\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Rare association of hypoplastic left heart syndrome(HLHS) with partial
monosomy X (Turner syndrome) and partial trisomy 14 (14q11.2
microduplication syndrome) in the neonate.}



\author[1]{Roya Huseynova}%
\author[2]{Oqtay Huseynov}%
\author[1]{Latifa A.Bin Mahmoud}%
\author[1]{Abduljabbar Alshenqiti}%
\author[1]{Khalid Alomran}%
\author[1]{Nabeel Abduallah Alodaidan}%
\affil[1]{King Saud Medical City}%
\affil[2]{Azerbaijan Medical University Nariman Narimanov}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Hypoplastic left heart syndrome is a fatal congenital complex heart
defect where the left side of the heart is critically undeveloped. HLHS
with complex partial monosomy and partial trisomy are rare conditions
that have not reported to occur together.%
\end{abstract}%



\sloppy


\textbf{Rare association of hypoplastic left heart syndrome(HLHS) with
partial monosomy X (Turner syndrome) and partial trisomy 14 (14q11.2
microduplication syndrome) in the neonate.}

Roya~Arif~Huseynova\textsuperscript{1}, Oqtay~Ilham
Huseynov\textsuperscript{2},~Latifa~A.Bin~Mahmoud\textsuperscript{1},~Abduljabbar
Alshenqiti\textsuperscript{3}, Khalid
A.AlOmran\textsuperscript{4},Nabeel Abduallah
Alodaidan\textsuperscript{1}.

\textsuperscript{~}

\textsuperscript{~}

\textsuperscript{1} Neonatal Intensive Care Unit, King Saud Medical
City, Riyadh, Kingdom of Saudi Arabia.

\textsuperscript{2}Azerbaijan Medical University, Baku, Azerbaijan.

\textsuperscript{3}Genetic and metabolic department, King Saud Medical
City, Riyadh, Kingdom of Saudi Arabia.

\textsuperscript{4} Cardiology department, King Saud Medical City,
Riyadh, Kingdom of Saudi Arabia.

\textbf{Corresponding author:} ~Roya~Arif~Huseynova,

Neonatal Intensive Care Unit,~King Saud Medical City, Al Imam Abdul
Aziz~Ibn~Muhammad Ibn Saud 12746, Riyadh, Kingdom of Saudi Arabia.

E-mail:~huseynova\_roya@yahoo.com,~~r.huseynova@ksmc.med.sa

Telefon:~00966508463068

ORCiD~id~0000-0002-8914-5892

\textbf{1 Key message}

Hypoplastic left heart syndrome (HLHS) is a fatal congenital complex
heart defect where the left side of the heart is critically undeveloped.

HLHS with complex partial monosomy and partial trisomy are rare
conditions that have not reported to occur together.

\textbf{Keywords}

Hypoplastic left heart syndrome, congenital heart disease,
translocation, chromosome, Turner syndrome, 14q11.2 microduplication
syndrome.

\textbf{2.Case presentation}

A term, no dysmorphic baby girl, was a product of consanguineous
marriage born to a 29-year-old primigravida mother by spontaneous
vaginal delivery. At 30 weeks of gestational age, fetal echocardiography
revealed the presence of hypoplastic left heart, atrial septal defect,
and patent ductus arteriosus. Amniocentesis requested at 32 weeks of
gestational age, and chromosomal microarray analysis (CMA) sent and
revealed partial monosomy and partial trisomy. An approximately 63 Mb
large pathogenic one copy loss (heterozygous deletion) encompassing the
entire small arm of the chromosome X (Xp) and extending to the long arm
of chromosome X (Xq), X p22.33q11.2 as well as an approximately 50 Mb
large pathogenic one copy gain (duplication) of the chromosomal region
14q11.2q 24.2 were detected.

These findings are suggestive of a chromosome translocation involving
the chromosomes X and 14.

There was no family history of similar conditions and no history of
radiation exposure or drug intake in any trimester.

The baby cried immediately after birth and required only the initial
steps of resuscitation.

Apgar scores were 8, 8, and 9 on the 1st, 5th, and 10 minutes. Birth
weight was 2270 gram (below 5th percentile), length of 48cm
(25\textsuperscript{th} centile), and head circumference of 32 cm (below
5\textsuperscript{th} percentile). No apparent dysmorphic features.

Clinical examination revealed mild tachypnea (respiratory rate 65 per
minute), tachycardia (heart rate 170 per minute), blood pressure (62/40
mmHg), and oxygen saturation of 90\% on room air.

Arterial umbilical blood gases showed pH-7.3, PaCO2 47 mmHg, and BE-2.

She had vesicular breath sounds with fine basal crepitations and equal
chest expansion. The first and second heart sounds auscultated with
normal intensity. Systolic murmur grade 3/6 maximal intensity at the
lower sternal edge heard.

An echocardiogram 2 hours after the birth confirmed HLHS with the
hypoplastic left ventricle, mitral atresia, aortic atresia, and moderate
tricuspid regurgitation (Figures 1, 2 and 3).

Continuous intravenous infusions of prostaglandin E1 started. Physical
examination of other systems on admission was normal with stable
hemodynamic values.

Laboratory blood tests showed normal ranges of white blood cells,
hemoglobin, and platelets counts.

The patient further investigated with an abdomen ultrasound and magnetic
resonance imaging of the brain, which were unremarkable.

A diagnosis of hypoplastic left heart syndrome and complex partial
monosomy and partial trisomy made.

The infant's poor prognosis explained to the family who refused further
intervention, and comfort care management was applied.

The patient died on day 7 of life.

\textbf{3 Discussion} .

HLHS is a congenital heart defect constituting 2\% to 9\% of all
congenital heart diseases\textsuperscript{1}.

This cardiac malformation includes varying degrees of the left
ventricle's underdevelopment, hypoplasia of the aorta, aortic valve, and
mitral valve stenosis or atresia\textsuperscript{2}. It is more common
in males than in females\textsuperscript{3}. The mortality rate is high,
and accounts for 23\% of neonatal deaths from congenital heart
malformations\textsuperscript{2,4}.

The etiology of HLHS is multifactorial and includes maternal,
infectious, immunosuppressive, and genetic factors\textsuperscript{5}.
Most of the cases with HLHS occur sporadically with no family history;
however, some occur with autosomal recessive or autosomal dominant
inheritance\textsuperscript{6,7}.

HLHS can be detected by prenatal ultrasonography between 18 and 22 weeks
of gestation.

The management options of HLHS include comfort care, palliative surgery,
and cardiac transplantation. Even with surgical intervention, life
expectancy may be affected\textsuperscript{8}.

It is generally known that HLHS may have a genetic predisposition, but
no specific gene has been identified until now\textsuperscript{9}.

Some reports have concluded that HLHS is genetically multigenic and
heterogeneous in etiology\textsuperscript{10}.

Also, several genetic disorders like Holt-Oram, Noonan syndrome, trisomy
21, trisomy 13, trisomy 18, and Turner syndrome may coexist with
HLHS\textsuperscript{3,11}.

The association of the hypoplastic left heart syndrome with Turner
syndrome reported being 13.2 \%\textsuperscript{12}, however, only 2.5\%
of HLHS cases presented with Turner syndrome\textsuperscript{13}.

The presence of chromosomal and other noncardiac abnormalities influence
the mortality rate in neonates with HLHS.

Interestingly, it was observed both a strong association of the HLHS
with Turner syndrome and a significant mortality rate in this group of
neonates\textsuperscript{13,14}.

The association of Turner syndrome with HLHS is well known; however,
isolated 14q11.2 microduplication syndrome was not described with HLHS.

14q11.2 microduplication syndrome is a rare chromosomal condition
characterized by hypotonia, mental retardation, developmental delay,
epilepsy, and dysmorphic craniofacial features like micrognathia, short
nose, abnormally rotated ears, broad nasal bridge, and narrow upper
lip\textsuperscript{15}.

Cranio-facial dysmorphic features were not so distinctive in the
presented case that underscores the need for a genetic investigation in
all cases with HLHS, even in non-dysmorphic neonates.

Ert\selectlanguage{ngerman}ürk et al. described the case of 14q11.2 microduplication with West
syndrome (infantile spasms, hypsarrhythmia, and intellectual
disability)\textsuperscript{16}. Other manifestations of 14q11.2
microduplication including microcephaly, behavior disturbance, obesity,
and speech delay\textsuperscript{17}.

Depending on the size of the duplication, clinical manifestations and
degree of mental retardation may vary from case to case. The size of
duplication varies from small size (e.g., 35KB) to large size (e.g.,
50MB).

The presence of deletion and duplication in the reported case indicates
these abnormalities may result from a balanced translocation in one of
the parents, and we sent chromosomal analysis for parents to prove it.

Remarkably, a combination of Turner syndrome (partial monosomy X),
14q11.2 microduplication syndrome (partial trisomy 14), and HLHS to date
unreported to the best of our knowledge.

\textbf{4 Conclusion}

We described the first case of HLHS reported in the literature to date,
which carries a combination of microduplication of the chromosomal
region 14q11.2q 24.2 and chromosome translocation involving the
chromosomes X and 14.

Reported case suggested that HLHS may appear in a modular style, through
the multiple mutations.

Timely provided prenatal ultrasonography and prompt genetic
investigation for each case of HLHS may reveal the natural origin of
this complex congenital heart disease that is essential for determining
the optimal decision-interventions options for physicians and parents.

\textbf{Conflict of interest}

None declared

Informed consent was obtained from parents for reporting this case.

No financial support or grant provided by any institute

\textbf{Author Contribution}

Roya Arif Huseynova wrote the clinical report,~collected and~analyzed
the data.

Oqtay Ilham Huseynov participated in the drafting and critically
revising the manuscript.

Latifa A~Bin~Mahmoud\textsuperscript{~} participated~in the drafting and
critically revising the manuscript.

Abduljabbar Alshenqiti participated~in the critically revising the
manuscript.

Khalid A. AlOmran in the drafting the manuscript.

Nabeel Abduallah Alodaidan in the drafting the manuscript

All authors approved the manuscript as submitted.

\par\null

\textbf{References:}

1.Barber G. Hypoplastic left heart syndrome. In: Garson A, Bricker JT,
Fisher DJ, Neish SR, editors.~The Science and Practice of Pediatric
Cardiology.~2nd edn. II. Baltimore: Williams and Wilkins;
1998.~~{[}Google Scholar{]}

2. Caplan WD, Cooper TR, Garcia-Prats JA, Brody BA. Diffusion of
innovative approaches to managing hypoplastic left heart syndrome.~Arch
Pediatr Adolesc Med.~1996; 150:487--90.~{[}PubMed{]}~{[}Google
Scholar{]}

3.Perloff JK. The hypoplastic left heart. In: Perloff JK, editor.~The
Clinical Recognition of Congenital Heart Disease.~4th edn. Philadelphia:
WB Saunders Co; 1994. pp. 727--37.~{[}Google Scholar{]}

4.Gillum RF. Epidemiology of congenital heart disease in the United
States.~Progress Cardiol.~1994; 127: 919--27.~{[}PubMed{]}~{[}Google
Scholar{]}

5.Connor JA, Thiagarajan R: Hypoplastic left heart syndrome. Orphanet J
Rare Dis. 2007, 2: 23-10.1186/1750-1172-2-23.

6.Shokeir, M. H. K.Hypoplastic left heart syndrome: an autosomal
recessive disorder.~Clin. Genet. 2: 7-14, 1971.
{[}PubMed:~5111754,~related citations{]} {[}Full Text{]}

7.Wessels, M. W., Berger, R. M. F., Frohn-Mulder, I. M. E.,
Roos-Hesselink, J. W., Hoogeboom , J. J. M., Mancini, G. S., Bartelings,
M. M., de Krijger, R., Wladimiroff, J. W., Niermeijer , M. F., Grossfeld
, P., Willems, P. J.~Autosomal dominant inheritance of left~ventricular
outflow tract obstruction.~Am. J. Med. Genet. 134A: 171-179, 2005.
{[}PubMed:~15712195,~related citations{]} {[}Full Text{]}

8.Marshall A. Hypoplastic left heart syndrome.~\emph{UpToDate} .
Waltham, MA: UpToDate; August, 2017

9.Cohen DM, Allen HD. New developments in the treatment of hypoplastic
left heart syndrome.~Curr Opin Cardiol.~1997;
12:44--50.~{[}PubMed{]}~{[}Google Scholar{]}

10.Yagi H, Liu X, Cabriel GC, Wu Y, Peterson K, Murray SA, Aronow BJ,
Martin LJ, Benson DW and Lo CW.\textsuperscript{~} The Genetic Landscape
of Hypoplastic Left Heart Syndrome. Pediatr Cardiol.2018
Aug;39(6):1069-1081.

11.Glauser TA, Rorke LB, Weinberg PM, Clancy RR. Congenital brain
anomalies associated with the hypoplastic left heart
syndrome.~Pediatrics.~1990; 85:984--90.~{[}PubMed{]}~{[}Google
Scholar{]}

12. Surerus E,Huggon IC,Allan LD.Turner's syndrome in fetal life.
Ultrasound Obstet Gynecol 2003 Sep;22(3):264-7.

13.Reis PM, Punch MR, Bove EL, van de Ven CJ. Outcome of infants with
hypoplastic left heart and Turner syndromes. Obstet Gynecol 1999;
93:532--5.

14.van Egmond H, Orye E, Praet M, Coppens M, Devloolancquaert A.
Hypoplastic left heart syndrome and 45X karyotype. Br Heart J 1988;
60:69--71.

15.Smyk M, Poluha A, Jaszczuk I, Bartnik M, Bernaciak J and Nowakowska
B.Novel 14q11.2 Microduplication Including the CHD8 and SUPT16H Genes
Associated with Developmental Delay 2016 Am J Med Genet Part A
170A:1325--1329.

16. Ertu\selectlanguage{english}rk O, \selectlanguage{english}Yalc Inkaya C, Karaman B, Demirbilek V, Tu\selectlanguage{english}ysu\selectlanguage{english}z B.
Chromosome 14q11.2-q21.1 duplication: a rare cause of West syndrome.
Clinical commentary \emph{Epileptic Disord 2018; 20 (3): 219-24}

17.Pascolini G, Agolini E, Fleischer N, Pierantoni R, Loddo S, Novelli
A, Bernardini L, Majore S and Grammatico P. Further delineation of the
neurodevelopmental phenotypic spectrum associated to 14q11.2
microduplication. Neurological Sciences June 2020

\textbf{Figure Legends:}

(Figure 1) Long axis view shows severe hypoplastic left ventricle,
aortic arch, aortic atresia and mitral atresia.

(Figure 2) 4 chambers view shows severe hypoplastic left ventricle,
mitral atresia and dilated right ventricle.

(Figure 3) Short axis view shows dilated main pulmonary artery with
large patent ductus arteriosus.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/PHOTO-2020-07-09-21-33-41/PHOTO-2020-07-09-21-33-41}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/PHOTO-2020-07-09-21-32-57/PHOTO-2020-07-09-21-32-57}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/PHOTO-2020-07-09-21-34-25/PHOTO-2020-07-09-21-34-25}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

