Considering the Embryopathogenesis of VACTERL Association

Abstract

The nonrandom co-occurrence of vertebral, anorectal, cardiac, tracheoesophageal, genitourinary, and limb malformations, recognized as the VACTERL association, has not been satisfactorily explained from either a causation or embryopathogenesis standpoint. Few familial cases have been identified and maternal diabetes is the only environmental influence implicated to date. Mutations in single genes have been found in a number of syndromes with one or more of the VACTERL malformations, but these syndromes usually have other features which distinguish them from the VACTERL association. Animal models have provided clues to molecular pathways that may be involved in the embryogenesis of the VACTERL structures. What is lacking is the systematic study of individual genes and pathways in well-composed cohorts of patients, which is now possible with high throughput molecular technologies.

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

“…The vertebrae develop early (23 to 32 days) in contrast to the formation of anorectal structures, which occur late in organogenesis (45 to 56 days). With this in mind several potential explanations need to be considered, as suggested by Stevenson and Hunter [36]: (1) teratogenic exposure throughout the entire organogenesis, (2) an inaugural malformation disturbing the development of other organs (malformation sequence), (3) disturbance of molecular pathways or single gene mutations involved in the formation of multiple organ systems, and (4) a general disturbance of the developmental process (for example vascular insufficiency). Most cases of VACTERL association are sporadic (~90%) [37] and high discordance rates in both monozygotic and dizygotic twin pairs have been reported [38] suggesting the impact of germline genetics to be minor in the majority of cases.…”

Prenatal exposure to environmental factors and congenital limb defects

“…Several studies have demonstrated that the diabetic environment increases ROS production in these regions of the neural tube and in the primordia of the thoracolumbar (and posterior) paraxial mesoderm and neighboring intermediate and lateral plate mesenchyme (Stevenson and Hunter, 2013)-the primordia of the affected tissues listed above. As a result of cell stress and death, the expression of several genes responsible for the patterning and/or survival of these tissues including: HoxD13 (Garcia-Barcel o et al, 2008;Winberg et al, 2014), LPP (Arrington et al, 2010), and FoxF1 (Stankiewicz et al, 2009) associated with sonic hedgehog (Shh) signaling (Kim et al, 2001;Herion et al, 2014), Pcsk5 and GDF-11 (Szumska et al, 2008), FRANCB (Holden et al, 2006), and CHD7 (Winberg et al, 2014) may be reduced or absent.…”

“…As a consequence of cell death, a number of developmental processes common to all VACTERL-affected organs, including the limb, could be disrupted (Mart ınez-Fr ıas et al, 1998;Bohring et al, 1999;Fr ıas et al, 2007;Stevenson and Hunter, 2013). The earliest potential process common to all the mesodermal organs affected in VACTREL is mesoderm production, resulting from migration of the epiblast through the primitive streak, distribution to sites of mesodermal precursors, and its subsequent proliferation (Mart ınez-Fr ıas et al, 1998;Bohring et al, 1999).…”

Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene

“…To further assess the potential role of BAZ1A in the formation of human malformations, as seen in Case 2, we investigated the expression of Baz1a by whole-mount in situ hybridization (WISH) on mouse embryos at embryonic days (E) 10.5 to 13.5. This time frame represents the equivalent of human gestational weeks 5-8 hence, the postulated time of VATER/VACTERL organogenesis in humans (Stevenson & Hunter, 2013) (Figure 2). Strong expression of Baz1a could be detected in VATER/VACTERL associated tissues, such F IGUR E 1 Schematic representation of human ACF1 protein adopted from Zaghlool et al (2016).…”