A Reply

To the Editor: We read with great interest the paper by Kim et al. (1) on the possible relationship between altered Sonic hedgehog (Shh) signaling and the VACTERL pattern of defects as the molecular basis for this ‘association’. Their hypothesis supports our proposal that the VACTERL phenotype is not an association but a developmental field defect (DFD) (2). As defined by an International Working Group (IWG) (3), a developmental field is ‘a region or part of the embryo which responds as a coordinated unit to embryonic induction and results in complex or multiple anatomic structures’. Kim et al. (1) mention the clinical and etiological heterogeneity of the VACTERL pattern of malformations, suggesting that not all cases of the VACTERL phenotype can be explained by defective Shh signaling, and that environmental factors are possible causative agents. Causal heterogeneity is one of the known characteristics of DFDs. Since a developmental field is a pathogenetic unit, it always responds in the same manner to the effect of different causes (4). Moreover, the fact that all defects that constitute a polytopic DFD have to be specifically associated and have a common pathogenesis explains why some of the malformations of a particular DFD are also observed in infants with other defects and/or syndromes and other etiological diagnoses. Clinical heterogeneity depends on the time when the different causes (genetic and/or environmental) act, thus resulting in either an isolated DFD or a DFD associated with other patterns of malformation. To conclude, we would like to insist in our previous recommendation of referring to the VACTERL (polytopic) developmental field defect, instead of VACTERL association or VACTERL syndrome. Use of the correct terminology will help to remind us of the pathogenetic mechanisms and of the need to look for different causal agents. From a clinical perspective, the presence of some of the VACTERL defects alone indicates that the causal agent may have acted during a defined period within the first 4 weeks after conception. On the other hand, if the VACTERL DFD is associated with other major and/or minor/mild defects, we should look for an agent that may have acted through a long period of time during development, such as maternal diseases (e.g., diabetes mellitus), genetic factors (chromosomal abnormalities, single gene defects), or gene environment interactions (4, 5).