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 Table of Contents  
INTERESTING CASE REPORT
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 88-92

Prenatal diagnosis of Ebstein's anomaly: An autopsy correlation predicting poor prognosis


1 Division of Pediatric and Fetal Cardiology, St. Gregorios Cardio-Vascular Centre, Parumala, Kerala, India
2 Department of Anatomy, Christian Medical College, Ludhiana, Punjab, India
3 Division of Pathology, St. Gregorios International Cancer Care Centre, Multi-specialty Hospital, Parumala, India
4 Division of Pathology, Laboratory Services, Lifeline Hospital and Frontier Mediville, Chennai, India

Date of Web Publication29-Aug-2019

Correspondence Address:
Saji Philip
Fetal and Pediatric Cardiologist, St. Gregorios Cardio Vascular Centre, Parumala, Pathanamthitta - 689 626, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiae.jiae_22_19

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  Abstract 

Ebstein's anomaly (EA) is rare but not an uncommon congenital heart disease in the fetus. Fetal echocardiogram has progressed to detect many forms of congenital heart diseases, especially to assess the prognosis of EA based on their anatomy and presentation in utero causing nonimmune hydrops. Fetal echocardiographic findings of cardiomegaly, apical displacement of tricuspid valve with severe regurgitation, can confirm the diagnosis of EA in utero. Severe cardiomegaly and nonimmune hydrops further contribute poor prognosis leading to fetal demise. Identifying fetal risk factors for predicting perinatal mortality is important, including the lack of antegrade flow across the pulmonary valve and retrograde duct flow. Here, we describe fetal echocardiographic findings of a case of EA causing severe cardiomegaly, restricted growth of the lungs, and hydrops in a 26-year-old primigravida at 20 weeks of gestation. The diagnosis was further correlated with the autopsy, characterized by severe cardiomegaly, huge right atrium, apical displacement, and tethering of septal and posterior leaflet, with markedly reduced lung volumes. Autopsy findings of dilated ductus further suggestive of possible reversed ductal flow causing circular shunt in EA raising the possibility of the poor postnatal outcome, even intrauterine death, and warranted for safe termination. Poor prognostic factors in EA have also been discussed with autopsy findings.

Keywords: Ebstein's anomaly, heart failure, hydrops, tricuspid valve anomaly


How to cite this article:
Philip S, Philip SE, Thampi L, Bharati S. Prenatal diagnosis of Ebstein's anomaly: An autopsy correlation predicting poor prognosis. J Indian Acad Echocardiogr Cardiovasc Imaging 2019;3:88-92

How to cite this URL:
Philip S, Philip SE, Thampi L, Bharati S. Prenatal diagnosis of Ebstein's anomaly: An autopsy correlation predicting poor prognosis. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2019 [cited 2019 Nov 17];3:88-92. Available from: http://www.jiaecho.org/text.asp?2019/3/2/88/265749


  Introduction Top


Ebstein anomaly (EA) is a rare congenital cardiac defect characterised by tethering and apical displacement of tricuspid valve (TV) leaflets, occurring in about 1-5 per 200,000 live births, as a result of failed delamination of the leaflets from the interventricular septum. This leads to an adherence of tricuspid leaflets to the underlying myocardium accounting 3-7% of congenital heart diseases in fetus.[1],[2],[3],[4],[5] Reversed ductal flow causing circular shunt in EA raising the possibility of the poor postnatal outcome, even intrauterine death especially in the presence of non-immune hydrops.[5] Fetal echocardiogram is an essential diagnostic tool for the early detection of EA and its severity. Here we describe fetal echocardiographic findings in EA, causing severe cardiomegaly, restricted growth of lungs and hydrops in a 26-year old primigravida at 20-weeks of gestation. Possible poor prognostic factors has been discussed with autopsy findings.


  Clinical Presentation Top


A 26-year-old primigravida, at 20 weeks of gestation was referred to us with a history of the fetal ultrasound diagnosis of congenital heart disease, cardiomegaly, effusion, and ascites for expert diagnosis. Fetal cardiac ultrasound showed severe cardiomegaly occupying 2/3rd of the chest cavity (12.2/14.4 cm 2; cardio-thoracic ratio 0.87, normal 0.53; 97.5thP(percentile) for gestational age (GA) of 20 week, massive pericardial effusion, hypoplasia of both lungs; area of the lungs was small and ascites bilaterally seen (7.5 mm) [Figure 1]a and [Figure 1]b, [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d and [Figure 3]d, and cardiac dimensions measured as, dilated right atrium 15 mm × 14 mm, 17.5 mm in autopsy (normal 9.37 mm 95.5th P) and right atrium area was 7 cm2, atrialized right ventricle 10.5 mm and right ventricle (RV) 7.8 mm, z-score 1.66 (normal 8.3 mm 97th P) [Figure 1]c. Septal tricuspid valve leaflet was apically placed, 4 mm from the mitral valve annulus (Becker's dysplasia classification [BDC] Grade III tethering valve >50% distance from the atrioventricular junction to the apex), TV annulus (7 mm/specimen 8 mm × 7 mm), severe TV regurgitation with peak velocity 148 cm/s, with right-to-left shunt through large fossa ovalis [Figure 1]d, [Figure 1]e, [Figure 1]f, ductal reversal flow, pulmonary artery 4.2 mm (normal 4.5 mm 97.5th P), no antegrade flow across the pulmonary valve, left atrium 10.2 mm (normal 8.6 mm 95.5th P), left ventricle 8.6 mm (normal 8.2 mm 95.5th P), aortic valve 4.3 mm (normal 4.2 mm 95.5 P), aorta 4.6 mm, mitral valve annulus (3.6 mm/specimen 4 mm × 5 mm), and unrestricted fossa ovalis 4–5.7 mm, were measured in routine recommended two-dimensional (2-D) echocardiographic views. Normal left aortic arch was well documented. Left side chambers, mitral valve, and interventricular septum were normal. Family members preferred for the termination in view of severe hydrops and its complication alerted. Gross morphologic findings from the fetal autopsy showed congested enlarged liver with granular surface, severe cardiomegaly with pericardial effusion, huge right atrium, normally related great arteries, dilated ductus, and mild growth restriction of the lungs with the lace-like appearance of medial border of both right and left lungs [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d and [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d. The transverse cut of right atrium superiorly showed paper thin atrial wall, dilated TV annulus and non-visibility of TV cusp [Figure 3]e. RV was opened by triangular cut through PA showed tethering of apically placed posterior leaflet [Figure 3]f. Histopathology studies of the lungs with hematoxylin and eosin stain (H and E) ×40 and × 100 magnification showed fetal lung in canalicular phase of development, corresponding to 16–24 weeks of gestation as tubule structures of varying sizes with wide lumen lined by low cuboidal and flattened cells, separated by mesenchyme invaded by capillaries and canalicular phase of development lungs [Figure 4]c and [Figure 4]d. Gross description of the liver was whole measuring 6.4 cm × 2.8 cm × 2 cm and entire surface showed closely placed multiple tiny nodularities measuring <0.2 cm. Further × 40 and × 100 of H and E stained section showed hepatocytes arranged in cords of 1–2 cell thick, separated by congested sinusoids filled with nucleated red blood corpus cells and hematopoietic cells. The portal triad showed bile ductules, hepatic arteriole, and venule. Central vein appeared congested. No features of cirrhosis, necrosis, fibrosis or interface hepatitis, or periportal infiltrates were noted. Moreover, findings were consistent with congested liver [Figure 4]a and [Figure 4]b. Many classifications are available to grade EA, but we had taken a modified version of BDC to classify EA during the morphological examination of the heart. The degree of leaflet tethering to the ventricular wall was calculated according to their extension by BDC: grade I up to 25% of the distance from the atrioventricular junction to the apex, Grade II from 25% to 50%, Grade III >50% of the distance. In this case, morphologically, Grade III EA was observed.[4] Echocardigraphic prognostic score was calculated as score ratio of the combined area of the right atrium and atrialized RV to that of functional RV in four-chamber view at end diastole as Grade 4 (1.68; ratio >1.5 prognostic score very poor and 100% mortality likely).[5]
Figure 1: Transabdominal two-dimensional echocardiogram of fetal heart at 20-weeks gestation with hydrops. (a) Axial view of fetal abdomen shows bilateral ascites (A), (b) parasagittal view of chest and abdomen shows severe pericardial effusion (PE) and ascites (A), (c) modified apical four-chamber view show large right atrium (RA), and atrialised right ventricle (ARV) with small right ventricle (RV), (d) Apical four-chamber view with color Doppler shows mosaic color pattern of severe tricuspid valve regurgitation with unrestricted wide fossa ovalis (<<) due to increased right-to-left shunt, (e) Note that, heart fills nearly whole chest shows dilated RA and ARV marked, (f) pulse wave Doppler shows holosystolic duration of the tricuspid valve regurgitant jet with peak velocity 150 cm/s and the origin of regurgitant jet was at the TV apical displacement level, whereas in tricuspid valve dysplasia jet is at the level of tricuspid annulus. LV: Left ventricle, LA: Left atrium, FO: Fossa ovalis, TR: Tricuspid regurgitation

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Figure 2: Autopsy specimens. (a and b) chest cut open view of terminated fetus shows enlarged heart with severe pericardial effusion in situ with hypoplastic right and left lung compressed by enlarged heart. (c and d) Anterior and posterior view of normally lobed right and left fetal lungs with restricted development of medial border evidenced by lace-like appearance due to compression of dilated heart

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Figure 3: Morphology of fetal specimens. (a) Huge right atrium (RA) with congested liver with granular surface. (b) Dilated right ventricle (area between the right coronary artery and left anterior descending coronary artery). (c) Normally related great artery with left aortic arch, demonstrating dilated ductus arteriosus due to circular shunt. With normal great artery (A=Aorta and P=Pulmonary artery) relationship with small caliber pulmonary artery (*) (normal for the gestation) compared to dilated aorta. D=Dilated ductus. (d) Large heart with severe pericardial effusion in situ with under developed thymus superiorly placed in the anterior mediastinum. (e) Right atrium cut open shows dilated tricuspid valve annulus without cusp visibility and downward displacement of septal cusp. (f) Right ventricle cut open through pulmonary artery to lateral border of RV shows tethering of posterior leaflet

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Figure 4: Histopathology of the liver and lungs (H and E, stain). (a and b) Liver ×10 and ×40 magnification shows hepatocytes arranged in cords of 1–2 cell thick, separated by congested sinusoids filled with nucleated red blood corpus cells and hematopoietic cells. The portal triad shows bile ductules, hepatic arteriole, and venule. Central vein appears congested. No features of cirrhosis, necrosis, fibrosis, or interface hepatitis or periportal infiltrates noted (c and d) ×40 and ×100 showed canalicular phase of development lungs; Sections from lung shows tubular structures of varying sizes with wide lumen lined by low cuboidal and flattened cells, separated by mesenchyme invaded by capillaries; Fetal lung in canalicular phase of development, corresponding to 16–24 weeks of gestation

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  Discussion Top


A German physician Wilhelm Ebstein reported EA in 1866 in a 19-year-old laborer with severe TV regurgitation.[1],[2] EA is rare but not uncommon occurs in about 1–5 in 200,000 live births and accounts for 3%–7% of congenital heart disease in the fetus.[3] EA is the result of the failure of delamination of the TV leaflets from the interventricular septum, resulting in adherence of the leaflets to the underlying myocardium, and further characterized by downward displacement of the functional annulus, dilation of atrialized portion of RV, redundancy, fenestrations, and tethering of TV leaflet. The malformed TV is usually regurgitant, but may rarely be stenotic. This anomaly may show various ultrasonographic manifestations, thus making the prenatal diagnosis sometimes difficult, especially valves are not visible.[6] TV dysplasia, a rare congenital TV malformation, characterized by leaflet deformation, most often which is attached to the annulus level and can easily differentiate from EA. However, sometimes, identifying these two entities by fetal echo alone may be difficult.[1],[2],[3] The difference between the two groups is largely academic in terms of functional effects. Genetic bases of this congenital heart defect may be related to the mutations in myosin heavy chain NKX2.5.[7]

Possible pathophysiology

In the context of displacement of the TV and severe TR in our case, lack of antegrade flow across the pulmonary valve leads to retrograde duct flow, which increases afterload on the RV. Meanwhile, the chronic volume overload from TR leads to RV dilatation and because TR favors the high-capacitance systemic venous circuit, the RV fails to generate adequate pressure which were found to be significantly associated with adverse outcome. Reason behind the left ventricular (LV) compression in the echo findings could be right-sided dilation and may cause ineffective LV loading and inadequate systemic cardiac output from direct compression. Meanwhile, cardiomegaly may restrict pulmonary growth and lead to deleterious cardiorespiratory interactions, particularly in the postnatal setting. Development of pulmonary valve regurgitation (PR) serves as the final insult that completes the circular shunt.

Predictors of poor outcome

Lack of antegrade flow across the pulmonary valve (PV) or retrograde duct flow seen in this case was considered as the most important markers of mortality risk. The relationship between mortality and TV annulus diameter z-score, presence of PR, and hydrops at the time of diagnosis could be more powerful hemodynamic indicator of risk and worse prognosis which were seen at our 20-week gestational echo screening. Grade III TV displacement and severe cardiomegaly with hydrops in early gestation can also predict fetal loss. The prognosis for a fetal diagnosed EA has been extremely poor in the past with a reported mortality rate as high as 81%.[8] In the fetus with severe TR may lead to cardiomegaly, hydrops, and arrhythmia, with demise rates as high as 48%.[9] In such cases, early safe termination can be advised.

Few studies focused on the lack of antegrade flow across the pulmonary valve or retrograde duct flow and low RV pressure, were found to be significantly associated with adverse outcome and most important markers of mortality risk in EA.[10] EA can be associated with aneuploidy, and chromosomal errors can be 50% with EA. Fetal demise or neonatal death was more pronounced when there was a moderate-to-severe TR, hydrops, and pericardial effusion.[7],[8] Selamet Tierney et al. designated the following as markers of poor outcome: absence of anterograde flow across the pulmonary valve, pulmonary valve regurgitation, cardiothoracic area ratio >0.48, LV dysfunction, or TV annulus Z-score > 5.6, and presentation age <24 GA. Another study had revealed that perinatal mortality is higher if TV annulus diameter Z-score 6.8 ± 3.0, moderate TR, and jet V max >200 cm/s.[11] Arrhythmia and fetal hydrops are also possible fetal manifestations of EA.[12] In addition, 25% of patients with EA also present with Wolf-Parkinson-White preexcitation syndrome.[13] In our case, no arrhythmia observed and PR interval was normal.

Pathology of specimens

Gross description of both lobe of the liver was congested and enlarged secondary to severe heart failure. Entire surface of the liver showed closely placed multiple tiny nodularities and the cause of this unusual nodulaties yet to be answered and we had ruled out other possible differential diagnosis of nodular liver such as cirrhosis, nodular regenerative hyperplasia, hepatocellular carcinoma, necrosis, fibrosis or interface hepatitis, or periportal infiltrates were especially overlooked in the histopathology studies [Figure 3]a. Authors presume that it could be the result of massive retention of blood secondary to severe heart failure. Fetal lung in canalicular phase of development, was corresponding to 16–24 weeks of gestation; hence, the possibility of lung hypoplasia with decreased bronchoalveolar development in EA were ruled out, though the volume of lung was much less and impressed as bilateral lung hypoplasia by 2-D echocardiogram and autopsy study [Figure 1]e and [Figure 2]a, [Figure 2]b. Growth restriction of the lungs may happen by compression of dilated heart evidenced by the lace-like appearance of medial border of the lungs [Figure 2]c and [Figure 2]d. It can eventually go into lung hypoplasia as the gestational age increases yet to be studied. Transplacental digoxin therapy may be helpful to control heart failure and effusion, and subsequently can reduce the severity of hydrops. The prenatal diagnosis of EA and its severity is essential in future because the outcomes of surgical and conservative management have improved a great deal in the current era.[14]


  Conclusion Top


Fetal echocardiogram is an essential diagnostic tool for the early detection of EA and its severity. The histopathology studies proved that lung hypoplasia may not be a feature of EA, but severe cardiomegaly and effusion can restrict the lung growth in later gestation. Looking at the routine essential echo parameters in the diagnosis of EA such as, cardiothoracic ratio, severity of TR, TV annulus diameter z score, pulmonary valve regurgitation, ductal reversal flow, no antegrade PV flow, pericardial effusion, hydrops, and fetal arrhythmia would be helpful in predicting severity and outcome, even intrauterine death, warranted for safe termination.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors would like to thank Dr. G Sulochana, visiting Senior Consultant Pathologist, International Centre for Cancer Research Institute, Parumala, Mannar, Kerala, for evaluating histopathology slides and for discussions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Mann RJ, Lie JT. The life story of Wilhelm Ebstein (1836-1912) and his almost overlooked description of a congenital heart disease. Mayo Clin Proc 1979;54:197-204.  Back to cited text no. 1
    
2.
Van Son JA, Konstantinov IE, Zimmermann V. Wilhelm Ebstein and Ebstein's malformation. Eur J Cardiothorac Surg 2001;20:1082-5.  Back to cited text no. 2
    
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Sharland GK, Chita SK, Allan LD. Tricuspid valve dysplasia or displacement in intrauterine life. J Am Coll Cardiol 1991;17:944-9.  Back to cited text no. 3
    
4.
Becker AE, Becker MJ, Edwards JE. Pathologic spectrum of dysplasia of the tricuspid valve. Features in common with Ebstein's malformation. Arch Pathol 1971;91:167-78.  Back to cited text no. 4
    
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Paranon S, Acar P. Ebstein's anomaly of the tricuspid valve: From fetus to adult: Congenital heart disease. Heart 2008;94:237-43.  Back to cited text no. 5
    
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Cha MY, Won HS, Lee MY, Woo KH, Shim JY. An unusual ultrasonographic manifestation of a fetal Ebstein anomaly. Obstet Gynecol Sci 2014;57:530-3.  Back to cited text no. 6
    
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Yuan SM. Ebstein's anomaly: Genetics, clinical manifestations, and management. Pediatr Neonatol 2017;58:211-5.  Back to cited text no. 7
    
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Ishii T, Tworetzky W, Harrild DM, Marcus EN, McElhinney DB. Left ventricular function and geometry in fetuses with severe tricuspid regurgitation. Ultrasound Obstet Gynecol 2012;40:55-61.  Back to cited text no. 8
    
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Yetman AT, Freedom RM, McCrindle BW. Outcome in cyanotic neonates with Ebstein's anomaly. Am J Cardiol 1998;81:749-54.  Back to cited text no. 9
    
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Freud LR, Escobar-Diaz MC, Kalish BT, Komarlu R, Puchalski MD, Jaeggi ET, et al. Outcomes and predictors of perinatal mortality in fetuses with Ebstein anomaly or tricuspid valve dysplasia in the current era: A multicenter study. Circulation 2015;132:481-9.  Back to cited text no. 10
    
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Hornberger LK, Sahn DJ, Kleinman CS, Copel JA, Reed KL. Tricuspid valve disease with significant tricuspid insufficiency in the fetus: Diagnosis and outcome. J Am Coll Cardiol 1991;17:167-73.  Back to cited text no. 11
    
12.
Selamet Tierney ES, McElhinney DB, Freud LR, Tworetzky W, Cuneo BF, Escobar-Diaz MC, et al. Assessment of progressive pathophysiology after early prenatal diagnosis of the Ebstein anomaly or tricuspid valve dysplasia. Am J Cardiol 2017;119:106-11.  Back to cited text no. 12
    
13.
Attie F, Rosas M, Rijlaarsdam M, Buendia A, Zabal C, Kuri J, et al. The adult patient with Ebstein anomaly. Outcome in 72 unoperated patients. Medicine (Baltimore) 2000;79:27-36.  Back to cited text no. 13
    
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Yu JJ, Yun TJ, Won HS, Im YM, Lee BS, Kang SY, et al. Outcome of neonates with Ebstein's anomaly in the current era. Pediatr Cardiol 2013;34:1590-6.  Back to cited text no. 14
    


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