3110jumonline.qxp:Layout 1 9/19/12 3:32 PM Page 1689 CLINICAL LETTER Sonographic Diagnosis of Multiple Cardiovascular Malformations in a Fetus With an Interstitial 8p23.1 Deletion Video online at www.jultrasoundmed.org 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. 1689 3110jumonline.qxp:Layout 1 9/19/12 3:32 PM Page 1690 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. 1690 J Ultrasound Med 2012; 31:1689–1692 3110jumonline.qxp:Layout 1 9/19/12 3:32 PM Page 1691 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. References 1. 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 deletion. 2. 3. 4. 5. 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; 115:1522–1531. 1691 3110jumonline.qxp:Layout 1 9/19/12 3:32 PM Page 1692 Clinical Letter 6. 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– 281. 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. Umbilical vein anomaly in fetuses with Down syndrome. Ultrasound Obstet Gynecol 2010; 35:297–301. 1692 J Ultrasound Med 2012; 31:1689–1692