Download A case report of Truncus Arteriosus Communis (TAC) and genetic

A case report of Truncus Arteriosus Communis (TAC) and genetic
consultation
Gh. Nourzad, PhD 1.M.Baghershiroodi, MSc2*
1Assistant Professor Department of Biology , Hormozgan University
2Center of molecular medicine research, Hormozgan University of Medical Sciences*
Tel : +987613354939
Fax: +987613354939
Email: [email protected]
1
Abstract
BACKGROUND: TAC is a rare heart disorder with the prevalence of approximately 1%,
mostly in male newborns. In this disease, aorta and aorta pulmonalis have not separated
during fetus development and both originate jointly from left ventricle. Besides, various
disorders are reported like ventricle septum defect (VSD), mitral and tricuspid valves
defects, aorta septum defect (ASD), reduction of lung and lung vessels' resistance,
pulmonia hypertony, increase in heart rate, high perspiration, bad digestion and
tetralogy of fallot.
CASE REPORT: parents of deceased patient referred for consultation after the death of
third girl due to severe cardiac disorder. Cardiologist declared the disease in deceased
girl as (TAC) based on findings along with VSD, VSDT, ASD and aortal arc hypoplasy
which has resulted to death in the first day of birth.
CONCLUSION: there was no chromosomal disorder in chromosome analysis of patient'
skin. Parents were interested to have another child, so they referred to university's
genetic consultation center to become aware of their next child's condition. This disorder
is genetically heterogeneous and multifactorial and because all external factors are not
recognized, the accurate estimation of risk is not possible and the probability of risk for
the next child is about 10 to 20 percent.
Keywords: heart disorder, truncus arteriosus communis, genetic consultation
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Introduction
Congenital cardiac disorders are one of the most common congenital disorders with the
prevalence of 5-1 percent in every 100 newborns (29). Among them, TAC is a rare cardiac
disorder (1,2,13), in which aorta and aorta pulmanalis were not separated completely during
fetus development and both originate jointly from left ventricle. In addition, various disorders
like VSD, mitral and tricuspid valves defect, aorta septum defect, reduction of lungs and
lungs' vessels resistance, pulmonia hypertony, increase in heart rate, high perspiration and
bad food digestion along with tetralogy of fallot are some of reported disorders (6,7,8,27).
Prevalence of this disease is low and in males is higher than females (26,27). During past 20
years, diagnostic and therapeutic methods along with immediate intervention for surgery in
infancy with complete reparation of VSD lead to evident improvement and less morbidity in
newborns. Along with genetic role including microdeletion of 22q11.2 in 30 percent of
isolated conotruncal disorders, the effect of external factors has been considered in these
disorders (1,2). Because of diversity in disease demonstration, its causes had been classified
by Collet and Edwards in 4 different types in 1949. Because of later reported deviances,
another classification was introduced by Van Praaghs in 1965 with modifications in 4 initial
types (4,9,33) but it seems that none of classifications are ideal because there are cases which
does not belong to any of classifications (5,10,11,13,32), defined as unpredictable differences
(16,17,18). In order to diagnose before birth, procedures like ultrasound, echocardiography
and levels' measurement of maternal serum Alpha-fetoprotein (Quadric test) were used and
methods like X-ray radiography Contrast Enhanced Magnetic Resonance (CEMR) and other
imaging techniques were used post-birth (25, 26, 19).
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REPORT
Parents were not relatives and have 34 years old at the birth of their first daughter. This
girl was 10 years old (IV/1) in the study time and she was healthy with natural growth.
The second pregnancy was a boy who was aborted before third month of pregnancy
(IV/3). Forth pregnancy has been resulted to early abortion without determining the
gender of fetus (IV/4). The study patient was fifth pregnancy which died in the evening
of the first birth day with TAC diagnosis (IV/5). Now parents were seeking consultation
for sixth pregnancy. Father had natural karyotype (III/1). Fathers' younger brother had
the same cardiac disorder (III/3), his disease was diagnosed by Munich university
cardiologists and was operated in US, now he has good physical health. A cousin of
patient (III/9) died after Hiatus hernia operation because of a sub-diaphragm abscess.
She suffered from tetralogy fallot (defect of ventricle septum, high discharge of right
ventricle, aorta pulmonalis constriction and Ductus Botalli). It was reported that 6
paternal brother and sister had died in childhood. One of the brothers had died because
of diphtheria (II/2). Death reasons of other brothers (II/5,7) were not clear. Among 10
sisters and brothers of mother two girls had died early, one in 5 months old because of
diarrhea (II/12) and the other because of septicemia (II/17).
I
1
8
7
II
6
3
III
1
2
3
4
5
IV
‫؟‬
4
17
Fig 1. Paternal pedigree
Even mother (III/8) has natural karyotype in chromosome analysis. One cousin of
mother had died in 3 months old due to convulsion caused by teeth fever. Other family
members were healthy. The dead patient is shown with an arrow.
I
II
1
8
III
IV
Fig 2. Maternal pedigree
Pregnancy, birth and newborn
In the 9th and 10th weeks of pregnancy, patient's mother has suffered from intestinal
infection and diarrhea without fever. She was weak with pain in her abdomen and back
like her second pregnancy but this time has not resulted in abortion. Monographic
examinations had not shown cardiac or ventricle disorder. Patient was in seated position
but then turned to head position. Delivery was in 40 th week of pregnancy without any
problem. Amniotic fluid was green. Length of body was 52cm at birth which was up
normal (<p90) for birth's week. Apcar values 10/10/90 and birth weight (3150g) and
head diameter (33.5cm) were normal. The patient had no apparent difference with her
sisters. According to her parents, she uttered a short cry after her birth. She smiled in
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first 15 minutes of her life, moved her eyes and month, even she was curious in physical
examinations. Cardiac sound was diagnosed in initial examinations. Infusion was
conducted because of cyanosis and reduction in saturated oxygen pressure. Then she
was transmitted to pediatric clinic and was not seen alive by her parents again.
Echocardiography results in pediatric ward showed that TAC with VSD, ASD and aortal
arc hypoplasy. Therefore, patient was transmitted to cardiac center by giving
Prostaglandin and artificial respiration to continue treatment. After establishing relatively
stable
condition
in
pediatric
clinic,
patient's
condition
was
serious
during
echocardiography. Deamination interventions were useless and patient died in the
evening of her first birth day. There was no chromosomal disorder or microdeletion of
22q11 in skin sampling. Despite interpretation of echocardiography, the reason of death
was not clear.
Genetic consultation
We talked about psychological aspects of this death in the first day of birth and
newborn's severe cardiac disorder which was known from paternal pedigree. We
reflected the mental condition of parents using a model image. They were in low mental
condition in consultation time (5 weeks after newborn's death) and asked themselves
why this disaster had happen for them. They remembered that they had lost 2 child and
must cope the fact that only two child were left for them from 5 pregnancies. Mother
was more eager for third child. We talked about this issue with the father that they must
end their mourning before a new pregnancy, because with remembering grief of lost
child, it is impossible to return their health. This is the first condition for health and
stability of family. After mourning, parents succeed in planning for new baby. This is the
first step to accept the destiny of next child.
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Probability of Recurrence risk
Paternal pedigree shows the risk of cardiac conotruncal defect in two generations and 3
family members (IV/5, III/6, III/3) which were relative via their healthy fathers (III/1,
II/4, II/1).
1
II
4
1
3
6
30
0
III
1
IV
5
‫؟‬
Fig 3. Pedigree of inheritance and disease in two generations.
Table 1. Patients Status
Patient (III/1)
Patient III/9
TAC with VSD
VSD
Patient III/5
Suspected to TAC with VSD
and ASD
Had surgery
Died after Hiatus hernia
surgery
Died
Inherited pattern is conforming with conotruncal cardiac defects reports which are not
related to a monogenic inheritance, but it is a multifactorial pathology. Accumulation and
various factors' effect are shown in the figure 4. This means that polygeny in father
family genome is responsible for conotruncal defect and their expression influenced by
external factors has not identified completely, as they are more than fetus tolerance
threshold.
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‫پدر‬
‫مادر‬
‫تاثیر فاکتورهای خارجی‬
‫آستانه تحمل‬
‫بیمار قلبی‬
Fig 4. An illustration of external and inherited factors accumulation
Epidemiologic studies about inheritance of conotruncal cardiac disorders in scientific
literature are limited. Because all factors has not identified, accurate statistical
calculations are not possible. Probability of risk is estimated 10-20% because the illness
of brother and sister was same.
Karyotype study and microdeletion of 22q11 which is reported in 30 percent of TAC was
rejected for deceased patient and her parents by Munich university genetic center and
there were no other genetic examinations.
Diagnosis before birth
regarding parents age, we can consider a chromosome analysis although it imposes
high costs in the absence of insurance. The probability of a new chromosome mutation
for parents between 35-40 years old in the first and second pregnancies is about 1-2%.
It is not possible to reject or prove conotruncal defects with these laboratory studies.
Early reference to specialized sonography and echocardiography clinic will be promising
for early diagnosis. We talked with parents, about consequences of prenatal diagnosis
which will result in abortion and they feared it because of past experiences. It is
important to know that there is no impulsion to receive more information about child
before pregnancy, because it has no medical result for them.
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Discussion
TAC is a rare congenital cardiac disorder with the prevalence of 0.056 to 0.03 in every
1000 births [1,2,11,13,25,27]. In most reported cases there is not an even and similar
picture among ill children. Attempts to prepare a clear detailed pattern or classification
which including all reported forms, have partially failed. In most cases, TAC has genetic
origin with the effect of teratogenese (virus, metabolic imbalance, industrial and
pharmaceutical factors) and caused by concurrent effect of both factors [30]. In more
than 30-50% of cases, consistency is shown with 22q11 chromosome microdeletion and
Di George syndrome, even in this case the picture of disease is not same[22,10,17,30].
Disorder in neural-fetus septum, where first neural cells of heart and aorta pulmonia
from, is reported as one of the conotruncal disorders factor [7,8,9,30]. Some disorders
of fetus cardiac-neural septum are related to growth factors (fibroblast growth factor
FGF8, bone morphogenesis protein BMP) and transcription factors (T-box, Pax, NKX2-9,
ANF, GATA-C)
[20,25,30] and cell membrane gap protein (connexion-40) [30 ,24]. Cardiac-
neural septum plays a role in forming smooth muscle of great vessels [35,34,30].
In some studies, extracellular changes are reported in hypoplastic syndrome of heart's
left part (HLHs) comparing with TAC group, apoptosis and increase in Fibronectin and
decrease in collagen type I [4]. Regarding this and various reported mutations relating
to TAC disorders including mutation in CFC1 (De George syndrome) with face dismorphic
or velo-cardio-facial syndrome in 90% of cases, mutation in NKX2.6 [20,24], deletion in
(22q11)22 chromosome [22,7,10,30] and chromosome 8,18,19 [30], mutation in
cardiac homeobox containing gene CSX (5q34) which has been expressed in heart cells
in fetus. Homeobox containing gene Msk2 [11], Tbx1-gene [28] and even disorder in
diabetic mother's child dependent on insulin [23,24] were reported which show the
polygenic and multifactorial nature of these disorders. In the absence of these various
mutations, it could be imagined a dominant autosomal inheritance with reduced
penetrance and variable expressivity.
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In our reported case, there was no chromosomal disorder in baby and her parents. In
genetic analysis, regarding multifactorial nature of congenital TAC and its diverse
epidemiologic and anatomic picture, parents could be aware of fetus health using
sonography, echocardiography [25,20] and quadric test before birth and control of
mentioned genes. In the case of birth and diagnosis, immediate intervention with
diagnostic methods for treatment, surgery and reparation of cardiac defects give an
acceptable survival chance to child. Even with selecting newborn gender due to high
resistance, we can increase the chance of healthy child [28]. Using stem cells as an
alternative treatment showed that during activity of these cells, 32000 various
transcripts (gene expression products) were constructed which help to improve some
disorders [1,14].
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Dr. Gholamreza Nourzad . Ass.Prof of Hormozgan University,Faculty of Siences,
Biology Dept.
Tel : +987617660048-55
Fax: +987617660012
Email:[email protected]
corresponding author:
Mahnaz baghershiroodi from center of molecular medicine research,
Hormozgan, University of Medical Sciences
Tel : +987613354939
09179376701
Fax: +987613354939
Email: [email protected]
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