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While mitotic errors commonly cause aneuploid clones soon after conception, the embryos often normalize as clones are rapidly eliminated. Although generally considered benign, evidence suggests clone elimination as the primary cause of the vertebral, ano-rectal, cardiac, tracheo-esophageal, renal, and limb (VACTERL) association of anomalies, and possibly other adverse outcomes as well. Here, clone elimination-related development disruption at specific locations is used as the basis of a comprehensive theoretical VACTERL association model that also elucidates mitotic mosaic aneuploidy effects. For the association, the model explains random temporal and spatial origins during a limited time frame and overlapping clusters of component anomalies. It supports early developmental effects involving the stage of determination, where the position in a specific morphogen field controls what a cell will become and where it will be located. Developmental properties related to determination also create specific vulnerabilities to the midline and distal defects, the latter explaining exclusively radial and tibial defects with duplications and deficiencies. The model also supports isolated anomalies as part of the association and, for mosaic mitotic aneuploidy, indicates that clone elimination nears completion at the time of lower limb determination. Although mosaic clone elimination may cause other defects, occurrences in different developmental fields separate them from VACTERL anomalies. Clone elimination may also be related to risks for a single umbilical artery and for non-structural adverse pregnancy outcomes such as losses, prematurity, and growth delays, while a paucity of clone lethality in non-humans explains the rarity of the association and of single umbilical arteries in animals.

Three systems with VACTERL association findings- mutations of the Sonic Hedgehog (SHH) signaling pathway in mice, murine adriamycin teratogenicity, and human Fanconi anemia (FA) pathway mutations, may all involve a similar mechanism. SHH is up-regulated in irradiated cells, and DNA breaks common with radiation damage in the adriamycin and FA systems are plausible signals for such effects, which would affect development. Since FA related DNA breakage occurs throughout life, SHH disturbances may account for later FA related findings involving hematopoietic and malignancy issues. In support, androgen, a standard treatment for FA hematologic failure, down-regulates SHH, and common FA malignancies such as squamous cell carcinomas and acute myeloid leukemia have been linked to enhanced SHH function. This suggests that interventions lowering SHH levels may be useful therapeutically. Also supporting a connection between pre- and post- natal findings, the frequency and number of VACTERL anomalies with FA correlate with the severity and onset of hematopoietic and malignancy issues. In FA, radial anomalies are the most common of these defects, followed by renal findings, while vertebral and gastrointestinal anomalies are relatively uncommon, a pattern that differs from observations of the VACTERL association. Genes with more severe effects also show a greatly increased incidence of brain abnormalities, and a paucity of such findings with other FA genes suggests that brain development is relatively refractory to SHH related effects, accounting for the rarity of such findings with the association., (© 2015 Wiley Periodicals, Inc.)

Associations of anomalies, with VACTERL as the prototype, have been the source of much debate, including questions about the validity and definition of this category. Evidence is presented for a teratologic basis for associations involving interactions between disruptive events and specific vulnerabilities. Because the embryo is organized in time and space, differences in the timing, location, and severity of exposures will create variable sequelae for any specific vulnerability, creating associations. The blastogenetic stage of development involves distinct properties that affect the nature of associations arising during this time, including relatively undifferentiated developmental fields and causally nonspecific malformations. With this, single anomalies can be part of the spectrum of findings that comprise a specific association. A specific defect defines a subset of disturbances, biasing frequencies of other defects. Processes are basic, integrated, and general, so disruptions are often lethal, and can have multiple effects, accounting for high incidences of multiple anomalies, and overlaps between associations. Blastogenetic disturbances also do not affect the late "fine tuning" of minor anomalies, although pathogenetic sequences can occur. This model suggests that certain combinations of congenital anomalies can arise from causally nonspecific teratogenetic fields determined by timing, location, and vulnerabilities, rather than polytopic developmental fields., (© 2015 Wiley Periodicals, Inc.)

Cases diagnosed as the VACTERL Association are heterogeneous, and can involve other associations arising from different developmental processes with midline effects. However, these often lack the classic radial ray anomalies that help make VACTERL distinct. A more specific association can be delineated based on teratogenic disturbances affecting vulnerabilities associated with the establishment of cell fate through positional information, with two basic weaknesses: (i) The midline, where topological properties such as reduced lateral information should make information losses more likely; (ii) Increased distal sensitivity at the end of a morphogen gradient in the limbs, where both duplications and deficiencies can arise from similar disturbances. Vertebral, cardiac, anal-rectal, and tracheo-esophaeal findings are primary midline derivatives. While the kidneys are bilateral, they can be influenced by the midline, although there may also be effects on the ureteral buds as distal structures. The pre-axial area is the most distal in limb development, giving radial/tibial deficiencies and duplications. Alternatively, spina bifida and orofacial clefts originate from bilateral structures that are less likely to be affected by problems with midline determination, explaining the rarity of these disorders with VACTERL. Suggested human genetic models typically involve the midline, but lack radial findings, and true Mendelian forms are rare. However, developmental genes such as Sonic Hedgehog may have a pathogenetic role without being causal., (© 2015 Wiley Periodicals, Inc.)