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\begin{document}

\title{Absent Pulmonary Valve Syndrome with Tetralogy of Fallot and Patent
Ductus Arteriosus at 14 Weeks of Gestation and Follow-up 2 weeks later:
Case Report and Review of Literature}



\author[1]{Yan Song}%
\author[1]{Yu-fen Zou}%
\author[1]{Yan-hui  Ru}%
\author[1]{Jing Qiu}%
\author[1]{Hong Yin}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Classical absent pulmonary valve syndrome (APVS) with tetralogy of
Fallot (TOF) is a rare congenital cardiac anomaly commonly associated
with absent of patent ductus arteriosus (PDA), which is mostly diagnosed
after 20 weeks of gestation by fetal echocardiography. This case of APVS
with TOF was suspected at 13 weeks of gestation and diagnosed at 14
weeks of gestation with an obvious PDA. The pulmonary arterial trunk and
the branches did not dilated obviously. 15 days later, the PDA narrowed
down with the discovery of pulmonary artery ectasia at the same time.
This progress indicated that the absent of PDA is not necessary for the
survival of APVS with TOF in utero, in contrast, the absent or
restriction of PDA may be nothing less than adaptation to the disease.
Fetal autopsy confirmed the accuracy of fetal echocardiography.
Chromosome microarray analysis (CMA) showed 20p12 deletion in this
fetus, which is rare among TOF cases.%
\end{abstract}%



\sloppy


\textbf{Absent Pulmonary Valve Syndrome with Tetralogy of Fallot and
Patent Ductus Arteriosus at 14 Weeks of Gestation and Follow-up 2 weeks
later: Case Report and Review of Literature}

Yan Song, Yu-fen Zou, Yan-hui Ru, Jing Qiu, Hong Yin\textsuperscript{1}.

Department of Ultrasound, Shandong Provincial Maternal and Child Health
Hospital, Jinan, China

1, Corresponding Author

Classical absent pulmonary valve syndrome (APVS) with tetralogy of
Fallot (TOF) is a rare congenital cardiac anomaly commonly associated
with absent of patent ductus arteriosus (PDA), which is mostly diagnosed
after 20 weeks of gestation by fetal echocardiography. This case of APVS
with TOF was suspected at 13 weeks of gestation and diagnosed at 14
weeks of gestation with an obvious PDA. The pulmonary arterial trunk and
the branches did not dilated obviously. 15 days later, the PDA narrowed
down with the discovery of pulmonary artery ectasia at the same time.
This progress indicated that the absent of PDA is not necessary for the
survival of APVS with TOF in utero, in contrast, the absent or
restriction of PDA may be nothing less than adaptation to the disease.
Fetal autopsy confirmed the accuracy of fetal echocardiography.
Chromosome microarray analysis (CMA) showed 20p12 deletion in this
fetus, which is rare among TOF cases.

\textbf{KEYWORDS} congenital heart disease, fetal echocardiography,
pulmonary valve, Tetralogy of Fallot

\textbf{1. case report}

At the outset, a 36-year-old pregnant woman without consanguineous
history was suspected absent pulmonary valve syndrome (APVS) in fetus in
the first trimester screening in our Hospital. The pregnancy is natural
with no history of fever, discomfort, allergies and medication in early
period. The biological parameters were in accordance with those of 13th
gestational weeks. Fetal nuchal translucency (NT) was in normal
range(0.19cm), the pulsed doppler spectrum of ductus venosus (DV) was
normal in shape. The blood flow through mitral valve and tricuspid valve
in the 4-chamber view was symmetrical. However, in the 3-vessel tracheal
view, there were anterograde blood flows in systole and retrograde blood
flow in diastole in pulmonary artery (PA) and patent ductus arteriosus
(PDA), which suggested absent of pulmonary valve. Due to the obesity and
rejection of transvaginal examination of the patient, a meticulous fetal
heart examination was arranged 7 days later and more positive results
were found: bidirectional blood flow in the upper segment of
interventricular septum (beam width 0.14 cm); overriding aorta; narrowed
pulmonary valve annulus with pulmonary valve unexplored; moderate reflux
flow of tricuspid valve. To-and-from blood flow was detected clearly
through pulmonary annulus, PA trunk, left pulmonary artery (LPA), right
pulmonary artery (RPA) and PDA. By these features, APVS with tetralogy
of Fallot (TOF) was diagnosed (Figure 1). The shape and size of PA
trunk, PA branches and PDA still seemed normal.

The fetus was reexamined 15 days later. The biparietal diameter (BPD)
was 3.2cm and femoral diameter (FL) was 1.9cm, which were consistent
with 16 weeks of pregnancy. The right heart was slightly larger than
left heart in 4-chamber view, the width of ventricular septal defect
(VSD) was 0.17cm. The diameter of aortic annulus riding over the VSD was
0.24 cm. Pulmonary valve leaflets were undetectable during dynamic
observation. The diameters of pulmonary valve annulus, pulmonary trunk,
LPA, RPA, DA were clearly measured as 0.16cm, 0.23cm, 0.19cm, 0.20cm,
0.13cm respectively. The ectasia of pulmonary trunk and branches
combined with the stenosis of annulus constituted a distinct ''goldfish
tail sign''. Despite of the to-and-fro flow, the blood flow mosaic was
detected in pulmonary trunk which proved the acceleration of flow
through pulmonary valve annulus. DA was much narrower than pulmonary
trunk and branches with comparatively dim blood flow through, suggesting
the restriction of DA with decreased blood flow (Figure 2). Except for
fetal cardiac anomalies, left renal cyst (0.4 \selectlanguage{ngerman}× 0.4cm) was found in
fetus with normal amniotic fluid.

Approved by the ethics committee of our hospital, fetal induction was
performed. Fetal autopsy approved by the pregnant mother confirmed the
diagnosis of APVS with TOF by fetal echocardiography (Figure 3).
Chromosome microarray chip analysis (CMA) showed that the 984.766kb
fragment at 20p12.2 deleted.

\textbf{2. DISCUSSION}

APVS is a rare congenital heart disease (CHD) with an incidence of
0.2\%--0.4\% in all live birth with CHD\selectlanguage{english},characterized by absent or
severe dysplasia of pulmonary valve leaflets\textsuperscript{{[}1-3{]}}.
APVS is commonly classified into two types: The majority of APVS fetuses
is accompanied with TOF, so defined as TOF-type APVS; the minority is
absent from VSD, defined as non-TOF-type
APVS\textsuperscript{{[}3,4{]}}. TOF-type APVS usually got stenosis of
pulmonary valve annulus, post-narrow expansion of PA and absent PDA in
the previous studies. The inflation of PA trunk and RPA may compress the
airway to collapse and softening, which leads to respiratory distress
and heart failure in neonatal period. The clinical manifestations are
critical, coupled with extracardiac malformations and / or chromosomal
abnormalities, the overall prognosis is poor. Non-TOF-type APVS is
commonly associated with intact ventricular septum, tricuspid valve
atresia or hypoplasia and PDA. The PA trunk usually does not expand, but
shows hypoplasia, which proceeds to the immaturity of vessel and tissues
in lung. The total mortality of APVS was 75\%, including intrauterine
death and postnatal death, only 25\% were alive after postnatal surgery;
therefore, prenatal diagnosis of APVS is
significant\textsuperscript{{[}3{]}}. Although the postoperative
survival rate has improved in recent years, the heart surgery is still
complicated. Sometimes heart transplantation is required in
emergency\textsuperscript{{[}5{]}}. So early diagnosis of APVS in utero
is meaningful.

Most TOF-type APVS fetuses are diagnosed after 20 weeks of gestation by
echocardiography. Except for positive grayscale images, Color doppler
flow imaging (CDFI) shows color mosaic to-and-from blood flow in PA.
Spectrum Doppler shows high-speed blood flow antegrade and retrograde in
PA. In this study, based on the high resolution of ultrasound, APVS was
suspected at 13 weeks of gestation by a skilled sonographer in the first
trimester screening, and was confirmed 7 days later. Two weeks later,
fetal echocardiography was performed again. In the last two checks, PA
and PDA were found with obvious morphological change\selectlanguage{english},which might be
helpful in the study of mechanism and development of TOF-type APVS in
early middle pregnancy.

In the past, absence of PDA has always been considered in company with
dilation of PA in fetus with TOF-type APVS, because the insufficient
pulmonary systemic shunt aggravated volume load of RV caused by
to-and-from blood flow in PA \textsuperscript{{[}6,7{]}}. However, such
claims are practically based on the discoveries of TOF-type APVS after
20 weeks of gestation. The process and pathogenesis before 20 weeks were
unclear with controversies in correlation between PA dilatation and PDA
absence. In the present case at 14 weeks of gestation, the diameter of
PDA was wide with unobstructed bidirectional shunt. PA expansion was not
distinct. At 16 weeks of gestation, there was PA expansion without PDA
absence, which was obviously inconsistent with previous study. The
restriction of PDA might be associated with the dilation of PA trunk and
PA branches, which leaded to the decrease of blood flow volume through
PDA. It advocated the controversial hypothesis that APVS with TOF leads
to depressed diastolic pressure of immature PDA and ultimately result in
the restriction or closure at an early gestational age
\textsuperscript{{[}8{]}}. It suggested the dynamic pathological change
of PDA in TOF-type APVS fetus in early middle pregnancy. If the fetus
developed further in utero, disuse atrophy or atresia of PDA might occur
in the future. In addition, it has been reported that several fetuses
with TOF-type APVS had constricted PDA after 20 weeks of gestation. It
also confirmed that the absence of PDA is not inevitable for the
existence of TOF-type APVS. It further proves the rationality of the
inference in this study.

APVS may be associated with fetal chromosomal abnormalities, among which
22q11 microdeletions, 13 trisomy and 18 trisomy are most
common\textsuperscript{{[}9{]}}. It is suggested that 70\% of TOF-type
APVS were associated with karyotype abnormality. In this case, 984.766kb
deletion was detected at 20p12.2 by chromosome microarray analysis
(CMA). JAG1 gene in this fragment is in autosomal dominant inheritance,
and the deletion is related to TOF and Alagille syndrome. The parents of
the fetus were in good health without genetic defects and the deletion
of JAG1 gene in fetus was thought to be caused by gene mutation and lead
to poor prognosis.

TOF-type APVS is combined with cardiac extracardiac malformations
sometimes which is independent influencing factor of prognosis. In this
case, a left renal cyst was found which might be sign of cystic
dysplasia of kidney.

In this case, the pregnancy was terminated. Fetal autopsy confirmed the
ultrasound diagnosis.

\textbf{3. CONCLUSION}

This case of TOF-type APVS with was diagnosed at 14 weeks of gestation
with an obvious PDA. 15 days later, the PDA narrowed down together with
ectasia of PA. This progress indicated that the absent of PDA is not
necessary for the survival of TOF-type APVS in utero, in contrast, the
absent or restriction of PDA may be nothing less than adaptation to the
disease. 20p12 deletion was found in this fetus. Prenatal diagnosis in
early stage is conducive to reasonable clinical decision-making.

\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
  Allan LD, Sharland GK, Milburn A, et al. Prospective diagnosis of
  1,006 consecutive cases of congenital heart disease in the fetus. J Am
  Coll Cardiol. 1994;23(6):1452--58
\item
  Szwast A, Tian Z, McCann M, et al. Anatomic variability and outcome in
  prenatally diagnosed absent pulmonary valve syndrome. Ann Thorac Surg.
  2014;98(1):152--158.
\item
  Volpe P, Paladini D, Marasini M, et al. Characteristics, associations
  and outcome of absent pulmonary valve syndrome in the fetus.
  Ultrasound Obstet Gynecol 2004;24:623--8
\item
  Zucker N, Rozin I, Levitas A, et al. Clinical presentation, natural
  history, and outcome of patients with the absent pulmonary valve
  syndrome. Cardiol Young. 2004;14(4):402--8.
\item
  Razavi RS\selectlanguage{english}, Sharland GK\selectlanguage{english}, Simpson JM. Prenatal diagnosis by
  echocardiogram and outcome of absent pulmonary valve syndrome. {[}J{]}
  Am J Cardiol 2003,91( 4): 429-432
\item
  Wertaschnigg D, Jaeggi M, Chitayat D, et al Prenatal diagnosis and
  outcome of absent pulmonary valve syndrome: contemporary single-center
  experience and review of the literature J Ultrasound Obstet Gynecol
  2013, 41( 2): 162-167
\item
  Joshi AN, Rane HS, Kamble RC, et al. Prenatal diagnosis of absent
  pulmonary valve syndrome: report of 2 cases, most common and most rare
  presentations {[} J{]}. J Ultrasound Med 2010,29(5): 823-829
\item
  Becker R, Schmitz L, Guschmann M, et al. Prenatal diagnosis of
  familial absent pulmonary valve syndrome: case report and review of
  the literature. Ultrasound Obstet Gynecol. 2001; 17(3):263--7
\item
  Sleurs E\selectlanguage{english}, De Catte L\selectlanguage{english},Benatar A. Prenatal diagnosis of absent
  pulmonary valve syndrome in association with 22q11 deletion {[}J{]}. J
  Ultrasound Med 2004 23 3 417-422
\end{enumerate}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1 Echocardiography of APVS at 14 weeks of gestation

A. Longitudinal view of DA showed the retrograde blood flow from DA to
PA; B. 3VT view showed the retrograde blood flow in PA; C. Oblique PA
branches view showed that RPA and LPA were not dilated and the blood
flow was unobstructed; D. 4 chamber view showed poorly aligned VSD

VSD: ventricular septal defect; AAO: aortic arch; DAO: descending aorta;
PA: pulmonary artery; LPA: left pulmonary artery; RPA: right pulmonary
artery; RV: right ventricle; LV: left ventricle; RA: right atrium; LA:
left atrium; IVC: inferior vena cava; VSD: ventricular septal defect

White arrow indicates right to left shunt through VSD\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2 Echocardiography of APVS at 16 weeks of gestation

A. 2D nonstandard axis view of DA showed the narrowed pulmonary annulus,
expansive pulmonary trunk and branches and narrowed DA ; B. CDFI showed
the wide and bright antegrade blood flow in PA trunk and branches, and
the dark blood flow in DA from PA to DAO; C. 5 chamber view showed the
blood flow from RV and LV to the overriding AO; D. PA longitudinal view
showed the retrograde blood flow from LPA and RPA to PA trunk and RV.

AAO: aortic arch; DAO: descending aorta; PA: pulmonary artery; LPA: left
pulmonary artery; RPA: right pulmonary artery; RV: right ventricle; LV:
left ventricle; AO: aortic artery.

White arrow showed DA\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 3 Anatomical images of APVS heart at 16 weeks of gestation

A. The front view of fetal heart removing the right ventricular wall
showed the upper VSD and ARSA ; B. PA view showed the expanded PA trunk
and branches; C. The upper view of TV, MV and AV, all the three valves
were clearly visible; D. The upper view of pulmonary annulus, there was
no relic of PV in the pulmonary annulus.

VSD: ventricular septal defect; AAO: aortic arch; PA: pulmonary artery;
VSD: ventricular septal defect; ARSA: the aberrant right subclavian
artery; R-LU: right lung; L-LU: left lung; T: trachea; TV: tricuspid
valve; MV: mitral valve.

White arrow showed the aortic valve leaflets. Black arrow showed the
pulmonary annulus without pulmonary valve leaflet.

\selectlanguage{english}
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\end{document}

