Fetal diagnosis of left isomerism not associated with other cardiac malformations

Introduction

Left atrial isomerism is a rare condition in which morphologically left atria are found on both sides of the body. It is frequently associated with visceral heterotaxy syndrome (situs ambiguous), which is characterized by an abnormal arrangement of thoracoabdominal organs, especially the lungs and spleen. The classic example of left atrial and visceral isomerism is the polysplenia syndrome, which implies that the patients have 2 atria with left atrium morphology, bilobated lungs, centralized liver, and polysplenia [1, 2].
Absence of an intrahepatic segment of the inferior vena cava and atrioventricular septal defect associated with heart block detected in the first or early second trimester are important features of left atrial isomerism [3-5]. Prenatal diagnosis of left isomerism is challenging, especially in cases where there are no associated heart defects. Antenatal diagnosis of left isomerism may alert to the risk of arrhythmias, including heart block (absence of sinus node located at the morphological right atrium), polysplenia (small hypofunctional multiple spleens), and gastrointestinal defects (gastrointestinal malrotations) [4, 6]. Therefore, since in left atrial isomerism the sinus node is could be absent or hypoplastic, this diagnosis should be considered in fetuses with persistent bradycardia.
In this report, we describe a rare case of left atrial isomerism with no associated cardiac defects, presenting with persistent bradycardia diagnosed at 20 weeks of gestation.

Case report

A 38-year-old woman, gravida 3 para 1, was referred for fetal echocardiography due to persistent fetal bradycardia and bilateral choroid plexus cyst (CPCs) at routine second trimester ultrasound. The mother had no comorbidities, and there was no history of infectious diseases or consumption of any drugs during pregnancy. Her previous child was born healthy.
First trimester ultrasound screening for chromosomal abnormalities was performed at 13 weeks. The nasal bone was present, and nuchal translucency and Doppler of the ductus venosus were normal with no tricuspid regurgitation. However, fetal heart rate (FHR) was slow (120 bpm). Non-invasive prenatal testing (NIPT) was performed after signed informed consent and indicated low risk for fetal aneuploidies and 22q11.2 deletion syndrome. NIPT reported fetal sex as male (identification of Y chromosome in the cell-free DNA sequences in the maternal blood sample).
Fetal echocardiogram performed at 20 weeks of gestation confirmed bradycardia with FHR ranging from 95 to 100 bpm with no signs of heart failure. The atrial and ventricular heart rate were similar with a 1:1 atrioventricular (AV) relationship and a normal AV interval time. In addition, the fetal echocardiogram showed left-sided atrial morphology (bilateral sickle-shaped atrium) and absence of the hepatic segment of the inferior vena cava (IVC) with azygous continuation (Figures 1 and 2A). No other associated cardiac defects were observed. Bilateral CPCs with no ventriculomegaly were the only associated extra-cardiac soft marker. The parents were warned about the possible risk of chromosomal abnormalities. After counselling, the patient refused an invasive karyotyping procedure. Autoimmune workup and screening for diabetes and thyroid function tests yielded normal results.
Serial ultrasound and fetal echocardiograms were performed on a monthly basis to monitor the finding of persistent bradycardia (FHR ranging from 100 to 90 bpm) and bilateral CPCs (Figure 2B). Between 24 and 38 weeks of gestation, FHR ranged from 100 to 90 bpm with no signs of hydrops. Fetal echocardiography at 33 weeks detected the presence of supraventricular extrasystoles. During follow-up scans, no fetal growth disorders were observed and the CPCs remained stable. The FHR remained stable until term with preserved fetal well-being, and a male baby weighing 3598 γ with Apgar scores of 9 and 10 at 1 and 5 min, respectively, was born at 38 weeks by an elective caesarean section.
Postnatal echocardiography confirmed left atrial isomerism with no other associated cardiac anomalies (Figure 3A). The neonatal electrocardiogram (ECG) demonstrated normal rhythm with normal measurements of PR and QTc intervals, and low HR for age (65-95 bpm) (Figure 3B). Holter monitoring confirmed persistent bradycardia. Abdominal ultrasound was performed, and a normal spleen was detected with normal liver position. Intestinal malrotations were excluded from the study. The cardiac arrhythmia NGS (next-generation sequencing) multi-gene panel test indicated the absence of genetic arrhythmias. The newborn was stable and was discharged home after 5 days of detailed evaluation. Currently, the 1-year-old child is well. The child alternates between sinus and junctional rhythm with a heart rate in the lower range of normality, and no cardiac pacemaker has been required.

Discussion

Left atrial isomerism is characterized by bilateral left morphological atria and is commonly associated with loss of normal asymmetry of thoraco-abdominal organs, known as heterotaxic syndrome [2]. This abnormal symmetrical development of organs during embryological rotation is a rare condition that accounts for 1-10,000 to 40,000 live births [7]. Familial history of visceral malrotations and maternal diabetes has been strongly linked to isomerism [8]. In the current case, family history was negative, and the fetal karyotype and neonatal genetic screening for arrhythmias were normal.
Classically, atrial and visceral left isomerism encompasses bilateral morphological atria and lungs, spleen anomalies (most common: polysplenia), and other gastrointestinal malformations (stomach in an indeterminate position, midline liver, intestinal malrotation, and biliary tract anomalies) [1, 3, 6]. Conversely, in the present case, no other cardiac anomalies were observed. Concerning the cardiac spectrum, the most common anomalies described in left isomerism are the absence of hepatic follow-up of the IVC with drainage through the azygos (Az) or hemiazygos veins (approximately 80%), and complete heart block associated with structural cardiac defects, such as atrioventricular septal defect (AVSD) [5, 6]. This can be explained by the duplicated left-sided atria in this condition.
Therefore, structures related to the morphological right atrium (intrahepatic part of the inferior vena cava and sinus node) are absent or undeveloped in almost all cases of left isomerism. In this case report, we observed the absence of the hepatic part of the IVC with the azygos vein and persistent bradycardia with no heart block. Furthermore, left isomerism is commonly associated with structural cardiac defects such as atrioventricular septal defect and left or right ventricular outflow tract obstruction [4, 6]. However, in 3% to 18% of cases, there are no associated cardiac defects, such as in the case reported [7]. The main characteristics of left isomerism are described in Table 1.
The central point of diagnosis of left atrial isomerism is the anatomy of atria, defined by their appendages and shapes. The morphological left atrium contains the membrane of the foramen ovale, and its appendage is finger-like (narrow base). However, visualization of the left atrium appendage in the fetus is not easy to achieve. Accordingly, Berg et al. [5] reviewed 30 cases of prenatally diagnosed isomerism, focusing on the shape of atrial morphology instead of analysing the characteristics of atrial appendages. The authors concluded that this assessment was sufficient to achieve a diagnosis in the majority of cases. In this study, bilateral sickle-shaped atrial morphology in the 4-chamber view was associated with left isomerism. In addition, interruption of the intrahepatic part of the IVC persisting as the azygos (or hemiazygos) vein is present in almost all cases of left isomerism. This is fundamental to the examination of the upper abdomen view of the fetus. In left isomerism, the aorta and the venous vessel are on the right (Az) or on the left (hemiazygos) of the fetal spine in the upper abdomen or in the 4-chamber views. Sheley et al. [9] described the dilated azygos or hemiazygos and the aorta side-by-side in left isomerism as the “double-vessel sign”. In the current study, it was a useful sign that enabled the suspicion of this diagnosis. Furthermore, the persistence of an azygos vein can be confirmed by colour Doppler in a longitudinal view of the descending aorta, as in the present case (Figure 3).
Congenital anomalies of the IVC are uncommon, accounting for up to 8.7% of the population, including anomalies of the left renal vein. The IVC develops at 6 to 8 weeks of gestation, and the complexity of its ontogeny can lead to a wide variety of anomalous venous return from the abdomen and lower limbs. The absence or agenesis of the intrahepatic IVC (‘interrupted IVC’) is classically associated with other congenital anomalies (atrial isomerism and heterotaxy syndromes) and is a risk factor for venous thrombosis of lower limbs, especially in young adults [10].
In conclusion, a prenatal ultrasound diagnosis of left isomerism with no other associated cardiac abnormalities, although associated with persistent bradycardia, was of critical importance in guiding an appropriate parental counselling concerning a potential favourable prognosis perinatally, and a thorough fetal echocardiogram could exclude complete heart block as well as an heterotaxy syndrome (cardiosplenic syndrome).

Conflict of interest

The authors declare no conflict of interest.

REFERENCES