Prenatal diagnosis of Shone’s syndrome: ultrasonographic features and differential diagnosis with coarctation of the aorta

Objective(cid:0)To improve the prenatal diagnosis of Shone’s syndrome and identify the mitral valve obstruction associated with the anomaly by comparing the fetal echocardiographic features between Shone’s syndrome and coarctation of the aorta (CoA). Method: Between January 2015 to December 2019, 17 fetuses were diagnosed with Shone’s syndrome prenatally and 8 were analyzed in our �nal study, their data were compared to normal controls and CoA cases. The main points of identi�cation were summarized. Results: By comparing data between three groups, elevated PA/AO ratio and RV/LV ratio were detected in both Shone’s syndrome and CoA cases. However, TVC/MVC ratios was only increased in Shone’s syndrome. Analysis revealed that the TVC/MVC ratio had the best capability in predicting Shone’s syndrome. Ultrasonographic features of mitral valve obstruction in Shone’s syndrome were unique which help clinicians to distinguish the anomaly from CoA, including (1) morphologic changes in short-axis view: restrictive opening of the mitral valve with diastolic deformity, thickened lea�ets, echo-enhancement of chordae tendineae and mitral valve, single papillary muscle or dominant papillary muscle; (5) in color Doppler image: decreased antegrade �ow and abnormal �ow pattern of mitral valve. Conclusion: There are two key points of prenatal diagnosis of Shone’s syndrome which could help fetal cardiologist to distinguish Shone’s syndrome from CoA in clinical practice, including (1) echocardiographic measurements: the elevated TVC/MVC ratio; (2) morphologic changes of mitral valve indicating left ventricle in�ow obstruction in two-dimension short-axis section view.


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 rst described in 1963 by Dr JD Shone 1 .Incomplete Shone's syndrome, which consists of at least 1 left ventricular in ow tract lesion and at least 1 left ventricular out ow 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 out ow 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 di cult 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 the main points of identi cation in mitral valve obstruction associated with the anomaly were summarized by comparing the fetal echocardiographic features between Shone's syndrome and CoA.

Methods
This was a single-center retrospective study conducted by Pediatric Cardiology Department of Xinhua Hospital A liated to Shanghai Jiaotong University School of Medicine between January 2015 to December 2019.Ethical approval was obtained from the Institutional Review Board of the Xinhua Hospital a liated to the Shanghai Jiao Tong University School of Medicine (No. XHEC-C-2016-105).Informed consent was obtained from each patient.
Between January 2015 and December 2019, a total of 1500 fetuses were examined in our center and 17 fetuses were diagnosed with Shone's syndrome prenatally.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 with a 4 to 8-MHz transabdominal probe.The following cardiac views were examined in each fetus: the abdominal view, the four chamber view, the left and right ventricular out ow tract view, the three vessel trachea view, the short-axis view of the great vessels, the short-axis view of the mitral valve, the vena cava view, and the long axis view of the aortic arch and the ductal arch.The following measurements were assessed: In ow tracts: tricuspid valve circle (TVC) dimension, mitral valve circle (MVC) dimension and Z score Out ow tracts: aortic valve dimension and z score, ascending aorta diameter and z score, aortic isthmus (in sagittal) diameter and Z score, transverse aortic arch diameter, pulmonary valve dimension, main pulmonary artery diameter, arterial duct diameter Ratios: Right ventricular diameter/left ventricular diameter (RV/LV), TVC/MVC, pulmonary valve dimension/aortic valve dimension (PA/AO) Doppler signs: mitral velocity (MV), aortic velocity (AoV), aortic isthmus peak systolic velocity, reversed or mixed ow at the aortic arch 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 twotailed t test, and one-way ANOVA were considered as statistically signi cant.Receiver-operating characteristic (ROC) curve were used to detect the predictors of Shone's syndrome.

General information
Among seventeen cases who were diagnosed with Shone's syndrome prenatally in our center, eight were contained in our nal study including three con rmed with the anomaly by postmortem autopsy, ve con rmed with the anomaly by postnatal echocardiography Fig. 1.Clinical information and echocardiographic data of these Shone's syndrome cases were summarized at Table 1.Of these eight fetuses, ve were diagnosed with mitral stenosis and CoA, two with mitral stenosis, CoA and aortic valve stenosis, one with mitral stenosis, CoA and bicuspid aortic valve (BAV).In ve cases genetic tests were performed, one had KMT2D mutation, one had 12q14.1deland three were with normal results.Results of postmortem autopsy showed smaller mitral annulus and parachute mitral valve in case B and D Fig. 2a,   b.
In ve cases who were delivered at term, four underwent operations within few months and one died shortly after birth.The median age at operation was 2 months (1 month to 3 month).The median postnatal follow-up time was 2 years (1year to 4 years).Except for one patient, who declared growth retardation after surgery, all patients remained asymptomatic following their operation.

Comparing and analyzing of echocardiographic measurements
The data were compared between normal controls (N=30), Shone's syndrome (N=8) and CoA (N=10) and several shared features between Shone's syndrome and CoA were detected, including (1) LVOT obstructions, with no signi cance in Z scores of ascending aorta (P=0.7333) or aortic isthmus (P=0.8894) between two groups Fig. 3a; (2) great vessel disproportion and ventricular disproportion, with elevated PA/AO ratio and RV/LV 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 and ventricular disproportion than CoA cases.The fetuses with Shone's syndrome had higher PA/AO ratio and RV/LV ratio than those with CoA Fig. 3b.The TVC/MVC ratio was increased in Shone's syndrome cases (P< 0.0001) but not CoA cases.The Shone's syndrome cases also seemed to get higher MV than control groups, although no statistical signi cance was detected (P= 0.250).ROC curve indicated that the fetuses with TVC/MVC ratio over 1.260 were more likely to have Shone's syndrome rather than CoA with a sensitivity of 100% and a speci city of 87.5%.Analysis of ROC curve for the TVC/MVC ratio revealed an area under the curve of 0.953 Fig. 3c.

Unique echocardiographic features of mitral valve obstruction in Shone's syndrome
Shone's syndrome fetuses had unique sonographic features indicating mitral valve obstruction in twodimension short-axis section view which hadn't been detected in normal controls or CoA cases, including (1) restrictive opening of the mitral valve with diastolic deformity were detected in three cases Video 1; (2) thickened lea ets were detected in two cases Video 1; (3) echo-enhancement of chordae tendineae and mitral valve were detected in two cases Video 2; (4) single papillary muscle or dominant papillary muscle were detected in two cases Video 3 and (5) decreased antegrade ow and abnormal ow pattern of mitral valve in color Doppler image were detected in one case Fig 4 .In CoA cases, on the contrast, developments of mitral valve and papillary muscle were normal Video 4.

Discussion
Shone's syndrome is a rare and under-recognized diagnostic entity 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, which remains infrequent in the literature 15 , is still challenging, the complex hemodynamic interactions between multiple levels of left-side obstructions challenge the clinical determination of prognoses 16 and sometimes the diagnosis at mid-gestation is misleading, as both steady state and worsening by the end point are possible 5 .
A key point in diagnosis of Shone's syndrome is a comprehensive evaluation of the number, position, morphology, and severity of left-sided obstructions.The LVOT is not di cult to be detected during clinical practice while mitral stenosis is hard to be accurately diagnosed.In our study, we found out that the TVC/MVC ratio seemed to have the best capability in predicting Shone's syndrome which provide a clue of mitral stenosis.Besides, morphologic changes of mitral valve are unique and can be used to distinguish the anomaly from CoA.These ndings 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 and missed diagnosis are inevitable in prenatal diagnosis 17 .The incidence of Shone's syndrome in our center is about 0.53%, which is lower than the reported 0.67%.A lower incidence means missed diagnosis during our clinical practice.In this study, there were 5 patients diagnosed with Shone's syndrome prenatally and opted termination of pregnancy but refused to have autopsy thus remained it unclear the exact diagnosis of fetuses.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 speci city 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 the obstructions.The lea et morphology, papillary muscle morphology and chordal length of left heart should be observed.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 18 .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 rst days of life.The patient outcome of Shone's syndrome is widely variable because of the diversity and complex nature of cardiac anomalies itself 4 .It is reported that operative outcome is excellent in Shone's syndrome patients 19 and surgical intervention is recommended to be undertaken early before the onset of pulmonary hypertension 20 .

Limitations
This is 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 treatment.Our results re ected a single center's experience.Larger sample sizes are needed to validate the result we got from this study.

Conclusion
There are two key points of prenatal diagnosis of Shone's syndrome by fetal echocardiography which could provide important clues for fetal cardiologist to distinguish the anomaly from CoA, including (1) echocardiographic measurements: the elevated TVC/MVC ratio has the best capability in predicting Shone's syndrome; (2) morphologic changes of mitral valve in two-dimension short-axis section view: restrictive opening of the mitral valve with diastolic deformity, thickened lea ets, echo-enhancement of chordae tendineae and mitral valve, single papillary muscle or dominant papillary muscle, decreased antegrade ow and abnormal ow pattern of mitral valve.

Declarations
Competing interests: The authors declare that they have no competing interests.Ethical approval Informed consents: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of the Xinhua Hospital a liated to the Shanghai Jiao Tong University School of Medicine and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Informed consents were obtained from all individual participants included in the study.
Availability of data and materials: All data generated analyzed during this study were included in this published article and its supplementary information les.
Funding: This was supported by the National Key R&D Program of China (No. 2018YFC1002400).
Authors' contributions: Zhuoyan Li drafted the manuscript and was responsible for collecting and analyzing patient data.Yurong Wu was in charge of informed consents of patients.Sun Chen designed this study.All authors read and approved the nal manuscript.

Supplementary Files
This is a list of supplementary les associated with this preprint.Click to download.

Figure
Figure 1.Flow chart of 17 patients diagnosed with Shone's syndrome prenatally.Among all the seventeen patients, eight patients were con rmed with Shone's syndrome by postnatal echocardiography or Figure 1.Flow chart of 17 patients diagnosed with Shone's syndrome prenatally.Among all the seventeen patients, eight patients were con rmed with Shone's syndrome by postnatal echocardiography or postmortem autopsy.Five patients opted termination of pregnancy without autopsy and three were con rmed other diagnosis by postnatal echocardiography.

Table 1
Clinical information of ten prenatally diagnosed Shone's syndrome cases.

Table 3
Measurements were compared between three groups.

Table 5
Main points of identifying mitral valve obstruction in Shone's syndrome.