VACTERL association, epidemiologic definition and delineation

Abstract

This study departed from a preconceived definition of VACTERL, including more than one of these six anomalies in the same infant: V (vertebral anomalies), A (anal atresia), C (congenital heart disease), TE (tracheoesophageal fistula or esophageal atresia), R (reno-urinary anomalies), and L (radial limb defect). Under this definition, 524 infants were ascertained by ECLAMC from almost 3,000,000 births examined from 1967 through 1990. Observed association rates among VACTERL components as well as between VACTERL and other defects were compared against randomly expected values obtained from 10,084 multiply malformed infants (casuistic method) from the same birth sample. Conclusions were: 1) Cardiac defects are not a part of VACTERL. 2) Single umbilical artery, ambiguous genitalia, abdominal wall defects, diaphragmatic hernia, and anomalies that are secondary to VACTERL components (intestinal and respiratory anomalies, and oligohydramnios sequence defects) are frequent enough to be considered an "extension" of VACTERL, and cardiac defects should be included in this category. 3) Neural tube defects are negatively associated with VACTERL which could not be explained by selection bias or any other operational artifact. High embryonic lethality or mutually exclusive pathogenetic mechanisms could be suitable explanations. 4) Results were not clear enough to determine whether VACTERL should be defined by at least two or three component defects.

Evidence for inheritance in patients with VACTERL association

“…We compared our data to: (1) the proportion (0.00248, CI, 0.00241–0.00255) of approximately 2.5 million infants in a Latin American registry with major component features of VACTERL association (Rittler et al 1996): ${\chi }_{(1)}^2$ = 127.9, p < 0.0001; (2) the proportion (0.0160, CI 0.01598–0.0161) of these features among approximately 11 million infants in a United States registry (Population-based Birth Defects Surveillance 2008): ${\chi }_{(1)}^2$ = 10.08, p = 0.0015. Comparing the prevalence of major component features of VACTERL association in first degree relatives of probands (not including those with insufficient evidence, such as features in individual II.1 in pedigree 6) to the general population (Rittler et al 1996), we find the following odds ratios (OR) V: OR = 216.0, CI, 79.5–587.2; C: OR = 12.9, CI, 3.2–52.1; R: OR = 44.8, CI, 11.1–181.4. The severity, type of findings, and presence of other anomalies did not appear to differ between probands with affected relatives and probands without affected relatives.…”

“…Several patients (including the proband in pedigree 5) appear to have urogenital anomalies and/or urorectal septal malformation sequence. This is unsurprising, as the embryology and developmental biology of the genitourinary (GU) tract is closely connected to that of the hindgut and renal systems; in addition, previous studies have provided statistical evidence that GU anomalies may be a “secondary” feature of VACTERL association (Rittler et al 1996). …”

“…The condition, sometimes termed VATER association depending on which features are included, is an acronym for the major component features, not all of which may be present in patients: vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheo-esophageal fistula (TE); renal abnormalities (R), and limb anomalies (L); other features (e.g., genitourinary anomalies) are not uncommon. Diagnostic criteria are controversial, and the many overlapping conditions make accurate diagnosis challenging (Rittler et al 1996; Källén et al 2001). Though there is some evidence for inheritance of component features, the condition is usually sporadic (in this context, meaning occurring in an isolated fashion), with low risk of having an affected relative (Weaver et al 1986; Brown et al 1999).…”

Long-term outcomes of adults with features of VACTERL association

“…Uncertainty persists regarding exact diagnostic criteria. For example, some studies, such as the relatively large clinical series described by Weaver et al in 1986 [39], required the presence of two component features for diagnosis, while others, including a follow-up study on that series [40], require at least three component features [3, 4, 14, 29]. While several genetic causes have been implicated in a small number of human patients or in animal models [6, 11, 16, 27, 30, 34, 36], evidence of causality has not been uniform, and no consistent etiology has been identified.…”

“…Several large studies have obtained patient information from databases on congenital malformations in infants [3, 4, 14, 15, 29]; other sizeable cohorts have been described by pediatric geneticists or by pediatric surgical specialists, and focus mainly on infants and children [7, 32, 39]. While the outcomes of each of the component features have been studied separately, we located only one study examining long-term prognosis of adults with VACTERL association [40]; this study included many patients previously described as children, some of whom were ultimately found to have alternate diagnoses.…”