VACTERL Manifestations in Two Generationsof a Family

M.M. Nezarati1* and D.R. McLeod1,2

1Department of Medical Genetics, Alberta Children’s Hospital, Calgary, Canada2Department of Pediatrics, Alberta Children’s Hospital, Calgary, Canada

Most cases of the VACTERL ‘‘association’’[Martınez-Frıas et al., Am. J. Med. Genet. 76:291–296, 1998] are sporadic, with an empiricrecurrence risk of 1% or less. Rare familieswith recurrence of VACTERL-H associationare described with patterns consistent withsingle gene inheritance. Also described areoccasional single anomalies of the VAC-TERL association in sibs or parents of af-fected individuals. We describe a motherand son with typical VACTERL anomalies.The patient was born by cesarean section toa 27-year-old G1 mother following an un-complicated pregnancy. He was found tohave an asymmetric crying face, preaxialpolydactyly on the right, a small midmuscu-lar ventricular septal defect with an incom-plete right bundle branch block on echocar-diogram, a small cleft in T3, and incompletedevelopment of the left half of the sacrum.The kidneys were normal ultrasonographi-cally. The patient’s mother was born with anH-type tracheo-esophageal fistula, imperfo-rate anus, rectovaginal fistula, a triphalan-geal thumb, hypoplastic left kidney, andvertebral anomalies. There were no otherindividuals with VACTERL anomalies in thefamily. No families with VACTERL associa-tion in the offspring of an affected indi-vidual have been reported previously. Am.J. Med. Genet. 82:40–42, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: VACTERL; VATER; autoso-mal dominant

INTRODUCTIONThe acronym VATER was first coined by Quan and

Smith [1973] to indicate the nonrandom association of

Vertebral anomalies, Anal atresia, Tracheo-Esopha-geal fistula with esophageal atresia, Radial ray defects,and Renal anomalies. The condition was subsequentlyexpanded to include cardiac defects [Temtamy andMiller, 1974], and the acronym was changed to VAC-TERL, (C for cardiovascular malformations, R for renalanomalies, and L for limb defects) [Kaufman, 1973;Nora and Nora, 1975]. Occasional manifestations in-clude pre- and post-natal growth deficiency, laryngealstenosis, ear anomalies, lower limb defects, rib anoma-lies, external genital defects, single umbilical artery,and spinal ‘‘dysraphia’’ with tethered cord. Most VAC-TERL individuals have normal intelligence. Patientswith X-linked VACTERL-H syndrome generally have apoorer prognosis [Evans et al., 1989].

VACTERL association is considered to be sporadic,and causally heterogeneous [Khoury et al., 1983; Czei-zel and Ludyani, 1985]. VACTERL malformations havealso been seen in aneuploidies (such as trisomies 13and 18), known syndromes (Townes-Brock, Holt-Oram,Meckel), sequences (caudal regression, sirenomelia)and environmental effects (thalidomide, diabetic em-bryopathy) [Evans et al., 1989]. This is the first pub-lished report of a parent and child both diagnosed withVACTERL association.

CLINICAL REPORT

The index patient was born to a 27-year-old G1mother following a normal pregnancy. The only medi-cation used during the pregnancy was salbutamol in-haler. Prenatal vitamin supplements were not taken.Two prenatal ultrasound studies showed a structurallynormal fetus small for gestational age.

The patient was born at term by cesarean section forfailure to progress. He was covered with thick meco-nium which required suctioning, and a brief period ofventilation for an episode of bradycardia and hypoto-nia. Apgar scores were 3, 9, and 10 at 1, 5, and 10 minrespectively, and birth weight was 3,010 g (25th–50thcentile). The patient was noted to have an asymmetriccrying face and right preaxial polydactyly. Physical ex-amination was otherwise normal. Radiographs of thespine identified a vertical cleft in the body of T3 andincomplete development of the left half of the sacrum.An echocardiogram demonstrated a small ventricularseptal defect (VSD). No renal abnormalities were noted

*Correspondence to: Marjan M. Nezarati, Department of Medi-cal Genetics, Alberta Children’s Hospital, 1820 Richmond Rd.S.W., Calgary, AB T2T 5C7, Canada. E-mail: mmnezara@acs.ucalgary.ca

Received 19 March 1998; Accepted 28 April 1998

American Journal of Medical Genetics 82:40–42 (1999)

© 1999 Wiley-Liss, Inc.

on ultrasound study. The patient was first seen at age4.5 months. At that time his length, weight, and headcircumference (OFC) were at or near the 50th centile.He had an asymmetric crying face, with no other minoranomalies. A grade II–III/VI systolic murmur was pre-sent at the lower left sternal border. There was pre-axial polydactyly with an adductible radial thumb anda flaccid ulnar thumb (Fig. 1). His testes were de-scended and he had a normal anus. Based on vertebralanomalies, VSD, and polydactyly, he was diagnosedwith VACTERL association. With the exception ofsome initial concerns about feeding and occasionalproblems with constipation, the patient has done well.He is currently 4 11/12 years old, and there are noconcerns about his growth and development.

The patient’s mother also had a constellation of con-genital anomalies consistent with a diagnosis of VAC-TERL: tracheoesophageal fistula, imperforate anuswith a rectovaginal fistula, triphalangeal left thumb,small left kidney, and vertebral anomalies comprised ofa foreshortened dysplastic sacrum, fusion abnormali-ties at the L4–L5 level, and spina bifida occulta at theL5 level. She required numerous operations to correctthese anomalies, and continued to have problems withregurgitation necessitating a fundoplication at 16years. She has asthma and occasionally uses a salbu-tamol inhaler but is otherwise in good health. On a

recent hearing evaluation she was found to have mildto moderate sensorineural hearing loss on the left, anda severe mixed hearing loss on the right. She was in-vestigated for the MELAS 3243 and 3277 mutations,which were not present. She has no minor anomaliesand is of normal intelligence.

The family history is unremarkable, and the two sib-lings are normal.

DISCUSSION

The VACTERL association is a recognized nonran-dom association of vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies (particularly ra-dial ray defects). There does not appear to be anagreed-upon consensus in the literature on the mini-mum diagnostic criteria for this entity. While some in-vestigators consider the involvement of three or moreof the VACTERL anomalies as a requirement for diag-nosis [Botto et al., 1997; Khoury et al., 1983; Czeizeland Ludanyi, 1985], others [Rittler et al., 1996] havemade the diagnosis in those with two of the associatedanomalies.

No specific cause has been identified for VACTERL,and causal heterogeneity has been reported as the mostlikely conclusion. Khoury et al. [1983] suggested that acommon denominator of the association is defectivemesodermal development during embryogenesis due toa variety of causes, leading to overlapping presenta-tions. Damian et al. [1996] reported finding the mito-chondrial NP 3243 (MELAS) mutation in the kidneytissue of an individual with VACTERL assocation. Thiswas the first instance of a molecular abnormality iden-tified in an individual with VACTERL. There havebeen reports in the literature of the recurrence of VAC-TERL-H consistent with single gene inheritance[Hunter and MacMurray, 1987; Evans et al., 1989;Wang et al., 1993; Corsello and Giuffre, 1994]. Indi-vidual VACTERL components may recur in families.McMullen et al. [1996] reported a study on the familialrecurrence of tracheoesophageal fistula (TEF). Theyproposed a risk of less than 0.5% for sibs and 2.4% foroffspring of individuals with TEF. There was also anincreased risk for relatives of TEF individuals for VAC-TERL malformations.

There have been very few reports of familial occur-rence of VACTERL. Fuhrmann et al. [1958] publisheda report on a family where the index case had analatresia, an unspecified congenital heart defect, andpreaxial polydactyly of the right hand. His brother hadisolated anal atresia, and their mother had preaxialpolydactyly. Say et al. [1971] observed a three-generation family, where the index patient had an im-perforate anus, hemivertebrae, hypoplasia of the leftiliac bone, unilateral renal agenesis, and a hypoplasticthumb. Her mother had one hypoplastic thumb, whileher maternal grandmother had a hypoplastic thumb,13 ribs with bilateral cervical ribs, and hypoplasia ofthe fourth dorsal vertebra and the right iliac bone. In1982 Auchterlonie and White reported on two brothersborn to healthy nonconsanguineous parents. The oldestboy had esophageal atresia and hemivertebrae, and didwell following surgery. The following pregnancy was

Fig.1. Radiograph of the index patient’s hand demonstrating polydac-tyly.

VACTERL Manifestations 41

complicated by severe oligohydramnios. The male in-fant was said to have ‘‘abnormal Potter-type facies,’’minor anomalies, and an imperforate anus. He died atage 1 hr and an autopsy demonstrated esophageal atre-sia, duodenal atresia, absent rectum, ventricular septaldefect, hypoplastic lungs, and absent kidneys.

The concept of ‘‘association’’ was reassessed recentlyby Martınez-Frıas et al. [1998] in terms of multiplepolytopic field defects, or multiple anomalies of blasto-genesis without minor anomalies. Individual anoma-lies of blastogenesis [Opitz, 1993] may be hereditary; arecent enumeration of X-linked blastogenesis (XLB)mutations listed almost four-dozen conditions (seeOpitz [1993] for an earlier such list). X-linked syn-dromes of multiple anomalies of blastogenesis are rela-tively uncommon; VACTERL-H and the ZIC3 muta-tions come readily to mind [Gebbia et al., 1997; Wanget al., 1993]. Multiple anomalies of blastogenesis arealso seen in aneuploidy or polyploidy syndromes (moreso in triploidy and trisomy 13 than in trisomy 18 thanin Down syndrome). However, parent-to-child trans-mission of multiple blastogenic anomalies is uncom-mon, probably because of the prenatal lethality of theanomalies or their combinations, making most (ge-netic) cases new mutations.

This is the first time that a parent and child bothmeet the diagnostic requirements for the diagnosis ofVACTERL association. Other syndromic diagnoses,such as Townes-Brock were considered, but were ex-cluded based on the clinical findings. While it is pos-sible that VACTERL association occurred as a result ofindependent sporadic events in these two individuals,one has to consider that vertical transmission of VAC-TERL may be taking place in this family. In quoting arecurrence risk for the mother of our index patient, weallowed the range to be up to 50% for future pregnan-cies to include the possibility of autosomal dominanttransmission. At present, a similar recurrence riskwould have to be quoted for any children of the indexpatient.

ACKNOWLEDGMENTS

We thank the family for their cooperation. The assis-tance of Janis Bell and Mary Anderson was invaluablein collecting the records necessary for preparing thismanuscript. As always, Carol Peterson-Malo’s help inphotography was appreciated. The contribution of Dr.John Opitz in editing the manuscript was much appre-ciated.

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42 Nezarati and McLeod