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Keywords:

  • 22 q11.2 deletion;
  • fetal heart;
  • thymus

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Objectives

To evaluate the thymic–thoracic ratio (TT-ratio) method in assessment of the fetal thymus in normal fetuses and in those with cardiac abnormalities, in the presence or absence of 22q11.2 deletion.

Method

Database records were reviewed for cases of conotruncal and arch abnormalities found on fetal echocardiography between January 2007 and September 2011. The 22q11.2 deletion status was retrieved and cases in which this was not known were excluded from the analysis, as were fetuses with aneuploidy or other genetic disorders. An additional 55 normal fetuses were analyzed as a control group. The TT-ratio was measured retrospectively using stored spatiotemporal image correlation (STIC) volume datasets.

Results

Sixty-nine fetuses with relevant cardiac diagnoses were identified and, of these, 18 (26%) had 22q11.2 deletion. The mean gestational age at diagnosis was 22 weeks. Significant pairwise differences, but also overlap, were observed between all three groups (i.e. fetuses with heart defects with and without the 22q11.2 deletion and controls). The mean TT-ratio was 0.44 in our normal control group and was significantly smaller in fetuses with 22q11.2 deletion, corresponding to previously published data. However, the mean TT-ratio in the group with conotruncal anomalies but without the 22q11.2 deletion was also smaller than that in controls, in contrast to previously published data. The TT-ratio was above the normal mean, regardless of fetal karyotype, in all cases of interrupted aortic arch.

Conclusion

The TT-ratio method is a feasible and potentially useful tool during detailed fetal heart assessment. However, the absolute measurement is not reliable for prediction of 22q11.2 deletion and the obtained results should therefore be interpreted with caution. Fetal karyotyping should be recommended in cases with conotruncal heart abnormalities, irrespective of the TT-ratio.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

There is a known association between 22q11.2 deletion and absence or hypoplasia of the thymus[1]. Congenital heart disease is commonly associated with genetic conditions, and conotruncal abnormalities in particular have a strong association with the 22q11.2 deletion[2-4].

The appearance of the normal thymus is well described by anatomists, consisting of two lateral lobes in close contact along the midline, situated partly in the anterior thorax and partly in the neck. The thymus lobes can differ in size and may be joined or separated. The gland is covered anteriorly by the sternum and is separated from the aorta and great vessels posteriorly by its fascia[5]. Different methods for evaluation of the thymus on fetal ultrasound examination have been described[6-11]. The thymus can often be seen in a transverse section[6], at the level of the three-vessel view[12], as a hypoechogenic structure in the anterior fetal mediastinum, lying between the great arteries and the sternum. However, subjective assessment of its size is challenging because of difficulty in clearly delineating thymic tissue from lung tissue.

Measurement of the thymic–thoracic ratio (TT-ratio) has been suggested as a reliable, easy and sensitive method for antenatally assessing the likelihood of 22q11.2 deletion[11]. We aimed to assess the association between the TT-ratio and the presence of 22q11.2 deletion in a cohort of our patients, and also to evaluate the reproducibility of this measurement.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Our database was reviewed for cases with an antenatal diagnosis of conotruncal or arch abnormalities, seen between January 2007 and September 2011. The 22q11.2 deletion status was retrieved and cases in which this was not known were excluded from the analysis, as were fetuses with aneuploidy or other genetic disorders.

Two-dimensional (2D) and four-dimensional (4D) fetal echocardiography were performed in all cases at the time of diagnosis using high-quality three-dimensional (3D) equipment (Voluson E8; GE Medical Systems, Zipf, Austria). Spatiotemporal image correlation (STIC) volumes were acquired using a transverse sweep through the fetal thorax starting at the level of the four-chamber view. The region of interest (ROI) box was set to include the whole thoracic cage. The STIC volume was acquired at the smallest possible angle of insonation (10–15° for first trimester and 20–25° for second trimester) in order to guarantee the highest frame rate and image quality. The optimal acquisition time was selected to be 7.5–11 s, depending on the gestational age.

In all cases included in the study, one or more cardiac STIC volume datasets were available for offline analysis. The acquired dataset was reviewed using 3D software (4D View version 9.0; GE Medical Systems) using the basic multiplanar display. Image quality was optimized using postprocessing image settings. The thoracic plane at the level of the three-vessel view was retrieved from the archived STIC volumes. Each STIC volume was standardized by rotational adjustment around x-, y- and z-axes and scrolling through the fetal heart, along the original plane of acquisition, in order to obtain an exact transverse plane. All measurements were made in the A-plane, which was the plane of acquisition with the highest image quality.

The method of thymic measurement (the TT-ratio) was adapted from that reported by Chaoui et al.[11]. The ratio of the thymic diameter to the thoracic diameter was measured at the level of the three-vessel view, in the midline of the chest. The thymic measurement was made from the anterior chest wall or sternum to the anterior border of the transverse aortic arch. The thoracic diameter was measured along the thymic diameter and continued to the anterior border of the thoracic spine (Figure 1). Measurements were made by an observer with expertise in 4D echocardiography who did not know the karyotype result.

image

Figure 1. Horizontal section at level of three-vessel view in upper mediastinum, showing measurement of thymic–thoracic ratio (TT-ratio). Both thymic and thoracic diameters were measured in midline of chest. Thymic measurement was made from anterior chest wall/sternum to anterior edge of transverse aortic arch (Caliper 1). Thoracic diameter was measured along thymic diameter and continued to anterior surface of thoracic spine (Caliper 2). This is an example of a normal TT-ratio (0.47) in a normal fetus.

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Morphologic cardiac diagnosis, karyotype, measurement of the TT-ratio and measurement of gestational age were recorded. Still images from all cases with an obtained TT-ratio measurement were stored for re-evaluation.

An additional 55 normal fetuses were analyzed as a control group. Karyotyping was not performed in this group as these were normal fetuses and the heart was considered to be normal; there was a normal clinical outcome in these pregnancies.

To assess intraoperator and interoperator variability, nine datasets (three from each category) were selected and re-analyzed by the same operator (R.B.), 2 months after the initial analysis and also by an additional observer (V.Z.).

Statistical analysis

We compared measurements of the TT-ratio in our series with previously published normal data[11]. The TT-ratio was compared between the different groups using the Student's t-test. Interoperator and intraoperator reproducibility was assessed using the intraclass correlation coefficient (ICC) (two-way random, absolute agreement).

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Sixty-nine fetuses with an antenatal diagnosis of conotruncal or arch abnormalities were identified (Table 1). The gestational age range was 13–34 weeks (mean = 22 weeks). Of these 69 cases, 18 had documented 22q11.2 deletion. The gestational age range of the 55 fetuses included in the control group was 19–34 weeks (mean = 21 weeks). The TT-ratio plotted against gestational age is shown for all patients by diagnostic group in Figure 2. The mean TT-ratio of 0.44 in our normal control group corresponded to previously published normal data[11].

Table 1. Diagnoses and karyotype of 69 patients with an antenatal diagnosis of conotruncal or arch abnormalities
Congenital heart defectWithout genetic abnormalityWith 22q11.2 deletion
  1. Data are given as n (%). APV, absent pulmonary valve; DAA, double aortic arch; PA, pulmonary atresia; RAA, right aortic arch; TOF, tetralogy of Fallot.

TOF, including with RAA, PA and APV38 (76)12 (24)
Common arterial trunk4 (67)2 (33)
Interrupted aortic arch3 (60)2 (40)
RAA

and DAA

6 (75)2 (25)
Total51 (74)18 (26)
image

Figure 2. Thymic–thoracic ratio (TT-ratio) plotted against gestational age displayed according to diagnostic group: normal hearts (image), conotruncal anomalies without 22q11.2 deletion (image) and conotruncal anomalies with 22q11.2 deletion (image). Mean (image) and 95% range (image) for the 55 normal cases are shown. The mean TT-ratio in our control group was similar to previously published data[11].

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Significant pairwise differences in the mean TT-ratio were seen between all three groups (i.e. fetuses with heart defects with and without the 22q11.2 deletion and controls) (Figure 3). Lower than normal mean values were observed in both groups with heart defects, with the lowest mean value in the group with 22q11.2 deletion. However, there was overlap in the range of observations in each group.

image

Figure 3. Mean and 95% CI thymic–thoracic ratio (TT-ratio) for each diagnostic group. Significant pairwise differences were found between each of the three groups (P < 0.05). CHD, congenital heart defect.

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Intraoperator and interoperator reproducibility for measurement of the TT-ratio were very good, at 0.946 (95% CI, 0.792–0.987) and 0.920 (95% CI, 0.705–0.981), respectively.

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Some forms of congenital heart malformation are associated with 22q11.2 deletion. This chromosomal abnormality is, in turn, known to be associated with variable degrees of hypoplasia of the thymus. A previous publication[11] suggested an easy method of thoracic measurement that seemed to act as a good indication of thymic hypoplasia and thus 22q11.2 deletion. Our aim was to test this method in a clinical setting in those forms of congenital heart disease particularly associated with this deletion: tetralogy of Fallot, common arterial trunk and interrupted aortic arch. Tetralogy of Fallot and common arterial trunk have a reported incidence of 22q11.2 deletion of 10–15%, rising to 50% in interrupted aortic arch[2]. The association was higher in our series but this may reflect a selection bias in those cases tested.

The TT-ratio in our normal control group corresponded to previously published normal data[11]. However, the mean TT-ratio in the group with conotruncal anomalies without 22q11.2 deletion was smaller than that in the controls. This observation contrasts with previously published data, which suggested that an abnormal TT-ratio was only seen in congenital heart disease with 22q11.2 deletion. In addition, overlap between all three groups was noted. In our study, a consistent method of TT-ratio measurement was maintained (Figure 4), only using the anterior border of the aorta to define the thymic diameter; this is in contrast to the study of Chaoui et al. in which the thymus was measured along the midline from the sternum to the anterior border of the most posterior vessel in fetuses with cardiac defects. For this reason, and because the study of Chaoui et al. included a mixture of different forms of congenital heart disease, the two studies are not directly comparable.

image

Figure 4. Horizontal section at level of three-vessel view demonstrating thymic–thoracic ratio (TT-ratio) measurement (Calipers 1 and 2) in a case of tetralogy of Fallot with absent pulmonary valve syndrome. TT-ratio was below normal range (0.29) and this fetus had 22q11.2 deletion.

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It was noted that the TT-ratio was significantly above the normal mean, regardless of the status of the 22q11.2 deletion, in all cases of interrupted aortic arch. The distal part of the ascending aorta in the three-vessel view is very posterior (Figure 5) and far from the sternum in this condition, with or without 22q11.2 deletion.

image

Figure 5. Horizontal section at level of three-vessel view demonstrating thymic–thoracic ratio (TT-ratio) measurement (Calipers 1 and 2) in a case of interrupted aortic arch. Note long distance between sternum and anterior wall of ascending aorta (Caliper 1). At 0.52, TT-ratio was greater than the normal mean. However, this fetus had 22q11.2 deletion.

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Using our method of assessing the TT-ratio, about half of the fetuses with 22q11.2 deletion in this series were identified as having thymic hypoplasia. A previous paper[13] suggested that thymic hypoplasia is seen in more than 80% of patients with 22q11.2 deletion, but it did not indicate whether this was anatomical or functional hypoplasia or how it was measured.

The assessment of the TT-ratio provided important additional information in one case with an isolated right aortic arch, with no extracardiac abnormalities, in which first-trimester nuchal translucency was normal. The appearance of thymic hypoplasia, found at 20 weeks in association with a right-sided aortic arch and confirmed by an abnormal TT-ratio of 0.24, directed counseling, which led to fetal karyotyping and identification of the 22q11.2 deletion.

Previously published studies6−10 have suggested several different methods of fetal thymus evaluation, including perimeter, diameter and volume measurements. However, the margins of the thymus are difficult to delineate in every case, especially in early gestation, and therefore perimeter measurements may not be entirely reliable. In addition, the diameter as a single measurement may not be sufficiently representative to judge the size of the thymus. As the thymus has a variable shape, size and volume, it may not be possible to produce entirely objective measurements in the fetus with currently existing technologies. The use of the course of the internal mammary arteries as a landmark to aid the visualization of the fetal thymus in normal and abnormal conditions has been described, with this method termed the ‘thy-box’[9]. Certainly, this can be helpful in recognizing the thymus, but color flow data would need to be acquired prospectively with this aim in mind and so this technique was not possible using the volume datasets that we had available.

A limitation of this study is that we exclusively focused on conotruncal abnormalities and those with isolated right aortic arch, although other forms of congenital heart disease are sometimes, albeit rarely, associated with 22q11.2 deletion. In addition, although the diagnosis of an isolated right aortic arch is fairly frequent during routine anomaly scanning, we were able to include only a small group of patients with this diagnosis in this analysis as the majority of parents declined invasive testing. As a result, the incidence of the 22q11.2 deletion in entirely isolated cases has not yet been established.

In conclusion, the TT-ratio is a useful tool during fetal heart assessment. However, the obtained results should be interpreted with caution. This method is feasible, but not entirely reliable for prediction of 22q11.2 deletion owing to an overlap between patients with and without the 22q11.2 deletion. Assessment of the thymus can support decision-making in those cases in which only an isolated subtle cardiac abnormality, such as right aortic arch, is diagnosed, and fetal karyotyping is under discussion. Currently, fetal karyotyping should be recommended in cases in which conotruncal heart abnormalities are identified, irrespective of the TT-ratio.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
  • 1
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  • 4
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    Piliero LM, Sanford AN, McDonald-McGinn DM, Zackai EH, Sullivan KE. T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood 2004; 103: 10201025.