Prenatal Diagnosis of Shone’s Syndrome by Fetal Echocardiography

BackgroundShone’s syndrome is a rare complex with few data published on its prenatal diagnosis, this study aimed to compare the fetal echocardiographic features between Shone’s syndrome fetuses and coarctation of the aorta (CoA) fetuses to improve the prenatal diagnosis of Shone’s syndrome and identify the mitral valve obstruction associated with the anomaly. Methods: Retrospective study was performed. Between January 2015 to December 2019, fourteen fetuses diagnosed with Shone’s syndrome were enrolled and ten were analyzed in our final study, their clinical information and echocardiographic features were compared to normal controls (N=30) and CoA cases (N=10). The main points of identification were summarized. Results: Comparing to normal controls, the PA/AO ratio was increased in both Shone’s syndrome and CoA, but Shone’s syndrome fetuses had higher PA/AO ratio than CoA fetuses (P=0.006). RV/LV and TVC/MVC ratios were only elevated in Shone’s syndrome cases (P<0.0001, P<0.0001). Analysis revealed that the TVC/MVC ratio had the best capability in predicting Shone’s syndrome and fetuses with TVC/MVC ratio over 1.290 were more likely to have Shone’s syndrome rather than CoA. Meanwhile, the main points of identification in mitral valve obstruction included (1) restrictive opening of the mitral valve, thickened leaflets, echo-enhancement of chordae tendineae and single papillary muscle in short-axis section view; (2) decreased antegrade flow and abnormal flow pattern of mitral valve in color Doppler image. Chi-square test revealed that restrictive opening of the mitral valve and single papillary muscle were the most relevant features of mitral valve obstruction. Conclusions: There are several parameters of prenatal diagnosis of Shone’s syndrome by fetal echocardiography, including (1) echocardiographic measurements: elevated RV/LV ratio, PA/AO ratio and TVC/MVC ratio, of these, the TVC/MVC ratio has the best capability in predicting Shone’s syndrome; (2) morphologic changes in short-axis section view: restrictive opening of the mitral valve and single papillary a comprehensive evaluation of mitral valve. In our study, out that the TVC/MVC ratio the best capability in predicting Shone’s syndrome. restrictive opening of the mitral valve and single papillary muscle mitral valve

Background Shone's syndrome is a rare complex with few data published on its prenatal diagnosis, this study aimed to compare the fetal echocardiographic features between Shone's syndrome fetuses and coarctation of the aorta (CoA) fetuses to improve the prenatal diagnosis of Shone's syndrome and identify the mitral valve obstruction associated with the anomaly.
Methods: Retrospective study was performed. Between January 2015 to December 2019, fourteen fetuses diagnosed with Shone's syndrome were enrolled and ten were analyzed in our final study, their clinical information and echocardiographic features were compared to normal controls (N=30) and CoA cases (N=10). The main points of identification were summarized.
Results: Comparing to normal controls, the PA/AO ratio was increased in both Shone's syndrome and CoA, but Shone's syndrome fetuses had higher PA/AO ratio than CoA fetuses (P=0.006). RV/LV and TVC/MVC ratios were only elevated in Shone's syndrome cases (P<0.0001, P<0.0001). Analysis revealed that the TVC/MVC ratio had the best capability in predicting Shone's syndrome and fetuses with TVC/MVC ratio over 1.290 were more likely to have Shone's syndrome rather than CoA.
Meanwhile, the main points of identification in mitral valve obstruction included (1) restrictive opening of the mitral valve, thickened leaflets, echo-enhancement of chordae tendineae and single papillary muscle in short-axis section view; (2) decreased antegrade flow and abnormal flow pattern of mitral valve in color Doppler image. Chi-square test revealed that restrictive opening of the mitral valve and single papillary muscle were the most relevant features of mitral valve obstruction.
Conclusions: There are several parameters of prenatal diagnosis of Shone's syndrome by fetal echocardiography, including (1) echocardiographic measurements: elevated RV/LV ratio, PA/AO ratio and TVC/MVC ratio, of these, the TVC/MVC ratio has the best capability in predicting Shone's syndrome; (2) morphologic changes in short-axis section view: restrictive opening of the mitral valve and single papillary muscle are the most relevant features of Shone's syndrome.

Background
Shone's syndrome is a constellation of congenital abnormalities characterized by four lesions including parachute mitral valve, supravalvular mitral ring, subaortic stenosis and coarctation of aorta. It was first described in 1963 by Dr JD Shone [1] . Incomplete Shone's syndrome, which consists of at least 1 left ventricular inflow tract lesion and at least 1 left ventricular outflow tract (LVOT) lesion, is more common than complete Shone's syndrome in clinical practice [2] . Shone's syndrome is compromising approximately 0.6% of all cases of congenital cardiac abnormalities [3] . The clinical setting is characterized by a congenital mitral valve anomaly resulting in stenosis, with resultant downstream underdevelopment of left heart outflow tract [4] .
Shone's syndrome is a rare complex with few data published on its prenatal diagnosis [5] which could provide less help for fetal cardiologist to clinical determination. Shone et al. [1] noted that mitral valve obstruction appeared to be the most critical problem associated with the anomaly. The severity of mitral valve obstruction correlates with poor long-term outcomes [5,6] . However, mitral stenosis is difficult to be accurately diagnosed and may go unnoticed in the fetus with coarctation of the aorta (CoA). Several Shone's syndrome cases were misdiagnosed with CoA and found mitral valve obstruction lesions not until adult [7,8] . So, evaluation of mitral valve is important in prenatal diagnosis of Shone's syndrome, especially in its differential diagnosis with isolated coarctation.
This study was conducted to improve the prenatal diagnosis of Shone's syndrome and summarize the main points of identification in mitral valve obstruction associated with the anomaly to provide actual help for fetal cardiologist to clinical determination.

Methods
This was a single-center retrospective study conducted by Pediatric Cardiology Department of Xinhua

Population
Between January 2015 and December 2019, a total of 1500 fetuses were examined in our center and fourteen cases of Shone's syndrome were contained in the study. The study inclusion criteria were (1) with suspected Shone's syndrome (2) singleton fetus without aneuploidy (3) absence of extracardiac malformations (4) the size of the fetus is consistent with the gestational age.

Measurements
A detailed fetal echocardiography was performed by at least 2 trained pediatric cardiology physicians with at least 3 years of experience in accordance with the 2013 guidelines of the American Institute of Ultrasound in Medicine [9] . All fetal echocardiographic examinations were performed on GE Voluson E8 RV and LV diameters were measured in the apical four-chamber view at end-diastole. TVC and MVC diameters were measured in diastole in the four-chamber view. We assigned z-scores for valve dimensions based on fetal biometry [10] .

Statistical analysis
All statistical analyses were performed with SPSS21.0 software, and p-values under 0.05 following two-tailed t test, one-way ANOVA and Pearson χ2 were considered as statistically significant.
Receiver-operating characteristic (ROC) curve and binary logistic regression analysis were used to detect the predictors of Shone's syndrome.

Results
General information fetuses (two confirmed with only CoA, one confirmed with no CHD after birth and one lost to postnatal follow-up) Fig. 1. Eight (80%) fetuses underwent the termination of pregnancy and two (20%) were born alive and received operation in our center. Of these ten fetuses, five were diagnosed with mitral stenosis and CoA, three with mitral stenosis and aortic valve stenosis, two with mitral stenosis, CoA and aortic valve stenosis. Among all, two were combined with ventricular septal defect (VSD). None of the cases had extracardiac findings. Clinical information and echocardiographic data of Shone's syndrome cases were summarized at Table 1 CoA (N = 10) cases then. No significance was detected in gestational weeks or ages between three groups Fig. 3.
The clinical information and echocardiographic data of CoA cases were summarized at Table 1S, 2S. Table 1 Clinical information of ten prenatally diagnosed Shone's syndrome cases.

Patient
Gestational

Comparing and analyzing of echocardiographic measurements
Of the ten Shone's syndrome cases, mean PA/AO ratio was 1.796 ± 0.47, mean RV/LV ratio was 1.391 ± 0.30, mean TVC/MVC ratio was 1.855 ± 0.70 and mean MV was 0.634 ± 0.21 Table 3. By comparing the measurements with control groups, shared features between Shone's syndrome and CoA were detected, including (1) LVOT obstructions, with no significance in Z scores of ascending aorta and aortic isthmus between two groups Fig. 4a,b; (2) great vessel disproportion, with elevated PA/AO ratio in both diseases Table 3, which were in accord with other centers' results [11,12] . However, Shone's syndrome cases exhibited more evident signs of great vessel disproportion than CoA cases. The fetuses with Shone's syndrome had higher PA/AO ratio than those with CoA (P = 0.006) Fig. 4c. Significance was also detected in ventricular disproportion between two diseases. The ratios of RV/LV, TVC/MVC were increased in Shone's syndrome cases (P < 0.0001, P < 0.0001) but not CoA cases. The Shone's syndrome cases also seemed to get higher MV than control groups, although no statistical significance was detected (P = 0.0714). Binary logistic regression analysis was used to detect predictors of Shone' syndrome, which showed that the TVC/MVC ratio had the best capability in predicting the anomaly    Table 4. Chi-square test revealed that restrictive opening of the mitral valve and single papillary muscle seemed to be the most relevant features of mitral valve obstruction in Shone's syndrome.

Discussion
Shone's syndrome is a rare and under-recognized diagnostic entity, associated with substantial morbidity related to arrhythmias, heart failure, and interventions [13] . The obstructive lesions in Shone's complex have a tendency to worsen over time as compared to other congenital heart defects [14] . The antenatal recognition of Shone's syndrome is still challenging, the complex hemodynamic interactions between multiple levels of left-side obstructions challenge the clinical determination of prognoses [15] and sometimes the diagnosis at mid-gestation is misleading, as both steady state and worsening by the end point are possible [5] .
The incidence of Shone's syndrome in our center is about 0.66%, which is close to the reported 0.67%. A key point in diagnosis of Shone's syndrome is a comprehensive evaluation of mitral valve. In our study, we found out that the TVC/MVC ratio had the best capability in predicting Shone's syndrome. Besides, restrictive opening of the mitral valve and single papillary muscle were the most relevant factors of mitral valve obstruction which provided important clues for prenatal diagnosis of Shone's syndrome. These findings could provide some information for fetal cardiologist to determine those with Shone's syndrome from those with just an isolated coarctation to help better counsel the family.
However, misdiagnosis is inevitable as the difficulty of distinguishing Shone's syndrome from other LVOT obstruction lesions. In this study, there were still three cases who had been misdiagnosed with Shone's syndrome prenatally but were confirmed other diagnosis postnatally, among whom two were confirmed only CoA, including one manifested as thickened leaflets Video 5 and one manifested as single papillary muscle Video 6 prenatally. In addition, another two cases in our center who were not enrolled in this study, had been diagnosed with isolated CoA prenatally but found to be combined with mitral stenosis after birth. Thus, the sensitivity and specificity of prenatal diagnosis of Shone's syndrome still need to be improved.
Mitral stenosis is a progressive process which could be missed occasionally if obstruction is mild in early stage of pregnancy or overlapped by signs of severe LVOT obstruction. In these patients, prenatal echocardiography diagnosis is less satisfactory and serial assessment after initial diagnosis is needed for evaluating progress of multiple-level obstructions. Fetal echocardiograms may be performed every 4 weeks based on the gestational age at the time of initial suspicion. In addition, prenatal echocardiography diagnosis relies on the quality of image extremely [16] . Sometimes suboptimal imaging of fetal heart could interfere the clinical determination by physicians.
Referring to a Fetal Medicine Unit is required in order to obtain a better monitor and management for Shone's syndrome patients after birth, especially for those who may require special intervention at birth or within the first days of life. The patient outcome of Shone's syndrome is widely variable because of the diversity and complex nature of cardiac anomalies itself. It is reported that operative outcome is excellent in Shone's syndrome patients [17] and surgical intervention is recommended to be undertaken early before the onset of pulmonary hypertension [18] .

Limitations
This was a retrospective study with its inherent limitations. In addition, our study population was limited to fetuses who were suspected with congenital heart defects and referred to our hospital for further diagnosis and Availability of data and materials: All data generated or analyzed during this study are included in this published article and its supplementary information files.
Funding: Figure 1 Flow chart of fetuses with suspected Shone's syndrome. The study group contained fourteen fetuses referred to our center during the study period. In the final study, four of fourteen were excluded, including three confirmed other diagnosis after birth and one lost follow-up.