PRECIS: Aberrant right subclavian artery (ARSA) may be the only antenatal ultrasound finding of trisomy 21, DiGeorge and Turner syndromes in the second or third trimester.

Introduction

Aberrant right subclavian artery (ARSA) is the most common congenital abnormality of the aortic arch with a frequency of 1-1.5% in an apparently healthy population^(1,2,3). In normal anatomy, the right subclavian artery originates from the brachiocephalic trunk, one of the three main branches of the aortic arch. In contrast, ARSA is an anatomic variation in which the right subclavian artery originates from the aortic arch directly as an additional artery, usually distal to the left subclavian artery. It must course from the left side to right of the midline, usually behind the trachea and esophagus⁽⁴⁾. Typically, ARSA is a benign finding and usually asymptomatic. However, ARSA occasionally causes dysphagia or dyspnea in the pediatric population^(5,6).

In recent years, ARSA has been associated with chromosomal abnormalities and has gained notoriety. The first report demonstrating the ARSA and relationship with Down syndrome was published in 2005⁽⁷⁾, and thereafter a few other studies emphasized the importance of this benign variant, even if isolated and showing the presence of trisomy 21 in isolated cases^(4,5,8,9). Most trials revealed that additional cardiac or extracardiac abnormalities accompanied ARSA in fetuses with trisomy 21^(10,11). Moreover, ARSA has been reported with other less common genetic disorders such as 22q11.2 deletion or Turner syndrome^(12,13).

This study aimed to determine the frequency and types of chromosomal anomalies among fetuses with ARSA and to evaluate the additional sonographic abnormal findings associated with ARSA in a large study group.

Materials and Methods

This study was approved by our institutional review board. A waiver of informed consent was obtained owing to the study’s retrospective nature. We performed a retrospective review of fetuses antenatally diagnosed as having ARSA between March 2014 and March 2020 in the perinatology unit of our hospital, which is a reference center in our city.

Fetuses with ARSA were identified from hospital databases and hospital charts. Both low and high-risk patients in the second and third trimesters were included in the study. We collected data by focusing on antenatal screening tests, fetal anatomy ultrasound scans, fetal echocardiograms, and reports of genetic analysis, and reviewed all neonatal and pediatric records. Examinations were performed using high-resolution equipment (Voluson E6 expert, GE Healthcare, Milwaukee, WI, USA) by perinatologists who were experts in fetal anatomic surveys and echocardiography. Color Doppler ultrasonography was used for visualizing the right subclavian artery as previously described by Chaoui et al.⁽⁷⁾ (Figure 1). ARSA was detected as an additional vessel arising from the junction of the aortic arch and ductus arteriosus, and passing behind the trachea to the opposite side. In all patients with a diagnosis of ARSA, detailed fetal anatomical scanning and echocardiography were performed to look for additional abnormal ultrasound findings.

The cases of ARSA were divided into two groups as isolated if ARSA was the only antenatal sonographic finding in the 2^nd or 3^rd trimester, and non-isolated, those with concomitant sonographic findings including cardiac or extracardiac abnormalities and soft markers. Nuchal fold thickness, aplasia or hypoplasia of nasal bone, echogenic intracardiac focus, hyperechogenic bowel, mild pyelectasis, and short femur or humerus (<5^th percentile) were accepted as soft markers. Extracardiac abnormalities referred to all abnormal sonographic findings including fetal growth restriction, except for cardiac anomalies. Fetal biometric measurements were made according to Hadlock nomograms and estimated fetal weight (EFW) was calculated with the Hadlock formula. Those with abdominal circumference (AC)/EFW <3^rd percentile or absent-reverse end-diastolic flow in the umbilical artery or AC/EFW <10^th percentile combined with a pulsatility index >95^th percentile in either the umbilical or uterine artery were considered to have an intrauterine growth restriction⁽¹⁴⁾.

Prenatal invasive diagnostic tests for karyotype analysis including fluorescence in situ hybridization (FISH) analysis were proposed in each case of ARSA. Blood samples were taken in the postnatal period for genetic analysis from infants whose parents did not accept the antenatal invasive test. The presence of ARSA in all cases was confirmed through postnatal echocardiography or computed tomography. Cases without prenatal or postnatal genetic diagnostic tests and postnatal confirmation were excluded from the study.

Statistical Analysis

We used the IBM SPSS 21.0 for Windows (SPSS Inc., Chicago, IL, USA) statistical package for the statistical evaluation of our research data. The measured variables are presented as mean ± standard deviation and categorical variables are presented as numbers and percentages (%). The Kolmogorov-Smirnov test was used to determine whether the numerical data matched normal distribution. The Student’s t-test and Mann-Whitney U test were used to compare the groups. A p-value <0.05 was considered to be statistically significant.

Results

The anatomic screening data of a total of 11,666 fetuses were assessed and ARSA was identified in 140 fetuses over the study period. The antenatal prevalence of ARSA in our study was 1.2%. ARSA was diagnosed in the second trimester in 92/140 (65.7%) patients and the third trimester in 48/140 (34.3%) patients. At the time of diagnosis, the mean gestational age was 22.3±4.5 weeks, and the mean maternal age was 31.2±5.5 years. ARSA appeared isolated in 47.1% (66/140) of cases and it was found to be associated with a cardiac or extracardiac abnormal finding and/or a soft marker in the remaining 52.9% (74/140). Cardiac anomalies, extracardiac malformations, and soft markers were detected in 21.6% (16/74), 51.3% (38/74), and 40.5% (30/74) of cases, respectively. Some of the fetuses had more than one type of abnormal finding (e.g. cardiac and/or extracardiac anomalies and soft markers in the same fetus).

Antenatal screening tests were performed in 97/140 (69.2%) patients, including 57 first-trimester screening, 18 triple tests, and 22 quadruple tests. In 24 of these patients, cell-free fetal DNA screening was also performed.

Prenatal invasive diagnostic tests and karyotype analysis using FISH were performed in 88/140 cases. Sampling was performed by amniocentesis in 65/88 cases, cordocentesis in 13/88, and chorionic villus biopsy in the remaining 10/88 cases. Postnatal genetic examinations were performed in the remaining 52/140 cases. Chromosomal abnormalities were detected in 17.8% (25/140) of all cases. The corresponding rate was 9% (6/66) and 25.6% (19/74) for isolated and non-isolated ARSA, respectively. Trisomy 21 was the most common chromosomal anomaly with a prevalence of 11.4% (16/140). The corresponding rate was 3% (2/66) and 18.9% (14/74) for isolated and non-isolated ARSA, respectively. The other chromosomal anomalies were trisomy 18, 22q11.2 deletion (DiGeorge syndrome), and Turner syndrome. The distribution of chromosomal abnormalities in fetuses with ARSA is shown in Table 1.

The list of sonographic findings observed in fetuses with non-isolated ARSA is shown in Table 2. The most common cardiac anomaly associated with ARSA was a ventricular septal defect (n=6, 4.2%), and the most common extracardiac finding and soft marker was fetal growth restriction (n=8, 5.7%) and echogenic cardiac focus (n=12, 8.5%), respectively.

Details of cases with a chromosomal abnormality are presented in Table 3.

Discussion

Previous studies revealed the prevalence rate of ARSA ranging between 0.4% and 2% among the general population^(3,10,15). Our study is one of the largest on ARSA in the literature and we identified 140 cases of ARSA with a prevalence rate of 1.2%.

During the last decade, many studies in the literature investigated isolated or non-isolated ARSA with additional abnormalities and its relationship with chromosomal anomalies⁽⁵⁾. Esmer et al.⁽⁵⁾ first reported 14 trisomy-21 cases between 18 and 33 weeks of gestation and ARSA was detected in 5/14 (35.7%). In one of these cases, ARSA was the only abnormal ultrasound finding. Gul et al.⁽⁹⁾ also reported 17 cases of ARSA and only one case was diagnosed with trisomy 21. ARSA was the only ultrasound finding in this fetus. Similarly, Borenstein et al.⁽³⁾ published a case series of 8 fetuses with Down syndrome with ARSA, and in one of them, the ARSA was isolated. Zalel et al.⁽¹⁶⁾ reported three cases of ARSA in eight fetuses with Down syndrome, but none of these cases was isolated. In another large study, Svirsky et al.⁽¹⁷⁾ found a high prevalence of trisomy 21 in fetuses with ARSA, but none in the isolated group.

In our study, we demonstrated 16 cases of trisomy-21 in fetuses with ARSA and two were in the isolated group. Paladini et al.⁽¹⁸⁾ reported a case series of 27 fetuses with ARSA and Down syndrome and ARSA was an isolated sonographic finding in eight (29.6%). In this study, the authors suggested that in addition to nasal bone aplasia/hypoplasia and nuchal fold thickness, ARSA should be one of the most important ultrasound markers of Down syndrome in the 2^nd trimester.

In 2006, Chaoui et al.⁽¹⁹⁾ reported the prevalence of ARSA in fetuses with major chromosomal abnormalities as 34% (16/47). Ratios were found as 28.5% (4/14), 55.5% (5/9), and 50% (2/4) in trisomy 21, trisomy 18, and trisomy 13, respectively. Also, ARSA was detected at a rate of 43% (3/7) in Turner syndrome and 14% (1/7) in DiGeorge syndrome. ARSA was not the only ultrasound finding in any of these cases.

Although the relationship between ARSA and Down syndrome has been demonstrated, there are conflicting data in the literature regarding the association of isolated ARSA and trisomy 21 or other chromosomal abnormalities to recommend karyotyping⁽²⁰⁾. Rembouskos et al.⁽²¹⁾ detected DiGeorge syndrome in a case of ARSA with only increased NT as an additional finding and emphasized the addition of FISH analysis for microdeletion syndromes to fetal karyotyping, even if ARSA was the only ultrasound finding on the second or third trimester.

We detected three cases with 22q11 deletion and in two of them, ARSA was the only ultrasound finding in the second-trimester fetal anatomic survey and one case with DORV and thymic hypoplasia.

Aortic arch abnormalities can be observed in Turner syndrome. However, there are limited data in the literature about the relationship between Turner syndrome and ARSA. In a study with 99 patients with Turner syndrome, ARSA was reported in 8% of cases⁽²²⁾.

ARSA was the only ultrasound finding in the second-trimester fetal anatomic screening in two fetuses in which we found Turner syndrome. Antenatal screening tests were not performed in one of the cases, but the other had increased nuchal translucency at the first-trimester screening.

Conclusion

ARSA may be the only ultrasound finding in trisomy 21 and also in DiGeorge and Turner syndrome in the second or third trimester. Hence, imaging the right subclavian artery should be part of the fetal anatomical survey and standard karyotyping and FISH analysis should be recommended, even in isolated ARSA, especially in patients who do not have antenatal screening tests.

Ethics

Ethics Committee Approval: This study was approved by our institutional review board (approved number: KAEK/2019.03.46).

Informed Consent: A waiver of informed consent was obtained owing to the study’s retrospective nature.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: M.B., S.S.Ç., S.S., A.Ç.E., Concept: M.B., S.S.Ç., S.C.O., S.S., A.Ç.E., Design: M.B., S.S.Ç., S.C.O., S.S., A.Ç.E., Data Collection or Processing: M.B., S.S.Ç., S.S., A.Ç.E., Analysis or Interpretation: M.B., S.S.Ç., S.C.O., Literature Search: M.B., S.S.Ç., S.C.O., Writing: M.B., S.S.Ç., S.C.O., Critical Review: M.B., S.S.Ç., S.C.O.

Conflict of Interest: The authors report no conflict of interest.

Financial Disclosure: Authors have no financial interests about the research.