Ectopia Cordis in a Fetus with Mosaic Trisomy 16

Ectopia Cordis in a Fetus with Mosaic Trisomy 16. Christos Arnaoutoglou, Soultana Meditskou, Anastasia Keivanidou, Marilena Manthou, Nikolaos Anesidis, Apostolos Athanasiadis, Efstratios Assimakopoulos, Sailesh Kumar

To cite this version:

Christos Arnaoutoglou, Soultana Meditskou, Anastasia Keivanidou, Marilena Manthou, Nikolaos Ane- sidis, et al.. Ectopia Cordis in a Fetus with Mosaic Trisomy 16.. Journal of Clinical Ultrasound, Wiley, 2010, 10.1002/jcu.20727. hal-00552407

HAL Id: hal-00552407 https://hal.archives-ouvertes.fr/hal-00552407 Submitted on 6 Jan 2011

HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Journal of Clinical Ultrasound

Ectopia Cordis in a Fetus with Mosaic Trisomy 16.

For Peer Review Journal: Journal of Clinical Ultrasound

Manuscript ID: JCU-09-078.R2

Wiley - Manuscript type: Case Report

extrathoracic heart, exocardia, ultrasound diagnosis, congenital Keywords: heart defects, chromosome anomalies

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1 2 3 TITLE: 4 5 6 Ectopia Cordis in a Fetus with Mosaic Trisomy 16. 7 8 9 10 SHORT TITLE/ RUNNING HEAD: 11 12 13 Ectopia Cordis with Trisomy 16 Mosaic. 14 15 16 17 18 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 ABSTRACT: 4 5 6 Ectopia cordis is a rare congenital cardiac malformation which occurs sporadically. 7 8 Mosaic Trisomy 16 is an extremely rare chromosomal disorder. An association 9 10 between these two anomalies has never previously been reported. We report a case 11 12 +3 13 of an isolated ectopia cordis at 11 weeks. Subsequent embryological examination 14 15 confirmed thoracic ectopia cordis with normal heart structure and array comparative 16 17 18 genomic hybridization of fetal tissue detected trisomy 16 mosaicism. 19 20 For Peer Review 21 22 23 24 25 KEYWORDS: 26 27 extrathoracic heart; exocardia; ultrasound diagnosis; congenital heart defects; 28 29 chromosome anomalies 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 INTRODUCTION 4 5 6 Ectopia cordis (EC) is a sporadic congenital heart defect occurring in 5.5 to 7.9 per 7 8 10 6 live births [1]. It is defined as a complete or partial displacement of the heart 9 10 outside the thoracic cavity [1]. EC may occur either as an isolated malformation or be 11 12 13 associated with a ventral body wall defect that affects the thorax, and/or the 14 15 abdomen. Five types are recognized: cervical, cervicothoracic, thoracic, abdominal, 16 17 18 and thoracoabdominal [2]. Thoracic and thoracoabdominal types are the commonest 19 20 followed by the abdominalFor and Peer cervical malformations. Review 21 22 Mosaic trisomy 16 (mosaic T16) is an extremely rare chromosomal disorder in which 23 24 25 an extra chromosome 16 is present in some of the cells of the affected. 26 27 Co-occurrence of EC and mosaic T16 has never previously been reported. We 28 29 present a prenatally diagnosed case. 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 CASE REPORT 4 5 +1 6 A 20-year-old primigravida woman had an early viability scan (7 weeks), performed 7 8 with a Voluson 730 Expert scanner (GE Healthcare , Kretztechnik , Zipf , Austria) using 9 10 a RIC 5-9 micro-convex endovaginal probe (5-9MHz). The examination showed a 11 12 13 normal intrauterine pregnancy consistent with the gestational age by the last 14 15 menstrual period (CRL: 9,2mm) and a normal heart rhythm without any obvious 16 17 18 abnormal cardiac findings. 19 20 For Peer Review 21 22 Subsequent nuchal translucency (NT) scan at 11 +3 weeks of gestation (CRL: 49mm) 23 24 25 detected an extrathoracic heart and a raised NT measurement (5.5mm). The 26 27 pulsating fetal heart was completely protruding from the thorax into the amniotic fluid 28 29 (Figure 1). No other malformations were identified. Both scans were performed by a 30 31 32 fetal medicine specialist. 33 34 35 36 After being counselled about the severity of the malformation and its dismal 37 38 39 prognosis the patient decided to proceed to medical termination of the pregnancy. 40 41 This was done at 13 +3 weeks gestation. The patient consented to a post mortem of 42 43 44 the fetus. The post mortem showed a 13 week male fetus, with thoracic ectopia 45 46 cordis. The heart was completely exposed without any associated intracardiac and 47 48 great vessels abnormalities. Additional extracardiac malformations included low set 49 50 51 ears, micrognathia, microstomia, a soft and discrete swelling in the area of the neck 52 53 and a hypoplastic sternum (Figure 2). Myocardial calcification was also found on 54 55 histology. 56 57 58 59 60

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1 2 3 Array comparative genomic hybridization (CGH) analysis (Spectral Chip, Perkin 4 5 6 Elmer Life and Analytical Science, Courtaboeuf; France) revealed a) mosaic trisomy 7 8 16, b) gain at 22q12.1-22q12.2 and c) deletion at 22q13.1-22q13.2. The results were 9 10 confirmed by fluorescent in situ hybridization (FISH) analysis. The gains and losses 11 12 13 of genetic material of chromosome 22 were confirmed as true imbalances by 14 15 controlling for putative polymorphisms. Single FISH experiments on the nuclei of the 16 17 18 ectopic cardiac tissue and normal peripheral blood as controls were performed. A 19 20 panel of FISH probesFor were derivedPeer by nick Review translation from BAC clones, tilling the 21 22 regions 22q12.1-22.12.2 (RP11-76E8, RP11-89A2, RP11-91K24, RP11-79G21, 23 24 25 RP11-79G6) and 22q13.1-22q13.2 (RP3-37OM22, RP5-979N1, RP1-185D5, 26 27 RP4.695020). The list of BAC/PAC clones and the details of each can be found at 28 29 National Center for Biotechnology Information. 30 31 32 33 34 After these results were available the parents were advised that parental karyotyping 35 36 was necessary. However they declined any further investigations. 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 DISCUSSION 4 5 6 Ectopia cordis develops secondary to failure of maturation and fusion of the midline 7 8 mesodermal components of the chest and abdomen. The sternum originates from 9 10 two longitudinal mesenchymal bands, which start fusing in a cephalocaudal direction 11 12 th 13 from the 7-10 week of gestation. The earliest prenatal sonographic EC diagnosis 14 15 has been reported at 8 +5 weeks of gestation [3]. However, very early diagnosis before 16 17 th 18 the 9 embryonic week may be extremely difficult because midline fusion and 19 20 formation of the thoracicFor cavity Peer is only completed Review after that gestation. In this particular 21 22 case, images from the early viability scan were reviewed retrospectively and it was 23 24 +1 25 concluded that the EC was not apparent at 7 weeks. 26 27 28 29 Increased nuchal translucency has previously been reported in a fetus with EC [4]. It 30 31 32 is likely that the nuchal edema arises as a consequence of cardiac dysfunction or 33 34 coexistence of a chromosomal abnormality. This is the likely explanation in our case. 35 36 37 38 39 In our case, cytogenetics of the fetus were explored using CGH array analysis 40 41 followed by FISH confirmation as this is a detailed and effective technique for fetal 42 43 44 karyotyping [5]. There is relative sparse evidence associating EC with chromosomal 45 46 anomalies or specific genetic mutations. Reported cases include an association with 47 48 triploidy [6], trisomy 18 [7], Turner syndrome [8] and 46,XX,17q+ [9]. A mosaic 49 50 51 trisomy 16 pregnancy originates from a trisomy 16 zygote as a consequence of non 52 53 disjunction in meiosis I. Some mosaics are products of ‘’trisomic rescue’’, the loss of 54 55 a 3 rd chromosome, resulting in a euploid cell line, where the two remaining 56 57 58 chromosomes may come from one parent (uniparental disomy). 59 60

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1 2 3 Trisomy 16 is the most frequently encountered trisomy in early abortion specimens 4 5 6 representing an occurrence of ~1.5% of all clinically recognized conceptions. Most of 7 8 these embryos undergo spontaneous abortion or developmental arrest between 8-15 9 10 weeks of gestation [10]. Micrognathia and microstomia (present in our case) has 11 12 13 previously been reported in mosaic trisomy 16 fetuses. Although cardiac anomalies 14 15 are commonly seen with mosaic trisomy 16, EC has never previously been reported. 16 17 18 Furthermore, most reported EC cases (95%) have associated intracardiac 19 20 malformations [11]. For In contrast, Peer this is one Review of very few reported cases with normal 21 22 cardiac structure [12]. Body stalk defects have been reported in a case of uniparental 23 24 25 disomy of chromosome 16 [13]. In our case the ventral body wall failure was indeed 26 27 associated with an abnormality of chromosome 16. 28 29 30 31 32 In general, mosaic T16 is characterized by variable anatomic findings and pregnancy 33 34 outcomes. A specific trisomy 16 mosaic syndrome has not been defined yet. It has 35 36 been suggested that the phenotype and the genetic aberration have a complex 37 38 39 relationship [14] and make precise genotype-phenotype correlation somewhat 40 41 difficult. 42 43 44 45 46 It was not possible to ascertain if the abnormalities in chromosome 22 seen in this 47 48 fetus were inherited from either parent (as they declined karyotyping). There have 49 50 51 been no reported fetal abnormalities associated with chromosomal gains of 22q12.1- 52 53 22q12.2 or losses of 22q13.1-22q13.2. Although the validity of gains and losses on 54 55 chromosome 22 was confirmed as real imbalances and not mere polymorphisms, 56 57 58 further parental testing would have been desirable in order to address the 59 60 significance of the finding in more detail.

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1 2 3 In conclusion, this case demonstrates that 1 st trimester diagnosis is possible for EC. 4 5 6 Our case also suggest that karyotyping should be performed in all cases as rare 7 8 chromosome abnormalities are sometime present, which may be of importance in 9 10 counselling parents about future pregnancies. 11 12 13 14 15 16 17 18 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 REFERENCES: 4 5 6 1. Khoury MJ, Cordero JF, Rasmussen S. Ectopia cordis, midline defects and 7 8 chromosome abnormalities: an epidemiologic perspective. Am J Med Genet 9 10 1988;30(3):811-7. 11 12 13 14 15 2. Skandalakis JE, Gray SW, Ricketts R, et al. Anterior Wall Defects; in 16 17 18 Skandalakis LJ, Gray SW (ed.) Embryology for surgeons. Baltimore, Lippincott 19 20 Williams & Wilkins, 1994,For p 552. Peer Review 21 22 23 24 25 3. Donald SH. First-Trimester Ectopia Cordis in a Twin Gestation, Using 3D 26 27 Surface Rendering and Reconstruction. Journal of Diagnostic Medical Sonography 28 29 2005;21(5):420-23. 30 31 32 33 34 4. Staboulidou I, Wustemann M, Schmidt P, et al. Increased fetal nuchal 35 36 translucency as a predictor of Cantrell's pentology - case report. Z Geburtshilfe 37 38 39 Neonatol 2005;209(6):231-4. 40 41 42 43 44 5. Benkhalifa M, Kasakyan S, Clement P, et al. Array comparative genomic 45 46 hybridization profiling of first-trimester spontaneous abortions that fail to grow in vitro. 47 48 Prenat Diagn 2005;25(10):894-900. 49 50 51 52 53 6. Sepulveda W, Weiner E, Bower S, et al. Ectopia cordis in a triploid fetus: first- 54 55 trimester diagnosis using transvaginal color Doppler ultrasonography and chorionic 56 57 58 villus sampling. J Clin Ultrasound 1994;22(9):573-5. 59 60

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1 2 3 7. Shaw SW, Cheng PJ, Chueh HY, et al. Ectopia cordis in a fetus with trisomy 4 5 6 18. J Clin Ultrasound 2006;34(2):95-98. 7 8 9 10 8. Garson A, Hawkins EP, Mullins CE, et al. Thoracoabdominal ectopia cordis 11 12 13 with mosaic Turner's syndrome: Report of a case. Pediatrics 1978;62(2):218-21 14 15 16 17 18 9. Say B, Wilsey CE. Chromosome aberration in ectopia cordis (46,XX,17q+). 19 20 Am Heart J 1978;95(2):274-5.For Peer Review 21 22 23 24 25 10. Yong PJ, Barrett IJ, Kalousek DK, et al. Clinical aspects, prenatal diagnosis, 26 27 and pathogenesis of trisomy 16 mosaicism. J Med Genet 2003;40(3):175-82. 28 29 30 31 32 11. Cabrera A, Rodrigo D, Luis MT, et al. Ectopia cordis and cardiac anomalies. 33 34 Rev Esp Cardiol 2002;55(11):1209-12. 35 36 37 38 39 12. Goncalves FD, Novaes FR, Maia MA, et al. Thoracic ectopia cordis with 40 41 anatomically normal heart. Rev Bras Cir Cardiovasc 2007;22(2):245-7. 42 43 44 45 46 47 48 13. Chan Y, Silverman N, Jackson L, et al. Maternal uniparental disomy of 49 50 51 chromosome 16 and body stalk anomaly. Am J Med Genet 2000;94(4):284-6. 52 53 54 55 14. Moradkhani K, Puechberty J, Blanchet P, et al. Mosaic trisomy 16 in a fetus: 56 57 58 the complex relationship between phenotype and genetic mechanisms. Prenat Diagn 59 60 2006:26(12):1179-82.

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1 2 3 FIGURE LEGENDS: 4 5 6 7 8 Figure 1: Sonographic detection of EC at 11+3 weeks of gestation (arrow shows 9 10 protruding heart). 11 12 13 14 15 Figure 2: Photograph of the same fetus at 13 weeks of gestation. 16 17 18 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 ABSTRACT: 4 5 6 Ectopia cordis is a sporadic rare congenital cardiac malformation which occurs 7 8 sporadically . and mo saic Mosaic Trisomy 16 is an extremely rare chromosomal 9 10 disorder. An association between these two anomalies has never previously been 11 12 +3 13 reported. We report a prenatal diagnosis case of an isolated ectopia cordis at 11 14 15 weeks associated with increased nucha l translucency. Subsequent embryological 16 17 18 examination displayed confirmed thoracic ectopia cordis with normal heart structure 19 20 Array and array comparativeFor genomicPeer hybridization Review of fetal tissue detected trisomy 16 21 22 mosaicism. 23 24 25 26 27 28 29 KEYWORDS: 30 31 32 extrathoracic heart; exocardia; ultrasound diagnosis; congenital heart defects; 33 34 chromosome anomalies 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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20 and thoracoabdominalFor types Peer are commonl Reviewy the commonest followed by the 21 22 abdominal and cervical malformations types . 23 24 25 Mosaic trisomy Trisomy 16 (mosaic T16) is an extremely rare chromosomal disorder 26 27 in which an extra chromosome 16 is present in some of the cells of the affected fetus . 28 29 Co-occurrence of EC and mosaic T16 concurrence is extremely rare and has never 30 31 32 previously been reported before . We present a prenatally diagnosed case. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 CASE REPORT 4 5 +1 6 A 20-year-old primigravida woman had an early viability scan (7 weeks), performed 7 8 with a Voluson 730 Expert scanner (GE Healthcare , Kretztechnik , Zipf , Austria) using 9 10 a RIC 5-9 micro-convex endovaginal probe (5-9MHz). The examination showed a 11 12 13 normal intrauterine pregnancy consistent with to the gestational age by the last 14 15 menstrual period LMP (CRL: 9,2mm) and a normal heart rhythm without any obvious 16 17 18 abnormal cardiac findings. 19 20 For Peer Review 21 22 Mother had a Subsequent nuchal translucency (NT) scan at 11 +3 weeks of gestation 23 24 25 (CRL: 49mm) detected an extrathoracic heart and a raised NT measurement 26 27 (5.5mm) performed with the same scanner using a RAB 2 -5 abdominal convex probe 28 29 (2 -5MHz). The pulsating palpating fetal heart was completely protruding from the 30 31 32 thorax into to the amniotic fluid (Figure 1 /A ) and the nuchal translucency was 5.5mm . 33 34 No other further malformations were identified. Both scans were performed by a fetal 35 36 medicine specialist. 37 38 39 40 41 Two weeks later, after After being counselled infor med about the severity of the 42 43 44 malformation and its dismal prognosis the patient couple decided to proceed to 45 +3 46 medical termination of the pregnancy, This was done at 13 weeks gestation. The 47 48 patient consented to a post mortem of the fetus. The autopsy post mortem showed a 49 50 51 13 week male fetus, with thoracic ectopia cordis. The heart was completely exposed 52 53 without any associated intracardiac and great vessels abnormalities. congenital heart 54 55 or major vessel defects. Additional extracardiac malformations The find ings of the 56 57 58 autopsy (Figure 1/B) included a low set ears, micrognathia, microstomia, a soft and 59 60

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1 2 3 discrete swelling in the area of the neck and a hypoplastic sternum (Figure 2). 4 5 6 Myocardial calcification was also found on histology in the histological exam . 7 8 9 10 Array comparative genomic hybridization (CGH) analysis (Spectral Chip, Perkin 11 12 13 Elmer Life and Analytical Science, Courtaboeuf; France) revealed a) mosaic trisomy 14 15 of chromosome 16, b) gain at 22q12.1-22q12.2 and c) deletion at 22q13.1-22q13.2. 16 17 18 The results were confirmed by fluorescent in situ hybridization (FISH) analysis. The 19 20 gains and losses ofFor genetic Peer material of chromosomeReview 22 were confirmed as true 21 22 imbalances by controlling for putative polymorphisms. Single FISH experiments on 23 24 25 the nuclei of the ectopic cardiac ectopia cordis tissue and normal peripheral blood as 26 27 control controls were performed. A panel of FISH probes were derived by nick 28 29 translation from BAC clones, tilling the regions 22q12.1-22.12.2 (RP11-76E8, RP11- 30 31 32 89A2, RP11-91K24, RP11-79G21, RP11-79G6) and 22q13.1-22q13.2 (RP3- 33 34 37OM22, RP5-979N1, RP1-185D5, RP4.695020). The list of BAC/PAC clones and 35 36 the details of each can be found at National Center for Biotechnology Information. 37 38 39 40 41 After these results were available the parents were advised that were counselled for 42 43 44 parental karyotyping was necessary. but they refused to be tested further. However 45 46 they declined any further investigations. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 DISCUSSION 4 5 6 Ectopia cordis EC develops secondary due to failure of maturation and fusion of the 7 8 midline mesodermal components of the chest and abdomen. The sternum originates 9 10 from two longitudinal mesenchymal bands, which start fusing in a cephalocaudal 11 12 th 13 direction from the 7-10 week of gestation. The earliest prenatal sonographic EC 14 15 diagnosis has been reported at 8 +5 weeks of gestation [3]. However, very early 16 17 th 18 diagnosis before the 9 embryonic week may be extremely difficult because be 19 20 impossible since theFor midline Peer fusion and theReview formation of the thoracic cavity is only 21 22 completed after that gestation time . In this particular case, All saved images from the 23 24 25 early viability scan were reviewed retrospectively and it was we concluded that the 26 27 EC was not apparent visible at 7 +1 weeks. 28 29 30 31 32 Increased nuchal translucency has been previously been reported in a fetus with EC 33 34 [4]. It is likely that the nuchal edema arises as a consequence of cardiac dysfunction 35 36 or coexistence of a chromosomal abnormality. The neck edema probably developed 37 38 39 due to the cardiac dysfunction. Increased NT is also found to aneuploid fetuses due 40 41 to alteratio n of the composition of extracellular matrix. The exact cause of this finding 42 43 44 in our occasion is probably due to the coexistence of both causes. This is the likely 45 46 explanation in our case. 47 48 49 50 51 In our case, the cytogenetics of the fetus were explored using wit h a CGH array 52 53 analysis followed by a FISH confirmation as this is a detailed and effective technique 54 55 for fetal karyotyping since previous use in investigating chromosomal anomalies has 56 57 58 been proved to be more detailed and effective [5]. There is little relative sparse 59 60 evidence associating EC with specific chromosomal anomalies or specific genetic

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1 2 3 mutations. Reported The reported cases include an association associate EC with 4 5 6 triploidy [6], trisomy 18 [7], Turner syndrome [8] and 46,XX,17q+ [9]. A The mosaic 7 8 trisomy 16 pregnancy pregnancies originates from a trisomy 16 zygote as a 9 10 consequence of non disjunction in meiosis I. a maternal meiosis I non -disjunction. 11 12 rd 13 Some mosaics are products of ‘’trisomic rescue’’, the loss of a 3 chromosome, 14 15 resulting in a euploid cell line, where the two remaining chromosomes may come 16 17 18 from one parent (uniparental disomy). 19 20 For Peer Review 21 22 Trisomy 16 is the most frequently encountered trisomy in early abortion specimens 23 24 25 representing presenting an occurrence of ~1.5% of all clinically recognized 26 27 conceptions gestations . Most of these embryos undergo spontaneous abortion or 28 29 developmental arrest between 8-15 weeks of gestation the 8th and 15 th weeks [10]. 30 31 32 Micrognathia and microstomia have been evidenced in our case (present in our case) 33 34 and have be en has previously been reported in mosaic trisomy 16 fetuses to be 35 36 associated with Trisomy 16 mosaicism . Although Even though cardiac anomalies are 37 38 39 most commonly seen with mosaic trisomy 16, EC has never previously been reported 40 41 to be associated with it . Furthermore, Moreover, most of EC most reported EC cases 42 43 44 (95%) are have associated with further intracardiac malformations [11]. In contrast, 45 46 On the contrary, this is one of very few reported cases associated with normal 47 48 cardiac structure heart anatomy [12]. Body stalk defects have been reported in a 49 50 51 case of uniparental disomy of chromosome 16 [13]. In our case the ventral body wall 52 53 failure was indeed associated with a mosaic trisomy an abnormality of chromosome 54 55 16. 56 57 58 59 60

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1 2 3 In general, mosaic T16 is characterized from by variable anatomic findings and 4 5 6 pregnancy outcomes .; therefore, a A specific trisomy 16 mosaic syndrome has not 7 8 been defined yet. It has been suggested that it’s the phenotype and the genetic 9 10 aberration mechanism have a complex relationship [14] . T he fact that all these 11 12 13 chromosomal abbreviations occurred simultaneously restrict us from a and make 14 15 precise genotype-phenotype correlation somewhat difficult . 16 17 18 19 20 The segmental abbreviationsFor mayPeer represent Review a familial variant of chromosome 22 and 21 22 parental test ing was suggested as a means of future family planning and a way to 23 24 25 identify any parental karyotypic abnormality. However, it was not feasible and 26 27 consequently, conclusions for these imbalances are difficult to be drawn, since we 28 29 cannot evaluate the link t o the parents. No previous developmental defects have 30 31 32 been attributed to the 33 34 It was not possible to ascertain if the abnormalities in chromosome 22 seen in this 35 36 fetus were inherited from either parent (as they declined karyotyping). There have 37 38 39 been no reported fetal abnormalities associated with chromosomal gains of 22q12.1- 40 41 22q12.2 or losses of 22q13.1-22q13.2. Although the validity of gains and losses on 42 43 44 chromosome 22 was confirmed as real imbalances and not mere polymorphisms, 45 46 further parental testing would have been be desirable in order to address the 47 48 significance of the finding in more detail. Sadly, further testing was rejected by the 49 50 51 parents, thus we were only able to present the findings in this case report. 52 53 Conclusively, EC can be diagnosed during the NT scan and an increased NT may be 54 55 one of the early findings. On the contrary, detection of such malformation is not 56 57 th 58 feasible before the 8 embryonic week. Also, investigation of cytogenetics should be 59 60

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1 2 3 performed with the most detailed method since spe cific chromosomal abnormalities 4 5 6 have not been totally associated with this condition. 7 8 9 10 In conclusion, this case demonstrates that 1 st trimester diagnosis is possible for EC. 11 12 13 Our case also suggest that karyotyping should be performed in all cases as rare 14 15 chromosome abnormalities are sometime present, which may be of importance in 16 17 18 counselling parents about future pregnancies. 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 FIGURE LEGENDS: 4 5 6 7 8 Figure 1: Sonographic detection of EC at 11+3 weeks of gestation (arrow shows 9 10 protruding heart). 11 12 13 14 15 Figure 2: Autopsy Photograph of the same fetus at 13 weeks of gestation. 16 17 18 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 Figure 1: Sonographic detection of EC at 11 +3 weeks of gestation (arrow shows protruding heart). 27 90x99mm (72 x 72 DPI) 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons Page 25 of 25 Journal of Clinical Ultrasound

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 Figure 2: Photograph of the same fetus at 13 weeks of gestation. 28 99x99mm (72 x 72 DPI) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons