RESUMEN
PURPOSE: Hirschsprung's disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype-phenotype relationship. METHODS: We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance. RESULTS: Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33-50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance. CONCLUSION: We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases.
Asunto(s)
Enfermedad de Hirschsprung , Obstrucción Intestinal , Receptor de Endotelina B , Humanos , Recién Nacido , China/epidemiología , Enfermedad de Hirschsprung/genética , Incidencia , Mutación , Receptor de Endotelina B/genéticaRESUMEN
BACKGROUND: Hirschsprung's disease (HD) is a rare congenital digestive tract malformation in children. Roles of long non-coding RNAs (lncRNAs) are highlighted in various human diseases. However, knowledge on lncRNAs in HD is still limited. METHODS: The profile of lncRNAs in 8 pairs of normal and stenosed intestinal tissue of HD patients were obtained using microarray analysis. Base on bioinformatics analysis, the level of selected LINC01579-204, NEFL and miR-203a-3p was detected by qRT-PCR in 36 pairs of normal and stenosed intestinal tissue of HD patients. Then the predictive accuracy of LINC01579-204, miR-203a-3p and NEFL level to evaluate the progression of HD patients was analyzed with receiver operating characteristic curve (ROC). RESULTS: A total of 90 differentially expressed lncRNAs were detected in normal and stenosed intestinal tissue of HD patients (|fold change| ≥ 1.5, p < 0.05). The level of LINC01579-204 and NEFL decreased and miR-203a-3p increased significantly in 36 pairs of stenosed intestinal tissue of HD patients compared to the control. A notable positive correlation was identified between LINC01579-204 and NEFL (r = 0.9681, p < 0.0001). Areas under the ROC curve of the LINC01579-204, miR-203a-3p and NEFL signature were 0.715, 0.777 and 0.829, respectively. CONCLUSIONS: LINC01579-204, miR-203a-3p, and NEFL are predicted to play important roles in the progression of HD. LINC01579-204, miR-203a-3p and NEFL had a significant overall predictive ability to identify progression of HD patients. The novel experimental and bioinformatic results achieved in this study may provide new insights into the molecular of HD.
Asunto(s)
Enfermedad de Hirschsprung , MicroARNs , ARN Largo no Codificante , Niño , Humanos , MicroARNs/metabolismo , Enfermedad de Hirschsprung/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Curva ROC , Proliferación CelularRESUMEN
BACKGROUND: Enhanced recovery after surgery (ERAS) has been widely used in adult surgery. However, ERAS has not been reported in neonatal surgery. The present prospective study explored the application value of ERAS in treating congenital duodenal obstruction (CDO). METHODS: A total of 68 cases of CDO were collected from October 1, 2017 to July 31, 2019. We divided patients with a prenatal diagnosis of congenital duodenal obstruction into the ERAS group and those who were diagnosed the disease after birth into the control group. The ERAS group adopted ERAS-related measures, and the control group followed the usual measures. The study compared the differences in the gestational age, birth weight, length of hospital stay (LOS), complications, feeding intolerance, and weight one month after surgery between the two groups. RESULTS: A total of 49 patients were included in the analysis, including 23 who were allocated to the ERAS group and 26 to the control group. The LOS was 9.696±1.222 days in the ERAS group and 12.654±1.686 days in the control group, resulting in a significantly shorter LOS in the ERAS group than in the control group (p<0.001). One month after surgery, the neonates in the ERAS group weighted significantly more than those in the control group. No differences were observed in birth weight, gestational age, and the incidence of complications or feeding intolerance between the two groups. CONCLUSION: In this single-center study, the implementation of neonate-specific ERAS for CDO surgery was feasible and safe and led to a shorter LOS without increasing the incidence of complications or feeding intolerance. TYPE OF STUDY: Treatment Study LEVEL OF EVIDENCE: Level III.
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Obstrucción Duodenal , Recuperación Mejorada Después de la Cirugía , Obstrucción Duodenal/congénito , Obstrucción Duodenal/cirugía , Femenino , Humanos , Recién Nacido , Tiempo de Internación , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Embarazo , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Hirschsprung disease (HD) is a congenital intestinal anomaly resulting from a failure to form enteric ganglia in the lower bowel. Surgery is the main therapeutic strategy, although neural stem cell transplantation has recently shown promise. However, HD remains a challenging disorder to treat. Our aim was to identify drugs that could counteract the dysregulated pathways in HD and could thus be potential novel therapies. METHODS: We used microarray analysis to identify genes differentially expressed in ganglionic and aganglionic bowel samples from eight children with HD. The signature of differentially expressed genes was then used as a search query to explore the Connectivity Map (cMAP), a transcriptional expression database that catalogs gene signatures elicited by chemical perturbagens. RESULTS: We uncovered several dysregulated signaling pathways, and in particular regulation of neuron development, in HD. The cMAP search identified some compounds with the potential to counteract the effects of the dysregulated molecular signature in this disease. One of these, pepstatin A, was recently shown to rescue the migration defects observed in a mouse model of HD, providing strong support for our findings. CONCLUSIONS: This study advances our understanding of the molecular changes in HD and identifies several potential pharmacological interventions. Further testing of the identified compounds is warranted.
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Minería de Datos , Bases de Datos Genéticas , Fármacos Gastrointestinales/uso terapéutico , Perfilación de la Expresión Génica , Enfermedad de Hirschsprung/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Transcriptoma , Femenino , Marcadores Genéticos , Enfermedad de Hirschsprung/tratamiento farmacológico , Humanos , Lactante , Masculino , ARN/análisisRESUMEN
OBJECTIVE: To investigate the operation timing of newborns with rectosigmoid Hirschsprung's disease (HD). METHODS: From March 2013 to September 2015, 35 newborns diagnosed as rectosigmoid HD in our department were prospectively and randomly divided into 2 groups: less than 3 months treatment group (18 cases) and more than 3 months treatment group (17 cases, conservative treatment for 3 months). They all underwent laparoscopic-assisted transanal endorectal pull-through (LATEP) (modified Soave) procedure. Clinical data, perioperative conditions, postoperative complication, postoperative anal function evaluated by Wingspread score and barium enema were compared between two groups. RESULTS: The baseline data of two groups were comparable (all P>0.05). All the cases completed single-stage LATEP procedure successfully without conversion to open operation. Compared with more than 3 months treatment group, preoperative bowel preparation time and operation time were significantly shorter [(6.2±3.3) vs. (9.3±4.1) days, P=0.042; (95±15) vs.(121±23) minutes, P=0.029, respectively], intra-operative blood loss was significantly less [(13±3) ml vs. (22±5) ml, P=0.036], length of resected bowel was significantly shorter [(16±5) cm vs.(23±8) cm, P=0.033], and bowel movement recovery time, parenteral nutrition time, hospital stay were also significantly shorter [(2.3±0.5) vs. (2.9±0.6) days, P=0.046; (5.1±2.1) vs. (5.9±2.3) days, P=0.048; (12.9±3.3) vs. (15.8±4.3) days, P=0.049, respectively] in less than 3 months treatment group. No short-term complications, such as anastomotic leak, interlayer infection and abdominal infection occurred in both groups. The follow-up period ranged from 2 months to 24 months. Only the incidence of perianal excoriation was significantly higher in less than 3 months treatment group compared with more than 3 months treatment group [50.0%(9/18) vs. 23.5%(4/17), P=0.045]. Wingspread score results at 6 and 12 months after operation showed excellent rate of postoperative anal function, which was not significantly different between two groups[ <3 months group : 81.3%(13/16) and 92.9%(13/14); >3 months group: 85.7%(12/14) and 92.3%(12/13), all P>0.05]. Postoperative barium enema results at 6 and 12 months after operation all showed normal shape of colon without residue of barium. CONCLUSIONS: For newborns with rectosigmoid HD, single-stage definitive operation performed at the age less than 3 months has the advantages of shorter preoperative preparation time, less operating injury, shorter resected bowel, and faster postoperative recovery as compared to the age more than 3 months. If rectosigmoid HD is definitively diagnosed, early operation is suggested to perform at the age less than 3 months.