Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with Ϸ50% of familial cases being heterozygous for mutations in the receptor tyrosine kinase RET. Even when identified, the penetrance of RET mutations is only 50 -70%, gender-dependent, and varies with the extent of aganglionosis. We searched for additional susceptibility genes which, in conjunction with RET, lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of families: six families harboring severe RET mutations (group I); and the six remaining families, five of which are RET-linked families with no sequence alterations and one RET-unlinked family (group II). Although the presence of RET mutations in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibility locus on 9q31 exclusively in group II families. As such, the gene at 9q31 is a modifier of HSCR penetrance. These observations imply that identification of new susceptibility factors in a complex disease may depend on classification of families by mutational type at known susceptibility genes.A major hallmark of phenotypes displaying a complex pattern of inheritance is the segregation of multiple factors. In principle, linkage analysis on a collection of families can identify multiple loci, although an individual family may segregate only a few of the relevant genes. Multilocus segregation is compatible with two distinct hypotheses. Thus, a phenotype could be multigenic or multifactorial, resulting from the cumulative effects of mutations in multiple genes; disease expression and penetrance may then be sensitive to an individual's genetic background. This hypothesis is in contrast to the simple association of a disorder with multiple genes, genetic (locus) heterogeneity, in which mutations in any one of several genes are sufficient for phenotypic expression and are independent of genetic background. In either scenario, linkage heterogeneity exists, but, for the multigenic hypothesis to prevail, we need to demonstrate multiple gene segregation in the same families (1). Although unequivocal evidence for multigenic inheritance exists in the many rodent models of human disease, and is strongly suspected in complex human disorders, it remains largely unproven. However, in the human, in rare instances, retinitis pigmentosa can arise from digenic inheritance (2); segregation of insulin-dependent diabetes mellitus depends on interactions between both HLA and an X-linked gene (3).Hirschsprung disease (HSCR), or congenital aganglionosis, is a model complex genetic disorder in which we can test these hypotheses. HSCR is associated with the lack of intrinsic ganglion cells in the myenteric and submucosal plexuses of the distal gastrointestinal tract. The phenotype has Ϸ100% heritability (4) but shows variable presentation and reduced p...

ObjectivesTrauma is a significant cause of morbidity and mortality worldwide. The literature on paediatric trauma epidemiology in low- and middle-income countries (LMICs) is limited. This study aims to gather epidemiological data on paediatric trauma.MethodsThis is a multicentre prospective cohort study of paediatric trauma admissions, over 1 month, from 15 paediatric surgery centres in 11 countries. Epidemiology, mechanism of injury, injuries sustained, management, morbidity and mortality data were recorded. Statistical analysis compared LMICs and high-income countries (HICs).ResultsThere were 1377 paediatric trauma admissions over 31 days; 1295 admissions across ten LMIC centres and 84 admissions across five HIC centres. Median number of admissions per centre was 15 in HICs and 43 in LMICs. Mean age was 7 years, and 62% were boys. Common mechanisms included road traffic accidents (41%), falls (41%) and interpersonal violence (11%). Frequent injuries were lacerations, fractures, head injuries and burns. Intra-abdominal and intra-thoracic injuries accounted for 3 and 2% of injuries. The mechanisms and injuries sustained differed significantly between HICs and LMICs. Median length of stay was 1 day and 19% required an operative intervention; this did not differ significantly between HICs and LMICs. No mortality and morbidity was reported from HICs. In LMICs, in-hospital morbidity was 4.0% and mortality was 0.8%.ConclusionThe spectrum of paediatric trauma varies significantly, with different injury mechanisms and patterns in LMICs. Healthcare structure, access to paediatric surgery and trauma prevention strategies may account for these differences. Trauma registries are needed in LMICs for future research and to inform local policy.

Lethal white foal syndrome (LWFS) is a congenital anomaly of horses characterized by a white coat colour and aganglionosis of the bowel, which is similar to Hirschsprung disease (HSCR). We decided to investigate possible mutations of the endothelin-B receptor gene ( EDNRB ) in LWFS as recent studies in mutant rodents and some patients have demonstrated EDNRB defects. First, we identified a full-length cDNA for horse EDNRB . This cDNA fragment contained a 1329 bp open reading frame which encoded 443 amino acid residues. The predicted amino acid sequence was 89, 91 and 85% identical to human, bovine and mouse as well as rat EDNRB respectively, but only 55% identical to the human, bovine and rat endothelin A receptor (EDNRA). Secondly, sequence analysis, together with allele-specific PCR and the amplification-created restriction site (ACRS) technique, revealed a dinucleotide TC-->AG mutation, which changed isoleucine to lysine in the predicted first transmembrane domain of the EDNRB protein. This was associated with LWFS when homozygous and with the overo phenotype when heterozygous.

Placental mesenchymal dysplasia is an uncommon disorder in which the placenta is enlarged with abnormal, large, and often cystic villi with dilated and/or thick-walled vessels. These placental changes can mimic a partial hydatidiform mole but in contrast to a partial mole can coexist with a fully viable fetus. Fetal anatomical and vascular anomalies frequently coexist with placental mesenchymal dysplasia. In this case, placental mesenchymal dysplasia was associated with preterm labor at 33 weeks' gestation, fetal compromise, and a large abdominal mass with a large hepatic cyst that was de-roofed at exploratory laparotomy. The neonate remained critically ill with hypoxic ischaemic encephalopathy and coagulopathy and died despite intensive care. Biopsy and autopsy findings showed a large cystic mesenchymal hamartoma affecting the left lobe of the liver. This appears to be the 3rd histologically confirmed association of placental mesenchymal dysplasia with mesenchymal hamartoma of the liver in the English language literature.

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Background/AimsRats with a spontaneous null mutation in endothelin receptor type B or Ednrb (sl/sl; spotting lethal) lack enteric neurons in the distal bowel and usually die within the first week after birth. This early postnatal lethality limits their use for examining the potential of cell therapy to treat Hirschsprung disease, and for studies of the influence of EDNRB on the mature CNS and vascular systems. MethodsWe have developed a surgical intervention to prolong the life of the spotting lethal sl/sl rat, in which we perform a colostomy on postnatal (P) day 4-6 rats to avoid the fatal obstruction caused by the lack of colonic enteric neurons. ResultsThe stomas remained patent and functional and the rats matured normally following surgery. Weight gains were comparable between control and Hirschsprung phenotype (sl/sl) rats, which were followed until 4 weeks after surgery (5 weeks old). We confirmed the absence of enteric neurons in the distal colon of rats whose lives were saved by the surgical intervention. ConclusionsThis study provides a novel approach for studying EDNRB signalling in multiple organ systems in mature rats, including an animal model to study the efficacy of cell therapy to treat Hirschsprung disease. (J Neurogastroenterol Motil 2015;21:552-559)

BackgroundMicro-CT holds promising potential for phenotyping and histological purposes. However, few have clarified the difference in the neuroimaging quality between ex vivo and in vivo micro-CT scanners. In addition, no direct comparison has been made between micro-CT scans and standard microscopy. Furthermore, while the efficacy of various stains for yielding soft-tissue contrast in CT scans have been compared in other studies for embryos, staining protocols for larger samples have yet to be clarified. Lastly, post-acquisition processing for image enhancements have not been addressed.MethodsComparisons of postnatal rat brain micro-CT scans obtained through custom-built ex vivo and commercially available in vivo micro-CT scanners were made. Subsequently, the scanned rat brains were then H&E stained for microscopy. Neuroanatomy on micro-CT scanning and 4× microscopy of rat brain were compared.Diffusion and perfusion staining using iodine or PTA were trialled on adult and neonatal encapsulated rat brains. Different combinations of stain concentration and staining time were trialled.Post-acquisition denoising with NLM filter was completed using a modern General-Purpose Graphic Processing Unit (GPGPU) and custom code for prompt processing.ResultsEx vivo micro-CT scans of iodine-stained postnatal rat brains yields 3D images with details comparable to 4× H&E light micrographs. Neural features shown on ex vivo micro-CT scans were significantly more distinctive than those on in vivo micro-CT scans.Both ex vivo and in vivo micro-CT scans required diffusion staining through small craniotomy. Perfusion staining is ineffective. Iodine staining was more efficient than PTA in terms of time.Consistently, enhancement made by NLM denoising on in vivo micro-CT images were more pronounced than that on ex vivo micro-CT scans due to their difference in image signal-to-noise indexes.ConclusionsMicro-CT scanning is a powerful and versatile visualization tool available for qualitative and potential quantitative anatomical analysis. Simple diffusion staining via craniotomy with 1.5% iodine is an effective and minimal structural-invasive method for both in vivo and ex vivo micro-CT scanning for studying the microscopic morphology of neonatal and adult rat brains. Post-acquisition NLM filtering is an effective enhancement technique for in vivo micro-CT brain scans.Electronic supplementary materialThe online version of this article (10.1186/s12880-018-0280-6) contains supplementary material, which is available to authorized users.

The changing profile of paediatric cholecystectomy is a little recognised aspect of the 'obesity epidemic'. This has implications when considering the impact of childhood overweight and obesity, and for clinicians involved in the diagnosis and management of these children.