![Karyotype and FISH images of Proband and father of the affected child. (A), GTG banded karyotype of proband showing 46,XY,+der(9)t(9;14)(q22.1;q11.2)pat,-14; (B), Balanced translocation showing 46,XY,t(9;14)(q22.1;q11.2) in father; (C), Whole chromosome painting (FISH) shows partial trisomy 9 [Green (9) and red (14)] in proband; (D), FISH image showing balanced translocation in father.](https://www.researchgate.net/profile/Somprakash-Dhangar/publication/331317548/figure/fig1/AS:729996469481472@1551056129128/Karyotype-and-FISH-images-of-Proband-and-father-of-the-affected-child-A-GTG-banded_Q320.jpg)
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Intractable & Rare Diseases Research Advance Publication P1
Partial trisomy 9 (9pter->9q22.1) and partial monosomy 14 (14pter-
>14q11.2) due to paternal translocation t(9;14)(q22.1;q11.2) in a
case of Dysmorphic features
Somprakash Dhangar, Seema Korgaonkar, Babu Rao Vundinti*
National Institute of Immunohaematology (ICMR), K.E.M Hospital campus, Parel, Mumbai, India.
1. Introduction
Trisomy 9 is one of the rare chromosomal abnormalities
associated with complex phenotype involving multiple
malformations of limbs, cardiac, renal and central
nervous systems (1). The clinical severity in trisomy 9
is not precisely correlated with the extent of trisomic
material (2). Prenatal growth retardation, postnatal
mental retardation and early mortality are known to be
associated with trisomy 9 (3). The trisomy 9 can classify
as pure trisomy and partial trisomy 9 (4,5). The pure
trisomy 9 can occurs due to different type of adjacent-2
segregation mechanism as well as non-disjunction of
chromosomes in one of the parent during gametogenesis
(6). The partial trisomy includes somatic mosaicism and
translocation. The phenotype associated with it relies
on the number of cellular lines that are trisomic and the
additional chromosome material translocated to different
chromosomes (7,8). However, majority of the pure and
partial trisomy 9 ends in spontaneous abortion (3,8).
The published literature of pure or partial trisomy 9
provides limited information mainly related to prenatal
diagnosis, electively terminated pregnancies or autopsy
cases and not on long time survivors of partial trisomy
9 (5,9,10). The developmental complications in partial
trisomy 9 have been reported in few case studies (11).
So far 150 cases of pure and partial trisomy 9 have been
reported in the database of National organization for rare
disorders (NORD) (12,13). However there is dearth of
information regarding developmental status of pure or
partial trisomy 9 cases in the literature.
Here, we report a novel case of partial trisomy 9 and
monosomy 14 in a five year old child with dysmorphic
features.
Summary Trisomy 9 including mosaic and partial trisomy is less frequently seen chromosomal
abnormality in live born children. The pure or partial trisomy 9 frequently been reported in
prenatal diagnosis and product of conception. However few studies reported partial trisomy
9 in live born children. In addition data on genotype and phenotype correlation of partial
trisomy is not well understood except few case reports. Here we report a case of partial
trisomy 9 and monosomy 14 with a 46,XY,der(9)t(9;14)(q22.1;q11.2)pat,-14 karyotype in a
5-year old dysmorphic child. The proband was confirmed as trisomic for 9pter->9q22.1 and
monosomic for 14pter->q11.2 due to paternal t(9;14)(q22.1;q11.2) balanced translocation
using a combination of conventional and molecular cytogenetic (fluorescence in situ
hybridization, array-comparative genomic hybridization) techniques. The clinical features
similar to pure trisomy 9 is due to duplication of the large region of chromosome 9. However,
the present report of partial trisomy 9 and monosomy 14 is a novel case report and showing
comparatively longer survival which have not been previously reported in the literature. The
parent of the proband was counseled for the future pregnancies.
Keywords: Partial trisomy 9, partial monosomy 14, unbalanced translocation, developmental
delay, dysmorphic features
DOI: 10.5582/irdr.2019.01000
Case Report Advance Publication
Released online in J-STAGE as advance publication February
25, 2019.
*Address correspondence to:
Dr. Babu Rao Vundinti, National Institute of Immuno-
haematology (ICMR), 13th oor, new multistoried building,
K.E.M Hospital campus, Parel, Mumbai 400012, India.
E-mail: vbaburao@hotmail.com
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Intractable & Rare Diseases Research Advance Publication
2. Case Report
A 5-year old male child, the first born of a healthy non-
consanguineous couple was referred to our clinic for
chromosomal analysis due to delayed milestones and
dysmorphic features. He had been born of full term
normal delivery with moderately low birth weight.
Mother's age was 33 years with no previous bad obstetric
history and the father was 35 years old.
On clinical examination, the child had facial
dysmorphic features like prominent forehead with mild
macrocephaly, low hair line, slight downward slanting
of the eyes with epicanthic folds, hypertelorism, low set
ears, large pinnae, long face, bulbous nose, thin upper lip,
long philtrum, high arched palate and webbed neck. The
proband also had skeletal and limb anomalies including
kyphoscoliosis rocker bottom feet, short middle
interphalangeal elevated foot, clinodactyly of fifth finger
and pilonidal sinus. Speech development was severely
retarded and the gross and fine motor development was
poor. The Social Quotient (SQ) was 80. The Magnetic
resonance imaging (MRI) and Computer tomography
(CT) scan of brain revealed generalized cerebral atrophy,
dilated ventricles, and arachnoid cyst. The 2-Dimentional
echocardiogram (2D-ECHO) reported tiny patent ductus
arteriosus (PDA) with normal left ventricular output.
Ultra sonography (USG) of abdomen revealed small
size of both kidneys. Brainstem Evoked Response
Audiometric (BERA) test revealed bilateral moderate
to severe hearing loss. Ophthalmic examination showed
telecanthus.
The study was carried out with the consent of one of
the parent.
3. Cytogenetics
Peripheral blood cultures were set up at 37°C for 72
hours according to standard procedure (14). The cultures
were stimulated with phytohaemagglutinin (PHA)
arrested with colchicine (50 ug/mL) and treated with
hypotonic solution (KCL- 0.56 g/100 mL). The cells
were fixed in carnoy's solution (Methanol: Glacial acetic
acid; 3:1). The chromosomal preparations obtained
were subjected to GTG banding (15). At least 30
metaphases were scored and karyotype (approximately
400 band resolution) according to International System
of Chromosome Nomenclature 2016 (ISCN 2016)
(6). Applied Spectral Imaging software system (Inc.
Carlsbad, USA) interfaced with Nikon 90i microscope
(Japan) was used for analysis.
The chromosomal analysis of child revealed
46,XY,+der(9)t(9;14)(q22.1;q11.2)pat,-14 karyotype
(Figure 1A). The karyotype of mother was normal while
the father had balanced translocation 46,XY,t(9;14)
(q22.1;q11.2) (Figure 1B). Fluorescence in situ
hybridization (FISH) was carried out using centromere
specific and whole chromosome painting probe
(Kreatech, Leica biosystems, Germany) of chromosome
9 (Cat. No. KBI30009G) and 14 (Cat. No. KBI30014R).
FISH results revealed partial trisomy 9 and monosomy
14 in proband (Figures 1C and 1D). The chromosome
breakpoints further confirmed by array-CGH (CytoPrime
P2
Figure 1. Karyotype and FISH images of Proband and father of the affected child. (A), GTG banded karyotype of proband
showing 46,XY,+der(9)t(9;14)(q22.1;q11.2)pat,-14; (B), Balanced translocation showing 46,XY,t(9;14)(q22.1;q11.2) in father;
(C), Whole chromosome painting (FISH) shows partial trisomy 9 [Green (9) and red (14)] in proband; (D), FISH image showing
balanced translocation in father.
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Intractable & Rare Diseases Research Advance Publication P3
our case, chromosome analysis using GTG banding
revealed der(9) chromosome and the karyotype was
46,XY,+der(9)t(9;14)(q22.1;q11.2)pat,-14. The array-
CGH detected the accurate break point to be 9p24.3-
>q22.1 which could not be confirmed by conventional
method. Total 432 genes are present in this breakpoint
region and out of which 222 genes are found to be
associated with Mendelian inheritance (22). It is evident
that the der(9) chromosome came from father due to
the presence of balanced translocation 46,XY,t(9;14)
(q22.1;q11.2). The adjacent-2 segregation taking place
during the gametogenesis in one of the parent may be
the reason for the unbalanced genotype (6). Molecular
cytogenetic analysis of proband using FISH revealed
that the der(9) was indeed derived from the father and
the child was trisomic for chromosome region 9pter-
>9q22.1 and monosomic for 14pter->14q11.2 region.
Hence, the karyotype of proband was confirmed to be
46,XY,+der(9)t(9;14)(q22.1;q11.2)pat,-14.
In literature review we found that nine such cases
with slightly similar breakpoint 9pter->9q22.2 have
been reported (Table 1). However, the other partial
trisomy related to region 9q12->9q32 also reported in the
literature. The National organization for rare disorders
(NORD) and Tracking Rare Incidence Syndromes (TRIS)
project are the important database for rare diseases like
trisomy 9. According to their database 150 cases of
trisomy 9 has been reported so far. Of them only few
microarray system with Chromosome Analysis Suite
software designed by affymetrix). Array-CGH revealed
arr[GRCh38] 9p24.3q22.1(203861_87860633)x3 pat
(Figures 2A and 2B). Array-CGH analysis shows a
single copy gain of chromosome 9 at band 9p24.3-
>q22.1 which spans 87.657 Mbps genomic material
consisting of 432 genes. The array-CGH result suggested
partial trisomy 9.
4. Discussion
Genomic imbalances due to chromosomal abnormalities
are major cause of multiple congenital anomalies
including dysmorphic features and developmental delay.
The chromosomal abnormalities including balanced
translocations, inversions and extra marker chromosomes
passed through the parents cause unbalanced genomic
changes in the fetus or children resulting in the abnormal
phenotype (16).
Trisomy 9 is a fairly uncommon aneuploidy
accounting for only 2.7% of all trisomy and mainly
results in early miscarriages (17). Pure trisomy 9 presents
a wide variety of congenital anomalies affecting most
of the vital organs and limb extremities. However,
the severity is highly variable from case to case
(18,19). Partial trisomy 9 due to balanced translocation
between chromosome 9 and other chromosomes of
parents have been reported in literature (20,21). In
Figure 2. Array-CGH findings. (A), Array-CGH image showing duplication of chromosome 9, region 9pter->9q22.1 (Proband);
(B), Array-CGH image showing duplicated region of chromosome 9 in our case and its comparison with previous studies.
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Intractable & Rare Diseases Research Advance Publication
P4
cases had longer survival more than 3-4 years (12,13).
According to published literature majority of trisomy
9 cases involving breakpoint region 9pter->9q22.2
manifest clinical features such as webbed neck, rocker
bottom feet, slanting eyes, growth retardation and
delayed milestones (23). Similar clinical abnormalities
were seen in this case, additionally classical anomalies
like CNS involvement (cerebral atrophy, dilated
ventricles), and cardio vascular involvement (PDA)
and renal impairment (hypoplastic kidneys) were also
present. The presence of these anomalies makes the
proband a classical case of partial trisomy 9 in terms of
clinical diagnosis and management. Hence reporting
of such cases is essential to characterize the disorder as
well as to increase the awareness and knowledge in the
medical community.
Table 1. Correlation of clinical features and chromosome breakpoints in patients with 9p duplication
Authors [Year] (ref.)
Our Patient
Fryns J P et al. [1979] (29)
Wilson GN et al. [1985] (2)
Smart RD et al.[1988] (30)
Chih C P et al. [1999] (31)
Von Kaisenberg CS et al.
[2000] (32)
Bouhjar IB et al. [2011] (27)
Lyons JM et al. [2013] (33)
Kowalezyk M. et al. [2013] (28)
Brambila-Tapia AJ et al.
[2014] (21)
Region/loci duplicated
9p24.3->q22.1
9p
9pter->q22
9pter->q22.1
9pter->q22
9pter->q22.2
9p13.3->pter
Partial 9p and partial monosomy Yq
9p13.1->pter duplication with 9 p deletion
Pure trisomy 9p13.1
Reported clinical anomalies
Macrocephaly, slight downward slanting of the eyes with
epicanthic folds, hypertelorism, low set ears, large pinnae, long
face, bulbous nose, thin upper lip, long philtrum, high arched
palate and webbed neck, kyphoscoliosis, rocker bottom feet,
short middle interphalangeal, clinodactyly of the fifth finger,
pilonidalsinus, cerebral atrophy, dilated ventricles and arachnoid
cyst, congenital heart disease, small size kidneys
Retardate psychomotor development, hypertelorism,
antimagoloid slant, globular nose, protruding ears, dilated
ventricles
Microcephaly , prominent nasal root, bulbous nose, and down-
turned comers of the mouth
Enlarged ventricles, facial dysmorphism
Enlarged cysternamegna with bilateral ventriculomegaly
Dandy Walker malformation* and cerebella vermis hypoplasia
in fetus
Typical dysmorphic features but not mental retardation
Neuro developmental delay, growth delay, dysmorphic
features, small genitalia
Craniofacial anomalies, Dandy Walker malformation*,
delayed development, mental retardation
Psychomotor delay, short stature, open anterior fontanelle,
dysplastic ears, facial dysmorphism, Long and broad first
toes, CNS and skeletal alterations
Bolding represents features in common with our patient. *Partial anomalies present in our case.
Table 2. Comparative clinical features and chromosome break points in patients with monosomy 14
Authors [Year] (ref.)
Our Patient
Short E M et al. [1972] (25)
Petek E et al. [2003] (24)
Prontera P et al. [2014] (26)
Region/loci duplicated
14pter-> 14q11.2
(14q-)+ deletion
14q interstitial deletion
14q11.2 deletion
Reported clinical anomalies
Macrocephaly, slight downward slanting of the eyes with epicanthic folds,
hypertelorism, low set ears, large pinnae, long face, bulbous nose, thin upper
lip, long philtrum, high arched palate and webbed neck, kyphoscoliosis,
rocker bottom feet, short middle interphalangeal, clinodactyly of the fifth
finger, pilonidalsinus, cerebral atrophy, dilated ventricles and arachnoid
cyst, congenital heart disease, small size kidneys
Delayed development, Intellectual disability
Small fontanelle, sloping forehead, micropthalmia, malformed pinnae
Macrocephaly, facial dysmorphism with Autism
Bolding represents features in common with our patient.
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Intractable & Rare Diseases Research Advance Publication P5
Moreover, partial monosomy 14pter->14q11.2 was
also detected through conventional cytogenetics in the
proband. Few cases of partial monosomy 14q11.2 have
been reported in the literature (Table 2) and most of
the anomalies overlap with trisomy 9 features (24,25).
However we have not found any gain or loss in array-
CGH results, showing involvement of heterochromatic
region in the translocation. The reported studies shows
recurrent 100 kb micro deletions in the chromosomal
region 14q11.2 involving CHD1 gene are associated with
autism and macrocephaly. Other study also suggested
that the deletion of 114 kb in the region of 14q11.2
involving genes SUPTT16H, CHD8, RAB2B which are
strongly associated with autism and facial dysmorphism
(26). Hence cytogenetic analysis of the children with
dysmorphic features is essential in view of autism
spectrum disorder and its further management.
The cytogenetic screening of future pregnancies
is important as there is a high risk of giving birth to
chromosomally abnormal child, due to the presence of
balanced translocation in the father which is likely to
undergo abnormal meiotic segregation. Over the last
decade recent advancement in molecular cytogenetic
has proved to be an important tool for identification of
complex chromosomal abnormalities including minor
losses and gains with accurate breakpoint (27). The Copy
number Variations (CNV's) are found to be associated
with several disease conditions (28).
In conclusion, the present case of partial trisomy
9 and monosomy 14 is novel findings and showing
comparatively longer survival which has not been
previously reported in the literature. Further, the
combination of conventional and advance molecular
cytogenetic tools have proven to be essential in accurate
identification of breakpoint in affected children. The
present case reports will help in appropriate genetic
counseling and prevention of genetic disease through
prenatal diagnosis.
Acknowledgements
The study was carried out with Institutional core grant.
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(Received January 3, 2019; Revised February 13, 2019;
Accepted February 18, 2019)
