Gastroschisis is a defect of the Umbilical ring: Evidence from Morphological evaluation of stillborn fetuses

Rittler, Mónica; Vauthay, Liliana; Mazzitelli, Nancy

doi:10.1002/bdra.23130

Cited by 38 publications

(46 citation statements)

References 53 publications

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“…Gastroschisis appears to be an abnormality of the rudimentary umbilical ring at the amnio‐ectodermal junction in which bowel and often other organs are prolapsed outside of the body (Opitz, Feldkamp, & Botto, ; Rittler, Vauthay, & Mazzitelli, ) leading to severe fetal and postnatal intestinal damage. Despite considerable research, the etiology and pathogenesis of gastroschisis are poorly understood (Castilla, Mastroiacovo, & Orioli, ; Feldkamp, Botto, Byrne, Krikov, & Carey, ).…”

Section: Introductionmentioning

confidence: 99%

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Feldkamp

Krikov

Gardner

et al. 2019

Birth Defects Research

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Objectives: Gastroschisis remains an etiologic dilemma. We posit that an underlying genetic susceptibility either separately or coupled with a periconceptional environmental exposure stimulates an inflammatory response resulting in gastroschisis. To investigate the genetic link, we applied shared genomic segment (SGS) analysis, a novel approach to discover chromosomal segments that inherit in high-risk multigenerational pedigrees. Methods: We studied pedigrees containing distantly related children with gastroschisis originating from a common ancestor. We used the Illumina OmniExpress genotyping array with >700,000 SNPs. Samples from 40 affected children in 13 pedigrees (≥3 affected children) were genotyped to generate the high-density SNP data necessary to perform SGS analysis. Assessment of significance in SGS was determined empirically using simulations based on precise pedigree structure and modeling linkage disequilibrium (LD) for SNPs in the general population to properly account for genetic architecture. The LD model was estimated from the 1000 Genome Project using the same set of SNPs. Genome-wide significance thresholds were determined for each pedigree. Results: We identified six pedigrees that contained genome-wide statistically significant SGS regions inherited from a common founder. These regions were different in each pedigree, all contained immune pathway genes. Discussion: The genome-wide significant regions support a genetic susceptibility for gastroschisis. The regions are compelling candidates for regionally focused genome sequencing, enabling the discovery of coding or noncoding (e.g., regulatory) risk variants, the latter of which are unlikely to be found using conventional exomic/genefocused approaches. This technique provides a comprehensive and focused genomic interrogation that will help to advance our understanding of gastroschisis. K E Y W O R D Sgastroschisis, genetics, high-risk multigenerational pedigrees

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Section: Introductionmentioning

confidence: 99%

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Feldkamp

Krikov

Gardner

et al. 2019

Birth Defects Research

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“…A possible role for thrombosis in this process has been suggested to account for an unusual epidemiology shared with other disorders with apparent disruptive origins [Lubinsky, ]. However, new evidence that herniation occurs solely between the umbilical cord and ring, plus other morphological findings, casts doubt on these developmental hypotheses, which see a full thickness separation between the abdominal wall and the cord [Rittler et al, ].…”

Section: Introductionmentioning

confidence: 99%

A vascular and thrombotic model of gastroschisis

Lubinsky¹

2014

American J of Med Genetics Pt A

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A binary vascular/thrombotic pathogenesis for gastroschisis, a form of congenital bowel herniation, is proposed, where normal right umbilical vein involution creates a possible site for thrombosis adjacent to the umbilical ring. If thrombosis occurs, it weakens the area, explaining overwhelmingly right-sided lesions. The model arises from the existence of two groups of risk factors with different maternal age associations. Older mothers show a greater association with vascular factors (although this may actually represent a lack of any significant maternal age effect), consistent with associations of gastroschisis with congenital heart lesions and with amyoplasia. Alternatively, other predispositions, and especially decreased maternal age, the greatest known risk factor, associate with factors raising maternal estrogen, with evidence that estrogen in turn acts here as a predisposition to thrombosis. Absorption of thrombotic by-products from the amniotic fluid can explain the unusual amniocyte inclusions that are common with gastroschisis, while a role for estrogens suggests a connection between rising gastroschisis prevalence and increasing environmental contamination with estrogen disruptors. This model explains a variety of structural and epidemiological findings, and suggests that stratification of data based on binary effects may clarify associated risks and mechanisms. The model also shows that what is often referred to as vascular disruption may actually reflect alternative or additional factors instead, including thrombosis as a primary mechanism.

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“…Other mechanisms of causation have also been postulated, including gastroschisis being related to a defect in the umbilical ring. In five affected stillborn infants, the umbilical cord was attached to the left side of the umbilical ring, but the right side was uncovered, which allowed for evisceration of the intestine as occurs in gastroschisis (Rittler, Vauthay, & Mazzitelli, ).…”

Section: Discussionmentioning

confidence: 99%

Malformations attributed to the process of vascular disruption

Holmes

Westgate

Nasri

et al. 2018

Birth Defects Research

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Malformations attributed to the process of vascular disruption were a distinctive entity, among the recognized etiologies. The timing of the causative event in the first trimester was established for infants with exposures to either the prostaglandin misoprostol or the prenatal diagnosis procedure chorionic villus sampling. One challenge is to identify the developmental steps in vascular disruption when no causative exposure can be identified.

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Gastroschisis is a defect of the Umbilical ring: Evidence from Morphological evaluation of stillborn fetuses

Cited by 38 publications

References 53 publications

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

A vascular and thrombotic model of gastroschisis

Malformations attributed to the process of vascular disruption

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