
FETAL CYSTIC HYGROMA ASSOCIATED WITH TERMINAL
2p25.1 DUPLICATION AND TERMINAL 3p25.3 DELETION:
CYTOGENETIC, FLUORESCENT IN SITU HYBRIDIZATION
AND MICROARRAY FAMILIAL CHARACTERIZATION
OF TWO DIFFERENT CHROMOSOMAL STRUCTURAL
REARRANGEMENTS Stipoljev F, Barbalic M, Logara M, Vicic A, Vulic M, Zekic Tomas S, Gjergja Juraski R *Corresponding Author: Feodora Stipoljev, Ph.D., Associate Professor, Cytogenetic Laboratory, Department
of Obstetrics and Gynecology, Clinical Hospital “Sveti Duh,” Sveti Duh 64, 10000 Zagreb,
Croatia. Tel.: +385-1371-2273. Fax: +385-1374-5534. E-mail: stipoljev@yahoo.com page: 79
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DISCUSSION
We have presented an extremely rare, prenatally diagnosed
case of partial trisomy 2p25.3-p25.1 and partial
monosomy 3p26.3-p25.3 of paternal origin. To date, only
one study by Chen et al. [7] from 1996 reported a very
similar unbalanced translocation involving partial 2p trisomy
and partial 3p monosomy. Both parents were phenotypically
normal and the mother was a balanced reciprocal
translocation carrier 46,XX, t(2;3)(p25.3;p25). Prenatal
sonographic findings included single umbilical artery,
shortening of the long bones and hypertelorism, while
10-month follow-up revealed craniofacial dysmorphy, hypotonia,
growth and mental retardation. In our case, the
fetal karyotype showed an unbalanced translocation with
a partial trisomy 2p25.1-pter, partial monosomy 3p25.3-
pter, and balanced paracentric inversion of chromosome 3
with breakpoint sites in 3p13 and 3p25.3, both of paternal
origin. The fetus had hypertelorism, low-set posteriorly
rotated ears and cystic hygroma. Father is a carrier of
two different structural rearrangements with a common
breakpoint in 3p25.3. As the total number of breakpoint
sites is three, it cannot be classified as a complex chromosomal
rearrangement. The investigation of patients with
apparently one type of balanced structural chromosomal
abnormality can give unexpected findings of another apparently
cryptic balanced rearrangement, which can be
overcame with use of FISH analysis. Partial trisomy 2p has been published in more than
50 cases, mostly in unbalanced translocations with other
chromosomes. The main clinical features referring to partial
trisomy 2p25.3-p25.1 include developmental delay
and craniofacial dysmorphia. Only few studies reported
pure duplication of the 2p terminal region. Wahita et al.
[8] described a patient with 2p25.1-pter duplication with
trigonocephaly, hypertelorism, anteverted nares, external ear anomalies, exophthalmos, arachnodactyly and joint
dysplasia, but without developmental delay. Roggenbuck
et al. [9] reported a case of 3-year-girl with a significant
psychomotor delay and dysmorphy including a prominent
forehead, malar hypoplasia, and a prominent nose with a
narrow alar base. Additionally, a long torax, a mild pectus
carinatum deformity and scoliosisis, with long and slender
extremities were found. She had a de novo pure partial
trisomy 2p24.3-2pter. Bonaglia et al. [1] reported a familial
10.0 Mb inverted duplication 2p25.3-25.1 and 270 kb
deletion of 2pter. Two children and their father exhibited
mental retardation and craniofacial dysmorphia including
hypertelorism, high forehead, low-set and irregular ears,
thin upper lip and flat philtrum.
The duplicated 10.5 Mb region 2p25.1p25.3 in our
case contains 45 different genes, where 12 (ODC1, KLF11,
RPS7, TPO, MYT1L, PXDN, RNASEH1, COLEC11, SOX11,
ADAM 17, KIDINS220, TRAPPC12) are reported as OMIM
morbid genes with different phenotypical implications.
Coffin-Siris syndrome 9 (CSS9) or autosomal dominant
mental retardation-27 (MRD27, MIM 615866) caused by
a heterozygous mutation in the SOX11 gene, is usually accompanied
by facial dysmorphia, growth deficiency and
mild intellectual disability. Tsurusaki et al. [10] emphasized
the importance of SOX11, which encodes SoxC group high
mobility group (HMG) box-containing transcription factor
as a downstream transcriptional factor of the PAX6 and
BAF complex in brain development. Moreover, SOX11 and
MYT1L were also duplicated in this as in our case. MYT1L
is a member of myelin transcription factor 1 family, acting
on neuronal differentiation. Disrupted function of one
MYT1L allele on 2p25.3 by cryptic gene deletion, intragenic
duplication, or point mutation will cause syndromic intellectual
disability (mental retardation, autosomal dominant
39) in large number of such patients [11]. Bonaglia et al.
[1] hypothesized that an increased expression of MYT1L
product could lead to developmental difficulties associated
with partial 2p trisomy. P
Lund et al. [12] analyzed 132 fetuses with an increased
nuchal translucency of >3.5 mm with chromosomal
microarray. Among 12 fetuses with pathogenic
copy number variants (CNV), one in whom the NT was
measured 6.6 mm had a 46.0 Mb duplication of region
2p25.3-p21. Mother was a balanced translocation carrier.
Lee et al. [3], described a fetus with cystic hygroma and
unbalanced karyotype with additional chromosomal material
on short arm of chromosome 9, designated as distal
part of short arm of chromosome 2. Aviron-Goldring et
al. [2] described a prenatally diagnosed case of partial
trisomy 2pter resulting from an unbalanced karyotype
46,XY,der(21) t(2;21)(p24;p11.1) of de novo origin. The
pregnancy was terminated at 24 weeks’ gestation, and
autopsy revealed high forehead, hypertelorism, small nose
with depressed nasal bridge, thin upper lip, epicantal folds,
micrognatia, low-set slightly rotated ears, short neck with
excess skin, proximally placed thumbs, and urogenital
anomalies (mildly distended ureters and enlarged kidneys,
hypoplastic testes). Thangavelu et al. [13] reported
a prenatal case with a terminal duplication 2p25.3-p22 and
anencephaly at 16.7 weeks’ gestation. Marlet et al. [14]
described a prenatal case of de novo inverted duplication
2p21p25.3 size of 43.75 Mb with present interstitial telomeric
sequences at the breakpoint 2p21 and a tetralogy
of Fallot. Nonspecific ultrasound findings described in
previous reports regarding prenatal findings in partial 2p
trisomy included increased NT/cystic hygroma, as in our
case, as well as heart defect, anencephaly, hypertelorism,
low-set ears, and urogenital anomalies.
Since the first case in 1978 [5], about 50 cases of
the 3pter-p25 contiguous gene deletion syndrome (MIM
613792) have been reported. The 11.6 Mb deletion in our
case contained 65 genes, out of which 27 are OMIM genes
such as CNTN4, SETD5, VHL CHL1 SLC6A1 ITPR1,
HRH1, ATG7, CRELD1 and MTMR14. Three of these
(CNTN4, SETD5 and VHL) were curated by Clingene
Dosage Gene Map (retrieved from www.ncbi.nlm.nih.gov/
projects/dbvar/clingen) and were given a high haploinsufficiency
score. The SETD5 (SET domain containing 5, MIM
615743) gene encodes a histone methyltransferase highly
conserved and expressed in the fetal brain. Heterozygous
mutations of SETD5 cause the autosomal dominant mental
retardation 23 (MIM 615761) with different dysmorphic
features [15]. Mattioli et al. [16] compared three groups
of patients; those who had disrupted only BRPF1, both
BRPF1 and SETD5, and only SETD5. The authors noted
that in patients with disruption of both genes the intellectual
disability was more severe, compared to either of these
genes. They concluded that BRPF1 haploinsufficiency, as
well as the SEDT5 significantly contributed to syndromic
intellectual disability (MIM 617333) in a 3p25-phenotype.
CNTN4 encodes a member of the immunoglobulin superfamily
of neuronal cell adhesion molecules (Contactin 4,
MIM 607280) and has a major role in brain development.
Fernandez et al. [17] reported a patient with phenotypical
features of 3p deletion syndrome which had de novo balanced
translocation t(3;10)(p26;q26). This translocation
disrupted the CNTN4 gene on the 3p26 region and caused
growth retardation, development delay and dysmorphic
features. Suzuki-Muromoto et al. [18] reported a patient
showing classical phenotypical features of 3p deletion
but also exhibiting cerebellar hemangioblastoma, which
was diagnosed as VHL syndrome. Array comprehensive
genomic hybridization analysis revealed a de novo deletion
of the 3p25 region encompassing VHL. Neurodevelopment difficulties are often present in 3p
deletion syndrome. Deletion or disruption of CHL1, ITPR1
and SLC6A1 genes could lead to neurodevelopmental difficulties
because of their high expression patterns in the
brain [19-22]. In approximately one-third of patients, a
congenital heart defect (CHD), commonly atrioventricular
septal defect, has been reported. Shuib et al. [23] reported
a detailed aCGH analysis of 14 patients with 3p deletion
syndrome. As well as the typical symptoms of 3p deletion
syndrome including neurodevelopment delay and different
structural malformations, five patients also exhibited CHD.
The authors suggested a candidate critical region for CHD
of approximately 200 kb in the region 3p25 containing
genes HRH1 and ATG7, although the involvement of the
previously proposed CRELD1 gene [24] located distally
could not be excluded. Our case had deleted HRH1, ATG7
and CRELD1 but without heart defects suggesting variant
penetrance in different cases.
CAV3 and MTMR14 were also suggested to contribute
to phenotype of 3p deletion syndrome [25,26]. CAV3 (Caveolin
3, MIM 601253) and MTMR14 (Myotubularin-related
protein 14, MIM 611089) that encodes a muscle-specific
inositide phosphatase, contribute to the development and
regulation of muscles. Disruption of the CAV3 gene can lead
to different types of skeletal muscle disorders of autosomal
dominant mode of inheritance such as familial hypertrophic
cardiomyopathy (MIM 192600), hyperCKemia (MIM
123320), Tateyama type of distal myopathy (MIM 614321)
and rippling muscle disease (MIM 606072), long QT syndrome
9 (MIM 611818), while disruption of the MTMR14
gene can lead to centronuclear myopathy (MIM 160150).
Chen et al. [27,28] reported two prenatal cases with
distal 3p deletion. In the first case, cytogenetic and aCGH
analysis showed a de novo deletion 3p25.3-pter, including
a large number of genes that are involved in neurodevelopment
disorders. The pregnancy was terminated at 24
weeks’ gestation and fetal autopsy showed brachicephaly,
micrognatia, short and thick nose, together with hypertelorism
and low-set ears, which were also present in our
case. The second prenatal case showed 3p deletion accompanied
with fetoplacental discrepancy [28].
A finding of isolated septated cystic hygroma during
the first trimester of pregnancy is associated with chromosomal
abnormalities in approximately 50.0% of cases,
most commonly numerical chromosomal aberrations, e.g.,
monosomy X or trisomies 21, 13 and 18 [29]. Structural
chromosomal abnormalities are considered as rare findings,
detected in approximately 2.5% of such pregnancies
[30]. The use of microarray analysis increases the probability
of detection of pathogenic CNV to approximately
4.0% in cases of isolated NT and to 7.0% when additional
malformations are present [31].
In conclusion, our case emphasizes the value of first
trimester NT measurement as a screening method not only
for the most common numerical chromosomal abnormalities,
but also for rare structural rearrangements. Furthermore,
the application of both conventional and molecular
cytogenetic methods, are essential for detection and precise
delineation of revealed aberrations, enabling detailed genetic
counseling regarding present and future pregnancies.
Acknowledgments. Authors’ contributions: M.
Vulic, S.Z. Tomas and R.G. Juraski contributed to the
identifica-tion of the local case; A. Vicic, F. Stipoljev and
M. Logara performed the cytogenetic, FISH and aCGH
analyses; M. Barbalic, R.G. Juraski and M. Logara drafted
the manuscript; F. Stipoljev contributed significantly to the
manuscript preparation. All authors read and approved the
final manuscript.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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