Sonographic Diagnosis of Multiple Cardiovascular

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Sonographic Diagnosis of Multiple Cardiovascular
Malformations in a Fetus With an Interstitial
8p23.1 Deletion
Video online at
A 26-year-old woman, gravida 2, para 0, was referred to our
tertiary prenatal referral center at a gestational age of 19
weeks 6 days for suspicion of a hypoplastic left heart. The
mother had grade 1 obesity (body mass index, 30.6 kg/m2),
and apart from a previous spontaneous miscarriage, the
patient’s medical history was otherwise unremarkable.
During a detailed anatomic survey including segmental
echocardiography, marked dilatation of the right atrium and
a small perimembranous ventricular septal defect were
detected (Figure 1 and Video 1). In transverse and sagittal
sections, the umbilical vein showed an atypical intraabdominal course deviating rightward adjacent to the lateralized gallbladder. This aberrant vessel, per definition of
the right umbilical vein, lacked a direct communication with
the inferior vena cava and drained directly into the consecutively dilated right atrium (Figure 2). The ductus venosus
could not be visualized reproducibly. All fetal biometric
measurements were consistent with dates. At 21 weeks’ gestation, an incomplete balanced atrioventricular septal defect
and an aberrant right subclavian artery (arteria lusoria) were
diagnosed (Figures 1 and 3). All of these abnormalities were
highly suggestive of an underlying genetic disorder, prompting immediate invasive testing.
Amniocentesis was performed, and the diagnosis of
an interstitial deletion at the terminal region of the short
arm of chromosome 8 was established by fluorescence in
situ hybridization. The diagnosis of a 5.25-megabase deletion containing parts of the GATA binding protein 4
(GATA4) gene was confirmed by array comparative
genomic hybridization analysis (ish 8p23.1 [RP11589N15x1]). The couple was interdisciplinary counseled
by obstetricians and medical geneticists, and the pregnancy
was terminated by parental request at 25 weeks. Pathologic
examination showed a male fetus weighing 770 g. The prenatally diagnosed cardiac anomalies were confirmed by
autopsy (Figure 4), with a perimembranous ventricular
septal defect of 3 mm size. Postmortem examination
revealed an atrial septal defect of 0.6 cm, which corresponded to the balanced atrioventricular septal defect as
suggested sonographically. The aberrant right subclavian
artery was also confirmed by pathologic examination.
The fetus showed low-set, posteriorly rotated ears and a
prominent occiput. The frontal features were narrow with
prominent supraorbital ridges, and the eyelids were also
J Ultrasound Med 2012; 31:1689–1692
prominent. This appearance was in contrast to the antenatal sonographic findings, describing the facial characteristics and the skull as normal, which may have been partly
attributed to severely reduced imaging clarity due to obesity. Unfortunately, the sonographically suspected right
umbilical vein and absent ductus venosus were not explicitly mentioned in the pathologic report. An additional array
comparative genomic hybridization analysis of a parental
blood specimen revealed no such deletion in either parent.
Although a considerable number of cases of interstitial, terminal, or inverted duplication deletions of chromosomal region 8p, mainly in the pediatric population,
have been reported in the past, little is known about the
spectrum of prenatal findings of affected individuals.1
The incidence of del8p23.1 is estimated to be 1 per 18.500
amniotic fluid samples and 1 per 5072 postnatal case studies.2 Most of these deletions are de novo mutations.3
Clinical and prenatal sonographic characteristics of
deletions in the short arm of chromosome 8 are developmental impairments such as mild to moderate mental
impairment, hyperactivity and impulsive behavior, minor
Figure 1. A and C, Gray-scale images showing an atypical 4-chamber
view with a markedly dilated right atrium and an incomplete atrioventricular septal defect at 20 weeks’ gestation. B and D, Corresponding
pathologic specimens showing the diagnosis of an atrioventricular septal defect (B, asterisk) and a perimembraneous ventricular septal defect
(D, asterisks). LA indicates left atrium; LV, left ventricle; RA, right atrium;
and RV, right ventricle.
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Clinical Letter
facial anomalies, microcephaly, intrauterine growth
restriction, congenital heart disease, and congenital
diaphragmatic hernias. Genotype-phenotype correlation
studies revealed chromosome region 8p23.1 as the critical
region responsible for congenital heart defects.3 It has
been suggested that haploinsufficiency of genes located
within 8p23.1 might impair heart differentiation, leading
to a broad spectrum of congenital heart diseases. A key
role is played by the GATA4 gene locus because mutations in GATA4 were recently shown to cause structural
heart defects most likely via dysregulation of cardiomyocyte proliferation and alteration of the morphogenesis of
the right ventricle and atrioventricular canal.4,5 Additionally, other candidate genes within 8p23.1 have been identified to contribute to the clinical phenotype, such as
sex-determining region Y box 7 (SOX7).3 Typical cardiac
anomalies in individuals with antenatally and postnatally
diagnosed del8p23.1 comprise septal defects (atrial/ventricular septal defect and atrioventricular septal defect) and
right heart anomalies, including pulmonary stenosis/
atresia, tetralogy of Fallot, double-outlet/inlet right ventricle, and, rarely, Ebstein anomaly.6 According to Wat et
al,3 those patients with terminal deletions tend to have
more severe defects compared to those with interstitial and
heterozygous GATA4 mutations. Apart from congenital
heart disease, congenital diaphragmatic hernias are reportedly a common finding in cases of interstitial and terminal
but not in inverted duplication.3 Anomalies of the fetal
venous system as described herein have only been previously reported once in a twin gestation discordant for
8p23.1 with complex congenital heart disease and hemiazygos continuation.3 However, the true incidence of subtle venous anomalies in healthy and aneuploid fetuses may
certainly be underestimated. In a very recent article,
Staboulidou et al7 stated the prevalence of an absent ductus venosus of 1 per 2.500 pregnancies. Tabulating all published reports of an absent ductus venosus, the authors
were able to show that 12% of affected cases (13 of 110)
had chromosomal abnormalities, and cardiac defects
accompanying the absent ductus venosus were found in
Figure 2. A, Oblique section of the fetal abdomen at 20 weeks showing the absence of the ductus venosus and lack of communication with the inferior vena cava (IVC). The course of the altered venous connection could be followed until drainage into the right atrium (RA). B, Transverse section
showing the aberrant course of the umbilical vein (UV) pointing toward the stomach (St). C, Glass body mode image of the fetal venous system.
J Ultrasound Med 2012; 31:1689–1692
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Clinical Letter
21% (23 of 110). According to Berg et al,8 it is suggested
that in the presence of cardiac malformations, complex
nonchromosomal malformation syndromes in combination with an absent ductus venosus are significantly associated with intrauterine or postnatal death independent of
the venous drainage site. The potential association of an
aberrant right subclavian artery with chromosomal anomalies (particularly Down syndrome) and nonchromosomal defects (congenital heart disease) has been well
established.9,10 The observed subclavian vessel rearrangement in our case was in line with previous reports of an
aberrant right subclavian artery accompanying cardiac
defects as part of underlying genetic disorders. To the best
of our knowledge, a concomitant absent ductus venosus
and aberrant right subclavian artery have not been reported
previously. Dysmorphic features of 8p23.1 deletions on prenatal sonography are rather nonspecific. The severity of
Figure 3. A, B-flow image of a 3-vessel and trachea view at 21 weeks with
an aberrant right subclavian artery (ARSA, arteria lusoria) originating from
the distal portion of the aortic arch coursing from the left side behind the
trachea and esophagus to the right. AAo indicates ascending aorta; and
MPA, main pulmonary artery. B, Corresponding macroscopic image
showing the abnormal branching of the descending aorta with the probe
pointing to the branching of the aberrant subclavian artery.
craniofacial abnormalities seems to be directly related to the
extent of the deleted genetic information. In distinct cases,
3-dimensional volume-rendered imaging as an adjunctive
tool to conventional gray-scale sonography might be helpful
for further delineation of both cardiovascular and craniofacial malformations caused 8p deletions in utero. Consistent
with our findings, microbrachycephaly as a relative common
postnatal feature has not been observed before 30 gestational weeks in the current literature.
The nonspecific phenotype of del8p23.1, reaching
from normal intelligence to severe mental impairment and
minor anomalies to complex malformations, accounts for
the variable prognosis of affected individuals. A characteristic cluster of antenatal features pointing exclusively to
deletions within this chromosomal region remains
elusive. Therefore, a detailed anatomic sonographic
survey and molecular testing (array comparative genomic
hybridization) are urgently recommended in all cases with
congenital heart disease (particularly atrioventricular septal defects) and concomitant congenital diaphragmatic
hernias suspicious for an underlying genetic disorder.
Friederike Hoellen, MD, Jan Weichert, MD, PhD
Division of Prenatal Medicine
University Hospital of Schleswig-Holstein
Luebeck, Germany
We thank Yorck Hellenbroich, MD, for karyotype examination and
performing fluorescence in situ hybridization analysis and array comparative genomic hybridization and Frank Noack, MD, for autopsy.
Figure 4. A and B, Pathologic images at autopsy showing nonpecific
features, such as low-set ears, a broad nasal bridge, prominent eyelids,
and a prominent occiput. The antenatal diagnosis was interstitial 8p23.1
J Ultrasound Med 2012; 31:1689–1692
Ballarati L, Cereda A, Caselli R, et al. Genotype-phenotype correlations in
a new case of 8p23.1 deletion and review of the literature. Eur J Med Genet
2011; 54:55–59.
Reddy KS. A paternally inherited terminal deletion, del(8)(p23.1)pat,
detected prenatally in an amniotic fluid sample: a review of deletion 8p23.1
cases. Prenat Diagn 1999; 19:868–872.
Wat MJ, Shchelochkov OA, Holder AM, et al. Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic
hernia. Am J Med Genet A 2009; 149A:1661–1677.
Pehlivan T, Pober BR, Brueckner M, et al. GATA4 haploinsufficiency in
patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am J Med Genet 1999; 83:201–206.
Zeisberg EM, Ma Q, Juraszek AL, et al. Morphogenesis of the right ventricle requires myocardial expression of Gata4. J Clin Invest 2005;
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Giglio S, Graw SL, Gimelli G, et al. Deletion of a 5-cM region at chromosome 8p23 is associated with a spectrum of congenital heart defects. Circulation 2000; 102:432–437.
7. Staboulidou I, Pereira S, Cruz Jde J, Syngelaki A, Nicolaides KH. Prevalence and outcome of absence of ductus venosus at 11(+0) to 13(+6)
weeks. Fetal Diagn Ther 2011; 30:35–40.
8. Berg C, Kamil D, Geipel A, et al. Absence of ductus venosus: importance
of umbilical venous drainage site. Ultrasound Obstet Gynecol2006; 28:275–
9. Zalel Y, Achiron R, Yagel S, Kivilevitch Z. Fetal aberrant right subclavian
artery in normal and Down syndrome fetuses. Ultrasound Obstet Gynecol
2008; 31:25–29.
10. Achiron R, Gindes L, Gilboa Y, Weissmann-Brenner A, Berkenstadt M.
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