RESUMEN
In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5% (4/266) of all patients, 4% (3/77) of all familial cases and 7% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , ADN Polimerasa II/genética , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal , Mutación Missense , Adenoma/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Neoplasias Colorrectales/enzimología , ADN Polimerasa Dirigida por ADN/genética , Salud de la Familia , Femenino , Frecuencia de los Genes , Humanos , Isoenzimas/genética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Fosfolipasa D/genética , Proteínas de Unión a Poli-ADP-Ribosa , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Adulto JovenRESUMEN
BACKGROUND: Advances in diagnostic imaging and the introduction of damage control strategy in trauma have influenced our approach to treating liver trauma patients. The objective of the present study was to investigate the impact of change in liver trauma management on outcome. METHODS: A total of 468 consecutive patients with liver trauma treated between 1986 and 2010 at a single level 1 trauma center were reviewed. Mechanisms of injury, diagnostic imaging, hepatic and associated injuries, management (operative [OM] vs. nonoperative [NOM]), and outcome were evaluated. The main outcome analysis compared mortality for the early study period (1986-1996) versus the later study period (1997-2010). RESULTS: 395 patients (84%) presented with blunt liver trauma and 73 (16%) with penetrating liver trauma. Of these, 233 patients were treated with OM (50%) versus 235 with NOM (50%). The mortality rate was 33% for the early period and 20% for the later period (odds ratio 0.19; 95% CI 0.07-0.50, P = 0.001). A significantly increased use of computed tomography (CT) as the initial diagnostic modality was observed in the late period, which almost completely replaced peritoneal lavage and ultrasound. There was a significant shift to NOM in the later period (early 15%, late 63%) with a low conversion rate to OM of 4.2%. Age, degree of hepatic and head injury, injury severity, intubation at admission, and early period were independent predictors of mortality in the multivariate analysis. CONCLUSIONS: Integration of CT in early trauma-room management and shift to NOM in hemodynamically stable patients resulted in improved survival and should be the gold standard management for liver trauma.
Asunto(s)
Hígado/lesiones , Tomografía Computarizada por Rayos X , Heridas no Penetrantes , Heridas Penetrantes , Adulto , Femenino , Hemodinámica , Mortalidad Hospitalaria , Humanos , Laparoscopía , Laparotomía , Hígado/diagnóstico por imagen , Hígado/cirugía , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índices de Gravedad del Trauma , Resultado del Tratamiento , Espera Vigilante , Heridas no Penetrantes/diagnóstico por imagen , Heridas no Penetrantes/mortalidad , Heridas no Penetrantes/terapia , Heridas Penetrantes/diagnóstico por imagen , Heridas Penetrantes/mortalidad , Heridas Penetrantes/terapiaRESUMEN
INTRODUCTION: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all birth defects. NSCL/P has a multifactorial etiology that includes both genetic and environmental factors. The IRF6 gene and three further susceptibility loci at 8q24, 10q25, and 17q22, which were identified by a recent genome-wide association scan (GWAS), are confirmed genetic risk factors for NSCL/P in patients of European descent. METHODS: A case-control association study was performed to investigate whether these four risk loci contribute to NSCL/P in a Mesoamerican population using four single nucleotide polymorphisms to represent IRF6 and the three novel susceptibility loci. A total of 149 NSCL/P patients and 303 controls of Mayan origin were included. RESULTS: Single marker analysis revealed a significant association between NSCL/P and risk variants in IRF6 and the 8q24 and 10q25 loci. In contrast to previous findings, the association at the 8q24 locus was driven solely by homozygote carriers of the risk allele. This suggests that this locus might act in a recessive manner in the Mayan population. No evidence for association was found at the 17q22 locus. This may have been attributable to the limited power of the sample. CONCLUSION: These results suggest that IRF6 and the 10q25 and 8q24 loci confer a risk for the development of NSCL/P in persons of Mayan origin.