Abstract
Background
The VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association is the non-random occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies. Diagnosing VACTERL patients is difficult, as many disorders have multiple features in common with VACTERL. The aims of this study were to clearly outline component features, describe the phenotypic spectrum among the largest group of VACTERL patients thus far reported, and to identify phenotypically similar subtypes.
Methods
A case-only study was performed assessing data on 501 cases recorded with VACTERL in the JRC-EUROCAT (Joint Research Centre-European Surveillance of Congenital Anomalies) central database (birth years: 1980–2015). We differentiated between major and minor VACTERL features and anomalies outside the VACTERL spectrum to create a clear definition of VACTERL.
Results
In total, 397 cases (79%) fulfilled our VACTERL diagnostic criteria. The most commonly observed major VACTERL features were anorectal malformations and esophageal atresia/tracheo-esophageal fistula (both occurring in 62% of VACTERL cases), followed by cardiac (57%), renal (51%), vertebral (33%), and limb anomalies (25%), in every possible combination. Three VACTERL subtypes were defined: STRICT-VACTERL, VACTERL-LIKE, and VACTERL-PLUS, based on severity and presence of additional congenital anomalies.
Conclusion
The clearly defined VACTERL component features and the VACTERL subtypes introduced will improve both clinical practice and etiologic research.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Quan, L. & Smith, D. W. The VATER association. Vertebral defects, anal atresia, T–E fistula with esophageal atresia, radial and renal dysplasia: a spectrum of associated defects. J. Pediatr. 82, 104–107 (1973).
Temtamy, S. A. & Miller, J. D. Extending the scope of the VATER association: definition of the VATER syndrome. J. Pediatr. 85, 345–349 (1974).
Khoury, M. J., Cordero, J. F., Greenberg, F., James, L. M. & Erickson, J. D. A population study of the VACTERL association: evidence for its etiologic heterogeneity. Pediatrics 71, 815–820 (1983).
EUROCAT. Prevalence Tables–Full Member Registries from 2012–2016 (2018). http://www.eurocat-network.eu/accessprevalencedata/prevalencetables. Accessed 15 Aug 2018.
Hilger, A. et al. Familial occurrence of the VATER/VACTERL association. Pediatr. Surg. Int. 28, 725–729 (2012).
Reutter, H. & Ludwig, M. VATER/VACTERL association: evidence for the role of genetic factors. Mol. Syndromol. 4, 16–19 (2013).
Salinas-Torres, V. M., Perez-Garcia, N. & Perez-Garcia, G. Clinical, cytogenetic, environmental and inheritance findings in Mexican neonates with VACTERL association. Indian J. Pediatr. 82, 84–88 (2015).
Solomon, B. D., Pineda-Alvarez, D. E., Raam, M. S. & Cummings, D. A. Evidence for inheritance in patients with VACTERL association. Hum. Genet. 127, 731–733 (2010).
Solomon, B. D. VACTERL/VATER Association. Orphanet J. Rare Dis. 6, 56 (2011).
Solomon, B. D. et al. An approach to the identification of anomalies and etiologies in neonates with identified or suspected VACTERL (vertebral defects, anal atresia, tracheo-esophageal fistula with esophageal atresia, cardiac anomalies, renal anomalies, and limb anomalies) association. J. Pediatr. 164, 451–457 e1 (2014).
Solomon, B. D. et al. Clinical geneticists’ views of VACTERL/VATER association. Am. J. Med. Genet. A 158A, 3087–3100 (2012).
Botto, L. D. et al. The spectrum of congenital anomalies of the VATER association: an international study. Am. J. Med. Genet. 71, 8–15 (1997).
Husain, M. et al. Phenotypic diversity of patients diagnosed with VACTERL association. Am. J. Med. Genet. A 176, 1830–1837 (2018).
Kallen, K., Mastroiacovo, P., Castilla, E. E., Robert, E. & Kallen, B. VATER non-random association of congenital malformations: study based on data from four malformation registers. Am. J. Med. Genet. 101, 26–32 (2001).
Oral, A. et al. Clinical characteristics of neonates with VACTERL association. Pediatr. Int. 54, 361–364 (2012).
Rittler, M., Paz, J. E. & Castilla, E. E. VACTERL association, epidemiologic definition and delineation. Am. J. Med. Genet. 63, 529–536 (1996).
Solomon, B. D. et al. Analysis of component findings in 79 patients diagnosed with VACTERL association. Am. J. Med. Genet A. 152A, 2236–2244 (2010).
Weaver, D. D., Mapstone, C. L. & Yu, P. L. The VATER association. Analysis of 46 patients. Am. J. Dis. Child 140, 225–229 (1986).
Jenetzky, E. et al. Bias in patient series with VACTERL association. Am. J. Med. Genet. A 155A, 2039–2041 (2011). author reply 2042–3.
Kinsner-Ovaskainen, A. et al. A sustainable solution for the activities of the European network for surveillance of congenital anomalies: EUROCAT as part of the EU Platform on Rare Diseases Registration. Eur. J. Med. Genet. 61, 513–517 (2018).
EUROCAT. Guide 1.4 and Reference Documents—Section 3 Coding and Classification—Section 3.2 Minor Anomalies for Exclusion (version 25-05-2018) (2018). http://www.eurocat-network.eu/aboutus/datacollection/guidelinesforregistration/guide1_4.
Loane, M., Dolk, H., Garne, E. & Greenlees, R., EUROCAT Working Group. Paper 3: EUROCAT data quality indicators for population-based registries of congenital anomalies. Birth Defects Res. Part A 91, S23–S30 (2011).
Solomon, B. D., Raam, M. S. & Pineda-Alvarez, D. E. Analysis of genitourinary anomalies in patients with VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association. Congenit. Anom. (Kyoto) 51, 87–91 (2011).
Acknowledgements
We would like to thank all those involved in providing and processing information in the individual EUROCAT registries throughout Europe, including affected families, clinicians, health professionals, medical record clerks, and registry staff.
Author information
Authors and Affiliations
Contributions
All authors meet the Pediatric Research authorship requirements. They have contributed to the conception and design, acquisition of the data, or analysis and interpretation of the data; they have drafted the article or revised it critically for important intellectual content; and all authors gave their final approval of the version to be published.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplemental information
Rights and permissions
About this article
Cite this article
van de Putte, R., van Rooij, I.A.L.M., Marcelis, C.L.M. et al. Spectrum of congenital anomalies among VACTERL cases: a EUROCAT population-based study. Pediatr Res 87, 541–549 (2020). https://doi.org/10.1038/s41390-019-0561-y
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41390-019-0561-y
This article is cited by
-
Congenital Heart Defects in Patients with Anorectal Malformations: A Retrospective Cohort Study of 281 Patients
Pediatric Cardiology (2025)
-
Anorectal malformations
Nature Reviews Disease Primers (2024)
-
Surveillance of multiple congenital anomalies; searching for new associations
European Journal of Human Genetics (2024)
-
Survival and factors associated with mortality among infants with anorectal malformation: a population-based study from a middle-income country
European Journal of Pediatrics (2023)
-
Rectal atresia and rectal stenosis: the ARM-Net Consortium experience
Pediatric Surgery International (2023)
