ORPHA: 887; DO: 14679;
VATER is a mnemonically useful acronym for the nonrandom association of vertebral defects (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R). This combination of associated defects was pointed out by Quan and Smith (1972). Nearly all cases have been sporadic.
VACTERL is an acronym for an expanded definition of the association that includes cardiac malformations (C) and limb anomalies (L). The VACTERL association is a spectrum of various combinations of its 6 components, which can be a manifestation of several recognized disorders rather than a distinct anatomic or etiologic entity (Khoury et al., 1983).
Also see VATER/VACTERL association with hydrocephalus (VACTERL-H; 276950) and VACTERL with or without hydrocephalus (VACTERLX; 314390).
Finer et al. (1978) reported 2 male sibs with several congenital anomalies suggestive of the VATER association with prominent features of a caudal regression syndrome (see 600145). The older infant had multiple cardiac abnormalities, including transposition of the great arteries and ventricular septal defect. Other features included imperforate anus, dislocated left hip, malformed sacrum, and hypoplasia of the lumbar vertebrae. The younger sib had suspected ventricular septal defect or patent ductus arteriosus, situs inversus of the abdominal viscera, hypoplasia of the lower limbs and pelvis, and absence of the sacrum and lower lumbar spine.
Auchterlonie and White (1982) described a family in which 1 brother had esophageal atresia and hemivertebrae D6-12, and a second brother had esophageal and duodenal atresia, absent rectum and anus, ventricular septal defect and renal agenesis with Potter facies and hypoplastic lungs. Other familial instances were reviewed.
Using a birth defects surveillance registry, Khoury et al. (1983) investigated the interrelation of the 6 components of the VACTERL association. There were 400 cases with 2 or more of the components, whereas only 29 cases would be expected if the defects had occurred together randomly. There were 76 cases with 3 or more defects, whereas less than 1 case was expected. Of these 76 cases, 7 had recognized causes (5 chromosomal anomalies and 2 single-gene disorders), and another 19 had recognized clinical phenotypes or syndromes of unknown etiology. Of the remaining 50 cases, which were considered to have VACTERL association, ventricular septal defect was the most common cardiovascular defect (30%) and renal agenesis was the most common renal anomaly (30%); the most common limb defects were reduction deformities (34%) and polydactyly (20%).
Nezarati and McLeod (1999) described a mother and son with typical VACTERL anomalies. The index patient was born by cesarean section to a 27-year-old gravida 1 mother following an uncomplicated pregnancy. Cesarean section was performed because of 'failure to progress.' At birth he was found to have an asymmetric crying face, preaxial polydactyly on the right, a small midmuscular ventricular septal defect with an incomplete right bundle branch block, a small cleft in the T3 vertebrae, and incomplete development of the left half of the sacrum. The kidneys were normal ultrasonographically. The patient's mother was born with an H-type tracheoesophageal fistula, imperforate anus, rectovaginal fistula, a triphalangeal thumb, hypoplastic left kidney, and vertebral anomalies. There were no other individuals with VACTERL anomalies in the family. No families with VACTERL association in the offspring of an affected individual had previously been reported. Occasional single anomalies of the VACTERL association had been described in sibs of parents of the affected individuals.
Hattori et al. (1999) emphasized the tracheobronchial anomalies, specifically ectopic bronchus, in VATER association. They described an 11-month-old boy who presented with recurrent wheezing and atelectasis in the right upper lobe of the lung. Bronchoscopy and bronchography confirmed the presence of an ectopic bronchus arising from the right main bronchus. The diagnosis of VATER association was made on the basis of multiple vertebral and rib anomalies, imperforate anus with a perineal fistula, unilateral hydronephrosis, atrial septal defect, and a preauricular tag; the patient did not have tracheoesophageal fistula.
Killoran et al. (2000) noted phenotypic overlap between the VATER/VACTERL association and what had been called PIV syndrome as described by Say and Gerald (1968), Filippi (1972), and Kaufman et al. (1972). Overlapping features included polydactyly (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, and imperforate anus. They viewed PIV syndrome as a historic antecedent to the VATER/VACTERL association.
Castori et al. (2008) reported a 5-year-old boy with VACTERL who had multiple costovertebral defects, dextrocardia, asymmetric bilateral radial ray hypo/aplasia, unilateral kidney agenesis, tracheoesophageal fistula, and anal atresia. He also had a complex lower limb malformation consisting of distal tibial aplasia, clubfoot, hallucal deficiency and preaxial polydactyly. Hemihypoplasia was also apparent. A literature review identified 24 additional patients with VACTERL manifestations and lower limb malformations. Tibial hypo/aplasia with or without additional tibial field defects were the most common finding (68%), while involvement of the fibular ray was rare (20%) and often accompanied tibial anomalies. Castori et al. (2008) concluded that the relatively high frequency of tibial ray anomalies in VACTERL patients reflected the principle of homology of the developmental field theory.
Townes-Brocks syndrome (107480) and MURCS association (601076) include some of the same features as VATER association.
In a group of 27 patients with Fanconi anemia group D1 (605724) due to biallelic mutations in the BRCA2 gene (600185), Alter et al. (2007) found that 5 patients had 3 or more VATER association anomalies. One patient had VACTERL-H (276950). Alter et al. (2007) noted that a VATER phenotype had also been reported in Fanconi anemia of complementation groups A (227650), C (227645), E (600901), F (603467), and G (614082).
The VACTERL association is typically a sporadic disorder. However, among 78 probands with VACTERL, Solomon et al. (2010) found that 7 (9%) had a primary relative with at least 1 component feature of the disorder, suggesting that there may be a genetic basis for the disorder in some families. For pedigrees in which detailed family data were available, 4 (5.0%) of 141 first-degree relatives had at least 1 major component, which is significantly higher than in the general population. Vertebral defects were the most common feature observed in relatives.
Associations Pending Confirmation
Damian et al. (1996) claimed to have described the first report of a precise molecular basis for a case of VACTERL. They studied a family in which a female infant with VACTERL was born in 1977 and died at age 1 month due to renal failure. Because her mother and sister later developed classic mitochondrial cytopathy associated with the A-to-G point mutation at nucleotide position 3243 of mitochondrial DNA (MTTL1; 590050.0001), they performed molecular analysis of mtDNA in preserved kidney tissue from the VACTERL case. They discovered 100% mutant mtDNA in multicystic and 32% mutant mtDNA in normal kidney tissue. Mild deficiency of complex I respiratory chain enzyme activity was found in the mother's muscle biopsy. Other maternal relatives were healthy but had low levels of mutant mtDNA in blood.
Stone and Biesecker (1997) studied a cohort of 62 patients with VACTERL association. All of the children had normal chromosomes and only 1 had symptoms suggestive of mitochondriopathy, i.e., deafness and muscle weakness. All of the children had at least 3 of the 6 categories of anomalies associated with VACTERL. None of the affected children had levels of the MTTL1 3243A-G mutation that were detectable by the methods used. Stone and Biesecker (1997) recognized the limitations of their study such as heteroplasmy of different tissues (only lymphocytes were studied). They suggested that the proposita reported by Damian et al. (1996) may have had oculoauriculovertebral dysplasia (164210) rather than VACTERL association.
For discussion of a possible association between VACTERL association and mutation in the HOXD13 gene, see 142989.0012.
From their mutant analysis of Gli genes (see 165220), which encode transcription factors mediating Sonic hedgehog (SHH; 600725) signal transduction, Kim et al. (2001) observed that defective Shh signaling leads to a spectrum of developmental anomalies in mice strikingly similar to those of VACTERL. They proposed that VACTERL could be caused by defective SHH signaling during human embryogenesis and suggested that the Gli mutant mice can serve as useful models for studying the pathogenesis of VACTERL.
Alter, B. P., Rosenberg, P. S., Brody, L. C. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J. Med. Genet. 44: 1-9, 2007. [PubMed: 16825431] [Full Text: https://doi.org/10.1136/jmg.2006.043257]
Auchterlonie, I. A., White, M. P. Recurrence of the VATER association within a sibship. Clin. Genet. 21: 122-124, 1982. [PubMed: 7083612] [Full Text: https://doi.org/10.1111/j.1399-0004.1982.tb00747.x]
Castori, M., Rinaldi, R., Cappellacci, S., Grammatico, P. Tibial developmental field defect is the most common lower limb malformation pattern in VACTERL association. Am. J. Med. Genet. 146A: 1259-1266, 2008. [PubMed: 18386801] [Full Text: https://doi.org/10.1002/ajmg.a.32288]
Damian, M. S., Seibel, P., Schachenmayr, W., Reichmann, H., Dorndorf, W. VACTERL with the mitochondrial NP 3243 point mutation. Am. J. Med. Genet. 62: 398-403, 1996. [PubMed: 8723071] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960424)62:4<398::AID-AJMG13>3.0.CO;2-J]
Filippi, G. The syndrome of polydactyly, imperforate anus and vertebral anomalies. Birth Defects Orig. Art. Ser. 8(2): 88-94, 1972.
Finer, N. N., Bowen, P., Dunbar, L. G. Caudal regression anomalad (sacral agenesis) in siblings. Clin. Genet. 13: 353-358, 1978. [PubMed: 657575] [Full Text: https://doi.org/10.1111/j.1399-0004.1978.tb01192.x]
Hattori, H., Okazaki, S., Higuchi, Y., Yoshibayashi, M., Yamamoto, T. Ectopic bronchus: an insufficiently recognized malformation causing respiratory morbidity in VATER association. Am. J. Med. Genet. 82: 140-142, 1999. [PubMed: 9934977]
Kaufman, R. L., Quinton, B. A., Ternberg, J. L. Imperforate anus, vertebral anomalies and preaxial limb abnormalities. Birth Defects Orig. Art. Ser. 8(2): 85-87, 1972.
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. [PubMed: 6835768]
Killoran, C. E., Abbott, M., McKusick, V. A., Biesecker, L. G. Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clin. Genet. 58: 28-30, 2000. [PubMed: 10945658] [Full Text: https://doi.org/10.1034/j.1399-0004.2000.580105.x]
Kim, J. H., Kim, P. C. W., Hui, C. The VACTERL association: lessons from the Sonic hedgehog pathway. Clin. Genet. 59: 306-315, 2001. [PubMed: 11359461] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.590503.x]
Nezarati, M. M., McLeod, D. R. VACTERL manifestations in two generations of a family. Am. J. Med. Genet. 82: 40-42, 1999. [PubMed: 9916841]
Quan, L., Smith, D. W. The VATER association: vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial dysplasia. Birth Defects Orig. Art. Ser. 8(2): 75-78, 1972.
Say, B., Gerald, P. S. A new polydactyly--imperforate-anus--vertebral-anomalies syndrome? (Letter) Lancet 292: 688 only, 1968. Note: Originally Volume II. [PubMed: 4175523] [Full Text: https://doi.org/10.1016/s0140-6736(68)92549-x]
Solomon, B. D., Pineda-Alvarez, D. E., Raam, M. S., Cummings, D. A. T. Evidence for inheritance in patients with VACTERL association. Hum. Genet. 127: 731-733, 2010. [PubMed: 20369369] [Full Text: https://doi.org/10.1007/s00439-010-0814-7]
Stone, D. L., Biesecker, L. G. Mitochondrial NP 3243 point mutation is not a common cause of VACTERL association. (Letter) Am. J. Med. Genet. 72: 237-238, 1997. [PubMed: 9382149]
Weaver, D. D., Mapstone, C. L., Yu, P. The VATER association: analysis of 46 patients. Am. J. Dis. Child. 140: 225-229, 1986. [PubMed: 3946352] [Full Text: https://doi.org/10.1001/archpedi.1986.02140170051027]