Strict delineation and clear limits to the VACTERL association (OMIM 192350) have been debated since the first description of the VATER association in 1972 [Quan and Smith, 1972]. We welcome the presentation of a complete series of 60 patients presenting at least three component features of the VACTERL association by Solomon et al. [2010b] in the September issue of the American Journal of Medical Genetics Part A. They mention among their cardinal findings that vertebral defects, cardiac malformations, and renal anomalies build the strongest cluster, suggesting that these three VACTERL component features tend to appear together more often than do any other component features (anorectal malformation (ARM), tracheo-esophageal (TE) fistula with esophageal atresia, and limb dysplasia). However, we have serious doubts about the external validity of the study results and we are not convinced that these can be extrapolated to the overall group of VACTERL patients for several reasons.
First, the authors claim the advantage of recruiting their patients based on a predefined association definition as inclusion criterion and not focusing on a population-based registry. However, this may be the most important study limitation. We wonder about the effect of sampling bias on the results, as the authors already mentioned that more severely affected individuals are more likely to seek participation in their study. Moreover, without reliable genetic or epidemiological proof of concept regarding the classification of component features or inclusion criteria of clinical features for VACTERL, all further results may be arbitrary. Even the ostensible proof of inheritance of component features of the VACTERL association [Solomon et al., 2010a] might be reduced to the inheritance of congenital anomalies of the VACTERL association spectrum among patients and families with TE. The current broad definition and classification of component features for the VAC-TERL association has not been supported by independent epidemiological studies. While the first population based studies [Khoury et al.