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
(25th centile), and head circumference of 32 cm (below
5th 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.
3 Discussion .
HLHS is a congenital heart defect constituting 2% to 9% of all
congenital heart diseases1.
This cardiac malformation includes varying degrees of the left
ventricle’s underdevelopment, hypoplasia of the aorta, aortic valve, and
mitral valve stenosis or atresia2. It is more common
in males than in females3. The mortality rate is high,
and accounts for 23% of neonatal deaths from congenital heart
malformations2,4.
The etiology of HLHS is multifactorial and includes maternal,
infectious, immunosuppressive, and genetic factors5.
Most of the cases with HLHS occur sporadically with no family history;
however, some occur with autosomal recessive or autosomal dominant
inheritance6,7.
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 affected8.
It is generally known that HLHS may have a genetic predisposition, but
no specific gene has been identified until now9.
Some reports have concluded that HLHS is genetically multigenic and
heterogeneous in etiology10.
Also, several genetic disorders like Holt-Oram, Noonan syndrome, trisomy
21, trisomy 13, trisomy 18, and Turner syndrome may coexist with HLHS3,11.
The association of the hypoplastic left heart syndrome with Turner
syndrome reported being 13.2 %12, however, only 2.5%
of HLHS cases presented with Turner syndrome13.
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
neonates13,14.
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
lip15.
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.
Ertürk et al. described the case of 14q11.2 microduplication with West
syndrome (infantile spasms, hypsarrhythmia, and intellectual
disability)16. Other manifestations of 14q11.2
microduplication including microcephaly, behavior disturbance, obesity,
and speech delay17.
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.