Trisomy 21 and Ebstein Anomaly: Diagnosis and Prognosis of a Rare Association

Abstract

Trisomy 21 is considered the most common chromosomal aneuploidy, and congenital heart disease (CHD) is highly prevalent and relevant to the morbidity and mortality of these patients. Ebstein anomaly (EA) is a rare CHD characterized by tricuspid valve dysplasia with inferior septal leaflet displacement. Herein, we described a patient with trisomy 21 who presented with EA and discuss the association between the two conditions based on a literature review. We conclude that the concomitant occurrence of both conditions is considered to be rare. These individuals are most frequently diagnosed during birth and childhood, and they usually have a good prognosis, as observed with our patient and is typical for EA patients in general. However, it is important to be aware that electrophysiologic anomalies may also be present.

Introduction

Trisomy 21, or Down syndrome, is a genetic condition that was initially described by Seguin and John Langdon Down in 1846 and 1866, respectively. ¹ It is the most common chromosomal aneuploidy, affecting approximately 1 in 800 to 1,000 live births. ^{2 3} Its clinical manifestations may be variable and involve both minor and major anomalies. However, the phenotype is usually easily recognized. ⁴ Major malformations include congenital heart disease (CHD), which has a frequency ranging from 40 to 63.5% ^{3 5 6} and is considered highly relevant to the morbidity and mortality of these patients, especially during the first 2 years of life. ^{6 7} Trisomy 21 is most commonly associated with endocardial cushion malformations, leading to the most commonly associated CHD, complete common atrioventricular canal defect. Other common CHDs observed include atrial septal defects, ventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot. ^{8 9}

Ebstein anomaly (EA) is a rare CHD that affects approximately 1 in every 20,000 live births, representing less than 1% of all cardiac defects. ^{10 11 12} This defect was first described in 1866 by Ebstein and is characterized by tricuspid valve dysplasia with inferior septal leaflet displacement and an atrialized right ventricle. ¹³ Although uncommon, EA is the most frequent tricuspid valve congenital disease, ¹⁴ and most cases are sporadic. Some studies have shown that lithium use during the first trimester of pregnancy could lead to a 400 times higher risk of EA in the fetus, although others have not shown this association. ¹⁵ Different genetic alterations have also been described in patients with EA, including some chromosomal anomalies. ¹⁶

The aim of this article was to describe a patient with trisomy 21 presenting with EA and discuss the association between these conditions based on a literature review.

Case Report

The patient was a 3-day-old male neonate, the first child of a 42-year-old (mother) and a 46-year-old (father) healthy couple. The family history was negative for genetic diseases or malformations. Her pregnancy was uneventful. The mother denied the occurrence of health problems or use of medications such as lithium. Fetal ultrasound evaluation was also considered normal. The child was born by cesarean section at term, weighing 3,775 g, measuring 49 cm, with a head circumference of 34 cm, and Apgar's scores of 8 and 10. At 3 days of age, the patient had jaundice and began to show cyanosis, requiring transfer to a referral hospital. Chest X-ray showed an enlarged cardiac area. Then, he was referred to a tertiary care center for further investigation. During this period, the patient did not need any oxygen therapy. On physical examination, minor dysmorphia was observed, including bilateral epicanthal folds, a low and wide nasal root, micrognathia, ears with overfolded helices, single palmar crease on the left, fifth finger clinodactyly, and increased space between the first and second toes bilaterally. In addition, the patient had a heart murmur. Thus, he underwent an echocardiogram at the age of 6 days, which revealed dilated right heart chambers, with a tricuspid valve presenting moderate regurgitation and apical displacement of the septal leaflet, which was consistent with the diagnosis of EA. The electrocardiogram showed sinus tachycardia with a short PR segment, right axis deviation, and findings suggestive of right ventricular conduction delay. Patient underwent triple phototherapy for neonatal jaundice. Subsequently, karyotyping revealed full trisomy 21 (47,XY, + 21), confirming the diagnosis of trisomy 21 or Down syndrome. The patient improved and did not require medical therapy or surgical intervention. At 2 years of age, the patient was still stable. We considered genetic testing for this patient to exclude the contribution of genetic variants in genes associated with the EA phenotype, such as NKX2.5 , MYH7 , and TPM1 ; however, this could not be performed since he was lost to follow-up.

Literature Review

To assess the relationship between trisomy 21 and EA, we conducted a literature review using the PubMed/Medline virtual database, looking for studies published in English as of August 21, 2019. The terms (found in the MESH keywords) and the methodology used to select articles are described in Table 1 and Fig. 1 , respectively. Subsequently, 11 studies were found, and we included nine case reports and two retrospective cohort studies ( Fig. 1 ).

Table 1. Mesh terms used in the search strategy.

((“Syndrome, Down” OR “Mongolism” OR “47,XY, + 21” OR “Trisomy G” OR “47,XX, + 21” OR “Down's Syndrome” OR “Downs Syndrome” OR “Syndrome, Down's” OR “Trisomy 21” OR “Trisomy 21, Mitotic Nondisjunction” OR “Down Syndrome, Partial Trisomy 21” OR “Partial Trisomy 21 Down Syndrome” OR “Trisomy 21, Meiotic Nondisjunction” OR “Down Syndrome”) AND (“Ebstein Anomaly” OR “Anomaly, Ebstein” OR “Ebstein's Malformation” OR “Ebstein Malformation” OR “Ebsteins Malformation” OR “Malformation, Ebstein's” OR “Ebstein's Anomaly” OR “Anomaly, Ebstein's” OR “Ebsteins Anomaly” OR “Familial Ebstein's Anomaly” OR “Ebstein's Anomaly, Familial” OR “Familial Ebstein Anomaly” OR “Familial Ebsteins Anomaly”))

Fig. 1.

Flow diagram for inclusion and exclusion of studies.

Discussion

The association between trisomy 21 and EA, as seen in our literature review, is extremely rare. The first description of this relation was reported by Johnson et al in 1989. Since then, nine more patients have been reported. ^{12 17 18 19 20 21 22 23 24} It is noteworthy that the scarcity of data are not only related to the patients' characteristics but also to their evolution and prognosis. Moreover, there is a lack of studies evaluating the presence of CHD in patients with trisomy 21, in which the existence of cases of EA has been described. The only study found was developed by Cua et al, ²⁵ with a cohort composed of 5,737 patients with trisomy 21. EA was present in 34 of these patients (0.6%). On the other hand, we found only one study with patients with EA that reported the presence of individuals with trisomy 21. Lupo et al ²⁶ described four patients presenting trisomy 21 (2%) among 175 total with EA.

Our patient had many findings similar to the 10 other trisomy 21 patients with EA described in the literature. For example, most of these patients were male (75%) and had full trisomy 21 (80%) (only five reports had a description of the chromosomal constitution of the patients). ^{18 20 22 23} It is noteworthy that one patient had trisomy 21 secondary to a derivative chromosome, der (21;21)(q22;q11.2). ²⁰ The maternal age of our case (42 years) was higher than that described in the other cases, which ranged from 23 to 39 years (mean = 32.8 years). ^{12 18 21 23} Half of the patients (50%) in the literature were diagnosed simultaneously with EA and trisomy 21. ²⁰ In our case, the EA was identified first, as described in 10% of the reports. ¹² There were more cases of a prenatal diagnosis of EA ( n  = 3) ^{12 18 22} than that of trisomy 21 ( n  = 1) ¹⁸ (in one case, the diagnosis of both conditions occurred during the prenatal period, and the pregnancy was interrupted). The age of diagnosis for EA ranged from the intrauterine period ( n  = 3) to the postnatal period ( n  = 7; three patients were diagnosed at birth, one in childhood, one in adolescence, and one in adulthood). ^{12 17 18 19 20 21 22 23 24} It is noteworthy that the prenatal diagnosis of EA can be performed as early as 16 to 20 weeks of pregnancy, where an observed enlargement of the cardiac volume is associated with a right-side dilation with tricuspid regurgitation. ²⁷ In our case, both conditions were identified in the postnatal period. EA was first diagnosed at 6 days of age, and the identification of trisomy 21 occurred soon later. It is noteworthy that, unlike our case report, virtually none of the reports from the literature mentioned dysmorphia presented by the patients. Regarding gestational exposure, none of the reports mentioned maternal use of lithium. In our case, the mother denied use of medications during pregnancy, including lithium.

The signs and symptoms of EA can manifest at any age, including prenatal period, and in different ways. ¹³ The age and form of clinical manifestation depend on various factors. ¹⁹ In patients younger than 2 years, hemodynamic dysfunction is usually the first and main clinical presentation of EA. In those older than 10 years, electrophysiologic anomalies are often the primary form of presentation. ^{28 29} Regarding the evolution of patients with EA and trisomy 21 described in the literature, only one patient presented with heart failure in the intrauterine period. Moreover, that was the only case report to present a description of the type of delivery, which was cesarean, ¹² like for our patient. Regarding symptoms, 44.4% of patients had cyanosis and difficulty in breathing shortly after birth, requiring oxygen therapy and hospitalization in a neonatal intensive care unit. Only one patient needed mechanical ventilation, which was the patient with intrauterine heart failure. ¹²

EA newborns, when symptomatic, usually have a poor prognosis. Some authors propose that 20 to 40% of these newborns will die in the first month, and less than 50% will survive for 5 years. ^{30 31 32} Four patients, including ours, had good development after some degree of dysfunction or cyanosis in the first days of life. ^{12 21 22 23} Just one patient progressed to death, which happened few days after delivery. ²² At the last evaluation of our patient at 2 years of age, he was not using medicines for EA and did not undergo cardiac surgery. The outcome is considered favorable for individuals who do not require intervention in the neonatal period. The majority of EA patients can be managed with oxygen while waiting for a reduction in pulmonary vascular resistance, and if they can be weaned from support and not need surgical intervention, the long-term outcomes are generally favorable. However, if individuals require neonatal intervention, the outcomes are usually considerably worse. ^{27 33} Only one of the patients described with EA and trisomy 21 underwent cardiac surgery at 108 days of life. ²³ He presented with low weight gain during his follow-up after the surgical procedure. ²³ Surgery is indicated in patients with EA when there is evidence of right cardiac dilation and progressive impairment of ventricular systolic function. Asymptomatic patients with EA can be treated conservatively and kept under close monitoring. ¹⁶ It is noteworthy that three patients with EA and trisomy 21 did not present any symptoms associated with the heart defect. ³⁴ EA was incidentally diagnosed in one patient at 17 years of age during an autopsy, ³⁴ in another at 20 years old after an episode of syncope, ¹⁹ and in the third at 55 years old during an examination. ¹⁷ These data suggest that trisomy 21patients with EA seem to have a similar prognosis to EA patients in general.

Some alterations can be observed in electrocardiograms of EA patients and include an uncommon high and wide P wave, right bundle branch block, tachyarrhythmias, and Wolff-Parkinson-White syndrome. ^{35 36 37} Two patients with EA and trisomy 21, including our patient, also had electrophysiologic anomalies. One had a first degree atrioventricular block, ²¹ and the other had an accessory pathway. ¹⁹ Our patient presented with sinus tachycardia and a short PR segment, right axis deviation, and findings suggestive of a right ventricular conduction delay.

Thus, in contrast to the findings reported by Cua et al, ²⁵ among patients with trisomy 21, those with EA have a higher risk of mortality than those without EA, but the majority of the reports described in the literature presented a good prognosis during follow-up, ^{12 17 19 20 21 22 23 24} as was observed in our patient. Nevertheless, associated electrophysiologic anomalies may be present and should be evaluated and monitored.

Considering, as we have seen before, the scarcity of cases of trisomy 21 with EA, we raised the possibility that the two events might occur together at random. The chance of this happening, based on the frequency of both conditions, would be 1:16,000,000 births. However, if we apply the frequency described in the study from Cua et al ²⁵ of 1 case of EA in every 166 patients with trisomy 21, this incidence would be greater than the frequency of this CHD described in the general population (1:20,000 live births), ^{10 11 12} suggesting a true association. However, as pointed out before, this was the only study to describe patients with EA in a sample of individuals with trisomy 21. Therefore, we believe that additional studies are also necessary to better elucidate the relationship between trisomy 21 and EA, as well as to verify the follow-up and prognosis of these patients. This data would be very important to improving the care and management of these patients.