DNA repair defects in XP patients.