What is the Difference Between an Association and a Syndrome?

Patient Presentation
A resident in his continuity clinic was describing a newborn infant who had been born that morning that he was taking care of in the intensive care unit with probable VACTERL association. “Right now we know he has anal atresia and abnormal thumbs, but his spine also doesn’t look entirely normal. He doesn’t have an obvious heart murmur and so far he is breathing well. But we’re in the process of evaluating him,” he said. “Why did you call VACTERL an association? I thought it was a syndrome,” asked another intern. “I don’t really know the difference but it’s written down as an association,” he replied. The other residents in clinic and the attending also we’re not sure of the specific differences in the terminology and decided to look it up in some online references.

VATER association was first described in the 1970s with additional congenital malformations being added to the association so it is most often called VACTERL association. It is a highly heterogeneous, overlapping condition estimated to occur in ~1/10,000-40,000 births. The cause is unknown. In animal models, some signaling pathway gene mutations have phenotypes of VACTERL association.

Experts suggest that patients having at least 2 components should be further evaluated (at least 3 for diagnosis) for VACTERL and other diseases in its differential diagnosis. There are more than 30 syndromes, mutations and diseases that have components of the malformations in VACTERL association. Alagille syndrome , CHARGE Syndrome, Blackfan-Diamond anemia, Holt-Oram syndrome, and Caudal regression syndrome are just a few examples.

All signs and symptoms can be obvious or extremely subtle. Some symptoms may not occur until years later or be surreptitious. Most patients do not have all of the components. Facial and brain malformations are not common with VACTERL association. Treatment depends on the specific malformations and their extensiveness. Surgical treatment is often necessary to manage one or more problems.

Components of the VACTERL association include:

  • Vertebral malformation
    • Occurs in 60-90% of patients
    • Usually segmentation defects, can occur in any vertebrae
    • Can also have rib anomalies and/or spinal curvature
    • Can also have tethered cord and/or similar neurological anomalies
    • May be diagnosed later in life after presenting with scoliosis or back pain
    • Initial evaluation: plain radiographs of the spine but patients may also need magnetic resonance imaging or computed tomography
  • Anorectal malformation
    • Occurs in 55-90% of patients considered by many geneticists as a “core” anomaly for this association
    • All types occur often with genitourinary anomalies. Incontinence or constipation are often problems for patients.
    • Initial evaluation: careful physical examination, cross-table radiographs, abdominal ultrasound for genitourinary anomalies
  • Cardiac malformations
    • Occurs in 40-80% of patients
    • All types occur from subtle anomalies to major malformations
    • Cardiovascular anomalies can also occur
    • Initial evaluation: Cardiac echocardiogram, electrocardiogram
  • Tracheo-esophageal fistula (TEF) with/without esophageal atresia
    • Occurs in 50-80% of patients,considered by many geneticists as a “core” anomaly for this association
    • All types but H-type TEF can be difficult to identify but patients may have choking or respiratory problems.
    • Initial evaluation: history showing increased amniotic fluid, unable to pass or having curling up of the nasogastric or orogastric tubing, or plain radiographs showing absent gastric bubble
  • Renal malformations
    • Occurs in 50-80% of patients
    • Many different types of renal anomalies occur and some patients may need renal transplantation.
    • Initial evaluation: renal ultrasound, other studies such as voiding cystourethrogram may be necessary.
  • Limb malformations
    • Occurs in 40-55% of patients
    • Classically radial anomalies are associated but other limb anomalies occur
    • Initial evaluation: physical examination and plain radiographs if an anomaly is suspected
  • Hydrocephalus
    • VACTERL with hydrocephalus (VACTERL-H) may or may not be a distinct condition.
    • Usually due to aqueductal stenosis
    • Initial evaluation: cranial ultrasound in infants
  • Single umbilical artery is frequently seen with VACTERL association

    Other evaluations:

    • Genetic evaluation for patient and potentially family members
    • Fanconi anemia testing
    • Complete blood count for other hematological conditions
    • Genetic testing – often to look for other conditions in the differential diagnosis as there is so much overlap

    Learning Point
    Many times commonly understood words are used in medicine without any loss of meaning. However sometimes more precise definitions are needed to communicate more specifically with improved accuracy.

    • Condition – “a usually defective state of health” such as a serious heart condition
    • Disease – “an impairment of the normal state of the living animal or plant body or one of its parts that interrupts or modifies the performance of the vital functions, is typically manifested by distinguishing signs and symptoms, and is a response to environmental factors (as malnutrition, industrial hazards, or climate), to specific infective agents (as worms, bacteria, or viruses), to inherent defects of the organism (as genetic anomalies), or to combinations of these factors”
    • Malformation – an abnormality in the formation of the body part or a faulty formation of the structure. It is an initial formational problem.
    • Deformation – an alteration in the form or shape of the body part after it is initially formed. It is a secondary problem. Amniotic band constriction is an example.
    • Associations – have more than 1 phenotypic features or are “…malformations that occur together more often than would be expected by chance…” and do not have evidence of a single unifying cause.
    • Syndromes – have more than 1 phenotypic feature or are malformations that occur together more than would be expected by chance that have with a single unifying cause or presumed cause.
    • Sequence – a consequence, result, or subsequent development (as of a disease). Pierre-Robin sequence is an example.

    Questions for Further Discussion
    1. If a patient has a single umbilical artery at birth, what should be done? A review can be found here.
    2. What are indications for a genetic evaluation?

    Related Cases

    To Learn More
    To view pediatric review articles on this topic from the past year check PubMed.

    Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

    Information prescriptions for patients can be found at MedlinePlus for this topic: Developmental Disabilities

    To view current news articles on this topic check Google News.

    To view images related to this topic check Google Images.

    To view videos related to this topic check YouTube Videos.

    Solomon BD. VACTERL/VATER Association. Orphanet J Rare Dis. 2011 Aug 16;6:56.

    Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, Tibboel D, Reutter H, Giampietro PF. Clinical geneticists’ views of VACTERL/VATER association. Am J Med Genet A. 2012 Dec;158A(12):3087-100.

    Solomon BD, Baker LA, Bear KA, Cunningham BK, Giampietro PF, Hadigan C, Hadley DW, Harrison S, Levitt MA, Niforatos N, Paul SM, Raggio C, Reutter H, Warren-Mora N. 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. 2014 Mar;164(3):451-7.e1.

    Merriam-Webster Online Medical Dictionary.
    Available from the Internet at:
    https://www.merriam-webster.com/dictionary/sequence (cited 11/28/17)

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa