NON-INVASIVE SCREENING TEST PARADOX IN A CASE BORN WITH MIXED GONADAL DYSGENESIS (45,X/46,XY)
Cobanogullari H., Akcan N., Ergoren M.C.
*Corresponding Author: Assoc. Prof. M.C. Ergoren, PhD, Near East University, Faculty of Medicine, Department
of Medical Genetics, 99138 Nicosia, Cyprus. E-mail address: mahmutcerkez.ergoren@neu.edu.tr
page: 57
|
|
DISCUSSION
Genome-wide studies allow scientists to detect fetal
and maternal (mosaic) aneuploidies [4,13]. According to
different studies, sequencing cffDNA from maternal plasma
can be helpful to detect all fetal chromosomal aneuploidies,
segmental imbalances, and submicroscopic copy number
variations (CNVs). However, it has been pointed out that
NIPT is not routinely used for screening sex chromosomal
aneuploidies (SCAs) because different phenotypes are observed
in SCAs, such as monosomy X (Turner syndrome),
XXY (Klienefelter syndrome), XYY and XXX, and some
of the phenotypes re not detected until adulthood due to
fertility problems [4,7,11]. Moreover, the use of NIPT for
the detection of mosaicism has not been fully elucidated.
In this particular study, we reported on a case whose
NIPT diagnosis was originally 45,X and who was diagnosed
with mixed gonadal dysgenesis 45,X/46,XY after
birth. A 38-year-old [G3P3] pregnant woman underwent
NIPT at 15 weeks’ gestation and was found to be at probable
risk for 45,X. The pregnant woman did not want to
undergo cordocentesis due to it is an invasive procedure.
Subsequently, karyotyping of peripheral blood and oral
mucosal epithelial cells was performed after birth and the
baby’s karyotype was determined as 45,X/46,XY+mar?
respectively. In addition, SRY gene duplication was detected
by fluorescence in situ hybridization (FISH) and
microarray analysis. Based on the findings from the microarray
analysis in the analyzed sample, one copy of the
X chromosome was detected in all cells and the presence
of one copy of the Y chromosome was detected in a ~40%
mosaic state: arr(X)x1,(Y)x1[0.4]. The patient’s clinical
examination showed ambiguous genitalia (clitoromegaly)
and dysmorphic facial features. Based on the clinical information
provided, the marker chromosome observed in the
karyotype of the patient is likely the mosaic chromosome
Y. The results are consistent with the genetic diagnosis of
45,X/46,XY mixed gonadal dysgenesis.
Individuals with mixed gonadal dysgenesis (MGD)
exhibit chromosomal mosaicism as well as dysgenetic
gonads and different internal and external reproductive
morphology [14]. Because of clinical variance, the true
prevalence of MGD is unclear. In our case, the ovaries
were examined and they were normally formed.
While mixed gonadal dysgenesis (MGD) is cytogenetically
45,X/46,XY, Turner syndrome is generally defined
as 45,X. Patients with 45,X/46,XY show a wide range
of phenotypes, including phenotypically normal males and
Turner syndrome [15,16]. Cardiovascular anomalies such
as bicuspid aortic valve, hypertension, aortic coarctation,
dilatation of the growing aorta are observed in 20-40%
of patients with MGD [17,18]. In a different study, it was
stated that patients who have MGD and whose karyotype
was characterized by 45,X/46,XY were known to
have complications of Turner syndrome. In that study, a
16-year-old social male with MGD was reported to develop
coarctation of the aorta, which is one of the most common
problems in Turner syndrome [19]. In our study, the baby
underwent surgery for aortic coarctation.
The physical appearence of an individual relies on
anatomical sex analysis. Karyotype analysis, however,
reveals the choromosomal sex which is mainly used to
classify sex developmental disorders. In these diseases,
although different conditions are detected, 45,X/46,XY
mosaicism, known as mixed gonadal dysgenesis, is commonly
observed. It has been hypothesized that this mosaicism
occurs mainly due to the loss of the Y chromosome
because of the non-disjunction that occurs during normal
disomic fertilization [20].
Moreover, Mosaic Turner syndrome cases may arise
incidentally during divisions that occur in early embryogenesis,
at cleavage stage. Patients with mosaic Turner
syndrome have a mosaic karyotype of 45,X/46,XX,
46,X,i(Xq) and other variants [1]. Genotype 45,X/46,XY
is observed in nearly 10-12% of patients with Turner syndrome
[21]. The mosaic Turner Syndrome may be underdiagnosed
due to several reasons, such as subtle phenotypic
characteristics and technical problems [12]. This
is especially common in patients who have low rates of
mosaicism due to an increased number of euploid cells that
may affect the true genetic diagnosis of Turner Syndrome
[1]. Mosaicism, which is unique to the fetus, and the very
low amounts of Y chromosomes in maternal blood could
explain false-negative results for the presence of a Y chromosome
upon NIPT [6,22]. Because the distribution and
proportion of euploid and aneuploid cells are different in
mosaic pregnancies, these could be important biological
factors which reduce the effective DNA proportion, thus
obtaining a false-negative aneuploidy [10].
In addition, Hayata et al., (2016) point out that most
cffDNA found in maternal blood plasma is derived from
trophoblastic cells of the placenta and not from the fetus.
Therefore, NIPT cannot provide a definitive diagnosis
[23]. In another study, it was discussed that false negative
NIPT results occur due to chromosomal mosaicism. It was
mentioned that two different mosaicisms are associated
with a normal karyotype in the cytotrophoblast, while the
fetus itself has a chromosomal abnormality [13]. The first
type of mosaicism is generalized mosaicism confined direct
normality (GMDD), which is defined by the presence
of a chromosomal abnormality in the fetus and the mesechymal
origin of the placenta, with the cytotrophoblast
being chromosomally not abnormal. On the other hand,
the very rare confined fetal mosaicism (CFM) shows a
normal karyotype in the villi of short-term and long-term
culture and abnormal cytogenetic results in the fetus. Importantly,
both types of mosaicism show normal NIPT
results because the karyotype in the cytotrophoblast is
normal, although the fetus has an abnormal karyotype.
Also, it has been pointed out that a normal NIPT result
may be a false negative result [13,24].
Importantly, each test and diagnostic procedure has
its own benefits and risks. Most prenatal genetic screening
tests are designed to reduce the risk of invasive procedures.
Analysis of karyotype by amniocentesis remains as the
most common method for detecting SCAs and the golden
standard for cytogenetic diagnosis [4,9]. In addition, prenatal
diagnosis of SCAs in a fetus might be complicated
due to several reasons, one of which is the lack of confirmatory
ultrasound findings beyond increased nuchal
translucency. Additionally, maternal factors such as SCA
mosaicism or age-related loss of the X chromosome can
affect the interpretation of the data, causing false positive
cfNIPT results. Furthermore, it has been emphasized that
when the fetus-driven cell-free DNA concentration is low
in the blood, non-invasive prenatal genetic testing is not
determinate [7].
Moreover, it has been indicated that cytogenetic analysis
may not be sufficient to detect Y-chromosome material
since it may be found in a small number of cells in small
amounts or even as part of marker chromosomes containing
Y-specific regions [5,25]. Thus, other techniques such
as molecular analysis should be used for the accurate diagnosis
of Turner Syndrome. The percentage distribution
of mosaicism in different tissues, which differs between
blood and gonadal tissue, determines the phenotype of a
45,X/46,XY mosaic patient [7,8].
According to the literature, although NIPT has been
introduced to detect sex chromosomal abnormalities,
these tests are far from replacing invasive diagnostic procedures.
Moreover, in several studies it has been stated
that mosaicism cannot be confirmed by NIPT [4,26]. For
example, one study reported that NIPT and karyotyping
results were inconsistent in Turner syndrome (TS). In summary,
a 35-year-old pregnant woman underwent NIPT and
showed probable risk for Xp deletion. However, amniocentesis
was performed and after cytogenetic analysis the
karyotype was determined as mos 45,X [28]/46,X,i(X)
(q1.0) [5]. In the second case, a 33-year-old woman underwent
NIPT and showed a probable risk of monosomy
X. However, amniocentesis was performed and after the
cytogenetic analysis the karyotype was determined as mos
45,X [8]/46,XY[8] [4].
Importantly, if the fetus is detected at high risk for
aneuploidy, further testing is required to confirm the NIPT
result. Positive NIPT results for sex chromosome abnormalities
should be carefully evaluated and confirmed with
an invasive procedure [4,22]. Therefore, it is crucial that
women interested in NIPT should be fully informed about
the procedure, its benefits, and limitations. Furthermore,
pregnant women who have had a positive ultrasound result
are strongly advised to undergo invasive prenatal testing
[10,11].
In invasive prenatal diagnostics, the use of chromosome
microarray analysis, and more recently next-generation
sequencing approaches, has significantly expanded
the prenatal diagnostic yield. According to the literature,
next-generation sequencing approaches should be used
in addition to normal routine testing including karyotype
and/or chromosome microarray analysis and not as the first
diagnostic test for fetal abnormalities. When using these
new techniques, parental counselling should be mandatory
before and after testing, and close collaboration in a
multidisciplinary team is strongly recommended [4,11].
In conclusion, although NIPT has been routinely
used to screen numerical abnormalities including trisomy
21,18 and 13, it still has potential limitations in correctly
identifying sex chromosomes and mosaicism that may
mislead clinicians and families. In routine clinical practise,
conventional cytogenetic analysis following invasive
prenatal testing remains as an important component of
prenatal care.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
