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1.
Artigo em Alemão | MEDLINE | ID: mdl-33296003

RESUMO

People with complex and rare diseases often have a difficult time in our health system. It can take years to reach a diagnosis and there is often no suitable therapy. Rare diseases are anything but rare among patients: around 4 million people are affected in Germany alone. Nevertheless, rare diseases can often only be diagnosed when they are well enough known and the population is made aware of their existence-this applies to both laypeople and medical professionals. The rather unusual form of imparting knowledge via entertainment television can make an important contribution to disseminate medical knowledge and to raise awareness of medical topics. In specific cases, entertainment television can help to diagnose rare diseases or encourage laypeople to take lifesaving measures, which we try to illustrate in this paper.Series and quiz shows reach more viewers than traditional health programs. They have also proven to be exceptionally effective in student teaching. Since the narrative form focuses on cheering and guessing, instead of simply conveying facts, the medical topics become more emotionally anchored memories and easier to recall. Entertainment television thus offers an innovative approach to increase the health literacy of the population-a potential that could be used more intensively in Germany.


Assuntos
Doenças Raras , Televisão , Alemanha , Humanos , Atividades de Lazer , Doenças Raras/diagnóstico , Estudantes
2.
Khirurgiia (Mosk) ; (11): 25-31, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33210504

RESUMO

OBJECTIVE: To analyze the capabilities of laparoscopy in the diagnosis and treatment of atypical diseases. MATERIAL AND METHODS: Laparoscopy was performed in 5188 patients with established, suspected and unclear diagnosis of acute surgical diseases for the period from 2008 to 2018. Rare atypical diseases were diagnosed in 114 (2.2%) patients. These diseases simulated established and suspected clinical diagnoses in 100 (87.7%) cases, and the diagnosis was unclear in 5 (4.4%) cases. In 9 (7.9%) patients, atypical diseases were concomitant. In 7 cases, atypical diseases competed with the underlying disease and required emergency surgery. Conservative treatment was required in 2 cases. Seventy (61.4%) patients with atypical diseases needed emergency surgery, and 44 (38.6%) patients required conservative treatment. Laparoscopic operations were performed in 61 (87.1%) patients including simultaneous procedures in 8 cases and video-assisted interventions in 2 (2.9%) patients. Laparotomy was applied in 7 (10.0%) patients. RESULTS: Histological examination confirmed laparoscopic diagnosis in 66 out of 68 specimens. Cells of mucus-forming adenocarcinoma were detected in one resected epiploic appendix, carcinomatosis - in one segment of resected omentum. CONCLUSION: Video-assisted laparoscopy was valuable to establish a diagnosis and determine surgical strategy, detect competing and concomitant diseases, perform operations including simultaneous procedures.


Assuntos
Laparoscopia , Doenças Raras/diagnóstico , Doenças Raras/cirurgia , Neoplasias Abdominais/cirurgia , Apêndice/cirurgia , Tratamento Conservador , Emergências , Humanos , Laparotomia , Omento/cirurgia , Cirurgia Vídeoassistida
3.
Artigo em Russo | MEDLINE | ID: mdl-33161658

RESUMO

The study was carried out to analyze detection of rare diseases that are not included into listings of rare (orphan) diseases to be treated at the expense of budget resources of the Russian Federation Russian Federation (hereinafter referred as rare diseases out of reimbursement). The analysis of detection of patients with rare diseases out of reimbursement in Russian Federation was carried out. The information was collected and summarized on the basis of open sources by the way of formalized personal request to the heads of patient and public organizations providing care of patients with rare diseases out of reimbursement. It is established that in the Russian Federation (85 subjects) reside patients with more than 250 forms and groups of rare diseases and only 28 out of them are included into the Federal registries of patients. Actually, there are more than 8 000 nosologic forms of rare diseases that are known thus far. The monitoring permitted to collect data concerning 30 particular nosological forms and groups of rare diseases out of reimbursement. Among them, 23 out of 30 analyzed pathologies have genetic nature. And only for 24 out of 30 diseases the registration of patients is applied. It is necessary to organize modern system of registration of patients within the framework of the Federal registry that includes full and actual data about patients, course of disease, therapeutic interventions that will permit to determine prevalence, disability, mortality, lethality, necessary medicinal maintenance and also to establish spectrum of diseases that are to be included into drug reimbursement programs.


Assuntos
Produção de Droga sem Interesse Comercial , Doenças Raras , Humanos , Prevalência , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Doenças Raras/epidemiologia , Sistema de Registros , Federação Russa/epidemiologia
4.
PLoS Genet ; 16(10): e1009054, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33001999

RESUMO

Genetic and molecular analysis of rare disease is made difficult by the small numbers of affected patients. Phenotypic comorbidity analysis can help rectify this by combining information from individuals with similar phenotypes and looking for overlap in terms of shared genes and underlying functional systems. However, few studies have combined comorbidity analysis with genomic data. We present a computational approach that connects patient phenotypes based on phenotypic co-occurence and uses genomic information related to the patient mutations to assign genes to the phenotypes, which are used to detect enriched functional systems. These phenotypes are clustered using network analysis to obtain functionally coherent phenotype clusters. We applied the approach to the DECIPHER database, containing phenotypic and genomic information for thousands of patients with heterogeneous rare disorders and copy number variants. Validity was demonstrated through overlap with known diseases, co-mention within the biomedical literature, semantic similarity measures, and patient cluster membership. These connected pairs formed multiple phenotype clusters, showing functional coherence, and mapped to genes and systems involved in similar pathological processes. Examples include claudin genes from the 22q11 genomic region associated with a cluster of phenotypes related to DiGeorge syndrome and genes related to the GO term anterior/posterior pattern specification associated with abnormal development. The clusters generated can help with the diagnosis of rare diseases, by suggesting additional phenotypes for a given patient and potential underlying functional systems. Other tools to find causal genes based on phenotype were also investigated. The approach has been implemented as a workflow, named PhenCo, which can be adapted to any set of patients for which phenomic and genomic data is available. Full details of the analysis, including the clusters formed, their constituent functional systems and underlying genes are given. Code to implement the workflow is available from GitHub.


Assuntos
Comorbidade , Predisposição Genética para Doença , Genômica , Doenças Raras/genética , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas , Estudos de Associação Genética , Genoma Humano/genética , Genótipo , Humanos , Mutação/genética , Fenótipo , Doenças Raras/diagnóstico , Doenças Raras/patologia
5.
Development ; 147(21)2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32988995

RESUMO

Next-generation sequencing has greatly accelerated the discovery of rare human genetic diseases. Nearly 45% of patients have variants associated with known diseases but the unsolved cases remain a conundrum. Moreover, causative mutations can be difficult to pinpoint because variants frequently map to genes with no previous disease associations and, often, only one or a few patients with variants in the same gene are identified. Model organisms, such as Drosophila, can help to identify and characterize these new disease-causing genes. Importantly, Drosophila allow quick and sophisticated genetic manipulations, permit functional testing of human variants, enable the characterization of pathogenic mechanisms and are amenable to drug tests. In this Spotlight, focusing on microcephaly as a case study, we highlight how studies of human genes in Drosophila have aided our understanding of human genetic disorders, allowing the identification of new genes in well-established signaling pathways.


Assuntos
Drosophila melanogaster/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Animais , Modelos Animais de Doenças , Técnicas Genéticas , Genética Humana , Humanos , Microcefalia/diagnóstico , Microcefalia/genética
6.
BMC Med Inform Decis Mak ; 20(1): 230, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938448

RESUMO

BACKGROUND: Patients with rare diseases (RDs) are often diagnosed too late or not at all. Clinical decision support systems (CDSSs) could support the diagnosis in RDs. The MIRACUM (Medical Informatics in Research and Medicine) consortium, which is one of four funded consortia in the German Medical Informatics Initiative, will develop a CDSS for RDs based on distributed clinical data from ten university hospitals. This qualitative study aims to investigate (1) the relevant organizational conditions for the operation of a CDSS for RDs when diagnose patients (e.g. the diagnosis workflow), (2) which data is necessary for decision support, and (3) the appropriate user group for such a CDSS. METHODS: Interviews were carried out with RDs experts. Participants were recruited from staff physicians at the Rare Disease Centers (RDCs) at the MIRACUM locations, which offer diagnosis and treatment of RDs. An interview guide was developed with a category-guided deductive approach. The interviews were recorded on an audio device and then transcribed into written form. We continued data collection until all interviews were completed. Afterwards, data analysis was performed using Mayring's qualitative content analysis approach. RESULTS: A total of seven experts were included in the study. The results show that medical center guides and physicians from RDC B-centers (with a focus on different RDs) are involved in the diagnostic process. Furthermore, interdisciplinary case discussions between physicians are conducted. The experts explained that RDs exist which cannot be fully differentiated, but rather described only by their overall symptoms or findings: diagnosis is dependent on the disease or disease group. At the end of the diagnostic process, most centers prepare a summary of the patient case. Furthermore, the experts considered both physicians and experts from the B-centers to be potential users of a CDSS. The experts also have different experiences with CDSS for RDs. CONCLUSIONS: This qualitative study is a first step towards establishing the requirements for the development of a CDSS for RDs. Further research is necessary to create solutions by also including the experts on RDs.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Doenças Raras , Criança , Feminino , Humanos , Masculino , Médicos , Pesquisa Qualitativa , Doenças Raras/diagnóstico , Doenças Raras/terapia , Software
7.
Am J Hum Genet ; 107(3): 403-417, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32755546

RESUMO

Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide measures of how much any individual phenotypic observation has contributed to the prioritization result. However, given that the overall success rate of genomic diagnostics is only around 25%-50% or less in many cohorts, a good ranking cannot be taken to imply that the gene or disease at rank one is necessarily a good candidate. Here, we present an approach to genomic diagnostics that exploits the likelihood ratio (LR) framework to provide an estimate of (1) the posttest probability of candidate diagnoses, (2) the LR for each observed HPO phenotype, and (3) the predicted pathogenicity of observed genotypes. LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) placed the correct diagnosis within the first three ranks in 92.9% of 384 case reports comprising 262 Mendelian diseases, and the correct diagnosis had a mean posttest probability of 67.3%. Simulations show that LIRICAL is robust to many typically encountered forms of genomic and phenomic noise. In summary, LIRICAL provides accurate, clinically interpretable results for phenotype-driven genomic diagnostics.


Assuntos
Biologia Computacional , Bases de Dados Genéticas , Genômica , Doenças Raras/diagnóstico , Algoritmos , Exoma/genética , Humanos , Fenótipo , Doenças Raras/genética , Software
8.
Artigo em Inglês | MEDLINE | ID: mdl-32824597

RESUMO

Background: Increasing attention is being paid to improve the quality of life of patients with rare diseases in China. However, we are currently unaware of the problems encountered in the medical services of rare diseases from the viewpoints of doctors and patients. This study addressed the differences in the perceived barriers of diagnosis and treatments for rare diseases between doctors and patients in China. Methods: Two independent cross-sectional surveys on the perception of Chinese doctors' and patients' experiences with rare diseases were launched online between January and February 2018. A non-probability, convenience sampling method was employed to recruit participants. Results: In all, 45 rare diseases were reported by 139 doctors and 1853 patients. Patients with rare diseases faced significantly more difficulties in receiving accurate diagnosis (72.0%) and accessing information related to diagnosis and treatment (77.3%) as compared with doctors (34.5% and 40.3%, p < 0.0001, respectively). Specially, patients felt more difficulties than doctors in obtaining sustainable treatment for rare diseases (84.3% vs. 49.6%, p < 0.001). A higher percentage of patients (58.7%) than that of doctors (39.1%) had concerns in terms of the affordability of drugs. Further, 66.3% patients claimed that the drugs used to treat their conditions were not covered by their current medical insurances, whereas only 21.6% for doctors (p < 0.0001). Moreover, 35.3% of doctors responded that they recommended patients to visit the specialist they knew or were acquainted with, whereas 30.0% of patients said that their doctors chose to treat them based on their past experiences (p < 0.001). Conclusion: The perceived experience of patients with regard to diagnosis and treatment was significantly different from that of doctors. An integrated medical service platform should be established to facilitate better communication and mutual understanding of rare diseases between patients and doctors.


Assuntos
Qualidade de Vida , Doenças Raras , Adolescente , Adulto , Idoso , China , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Raras/diagnóstico , Doenças Raras/terapia , Inquéritos e Questionários , Adulto Jovem
9.
Folia Med Cracov ; 60(1): 55-60, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658212

RESUMO

An incarcerated epigastric hernia (localized in linea alba) is a very rare observation. Here, we present a case of a 66-year-old white male who was admitted to the emergency department due to vomiting and epigastric pain. On physical examination, the only observed abnormality was a painless soft epigastric tumor located in the upper midline, measuring about 12 cm in diameter. The patient claimed that he had the tumor for more than 30 years and it never changed in diameter nor caused him any discomfort. A lipoma was initially suspected. However, an ultrasound of the abdomen revealed an incarcerated stomach, trapped due to the defect in the epigastric abdominal wall. The patient was sent for surgery and the presence of an incarcerated epigastric hernia of the linea alba, which contained the anterior wall of the stomach was confirmed. The presented case confirms that the use of ultrasonography may be an effective method to recognize unusual types of hernias, and that ultrasonography should be routinely used in emergency departments.


Assuntos
Artérias Epigástricas/cirurgia , Hérnia Abdominal/diagnóstico , Hérnia Abdominal/cirurgia , Herniorrafia/métodos , Doenças Raras/diagnóstico , Doenças Raras/cirurgia , Ultrassonografia/métodos , Idoso , Humanos , Masculino , Período Pré-Operatório , Resultado do Tratamento
10.
Fortschr Neurol Psychiatr ; 88(8): 528-531, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32634845

RESUMO

Posterior cortical atrophy (PCA) is a rare neurodegenerative disease, which manifests with complex visual disturbances. PCA can present in isolation ('PCA-pure') or in association with other neurodegenerative disorders ('PCA-plus'). Diagnosis is nevertheless frequently delayed, as PCA is a less known disease entity and initially a primary ocular disease is taken into consideration.


Assuntos
Atrofia/patologia , Córtex Cerebral/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/patologia , Transtornos da Visão/diagnóstico , Diagnóstico Tardio , Humanos , Doenças Raras/diagnóstico , Doenças Raras/patologia , Síndrome , Transtornos da Visão/patologia
11.
Nature ; 583(7814): 96-102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581362

RESUMO

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.


Assuntos
Internacionalidade , Programas Nacionais de Saúde , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Bases de Dados Factuais , Eritrócitos/metabolismo , Fator de Transcrição GATA1/genética , Humanos , Fenótipo , Locos de Características Quantitativas , Receptores de Trombopoetina/genética , Medicina Estatal , Reino Unido
12.
Pediatr Pulmonol ; 55(7): 1828-1837, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32533908

RESUMO

Childhood rare lung diseases comprise a large number of heterogeneous respiratory disorders that are individually rare but are collectively associated with substantial morbidity, mortality, and healthcare resource utilization. Although the genetic mechanisms for several of these disorders have been elucidated, the pathogenesis mechanisms for others remain poorly understood and treatment options remain limited. Childhood rare lung diseases are enriched for genetic etiologies; identification of the disease mechanisms underlying these rare disorders can inform the biology of normal human lung development and has implications for the treatment of more common respiratory diseases in children and adults. Advances in "-omics" technology, such as genomic sequencing, clinical phenotyping, biomarker discovery, genome editing, in vitro and model organism disease modeling, single-cell analyses, cellular imaging, and high-throughput drug screening have enabled significant progress for diagnosis and treatment of rare childhood lung diseases. The most striking example of this progress has been realized for patients with cystic fibrosis for whom effective, personalized therapies based on CFTR genotype are now available. In this chapter, we focus on recent technology advances in childhood rare lung diseases, acknowledge persistent challenges, and identify promising new technologies that will impact not only biological discovery, but also improve diagnosis, therapies, and survival for children with these rare disorders.


Assuntos
Pneumopatias , Doenças Raras , Animais , Criança , Genômica , História do Século XXI , Humanos , Pneumopatias/diagnóstico , Pneumopatias/genética , Pneumopatias/história , Fenótipo , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/história
13.
HNO ; 68(8): 581-589, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32583063

RESUMO

BACKGROUND: Silent sinus syndrome (SSS), organized hematoma (OH), and pneumosinus dilatans (PD) are rare, usually unilateral diseases of the maxillary sinus. Due to misinterpretation, excessive diagnostics and unnecessarily aggressive surgery or a delay in diagnostics and treatment are common. OBJECTIVE: The objective of this study was to develop reasonable and comprehensible diagnostic criteria to improve diagnosis and treatment of these rare diseases. METHODS: In this retrospective study, all patients treated for SSS, OH, and PD from 2012 to 2019 were identified. Patient history, diagnostic tests and results, and postoperative course were analyzed and compared with the available literature. RESULTS: During the study period, 7 patients with SSS, 3 patients with PD, and 2 patients with OH were treated and available for follow-up. Comparison of these patients with the literature allowed us to develop diagnostic criteria. CONCLUSION: Medical history combined with endoscopic and radiologic criteria should improve preoperative diagnosis of these three rare diseases of the maxillary sinus and help to distinguish them from other differential diagnoses. This approach should minimize morbidity for the patients.


Assuntos
Seio Maxilar , Doenças dos Seios Paranasais , Doenças Raras , Humanos , Doenças dos Seios Paranasais/diagnóstico , Doenças Raras/diagnóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
14.
BMC Infect Dis ; 20(1): 366, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448208

RESUMO

BACKGROUND: Kosakonia cowanii, formerly known as Enterobacter cowanii, is a Gram-negative bacillus belonging to the order Enterobacterales. The species is usually recognized as a plant pathogen and has only anecdotally been encountered as a human pathogen. Here we describe the rare case of a K. cowanii infection presenting as an acute cholecystitis and provide a review of available literature. Evident difficulties in species identification by biochemical profiling suggests that potentially, K. cowanii might represent an underestimated human pathogen. CASE PRESENTATION: A 61-year old immunocompromised man presented to the hospital with fever and pain in the upper right abdomen. Sonography revealed an inflamed gall bladder and several gall stones. A cholecystectomy proved diagnosis of an acute cholecystitis with a partial necrosis of the gall bladder. Surgical specimen grew pure cultures of Gram-negative rods unambiguously identified as K. cowanii by MALDI-TOF, 16S-rRNA analysis and whole genome sequencing. CONCLUSIONS: Reporting cases of Kosakonia species can shed light on the prevalence and clinical importance of this rare cause of human infection. Our case is the first to describe an infection without prior traumatic inoculation of the pathogen from its usual habitat, a plant, to the patient. This raises the question of the route of infections as well as the pathogen's ability to colonize the human gut.


Assuntos
Colecistite Aguda/diagnóstico , Colecistite Aguda/microbiologia , Infecções por Enterobacteriaceae/diagnóstico , Enterobacteriaceae/genética , Doenças Raras/diagnóstico , Doenças Raras/microbiologia , Colecistectomia , Infecções por Enterobacteriaceae/microbiologia , Vesícula Biliar/patologia , Cálculos Biliares/cirurgia , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Necrose , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Resultado do Tratamento , Sequenciamento Completo do Genoma
15.
Ned Tijdschr Geneeskd ; 1642020 04 30.
Artigo em Holandês | MEDLINE | ID: mdl-32395952

RESUMO

According to the European definition, rare diseases are life-threatening or chronically debilitating conditions that affect only 5 out of 10,000 people in the European Union. It is estimated that there are around 6000-8000 different rare diseases, affecting 6-8% of the population in the course of their lives. For the Netherlands, this means that about 1 million people are affected by a rare disease, or one in 17 people. Patients with rare diseases indicate that they often have a long and uncertain diagnostic journey behind them, while the first symptoms present in childhood in 75% of the rare diseases. In this perspective, we discuss some of the results from the research report 'Scherperzicht op diagnostischevertragingbijzeldzameaandoeningen' in which the diagnostic journey for patients with rare diseases is mapped out with figures. We also make recommendations to speed up the diagnostic process for patients with rare diseases.


Assuntos
Diagnóstico Tardio/tendências , Doenças Raras/diagnóstico , Adulto , Criança , União Europeia , Feminino , Humanos , Masculino , Países Baixos/epidemiologia , Doenças Raras/epidemiologia
16.
Ned Tijdschr Geneeskd ; 1642020 04 30.
Artigo em Holandês | MEDLINE | ID: mdl-32395955

RESUMO

Not only rare diseases are uncommon. There are also rare presentations of common diseases, not to mention rare side effects of infrequently prescribed or new drugs. Not all of these rare disease presentations have a genetic causal component. Additional (genetic or non-genetic) ancillary diagnostic tests, in which some of the inevitably occurring chance findings will present us with new problems, are not the solution for this problem, nor are disease or therapy oriented centres of expertise. The solution should be sought in pattern recognition; not by the individual physician, but through collaboration of physicians who take the time to give meaning to carefully obtained clinical parameters in individual patients. The size and composition of such a - often ad hoc - partnership should be adapted to each individual situation.


Assuntos
Comunicação Interdisciplinar , Administração dos Cuidados ao Paciente/métodos , Doenças Raras/diagnóstico , Diagnóstico Diferencial , Humanos
17.
Oncology ; 98(8): 513-519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32408297

RESUMO

Background and summary: Among all vulvar cancers, primary adenoid cystic carcinoma (ACC) of Bartholin's gland is a very rare tumor characterized by a slow growth, a high local aggressiveness, and a remarkable recurrence rate. Due to its rarity, treatment remains a challenge for oncologists and gynecological surgeons. Key message: The present paper reports clinical, radiological, and histological features of ACC of Bartholin's gland and reviews the literature data on the treatment options with a particular focus on the potential role of particle radiation therapy.


Assuntos
Glândulas Vestibulares Maiores/patologia , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoide Cístico/radioterapia , Neoplasias Vulvares/patologia , Neoplasias Vulvares/radioterapia , Carcinoma Adenoide Cístico/diagnóstico , Carcinoma Adenoide Cístico/tratamento farmacológico , Feminino , Radioterapia com Íons Pesados/métodos , Humanos , Recidiva Local de Neoplasia , Prognóstico , Doenças Raras/diagnóstico , Doenças Raras/patologia , Doenças Raras/radioterapia , Fatores de Risco , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/tratamento farmacológico
18.
Nature ; 581(7809): 452-458, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32461655

RESUMO

The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)1, we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the 'proportion expressed across transcripts', which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project2 and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies.


Assuntos
Doença/genética , Haploinsuficiência/genética , Mutação com Perda de Função/genética , Anotação de Sequência Molecular , Transcrição Genética , Transcriptoma/genética , Transtorno do Espectro Autista/genética , Conjuntos de Dados como Assunto , Deficiências do Desenvolvimento/genética , Éxons/genética , Feminino , Genótipo , Humanos , Deficiência Intelectual/genética , Masculino , Anotação de Sequência Molecular/normas , Distribuição de Poisson , RNA Mensageiro/análise , RNA Mensageiro/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Reprodutibilidade dos Testes , Sequenciamento Completo do Exoma
19.
BMC Med Genet ; 21(1): 79, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295532

RESUMO

BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.


Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Erros Inatos do Metabolismo/genética , Transportadores de Sulfato/genética , Diarreia/diagnóstico , Diarreia/genética , Diarreia/patologia , Feminino , Genes Recessivos/genética , Testes Genéticos , Bócio Nodular/diagnóstico , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Mutação , Linhagem , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Irmãos
20.
Bull Cancer ; 107(5): 601-611, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32305127

RESUMO

Sinonasal carcinomas account for 3% of ENT cancers. They are subdivided into squamous cell carcinomas (50%), adenocarcinomas [20%, mostly of intestinal type (ITAC)], and more rarely, adenoid cystic carcinomas, olfactory neuroblastomas (=esthesioneuroblastomas), neuroendocrine carcinomas or undifferentiated sinonasal carcinomas (SNUC). The 5-year survival rates are, in descending order, 72% for neuroblastomas, 63% for adenocarcinomas, 50-60% for large-cell neuroendocrine carcinomas, 53% for squamous cell carcinomas, 25-50% for adenoid cystic, 35% for small-cell neuroendocrine carcinomas and 35% for SNUC and newly discovered histologies. Surgery is the main treatment; endoscopic approaches reduce the morbidity with equivalent tumour control. Intensity-modulated radiation therapy (IMRT) is almost systematic. Nodal involvement is rare in ethmoidal adenocarcinomas and adenoid cystic carcinomas; it is intermediate and may justify prophylactic radiotherapy for N0 necks in SNUC, neuroblastoma, squamous cell carcinomas and sinonasal neuroendocrine carcinomas. IMRT or proton therapy is the mainstay of treatment of unresectable disease. Radiotherapy optimization by carbon ion therapy for adenoid cystic carcinomas, or by chemotherapy for all carcinomas with IMRT or proton therapy, is investigated within clinical trials in France. Neoadjuvant chemotherapy is reserved for rapidly progressive disease or histologies with a high metastatic potential such as neuroendocrine carcinomas or SNUC. Given their histologic and molecular specificities and different relapse patterns, an expertise of the REFCOR network, with REFCORpath review, is likely to correct diagnoses, rectify treatments, with an impact on survival.


Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias dos Seios Paranasais , Doenças Raras , Adenocarcinoma/classificação , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Carcinoma Adenoide Cístico/diagnóstico , Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/terapia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/terapia , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Humanos , Neoplasias dos Seios Paranasais/classificação , Neoplasias dos Seios Paranasais/diagnóstico , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/terapia , Prognóstico , Doenças Raras/diagnóstico , Doenças Raras/mortalidade , Doenças Raras/terapia
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