An association is a term used to designate the nonrandom tendency of some malformations to occur together more commonly than would be expected by chance, without being components of a syndrome. VACTERL is an acronym that stands for v ertebral, a nal, c ardiac, t racheal, e sophageal, r enal, and l imb. VACTERL association defects include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, renal dysplasia, and limb/radial defects. For a diagnosis of VACTERL to be entertained, it has been suggested that three or more of the associated malformations be present. Prenatal growth deficiency and single umbilical artery are also nonrandom features of this pattern of anomalies. The general spectrum of the pattern in 34 cases is presented subsequently, as summarized by Temtamy and Miller. Initially described as VATER association, another “R” was added when renal anomalies were included, followed by a “C” for cardiac; “L” for limb eventually replaced the “R” for radial anomaly.
|Anal atresia with or without fistula||50%|
|Tracheoesophageal fistula with esophageal atresia||50%|
|Radial dysplasia, including thumb or radial hypoplasia, preaxial polydactyly, syndactyly||50%|
|Single umbilical artery||35%|
Other, Less Frequent Defects
Prenatal growth deficiency, postnatal growth deficiency, laryngeal stenosis, bronchial anomalies, ear anomaly, large fontanels, defect of lower limb (23%), rib anomaly, defects of external genitalia, occult spinal dysgraphia with tethered cord.
Although many of these patients may fail to thrive and have slow developmental progress in early infancy related to their defects, most of them have normal brain function. Adults with VACTERL association have a number of difficulties often related to the primary malformations. Those with vertebral defects often experience significant back, shoulder, and/or neck pain. Sequelae of anal anomalies include constipation and obstruction as well as functional stooling problems. Following surgical repair of tracheoesophageal fistula, dysphagia, choking, and reflux, both reactive airway disease and tracheomalacia can occur. Nephrolithiasis and urinary tract infections are common sequelae of renal defects.
This pattern of malformation has generally been a sporadic occurrence in an otherwise normal family. The etiology is unknown and it is both clinically and etiologically heterogeneous. It has more frequently appeared in the offspring of diabetic mothers, and a few cases of ZIC3 mutation or deletion have been identified in affected individuals. In addition, it occurs more frequently in individuals who have Fanconi anemia, particularly in association with complementation groups D1, E, and F. Because Fanconi anemia has an autosomal recessive mode of inheritance, with a 25% recurrence risk, it is critical to be aware of that possibility. Chromosomal breakage studies to rule out Fanconi anemia should be seriously considered in all cases of VACTERL association, particularly those cases in which additional features, including skin pigmentation abnormalities, growth retardation, and microcephaly, are present. Features of this association may occur in an otherwise normal child or as a part of a broader pattern, such as the trisomy 18 or del(13q) syndromes, in which case the prognosis is not favorable. It is also important to recognize that VACTERL association is not in and of itself a diagnosis, but rather a nonrandom association of defects. As such, when one of the associated features is identified, careful evaluation for other VACTERL association defects should be undertaken. In cases in which a malformation not usually encountered with VACTERL association defects is identified, further investigation is warranted.
A distinct, genetically determined disorder referred to as VACTERL with hydrocephalus owing to aqueductal stenosis (VACTERL-H) has been reported. Both autosomal and X-linked recessive inheritance have been documented for that disorder. No clinical distinction is possible to differentiate between autosomal and X-linked recessive families. Although a poor prognosis is the rule, survival with a relatively good outcome has been noted in some cases. An association with Fanconi anemia is stronger than is seen in VACTERL association without hydrocephalus. Mutations or deletions of the FANCB gene, which is responsible for Fanconi anemia complementation group B, are common in X-linked recessive VACTERL-H. Similarly, a diagnosis of Fanconi anemia and autosomal recessive VACTERL-H has been documented.
Say B, Gerald PS: A new polydactyly, imperforate anus, vertebral anomalies syndrome, Lancet 2:688, 1968.
Say D, et al: A new syndrome of dysmorphogenesis–imperforate anus associated with polyoligodactyly and skeletal (mainly vertebral) anomalies, Acta Paediatr Scand 60:197, 1971.
Quan L, Smith DW: 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, 1973.
Temtamy SA, Miller JD: Extending the scope of the VATER association: Definition of a VATER syndrome, J Pediatr 85:345, 1974.
Evans JA, et al: VACTERL with hydrocephalus: Further delineation of the syndrome(s), Am J Med Genet 34:177, 1989.
James HE, et al: Distal spinal cord pathology in the VATER association, J Pediatr Surg 29:1501, 1994.
Botto L, et al: The spectrum of congenital anomalies of the VATER association: An international study, Am J Med Genet 71:8, 1997.
Källén K, et al: VATER non-random association of congenital malformations: Study based on data from four malformation registers, Am J Med Genet 101:26, 2001.
Faivre L, et al: Should chromosomal breakage studies be performed in patients with VACTERL association? Am J Med Genet 137:55, 2005.
Kanu A, et al: Bronchial anomalies in VACTERL association, Pediatr Pulmonol 43:930, 2008.
Solomon BD, et al: Evidence for inheritance in patients with VACTERL association, Hum Genet 127:731, 2010.
McCauley J, et al: X-linked VACTERL with hydrocephalus syndrome: Further delineation of the phenotype caused by FANCB mutations, Am J Med Genet 155:2370, 2011.
Raam MS, et al: Long-term outcomes of adults with features of VACTERL association, Eur J Med Genet 54:34, 2011.
Stevenson R, Hunter A: Considering the embryogenesis of VACTERL association, Mol Syndromol 4:7, 2013.