Ebstein’s anomaly is a relatively rare congenital heart defect characterized by a compromised tricuspid valve and resultant regurgitant blood flow. Most reported cases are sporadic, but a few cases of the familial variant have also been reported. Symptoms range from mild to severe. For the latter, neonatal survival is unlikely, making our case presentation unusual. Maternal use of certain drugs has been implicated in some cases. The etiology of Ebstein’s anomaly remains unknown. The authors discuss the characteristics and management of this condition and present the case of 2 siblings with severe symptoms born to nonconsanguineous parents. One of the siblings survived the neonatal period and is currently doing well.

Ebstein’s anomaly of the tricuspid valve is a rare congenital heart defect characterized by a downward displacement of the proximal attachments of the tricuspid leaflets into the right ventricle (RV), resulting in dilation of the RV secondary to regurgitant flow. Right-heart enlargement can become quite marked. Heart size and symptom severity are directly related to the degree of downward displacement of the tricuspid valve. The exact cause of this anomaly remains unknown. The lesion was first described in 1866 by Wilhelm Ebstein and was named Ebstein’s disease in 1927.

The incidence of Ebstein’s anomaly of the tricuspid valve is about 5.2 per 100,000 live births.¹ The condition accounts for about 1% of all congenital heart defects1 and occurs in males and females with equal frequency. Although most cases of Ebstein’s anomaly are sporadic, cases with a familial connection have been documented.

Maternal lithium (Eskalith, Lithobid)1 and benzodiazepine exposures have been implicated as a cause of Ebstein’s anomaly. This anomaly is not often linked with a chromosomal abnormality, but it has been reported in association with trisomy 9p and trisomy 21,^2,3 as well as with rearrangements of the chromosomal region 11q.⁴

The Familial Variation
A Medline search of “familial Ebstein’s anomaly” identified 34 well-documented cases in English-language literature.^5-17 Using all languages and the same search methods, we identified 2 additional cases of familial Ebstein’s anomaly (Table 1).¹⁸ Thus, very few reports of the familial type exist. This article describes the fifth documented case of father-to-son and/or to-daughter transmission. Although a congenital disorder, Ebstein’s anomaly is often not identified until later in life, when a patient presents with associated signs and symptoms.

Case 1
In 1995, a 17-year-old pregnant girl presented for her initial prenatal visit at 8 weeks of gestation. She denied any adverse genetic history in her family or her partner’s. All prenatal laboratory test results were within normal limits. The mother was not taking any medications except for prenatal vitamins. Her prenatal course was uneventful, and she had a total of 12 visits to her physician.

At 36 weeks of gestation, based on the first-trimester sonogram, she presented to the labor and delivery department complaining of clear vaginal discharge. She continued to report good fetal movement and experienced no complications. Fetal heart tones were 120 to 130 beats/min, but the nonstress test was nonreactive. A limited bedside ultrasound scan was performed. Significant cardiomegaly was noted, and the cardiac chambers were difficult to delineate. The father, who was at the bedside during this examination, reported that he, as well as one of his cousins, had Ebstein’s anomaly. A biophysical profile and standard ultrasonography were performed. The findings were consistent with a congenital malformation and included a significantly enlarged heart and an enlarged ventricle, with no visible interventricular septum. The position of the fetus was cephalic presentation, fundus posterior, and normal, without previa or abruption. Oligohydramnios was noted. Fetal heart tones were 129 beats/min. A sonar gestational age was reported at 33.4 weeks. The final biophysical profile score was 4/8, which is abnormally low (a score of zero was given for fine movement and amniotic fluid index).

The patient was transported to another hospital. Two days later, a girl weighing 2.775 kg was delivered via cesarean section secondary to fetal bradycardia. Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. The newborn was intubated after birth because of severe cyanosis.

Postnatal echocardiography revealed severe Ebstein’s anomaly of the tricuspid valve, with a massively dilated right atrium in the newborn. There was flow across the pulmonary valve, and the ductus arteriosus remained widely patent with continuous use of alprostadil (Prostin VR Pediatric), which was instituted immediately after birth to increase pulmonary blood flow until the pulmonary vascular resistance dropped.

Consultation with pediatric cardiologists indicated that no surgical intervention could increase the infant’s chances of survival. Despite full ventilatory support, the infant’s oxygen saturation slowly decreased, and she died at 7 days of age.

Case 2
Approximately 6 months later, the same mother presented with an intrauterine pregnancy of about 8 weeks of gestation as confirmed by ultrasound. Of note, the couple had been counseled extensively regarding the risk of Ebstein’s anomaly in any future child. Prenatal workup and physical examination findings were unremarkable. There were no complications during her pregnancy. She presented for 13 prenatal visits and was evaluated with a pelvic ultrasound at 9, 27, and 38.5 weeks. The ultrasonograms were normal. Fetal echocardiograms were performed at 23 and 33 weeks. A small ventricular septal defect was noted on the first echocardiogram but not on the second. Exaggerated septal motion and focal color flow disturbance were evident in the area of the septal leaflet of the tricuspid valve. A postnatal echocardiogram was recommended.

A boy was delivered vaginally, and the follow-up echocardiogram revealed severe Ebstein’s anomaly. The neonate was transferred to another hospital. It was believed he had some forward flow into the pulmonary artery, and a number of attempts were made to wean him off alprostadil for as long as 24 to 48 hours, but he subsequently had cyanotic episodes. Eventually he had a modified Blalock-Taussig shunt procedure.

The child is currently doing well at age 8 years. It is expected that the Blalock-Taussig shunt will need to be removed and a bidirectional Glenn procedure performed. He receives subacute bacterial endocarditis prophylaxis when required, following the American Heart Association guidelines. It is assumed that the Blalock-Taussig shunt was instrumental in this infant’s survival, since he had severe cyanosis after a number of attempts to wean him from the prostaglandin before his surgery at the age of 16 days. In addition, he has had multiple echocardiograms and cardiac catheterizations and is taking aspirin daily.

Cardiac Abnormalities
Ebstein’s anomaly is a defect that involves the tricuspid valve and abnormal attachments of the tricuspid valve leaflets to the annulus of the tricuspid valve. The tricuspid valve is displaced downward in the RV, and that portion of the RV becomes part of the right atrium, or atrialized (Figure 1). The most common associated defect in Ebstein’s anomaly is an atrial septal defect. Approximately 25% of patients have an additional so-called accessory pathway, which can bypass the normal impulse circuit and cause fast and irregular heart rhythms.¹⁹

Hemodynamic consequences of an Ebstein’s lesion are directly related to the severity of leaflet displacement and resultant tricuspid valve regurgitation. With mild displacement and mild valvular regurgitation, an individual can be asymptomatic for many years. If the leaflet displacement and valvular regurgitation are severe, pulmonary blood flow is decreased, and the right atrium becomes dilated as a result of blood being shunted from right to left across the atrial septal defect or patent foramen ovale, and the patient becomes cyanotic.

An atrial septal defect or patent foramen ovale is present in approximately 80% to 90% of patients; pulmonary stenosis or atresia occurs in 20% to 25%.²⁰ Additional problems in these patients (most often found in teenagers or young adults) include an associated paroxysmal supraventricular tachycardia, occurring in 25% to 40% of patients, and Wolff-Parkinson-White syndrome, occurring in 10% to 18%.²¹

Diagnosis
The majority of patients are identified in the neonatal period, but individuals with a mild case of the anomaly often are not identified until childhood or adulthood. Physical findings vary, depending on the age of the patient and the degree of tricuspid regurgitation and RV outflow obstruction. In infants with a right-to-left shunt, cyanosis may occur; in older children, cyanosis is accompanied by clubbing. The first heart sound is widely split, secondary to increased excursion of the anterior leaflet and delayed closure of the tricuspid valve. The second heart sound is also widely and persistently split because of the delayed closure of the pulmonary valve. A pansystolic murmur is heard at the left lower sternal edge and epigastrium secondary to tricuspid regurgitation. There may also be low-intensity diastolic murmurs secondary to anterograde flow across the valve. Other signs and symptoms leading to identification in older children and adults include heart failure, incidental heart murmur, and arrhythmia.

On chest x-ray, the right atrium is often grossly enlarged and the pulmonary vasculature is decreased because of right-to-left shunting through the atrial septal defect or patent foramen ovale. Often the heart is massively enlarged as a result of right atrial dilatation. The heart may take up most of the chest and is sometimes called a “wall-to-wall” heart or “boxlike” heart.

Arrhythmias are common in Ebstein’s anomaly, therefore an electrocardiogram (ECG) is recommended. In most patients with this condition, the ECG will be abnormal (Figure 2). Typical findings on ECG are a prolonged PR interval, large P waves, right-axis deviation, and right bundle-branch block. Atrial or ventricular arrhythmias or a delta wave suggestive of Wolff-Parkinson-White syndrome may also be noted. The PR interval may be normal or shortened in Ebstein patients with Wolff-Parkinson-White syndrome.

Ebstein’s anomaly can be diagnosed in utero.²² The optimal time for examination when this condition appears to be a possibility is between 16 and 32 weeks of gestation.¹⁵

Fetal echocardiography is considered the definitive diagnostic test (Figure 3), but it, too, may miss the diagnosis, as was the case in our second patient. Typical echocardiographic findings include dilated right atrium and RV, tricuspid valve regurgitation, atrial septal defect or patent foramen ovale, inferior displacement of the septal and/or posterior leaflets of the tricuspid valve, large annulus, and right ventricular outflow tract obstruction.

Other conditions may cause the cardiac symptoms seen in Ebstein’s anomaly. Therefore, the differential diagnosis of Ebstein’s anomaly includes:

• Tricuspid valve dysplasia. This anomaly is associated with abnormal tricuspid valve leaflets, but the attachment and location of the leaflets are normal.

• Arrhythmogenic right ventricular cardiomyopathy.

• Uhl’s anomaly. This anomaly involves thinning of the right ventricular wall, but the tricuspid valve is normal though often incompetent.

Treatment
The clinical symptoms of Ebstein’s anomaly vary from mild to severe. Patients with mild cases require no therapy other than continued outpatient follow-up by a cardiologist, or by a pediatric cardiologist when dealing with a child. Treatment should be tailored to the specific problems posed by the condition, such as heart failure, cyanosis, or arrhythmia. Therefore, it is important to consult a cardiologist early. Treatment options include drug therapy, radiofrequency ablation, and surgery. The surgical strategy is based on individual characteristics and patient physiology. Antibiotic prophylaxis is required for infective endocarditis. A low-sodium diet is recommended for the relief of symptoms of fluid overload. Arrhythmia treatment can be accomplished medically with antiarrhythmic drugs or with radiofrequency ablation of the accessory pathways. Indications for surgery (which apply mostly to older patients) are listed in Table 2.

Generally, surgery is performed earlier rather than later in the course of heart failure. Surgical results are quite good; one series of 191 patients (aged 1-65 years) reported an actuarial survival of 82% at 20 years using conservative surgery (ie, mobilization of the anterior leaflet, longitudinal plication of the RV, and prosthetic annuloplasty in adults).²³ Since there is a known risk for sudden death in patients with surgically corrected Ebstein’s anomaly, cardiac electrophysiologic studies and ablation of arrhythmias are mandatory.²⁴ There are various approaches to the treatment of structural abnormalities. Tricuspid valve repair is preferred over valve replacement, and bioprosthetic valves are preferred over mechanical prosthetic ones. Rarely, cardiac transplantation is required.

The prognosis for patients with Ebstein’s anomaly varies significantly, based on the severity of leaflet displacement. Survival has been reported to be approximately 67% at 1 year and 59% at 10 years.²⁵

Conclusion
Most cases of Ebstein’s anomaly are sporadic, but some familial cases have been reported, suggesting a genetic component. This stresses the importance of taking a good history during prenatal visits. Screening questions should include family history of congenital heart disease and medication use. When a family history of congenital heart disease is involved, the physician may suggest a fetal echocardiogram. Echocardiography should be repeated postnatally if any abnormality is noted. With advances in cardiac surgery, it is likely that the life expectancy of patients with Ebstein’s anomaly would be extended. Early diagnosis may potentially increase the chances of survival.

Acknowledgments
We would like to express our gratitude to Michael Wolkomir, MD, and Timothy E. Cooney, MS, for their review of the manuscript, and their comments, encouragement, and support.

Self-assessment test
1. All these statements about Ebstein’s anomaly are true, except:
A. Familial cases are more common than sporadic cases
B. The proximal attachments of the tricuspid leaflets are displaced down into the RV
C. It is characterized by dilation of the RV
D. It has been associated with chromosomal abnormalities

2. Which of these defects is most often associated with Ebstein’s anomaly?
A. Pulmonary stenosis
B. Wolff-Parkinson-White syndrome
C. Atrial septal defect
D. Paroxysmal supraventricular tachycardia

3. Which of these auscultory findings is NOT characteristic of Ebstein’s anomaly?
A. Widely split first heart sound
B. Widely split second heart sound
C. Pansystolic murmur
D. Pericardial friction rub

4. Which of these ECG findings is NOT suggestive of Ebstein’s anomaly?
A. Left bundle-branch block
B. Prolonged PR interval
C. Large P waves
D. Right-axis deviation

5. Which of these statements about the treatment of Ebstein’s anomaly is NOT true?
A. Antibiotic prophylaxis is required to prevent bacterial endocarditis
B. A low-sodium diet can help relieve symptoms of fluid overload
C. Valve replacement is preferred over tricuspid valve repair
D. Bioprosthetic valves are preferred over mechanical prosthetic valves

References
1. Correa-Villasenor A, Ferencz C, Neill CA, et al. Ebstein’s malformation of the tricuspid valve: genetic and environmental factors. The Baltimore-Washington Infant Study Group. Teratology. 1994;50:137-147.

2. Nakagawa M, Kato H, Aotani H, et al. Ebstein’s anomaly associated with trisomy 9p. Clin Genet. 1999;55:383-385.

3. Silva SR, Bruner JP, Moore CA. Prenatal diagnosis of Down’s syndrome in the presence of isolated Ebstein’s anomaly. Fetal Diagn Ther. 1999;14:149-151.

4. de Lonlay-Debeney P, de Blois MC, Bonnet D, et al. Ebstein anomaly associated with rearrangements of chromosomal region 11q. Am J Med Genet. 1998;80:157-159.

5. Zalzstein E, Koren G, Einarson T, et al. A case-control study on the association between first trimester exposure to lithium and Ebstein’s anomaly. Am J Cardiol. 1990;65:817-818.

6. Gueron M, Hirsch M, Stern J, et al. Familial Ebstein’s anomaly with emphasis on the surgical treatment. Am J Cardiol. 1966;18:105-111.

7. Donegan CC Jr, Moore MM, Wiley TM Jr, et al. Familial Ebstein’s anomaly of the tricuspid valve. Am Heart J. 1968;75:375-379.

8. Simcha A, Bonham-Carter RE. Ebstein’s anomaly. Clinical study of 32 patients in childhood. Br Heart J. 1971;33:46-49.

9. Watson H. Natural history of Ebstein’s anomaly of tricuspid valve in childhood and adolescence. An international co-operative study of 505 cases. Br Heart J. 1974;36:417-427.

10. Rosenmann A, Arad I, Simcha A, et al. Familial Ebstein’s anomaly. J Med Genet. 1976;13: 532-535.

11. Lo KS, Loventhal JP, Walton JA Jr. Familial Ebstein’s anomaly. Cardiology. 1979;64: 246-255.

12. Pierard LA, Henrard L, Demoulin JC. Persistent atrial standstill in familial Ebstein’s anomaly. Br Heart J. 1985;53:594-597.

13. Balaji S, Dennis NR, Keeton BR. Familial Ebstein’s anomaly: a report of six cases in two generations associated with mild skeletal abnormalities. Br Heart J. 1991;66:26-28.

14. Davido A, Maarek M, Jullien JL, et al. Ebstein’s disease associated with Fallot’s tetralogy. Apropos of a familial case, review of the literature, embryologic and genetic implications [in French]. Arch Mal Coeur Vaiss. 1985;78:752-756.

15. McIntosh N, Chitayat D, Bardanis M, et al. Ebstein anomaly: report of a familial occurrence and prenatal diagnosis. Am J Med Genet. 1992;42:307-309.

16. Grant JW. Congenital malformations of the tricuspid valve in siblings. Pediatr Cardiol. 1996;17: 327-329.

17. Uyan C, Yazici M, Uyan AP, et al. Ebstein’s anomaly in siblings: an original observation. Int J Cardiovasc Imaging. 2002;18:435-438.

18. Margalit-Stashefski R, Lorber A, Margalit E. Familial occurrence of Ebstein anomaly [in Hebrew]. Harefuah. 1998;134:762-764, 832.

19. Hebe J. Ebstein’s anomaly in adults. Arrhythmias: diagnosis and therapeutic approach. Thorac Cardiovasc Surg. 2000;48:214-219.

20. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. Second of two parts. N Engl J Med. 2000;342:334-342.

21. Laks H, Marelli D, Plunkett M, et al. Adult congenital heart disease. In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. 2nd ed. New York, NY: McGraw-Hill; 2003:1329-1358.

22. McElhinney DB, Salvin JW, Colan SD, et al. Improving outcomes in fetuses and neonates with congenital displacement (Ebstein’s malformation) or dysplasia of the tricuspid valve. Am J Cardiol. 2005;96: 582-586.

23. Chauvaud S, Berrebi A, d’Attellis N, et al. Ebstein’s anomaly: repair based on functional analysis. Eur J Cardiothorac Surg. 2003;23:525-531.

24. Huang CJ, Chiu IS, Lin FY, et al. Role of electrophysiological studies and arrhythmia intervention in repairing Ebstein’s anomaly. Thorac Cardiovasc Surg. 2000;48: 347-350.

25. Celermajer DS, Bull C, Till JA, et al. Ebstein’s anomaly: presentation and outcome from fetus to adult. J Am Coll Cardiol. 1994;23:170-176.