Definition

Although the majority of reports define VATER as requiring three anomalies in the association, some studies include subjects with two of the anomalies. Furthermore, studies disagree as to whether or not cardiac defects are associated with VATER, and no single cardiac defect has been specifically associated with VATER. One study noted that anomalies tended to group in “upper” and “lower” malformations, where upper malformations included upper preaxial limb reduction defects, esophageal atresia, and costovertebral malformations, whereas lower malformations included costovertebral malformations with anal atresia. This same study noted that cardiac defects tended to occur in the upper group, whereas kidney anomalies occurred in the lower group. VATER/VACTERL association is considered a clinical diagnosis.

Prevalence and Epidemiology

The reported prevalence of the VATER association ranges from 1.43 : 10,000 to 13.06 : 10,000. The variance in reported prevalence is likely caused by discrepancies in the number of anomalies required for diagnosis in VATER, the inclusion or exclusion of subjects with other syndromes, and the type of radial limb anomalies included in the definition.

Etiology and Pathophysiology

The proposed etiology of VATER is a defect in mesodermal development. The mesoderm contributes to the development of the vertebrae (paraxial mesoderm developing in a craniocaudal direction), limb buds, renal structures (intermediate mesoderm), the urorectal septum (intermediate mesoderm), and the heart (lateral plate mesoderm). This defect in mesodermal development may be termed a primary developmental field defect and may represent an insult to the embryo at the blastocyst stage.

Animal models have been proposed to study VATER. In rats and chicks, exposure to adriamycin, a cytotoxic agent, creates anomalies consistent with VATER. These animal models demonstrate abnormal development of the notochord, which leads to the vertebral, tracheoesophageal, and anal anomalies associated with VATER.

VATER/VACTERL association has typically been considered a diagnosis of exclusion. VATER seems to be a sporadic event in the majority of cases (90%). Copy number variations (CNVs) may play a role in this association. A region affecting chromosome band 17q23 containing two candidate genes ( TBX2 and TBX4 ) has been observed. Another possible locus is chromosome 8q24.3. This locus includes several genes including GLI4 . The exact function of this gene is not well understood; however, similar zinc-finger protein gene mutations have been observed in mice with a VACTERL phenotype. Other CNVs of interest include chromosome 10q25.3 (duplication), 22q11.2 (duplication), and CNVs involving a gain in SHOX , which plays an important role in limb development. Deletions in other regions (5q11.2, 6q, 7q35-qter, distal 13q, 19p13.3, and 20q13.33) and duplications on 1q41 and 2q37.3 have also been reported. Another case report exists of VATER associated with a supernumerary ring chromosome derived from chromosome 12. Two case series of patients with VATER and hydrocephalus suggest that this may be a separate syndrome with autosomal recessive inheritance or X-linked inheritance, and one case report suggests a PTEN gene mutation could be responsible for this syndrome. It is difficult to provide accurate recurrence risk in general, although it is likely low, as long as similar conditions with inherited forms are ruled out. It is also necessary to obtain a detailed family history to adjust recurrence risk appropriately.

Reported environmental factors associated with VATER include maternal diabetes, uterine vascular pathology, and infertility treatment.

Manifestations of Disease