Introduction

VACTERL association (VA) is the non-random co-occurrence of vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheo-esophageal fistula/esophageal atresia (TEF/EA), renal anomalies (R), limb abnormalities (L) [1]. Studies investigating clinical, cytogenetic, environmental, inheritance characteristics of VA patients and probing of aforementioned six components are limited [2–6]. Moreover, studies in neonates are restricted to clinical analysis [7, 8]. The aim of the present study was to evaluate clinical, cytogenetic, environmental, and inheritance characteristics of neonates with VA.

Material and Methods

Neonates with at least three-of-six VA components, admitted at Civil Hospital Guadalajara Fray Antonio Alcalde, Mexico, between May-2010/July-2012 were retrospectively enrolled. All subjects underwent a detailed clinical and genetic family history. After a complete physical examination, all suspected neonates were screened for vertebral, urinary, CNS, cardiac or limb anomalies by means of appropriate X-ray, ultrasonography, or echocardiography studies. G-banded karyotyping (>550 bands) as well as additional follow-up was performed to exclude other pathologies.

Weight, length, and head circumference at birth, sex, gestational age, postnatal age, parental age, VA anomalies, associated malformations, familial occurrence, environmental factors, and karyotype were recorded. Data were expressed as mean, SD, median, and IQR for continuous variables, or as percentage for categorical variables. This study was approved by the institutional review board (HCG/CI-857/10).

Results

Demographic, clinical, cytogenetic, environmental, and inheritance features of all 26 patients are given in Table 1.

Table 1 Individual demographic, clinical, cytogenetic, environmental, and inheritance features of the study group
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The frequency of each component was: V, 77 %; A, 62 %; TEF/EA, 58 %; R, 58 %; L, 50 %, and C, 42 %. The commonest subtypes were hemivertebrae; anal vestibular fistula; proximal esophageal atresia with distal fistula; unilateral renal hypoplasia; preaxial polydactyly; and ventricular septal defect. The most frequent combination was VAR (n = 3). Additional anomalies such as bilateral cryptorchidism (n = 4) were detected.

Two of 26 probands (8 %) had a second-degree or first-degree relative with two components (Fig. 1). In another five patients (19 %) environmental noxious influences (at pre-conception and during the first trimester of pregnancy) were identified. All patients had a normal karyotype.

Fig. 1
figure 1

Pedigrees of probands diagnosed with VACTERL association as well as findings in affected first and second-degree relatives

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Discussion

Results from this study highlight significant issues regarding VA during neonatal period. First, the index patients showed a normal somatometric profile; second, as it was previously reported, [7] most patients were male and born at term, and third, assessment of mean parental ages and the fact that most cases occurred in the first pregnancy are novel findings; yet, the small sample size makes it difficult to generalize.

The frequency order was VATRLC with any component being observed in at least 42 % of the patients; indeed, the present figures were similar to Oral et al. Likewise, the combination of three components was commonest in this study [7]. In contrast, the variety of combinations regarding specific anomalies diverges from previous studies [7, 8]. As for associated anomalies, the authors found sixteen patients (62 %) with non-VACTERL anomalies among which bilateral cryptorchidism was most frequent. Of note, ambiguous genitalia were the most frequent non-VACTERL anomaly seen in previous studies [7, 8]. Whether these differences reflect ethnicity remains unclear.

The present results confirm the great clinical heterogeneity of VA [1, 2]. While some manifestations can be subtler, others may be obvious immediately after delivery or prenatally such as some vertebral, cardiac, and renal anomalies picked up in few patients of this series (data not shown). In contrast, no information about single umbilical artery could be found. Because the authors have identified subtle non-VACTERL anomalies, they advise clinicians to do a careful search for associated anomalies. Whereas many of these findings may have no clinical significance, the presence of hydrocephalus found in VACTERL-H, justify immediate medical intervention given its poor prognosis and high mortality [2, 9, 10]. In addition to VACTERL-H, Fanconi anemia may also overlap virtually all features of VA, however, radial anomalies are considered an especially key feature along with hematologic and pigmentation anomalies [1, 9, 10].

VA is a well-known pathology but its cause is still unresolved [1, 3]. Nevertheless, the present results, along with those by Solomon et al. [5] suggest that an autosomal dominant allele with reduced penetrance and variable expressivity or polygenic inheritance account for some familial aggregations. Additionally, recognized environmental factors in VA mainly include maternal diabetes, in utero exposure to estrogen/progesterone, statins, and lead [1, 4]. The authors identified cocaine and marijuana (when used by the pregnant mother) as novel environmental influences. These findings expand the list of teratogens probably underlying VA. Altogether, the apparent inherited and environmental factors found in 27 % of the index patients may prove useful in the characterization of VA. In contrast to previous reports linking the clinical spectrum of VA with certain chromosomal aberrations [1, 3] the authors did not find any cytogenetic abnormality in this series.

Conclusions

The authors emphasize the relevance of a careful family and clinical investigation in neonates with VA. The presence of specific clinical and genetic findings in patients and their families points to a complex interplay between genes and environmental factors. Because causality in VA is still elusive, provision of an accurate genetic counseling remains challenging.