Case Report
MOSAICISM OF TRISOMY OF 16 PAIRS OF CHROMOSOMES WITH PARTIAL
SITUS INVERSUS AND LEVOCARDIA OBSERVATION OF EXTREMELY RARE
ANOMALY FROM 1ST TRIMESTER TO NEONATAL PERIOD- CASE REPORT
Authors:
Beata Radzymińska- Chruściel1 , Urszula Dajda2, Sebastian Zalewski2, Anna Piatkowska3, Julia Wieczor3,
Dariusz Gołąbek4, Daniel Porada5, Andrzej Rudzinski5
Fetal Echocardiography Laboratory Ujastek Medical Centre in Krakow 2Department of Obstetrics and Gynecology Specialist Hospital. Louis
Rydygiera in Krakow 3Neonatal Intensive Care Unit Medical Centre Ujastek Krakow 4Department of Pathology Pregnancy Ujastek Medical
Centre, Krakow 5Department of Pediatric Cardiology, Jagiellonian University
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PRENAT CARDIO 2013 MAR;3(1):34-39
DOI 10.12847/03136
Abstract
This is case report of extremely rare mosaic trisomy of 16th pair of chromosomes from the high risk pregnancy (maternal
age 35 years old, positive screeining in 1st trimester) . The fetus presented with intrauterine growth retardation, congenital
heart defect, dysmorphic features and skeletal anomalies. The case has been observed until hospitalization in pediatric
cardiology department. Other similar cases have been analysed.
Key words: Trisomy of 16th pair of chromosomes, congenital heart defect, ectrodactyly
CASE PRESENTATION:
Prenatal period:
How to cite this article:
Radzymińska-Chruściel B, Dajda U,
Zalewski S, Piątkowska A,
Wieczór J, Gołąbek D, Porada D,
Rudziński A.
Mosaicism of trisomy of 16 pairs of
chromosomes with partial situs inversus
and levocardia observation of extremely
rare anomaly from 1st trimester to
neonatal period- case report.
Prenat Cardio. 2013 Mar;3(1):34-39
In a 35-year-old woman
pregnant with her 4th child
(the other three children were
normal), ultrasonography
performed in the first trimester
of pregnancy demonstrated
abnormalities – Doppler
ultrasound showed abnormal
blood flow in the venous
duct (Fig. 1). Based on
ultrasonography and repeated
PAPP-A tests, elevated risk was estimated for the following
aneuploidy syndromes: high for trisomy 21 (1:5) and
moderate for trisomy 13 and 18 (1:367 and 1:384,
respectively). When 17 weeks pregnant, the mother was
subjected to an amniopunction, whose result indicated
incomplete trisomy 16 – in two separate cultures, a mosaic
karyotype was obtained (in both the cultures, trisomy 16
was seen, but the percentages differed - above 80% and
below 20%, respectively).
With the mother 22 weeks pregnant, obstetric
ultrasonography demonstrated a normal facial profile of
the fetus, complete with nasal bones of normal length,
moderate shortening of long bones
for gestational age and a ventricular
septal defect (Fig. 2).
Subsequent
prenatal
echocardiography procedures
performed at 24 and 30 weeks of
gestation confirmed a congenital
heart defect – a ventricular septal
defect with moderate cardiomegaly
(Ha/CA 0.4) and coronary sinus
enlargement (Fig. 3), while a small
volume of fluid was noted in the
pericardium. The cardiovascular
profile score was 8 (score -1 for Ha/Ca, score -1 for
PE). Extracardiac abnormalities included the midline
location of the liver (Fig. 4). A 3D presentation allowed
for interpreting the images of the facial skeleton and right
palm as normal (Fig. 5, 6). No left hand of the fetus was
visualized. The biometric parameters were estimated at
10 percentile for gestational age.
Further echocardiographic examinations did not
demonstrate increasing signs of fetal cardiac failure;
however, the analysis of growth trends showed the
biometric parameters persisting within the same
percentile channel.
Corresponding author: [email protected]
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PRENAT CARDIO. 2013 MAR;3(1):34-39
Fot. 1. Abnormal ductus venosus flow in 1 st trimester sonographic scan
Beata Radzymińska-Chruściel et. al.
Fot. 4. Bilateral localisation of liver
Fot. 2. Ventricular septal defect in 2nd trimeter sonographic examination
Fot. 5. Face of the fetus in 3D examination
Fot. 3. Visualisation of ventricular septal defects in fetal echo exam
Fot. 6: Right hand of the fetus
The pregnant mother was referred to Out-patient
Department of Genetics, where she was consulted and
provided information on the type and incidence of the
genetic syndrome diagnosed in the fetus and the type
of concomitant anomalies. Tentative postnatal prognosis
was also presented.
35
Neonatal period:
A female newborn was born spontaneously at 37
weeks of gestation, with birth body weight of 2090 g
(ctrodactyly,”lobster claw hand”, from Greek εκτρομα
= spontaneous abortion + δακτίλος = finger), i.e.
malformation of the extremity consisting in a complete
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Mosaicism of trisomy of 16 pairs of chromosomes with partial situs inversus and levocardia observation of extremely rare anomaly from 1st trimester to neonatal period- case report
or partial absence or deficiency of toes and/or fingers.
The degree of lesion varies; in the upper limb, the affected
individuals present with the absence of phalanges 3 with
a deep cleft extending to the wrist).
As additional dysmorphic features, the newborn
presented with dysplasia of the left mammilla and
a supernumerary mammilla situated in the left maxillary
line, as well as abnormal external genitals (hypoplastic
greater pudendal lips).
Cytogenetic examination of the peripheral blood
sample showed normal female karyotype (46, XX).
Ultrasonography of the brain, abdominal cavity and lungs
showed no abnormalities.
On the 6th day of life, echocardiography demonstrated
right atrial and ventricular enlargement, patent foramen
ovale with a left-to-right shunt and a subaortic ventricular
septal defect with a bidirectional shunt. The patient
showed anomalous arising of both large arteries, with
the aorta partially situated above the right ventricle.
Additionally, the aorta and pulmonary artery were found
to be markedly disproportional (the ascending aorta was
distended to a diameter of 8 mm, after the branching
off of the brachiocephalic trunk, the aortic arch was
stenotic, measuring 4 mm, the aortic isthmus was narrow
and difficult to assess due to superimposition of the
ductus arteriosus image and bidirectional shunt). In
view of the suspected aortic isthmus stenosis (Fig. 8),
Prostin VR infusions were prescribed. On the 14th day
of life, the newborn in the moderate medical condition
was transferred to Department of Pediatric Cardiology,
Jagiellonian University Medical College, Krakow.
Follow-up period in the referral center of pediatric
cardiology
On admission, the general medical condition of the
patient was moderate. Her heart action was rhythmical
140-150/min, at the left sternal margin a systolic murmur
2/6, prominent right ventricular impulse, symmetric but
poorly palpable femoral pulse, normal capillary return.
Physical examination additionally revealed dysmorphic
Fot. 7. Ecrodactyly of the left hand of the newborn
Fot. 8. The inflow of Left Superior Vena Cava to Coronary Sinus
features, as described above, and umbilical hernia. Sa02
on admission was 95-99%, but p02 53 - mm Hg. ECG
showed regular sinus rhythm, approximately 170/min,
additionally dextrogram and left ventricular hypertrophy.
In chest X-ray, the cardiac silhouette was enlarged in the
transverse diameter CTR – 0.63 (the roentgenogram was
asymmetric due to chest deformity), while the vascular
pulmonary markings were increased.
Echocardiography showed right atrial and ventricular
enlargement, a supernumerary superior vena cava
emptying to the enlarged coronary sinus, an ostium
secundum type ventricular septal defect, a 4 mm subaortic
VSD and additionally another, a smaller interventricular
shunt in the paraapical region and patent ductus
arteriosus with a bidirectional shunt indicating systemic
pulmonary hypertension. Additionally, echocardiography
demonstrated a markedly atypical branching of the left
pulmonary artery branch from the pulmonary trunk. No
stenosis of the aortic isthmus was observed and thus
Prostin infusions were discontinued. In order to assess
more precisely the anatomy of the defect and the character
of pulmonary hypertension, cardiac catheterization
was performed. Angiocardiography of the pulmonary
hypertension showed enlarged pulmonary trunk (10 mm)
and atypical branching off and course of the branches. The
origin of the right branch was situated more inferiorly than
normally and corresponded with the anatomical image
of the left branch, while the latter branched off from the
right circumference of the pulmonary trunk superiorly to
the right branch and extended leftwards and downwards
(above the left bronchus), its course and segmentation
corresponding to the right branch (Fig. 10). The remaining
morphological abnormalities were the same as previously
noted in echocardiography. Hemodynamic tests showed
systemic pulmonary hypertension with a significant leftto-right shunt (Qp/Qs – 2.6:1) and increased pulmonary
resistance (3.6jW/m2) as well as an abnormal Rp/Rs ratio
– 0.36 (reference value 2 test resulted in an increase of
the left-to-right shunt (Qp/Qs 2.9:1) and a slight decrease
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PRENAT CARDIO. 2013 MAR;3(1):34-39
Beata Radzymińska-Chruściel et. al.
of pulmonary hypertension (3.0jW/m2), but in spite of its
decrease, Rp/Rs continued to be abnormal (0.24). The liver
situated in the midline (with the stomach body situated on
the left side), normal position of the heart in the left chest,
with the apex directed to the left (levocardia), bilateral
superior vena cava emptying to the coronary sinus, the
presence of shunt-associated cardiac defects and the
image of the pulmonary branches that was reverse of
normal positioning and suggested an inverse position of
the lungs (the trilobed lung on the left, the bilobed on the
right) was indicative of a heterotactic position of the chest
organs. A roentgenogram (AKG, babygram) showed IVC
and the abdominal aorta on the right side of the spine,
the liver situated in the midline, both the phrenic domes
at the same level, left thoracic spinal curves (scoliosis)
and the course of the trachea and esophagus along the
right spinal margin (Fig. 11).
Thus, the entire clinical picture corresponded to a very
rare variant of partial situs inversus with levocardia, which
is usually encountered concomitant with much more
complex congenital circulatory system anomalies.
In view of the congenital defect syndrome, the child
was consulted by a multi-specialist team: an ENT
specialist diagnosed left bone choanal atresia, which
did not require emergency management, an orthopedic
surgeon recommended a temporary delay in diagnostic
and therapeutic management of the skeletal defects,
a neurologist and a specialist in rehabilitation prescribed
positioning practices and rehabilitation. In view of the discrepancy between the prenatal
karyotype and the result of the postnatal cytogenetic
peripheral blood test, karyotyping was performed in
a skin fibroblast culture, confirming the abnormal result
(47,XX+16 [70%] / 46,XX [30%]). The aberration did not
disqualify the girl from cardiac-surgical treatment.
During hospitalization, the girl had Klebsiella pneumoniae
Fot. 10. Babygram
sepsis. In view of her very weak sucking reflex, the patient
initially required feeding through a nasogastric tube; oral
feeding was gradually introduced, being well tolerated
by the child and resulting in a gradual body mass gain.
Following a cardiac-surgical consult, the patient was
qualified for surgery of PDA ligation and banding of the
pulmonary artery. DISCUSSION
Trisomy 16 is one of the most common fetal genetic
abnormalities; it may affect as many as 1.5% pregnancies
1,2
. In the majority of cases, it is a result of a maternal
nondisjunction in meiosis I.
Full trisomy 16 is the most common cause of
spontaneous abortion in the first trimester of pregnancy3,
yet in consequence of trisomic rescue, mosaic karyotypes
may develop or else trisomy may be limited solely to
extrafetal tissues (the so-called CPM - confined placental
mosaicism)4,5,6 and then the affected patients may survive.
To date, no full spectrum of signs and symptoms that may
accompany trisomy 16 mosaicism have been described,
since no data are available on the incidence of mosaic
karyotypes or balanced translocation in the population.
In consequence of a loss of a single chromosome from
trisomic cells in embryos (trisomic rescue), in almost
2/3 cases there occurs uniparental disomy, where both
chromosomes 16 are maternal in origin. To date, it has not
been determined whether and to what degree the above
situation affects the functioning of the body, the more so
that mouse models suggest a possibility of imprinting on
chromosome 164,5,6.
Fot. 9. Angiography- atypical view of the right and left pulmonary arteries
37
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Mosaicism of trisomy of 16 pairs of chromosomes with partial situs inversus and levocardia observation of extremely rare anomaly from 1st trimester to neonatal period- case report
In addition, various authors describe phenotypic variation
in patients with chromosome 16 mosaicism depending
on the described karyotype (“from which chromosome
some part of genetic material has been translocated to
chromosome 16 “)7, 8.
The present information on signs and symptoms in
incomplete trisomy 16 originates from scarce descriptions
of infrequent (approximately 40) cases available in the
literature on the subject2.
The most common and most frequently described
symptom is intrauterine growth retardation9, 10. The mean
birth body mass is lower by 1.93 standard deviations
than the mean value for the entire population. Growth
retardation also occurs when a trisomic cell line is
present in the placenta only, while the fetus has a normal
number of chromosomes (CPM), thus, it is predominantly
associated with placental insufficiency resulting from
increased apoptosis and decreased proliferation of
the trophoblast, as well as from abnormal spiral artery
remodeling and abnormal placental flow (similarly as in
other trisomies). The higher the percentage of abnormal
cells in the placenta, the higher the probability of IUGR2.
Another phenotypic feature described in the literature
is facial dysmorphia (protruding forehead, periorbital
edema, low set, dysplastic ears, micrognathia, short
neck, wide root of the nose and hypertelorism), as well
as abnormal structure of extremities – especially fingers,
scoliosis and supernumerary mammillae. Moreover, such
newborns were described to present with respiratory failure
requiring ventilatory support and abnormal sucking reflex
necessitating nasogastric feeding, both resulting from
decreased muscle tone7. Many of the above symptoms
were also encountered in the presently described patient.
In newborns with partial trisomy 16 there is an increased
risk of severe developmental anomalies. Of all live-born
neonates, approximately 45% showed at least one
malformation 2. The most common defects include
hypospadia (26.9% boys), single umbilical artery (10.9%),
clinodactyly (7.8%), pulmonary hypoplasia (7%) – often
secondary to such anomalies as meningocele, renal
malformation or severe scoliosis.
The most common cardiac anomalies include septal
defects (VSD - 17.8%, ASD - 7.8%)2. Single cases were
described of prenatally diagnosed pulmonary artery
stenosis11 and cardiac ectopy12. A search of the available
literature has failed to show a description of cardiac defects
belonging to the heterotaxy group and especially inverse
position of the lungs with normal positioning of the heart in
the chest. Such a coexistence of circulatory anomalies is
extremely rarely described in pediatric cardiology. A variant
of such an abnormality was described by Padmavati and
Gupta in the sixties of the last century, but they provided
no information on the genetic or at least dysmorphological
status of the patient they presented 13.
Proximal duplication of the long arm of chromosome
16 is associated with less specific clinical symptoms,
involving – among others – the central nervous system,
such as microcephaly, distended cerebral ventricular
system, gyrus enlargement, deepening of the Sylvian
fissure, thinning of the corpus callosum and delayed
myelination of the cerebral cortex, as well as cerebellar
cortical dysplasia. CNS morphological abnormalities are
associated with abnormal psychomotor and intellectual
development 14, 15 .
In cases of incomplete trisomy 16, an increased risk
of preterm delivery was observed - the mean gestational
age of neonates was 35.7 weeks 2, 16, 17.
Of the analyzed pregnancies with diagnosed trisomy 16,
66% was terminated by birth of a live neonate. Almost all
the children (93%) survived the neonatal period, yet the
majority died in the first year of life1, 2. Literature presents
single reports on mosaic karyotypes in adults. An adult
male was described, in whom trisomy 16 was detected
both in peripheral blood lymphocytes and in fibroblasts.
Four of five fetuses fathered by this individual were aborted
spontaneously in early pregnancy; in one of them, trisomy
was confirmed 18.
Isolated adult patients were described as overweight or
obese what was associated with duplication of the FTO
gene (fat mass and obesity-associated gene), situated
on the long arm of chromosome 1619.
Prenatal diagnostic management of partial trisomy
16 may demonstrate nuchal enlargement or edema,
abnormal biochemistry or other aneuploidy markers
in the first trimester. Ultrasonography performed in the
second trimester and fetal echocardiography allow for
visualizing abnormalities of the circulatory system and
extracardiac anomalies 20.
While interpreting results of invasive cytogenetic
diagnostic management, it should be borne in mind that in
view of natural selection of trisomy cells, even patients with
a high percentage of cells characterized by an abnormal
karyotype may escape prenatal diagnosis, similarly as
it is often difficult to diagnose the aberration based on
karyotype examination in peripheral blood cells (in such
cases, diagnostic management must be necessarily
based on fibroblast cultures3). Such a diagnostic situation
occurred in the presently reported patient.
CONCLUSION
The presented case of chromosome 16 mosaicism
is among scarce examples of this kind reported in the
literature on the subject. At each stage of development,
the patient provided new information, starting for the
early prenatal period (screening in the first trimester)
through detection of a cardiac defect in mid-pregnancy,
diagnostic management of the said cardiac anomaly in
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PRENAT CARDIO. 2013 MAR;3(1):34-39
subsequent weeks of gestation in a referral center, fetal
growth retardation shown in the third trimester, clinical
assessment of the neonate after delivery to detection
of additional anomalies in subsequent imaging studies
(Fig. 1)
References:
1. Roberts SH, Duckett DP.: Trisomy 16p in a liveborn infant and
a review of partial and full trisomy 16. Med Genet. 1978 Oct;15(5):37581
2. Yong PJ, Barrett IJ, Kalousek DK, Robinson WP. : Clinical aspects,
prenatal diagnosis, and pathogenesis of trisomy 16 mosaicism. J
Med Genet. 2003 Mar;40(3):175-82
3. Abaneh H, Asim M Momani, Rame H. Khasawneh.: Trisomy16
in Products of conception. Int JBiol Med Res, 2012;3(3):2196-2198
4. de Carvalho AF, da Silva Bellucco FT, dos Santos NP, Pellegrino
R, de Azevedo Moreira LM, Toralles MB, Kulikowski LD, Melaragno
MI.: Trisomy 16q21 --> qter: Seven-year follow-up of a girl with
unusually long survival. Am J Med Genet A. 2010 Aug;152A(8):2074-8
5. Basinko A, Audebert-Bellanger S, Douet-Guilbert N, Le Franc
J, Parent P, Quemener S, La Selve P, Bovo C, Morel F, Le Bris MJ,
De Braekeleer M.: Subtelomeric monosomy 11q and trisomy 16q in
siblings and an unrelated child: molecular characterization of two
der(11)t(11;16). Am J Med Genet A. 2011 Sep;155A(9):2281-7. doi:
10.1002/ajmg.a.34162. Epub 2011 Aug 10.
6. Lonardo F, Perone L, Maioli M, Ciavarella M, Ciccone R, Monica
MD, Lombardi C, Forino L, Cantalupo G, Masella L, Scarano F. Clinical,
cytogenetic and molecular-cytogenetic characterization of a patient
with a de novo tandem proximal-intermediate duplication of 16q and
review of the literature. Am J Med Genet A. 2011 Apr;155A(4):769-77.
doi: 10.1002/ajmg.a.33852. Epub 2011 Mar 17.
Beata Radzymińska-Chruściel et. al.
13. Padmavati S, Gupta S: Partial Situs Inversus with Levocardia :
An Unusual Combination of Anomalies . Circulation;1962:26:108-113
14. McCullagh BG, Kerr B, Trueman S, Tomlin PI, Thomas M, Wynn
R, de Goede CG. Distinctive neurological phenotype associated with
partial trisomy of chromosome. Eur J Paediatr Neurol. 2012 Aug 23.
[Epub ahead of print]
15. Zerem A, Vinkler C, Michelson M, Leshinsky-Silver E, Lerman-Sagie
T, Lev D. Mosaic marker chromosome 16 resulting in 16q11.2-q12.1
gain in a child with intellectual disability, microcephaly, and cerebellar
cortical dysplasia. Am J Med Genet A. 2011 Dec;155A(12):2991-6.
doi: 10.1002/ajmg.a.34316. Epub 2011 Nov 3
16. Gilbertson NJ, Taylor JW, Kovar IZ. Mosaic trisomy 16 in a live newborn
infant. Arch Dis Child. 1990 Apr;65(4 Spec No):388-9. PubMed PMID:
2337367; PubMed Central PMCID: PMC1590154.
17. Kalousek DK, Langlois S, Barrett I, Yam I, Wilson DR, HowardPeebles PN, Johnson MP, Giorgiutti E. Uniparental disomy for
chromosome 16 in humans. Am J Hum Genet. 1993 Jan;52(1):8-16.
PMID: 8434609 [PubMed - indexed for MEDLINE]
18. Arakaki DT, Waxman SH. Trisomy-16 in a mosaic carrier father
and his aborted foetus J Med Genet. 1969 Mar;6(1):85-8. No abstract
available.PMID:5814232 [PubMed - indexed for MEDLINE]
19. Van den Berg L, Delemarre-van de Waal H, Han JC, Yistra B, Eij
P, Nesterova W, Heutink P, Stratakis CA.: Investigation of patiens with
partial trisomy 16q including the Fat mass and Obesity Associated
gene (FTO): Fine Mapping and FTO Gene Expression Study. Am J
Med Genet, 2010, March;152A(3):630-637
20. Chen CP, Ko TM, Su YN, Hsu CY, Chen YY, Su JW, Chen WL, Pan
CW, Wang W. Prenatal diagnosis of partial trisomy 16p (16p12.2→pter)
and partial monosomy 22q (22q13.31→qter) associated with increased
nuchal translucency and abnormal maternal serum biochemistry in
the first trimester. Taiwan J Obstet Gynecol. 2012 Mar;51(1):129-33.
doi: 10.1016/j.tjog.2012.01.029.
7. Laus AC, Baratela WA, Laureano LA, Santos SA, Huber J, Ramos
ES, Rebelo CC, Squire JA, Martelli L.: Karyotype/phenotype correlation
in partial trisomies of the long arm of chromosome 16: case report
and review of literature. Am J Med Genet A. 2012 Apr;158A(4):821-7.
doi: 10.1002/ajmg.a.32988. Epub 2012 Feb 21.
8. Noruzinia M, LefortG, Chaze AM, Puechbert J, Pellestor F, Blanchet
P, Cacheux V, Sarda P.: Phenotypic and cytogenetic variety of pure
partial trisomy of chromosome 16p. Acta Med Iran 2009, 47(3),
233-239
9. Buckton KE, Barr DG.: Partial trisomy for long arm of chromosome
16. J Med Genet. 1981 Dec;18(6):483
10. Davison EV, Beesley JR. Partial trisomy 16 as a result of familial
16;20 translocation. J Med Genet. 1984 Oct;21(5):384-6
11. Hidaka N, Yamamoto N, Tsukimori K, Hojo S, Suzuki SO, Wake N.:
Prenatal diagnosis of trisomy 16 mosaicism manifested as pulmonary
artery stenosis. J Clin Ultrasound. 2009 Feb;37(2):107-11. doi:
10.1002/jcu.20499
12. Arnaoutoglou C, Meditskou S, Keivanidou A, Manthou M, Anesidis
N, Assimakopoulos E, Athanasiadis A, Kumar S. Ectopia cordis in a fetus
with mosaic trisomy 16. J Clin Ultrasound. 2010 Sep;38(7):386-8.
doi: 10.1002/jcu.20727
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