This study examined fetuses with microdeletion 22q11 (del 22q11), the most common genetic deletion. The study found: 1) 65% of fetuses with del 22q11 had an enlarged cavum septi pellucidi (CSP), compared to the reference range. 2) The CSP was even more likely to be enlarged (89%) in fetuses with del 22q11 after 22 weeks gestation. 3) An enlarged CSP may be an important additional sonographic marker for del 22q11 when detected along with cardiac defects and thymic hypoplasia.

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doi: 10.1002/pd.4911
This article is protected by copyright. All rights reserved.
Dilated Cavum Septi Pellucidi in Fetuses with Microdeletion 22q11
Running head: Dilated CSP in fetal del.22q11
Rabih Chaoui (1), Kai-Sven Heling (1), Yili Zhao (2), Elena Sinkovskaya (2), Alfred
Abuhamad (2), Katrin Karl (3)
1) Center for Prenatal Diagnosis and Human Genetics, Berlin, Germany
2) Division of Maternal-Fetal Medicine of the Department of Obstetrics & Gynecology at
Eastern Virginia Medical School, Norfolk, VA, USA
3) Center for Prenatal Diagnosis, Munich, Germany
Correspondence:
Prof. Dr. med. Rabih Chaoui
Center for Prenatal Diagnosis and Human Genetics,
Friedrichstrasse 147, Berlin-Germany
chaoui@feindiagnostik.de
Funding source: none
Conflicts of interest: none declared
Keywords: Cavum septi pellucidi, del.22q11, DiGeorge Syndrome, Fetal neurosonography,
biparietal diameter

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What is already known about this topic?
-Deletion 22q11 is the most common deletion and is prenatally detected primarily in the
presence of a fetal cardiac defect.
- In infants and adults patients with deletion 22q11 have a persistence of the cavum septi
pellucidi
- The cavum septi pellucidi is easy visualized in the fetus since it is part of the basic obstetric
ultrasound examination of the fetal head.
What does this study add?
-The study found that 65% of fetuses with deletion 22q11 have a dilated cavum septi
pellucidi in the second half of gestation
-A dilated cavum septi pellucidi can raise the suspicion for the presence of deletion 22q11
especially in the presence of a cardiac defect.

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ABSTRACT
Objectives: The cavum septi pellucidi (CSP) is an easily recognizable landmark in the fetal
brain. CSP disappears after birth to form the septum pellucidum. Children with microdeletion
22q.11 (del. 22q11) were however reported to have a persistent dilated CSP. This study was
designed to examine whether the CSP is dilated in fetuses with del.22q11.
Methods: This was a case-control study where the CSP width was measured in normal
fetuses from 16 to 34 weeks and in fetuses with del. 22q11. CSP width was correlated to the
biparietal diameter (BPD). Reference curves were constructed and z-scores calculated.
Results: CSP width in 260 normal fetuses showed a linear correlation with BPD. The study
group consisted of 37 fetuses with del. 22q11. In 25/37 (67.5%) of fetuses with del. 22q11,
the CSP was enlarged with a mean z-score of 2.64 (p<0.0001). Fetuses with a BPD > 50mm
(>22 weeks gestation) had a dilated CSP in 89% (24/28).
Conclusions: The CSP is a structure routinely evaluated in screening ultrasound. A wide
CSP is found in second trimester fetuses with del. 22q11. A dilated CSP may be an
important sonographic marker for the presence of del. 22q11 along with conotruncal
malformations and thymic hypoplasia.

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Introduction
The cavum septi pellucidi (CSP) is an easily identifiable structure in the axial views of the
fetal head, which are obtained on routine obstetric scans as recommended by guidelines of
fetal neurosonography [1,2]. The CSP is identifiable between 16 weeks and term and the
CSP resolves after birth as the two laminae of the cavum form the septum pellucidum. The
visualization of the fetal CSP was originally used in the eighties as a landmark for obtaining
the correct plane for the measurement of the biparietal diameter. Later the identification of
an absent CSP was emphasized as a clue to the presence of a number of midline anomalies
[3-5], which include holoprosencephaly, complete agenesis of the corpus callosum, agenesis
of the septum pellucidum and others [6]. Interest in the CSP has emerged recently with the
association of a wide CSP with fetuses with aneuploidy, such as trisomy 18, 21 and 13 [7]. A
recent postnatal study reported on the presence of a dilated CSP in children with a
microdeletion 22q11 (del. 22q11)[8]. This observation led us to address the question of
whether fetuses with del. 22q11 have a dilated CSP in utero.
Patients and Methods
This was a retrospective case-control study on stored images of the fetal head with a
documented cavum septi pellucidi. All ultrasound examinations were performed using high-
resolution equipment (Voluson E8, Voluson E10, GE Medical Systems, Zipf, Austria) and
convex transabdominal transducers (RAB-4-8, RM-6C, RAB6C). Ultrasound images were
stored in an image archiving system (Viewpoint® - GE-Healthcare Medical Systems,
Solingen-Germany), which allowed offline measurements. As a standard requirement of our
institution, all patients provided signed informed consent for fetal examination and agreed to
storage of digital images for quality control and later data evaluation. The control group
included fetuses with no known anatomic or genetic malformations and with normal neonatal
outcome. Additional criteria for inclusion in the control group included singleton pregnancies
and gestational age between 16+0 and 34+0 weeks, confirmed by a crown-rump length
measurement in early gestation. Pregnancies complicated with maternal diabetes, fetal

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growth restriction or other pregnancy complications were excluded from participation in the
control group. The study group included fetuses with a confirmed del. 22q11 either after
invasive procedures or after postnatal FISH or microarray examinations. The following
prerequisites were required for the evaluation and measurement of the CSP: Axial plane of
the fetal head at the transventricular plane with clearly visible CSP (Figures 1,2). The width
of the CSP was measured in its middle part by placing the calipers on the inner portion of its
lateral borders as described by Abele et al [7]. All measurements were performed by one
examiner using the Viewpoint®
software of the imaging archiving system. Intraobserver
variability was evaluated for the CSP width, by re-measuring the CSP in 30 randomly
selected head images from the control population. The corresponding BPD measurement
was also retrieved from the ultrasound reports for correlation with CSP width. In order to
minimize bias, head images of fetuses with del. 22q11 were mixed with head images from
the control group prior to CSP measurements. The examiner measuring the CSP was
therefore blinded to the origin of the images from cases or controls. Data acquired from each
fetus in the study included gestational age, fetal biparietal diameter (BPD), CSP width, width
of the lateral ventricles, presence and type of cardiac or extracardiac defects and fetal
outcome. Only the images from the earliest acceptable ultrasound examination were
included in the statistical analysis.
Statistical analysis
Regression analysis was applied to assess the relationship between CSP width and
biparietal diameter. Measurements of CSP width were transformed into z-scores and
compared using Student’s t-test after verifying a normal data distribution by the Kolmogorov–
Smirnov test. Statistical comparison between subgroups was also performed using Student’s
t-test. A Bland–Altman plot with 95% limits of agreement was applied to evaluate the
intraobserver variability for systematic error. Analysis was performed using the statistical
packages GraphPad Prism 4 and GraphPad InStat for Windows (GraphPad Software, San
Diego, CA, USA).

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Results
The reference range for CSP width was produced using data from 260 fetuses in the control
group. There was a significant linear increase in CSP width in relationship to the BPD from a
mean of 3.0 to 6.3 mm for a BPD of 40 and 90 mm respectively (CSP width (mm) = 0.495 +
0.0642 BPD (mm) + 0.614; r2 = 0.69; P < 0.0001; Figure 3) similar to previously reported
results [7]. The Bland–Altman plot with 95% limits of agreement from −0.35 to 0.33 mm
confirmed reliable reproducibility and an absence of systematic error.
The study group was comprised of 37 fetuses with confirmed del. 22q11 and who fulfilled the
study inclusion criteria. All cases were detected due to the presence of a cardiac
abnormality. Cardiac anomalies in the cases included are listed in Table 1. 15/37 cases had
more than one cardiac diagnosis. Additional structural extracardiac anomalies found were
spina bifida (n=1), multicystic kidney (n=1) and mega cisterna magna (n=1). An absent or
hypoplastic thymus on ultrasound was observed in all but three fetuses, 2 with pulmonary
atresia with VSD and one with an isolated right aortic arch. Pregnancy termination was
performed in 25 pregnancies and live birth occurred in the remaining 12. Out of the 12 live
born children, six children were surgically operated, one of whom died at day 45 postnatally.
In the study group the width of the CSP was increased with a mean of 5.6mm (median
5.8mm) (Fig. 3). The calculated CSP z-scores in deletion 22q11 fetuses were significantly
higher than in the euploid group, with a median of 2.64 ± 1.44 for del. 22q11 (p < 0.0001)
(Fig. 4) in comparison to zero for controls. In 67.5% (25/37) of the fetuses with del.22q11,
CSP width was above the 95th percentile.
The 12 fetuses in the cases with normal sized CSP had similar cardiac anomalies when
compared to the 25 fetuses with enlarged CSP. The size of the lateral ventricles was not
different within the subgroups (5.6mm vs. 5.9mm.). CSP enlargement appears to be more
striking in fetuses after 22 weeks’ gestation or with a BPD >50mm. In the total study
population (del. 22q11) 25/37 (67.5%) had a dilated CSP but considering fetuses after 22

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weeks with a BPD > 50mm, 24/28 fetuses (85.7%) had a dilated CSP.
Discussion
Deletion 22q11 (DiGeorge Syndrome), with an estimated prevalence of 1:2000 - 1:4000 live
births, is the most common deletion in humans and is the second most common
chromosomal abnormality in infants with cardiac defects after trisomy 21 [9-11]. In the fetus,
this deletion is typically suspected when a conotruncal cardiac defect is detected, in
combination with a small thymus [12-14], and/or in the presence of additional sonographic
signs such as facial dysmorphism [15], polyhydramnios [16], fetal growth restriction, and
others [10]. The presence of fetal right aortic arch abnormalities increases the risk of del.
22q11 [17]. Del. 22q11 is associated with wide spectrum of abnormalities and is considered
as the most common genetic abnormality in the presence of psychiatric disorders, mainly
schizophrenia [9,18,19].
Reference ranges for the width of the CSP have been previously reported [7,20,21]. In a
large systematic study on CSP size in 139 fetuses with aneuploidy, CSP was noted to be
dilated in 92%, 40 % and 41% in trisomy 18, 13 or 21 respectively [7]. Other anecdotal
reports have correlated dilated CSP in fetuses with CNS malformations, chromosomal
aberrations or as a normal variant [23].
To our knowledge, this is the first report of dilation of the CSP in fetuses with del. 22q11. In
this study we show that the width of the CSP is increased in 67.5% of fetuses with del.
22q11 in the second half of gestation. Interestingly in fetuses with del.22q11 after 22 weeks
of gestation with a BPD > 50mm, the rate of dilated CSP was even higher at 85.7%. In
addition no difference in the type of cardiac anomalies was found between fetuses with
normal versus those with dilated CSP. Since in our study no fetus had a normal structured
heart we cannot speculate on the significance of a dilated CSP as a single ultrasound
marker for del. 22q11.
Dilation of the CSP has been previously reported in children with del. 22q11 [8]. MR
examination in postnatal population, however, suggests that the CSP decreases in size and

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closes to form the septum pellucidum in almost all individuals [25]. As our study was limited
to prenatal sonography, we were unable to confirm whether fetuses with dilated CSP had
progression in CSP size in infancy and whether the CSP size would have reverted to normal
with long term follow up.
The pathophysiologic mechanism for the dilation of the CSP in fetuses with del. 22q11 is
currently unclear. Seepage of cerebrospinal fluid from the anterior horns of the lateral
ventricles to the CSP may explain the dilation of CSP in association with fetal aneuploidy
given the presence of dilated lateral ventricles in such cases. This however may not explain
the dilated CSP in association with del. 22q11 as the lateral ventricles were of normal size in
our study population (mean value 5.8 mm). An alternate explanation was suggested by
Beaton et al[8], who proposed that the dilated CSP is primarily related to a generally
decreased cerebral cortical mass and a smaller temporal lobe structures in individuals with
del. 22q11. The authors state that likely contributing factors include a generally decreased
cerebral cortical mass which does not exert enough medial force combined with diminished
downward pull exerted by smaller temporal lobe structures such as the hippocampus [8].
Overall brain volume, including gray and white matter, is reduced by about 8-11 % in
children with del. 22q11 when compared to normal controls [24,26]. Indeed subtle changes
in the brain at the perisylvian region, at the same anatomic level as the CSP, have also been
reported in del. 22q11 [27]. Interestingly postnatal reports correlate the persistence of dilated
CSP with psychiatric disorders such as schizophrenia [28]. Whether the presence of a
dilated CSP in a fetus with del. 22q11 increases the associated risk for schizophrenia later in
life is currently unknown, but this observation warrants further investigation. In their study on
persistent and dilated CSP in patients with del22q11, Beaton et al. [8] did not correlate their
observation on MR with the psychiatric outcome.
Our study has some limitations. The retrospective nature of data collection from referral
centers with advanced expertise in fetal echocardiography may introduce selection bias as
the study population is at high risk for complex congenital heart disease and genetic
malformations. The application of our results to the low-risk population needs to be validated

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in future studies. Furthermore, due to the retrospective nature of our study design, we were
not able to get postnatal longitudinal follow-up and thus were unable to evaluate the CSP
size in the neonatal period and beyond. Postnatal studies on the subject however confirm
the association of dilated CSP with del. 22q11[8]. Finally, we were not able to fully assess
the false positive and false negative rate of a dilated CSP in del. 22q11 due to the nature of
the study design.
Our observation may have significant clinical implications and provide an additional clue for
the presence of del. 22q11 in a fetus with congenital heart disease. Confirming the presence
of a normal CSP is part of the national and international guidelines for the performance of
the obstetric ultrasound examination [1]. Given the technical difficulty involved in the
diagnosis of fetal conotruncal malformations and in the assessment of the upper chest for
thymic hypoplasia in such cases, the presence of a dilated CSP, imaged in the standard
biparietal diameter plane, is therefore an important sign, warranting referral for detailed fetal
anatomic survey and fetal echocardiography. Furthermore, with the wide application of non-
invasive prenatal screening for aneuploidy, the option for del. 22q11 screening is now
available. The presence of additional ultrasound markers may help in enhancing accuracy of
non-invasive screening and thus minimize false-positive findings [30]. A dilated CSP may
help in identifying fetuses at risk for del. 22q11 in addition to the presence of conotruncal
cardiac malformations and thymic hypoplasia.

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Table 1: The pattern of cardiac defects in the 37 study cases and the associated findings as
right aortic arch (RAO), aberrant right subclavian artery (ARSA) and the normal or dilated
cavum septi pellucidi (CSP). VSD, Ventricular septal defect, AVSD, Atrioventricular septal
defect, DA Ductus arteriosus. Thymus was hypoplastic or absent in 34/37 of fetuses. A right
or double aortic arch was present in 14/37 fetuses.
N CSP
Normal
/Dilated
Common arterial trunk 9
( 2xRAO, 2xARSA)
2/7
Pulmonary atresia with VSD 6
(1xRAO, 1xARSA)
2/4
Interrupted aortic arch 5
(1xARSA )
3/2
Tetralogy of Fallot 5
(3x RAO,1xARSA)
1/4
RAO (isolated) 5 1/4
VSD 2 0/2
AVSD 2
(2xRAO)
2/0
Double aortic arch 1 0/1
Abnormal DA 1 1/0
Absent pulmonary valve 1 0/1
TOTAL 37
(14xRAO,5x ARSA)
12/25

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Figure 1: Axial plane of the fetal head showing at 22 weeks the normal wide cavum septi
pellucidi of 4mm for a BPD of 55mm

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Figure 2: In comparison to figure 1, the head of two fetuses at 24 (left) and 22 (right) weeks
of gestation with deletion 22q11 shows a dilated of cavum septi pellucidi. Left fetus CSP
diameter is 7.4mm and right fetus 6.7mm for a BPD of 64mm and 56mm respectively.

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Figure 3: Individual measurements of the width of cavum septi pellucidi (CSP) in normal
fetuses (°) with the reference range in relation to biparietal diameter (BPD). In comparison
are plotted the CSP width measurements in 37 fetuses with deletion 22q11 ( ). Lines
represent median (solid line) and 5th and 95th centiles (dashed lines) of the normal fetuses.

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Figure 4: Box-and-whisker plot of cavum septi pellucidi width expressed as z-scores in
normal fetuses (left box) and in the study group with deletion 22q11 (right box). Boxes and
internal lines show median interquartile range. Fetuses with deletion 22q11 have a highly
significantly larger CSP (p<0.0001) than the normal population.