Content uploaded by Milan Stanojevic
Author content
All content in this area was uploaded by Milan Stanojevic on Jul 17, 2018
Content may be subject to copyright.
J. Perinat. Med. 2017; 45(6): 651–665
Review article
Lara Spalldi Barišić*, Milan Stanojević, Asim Kurjak, Selma Porović and Ghalia Gaber
Diagnosis of fetal syndromes by three- and
four-dimensional ultrasound: is there any
improvement?
DOI 10.1515/jpm-2016-0416
Received December 19, 2016. Accepted February 15, 2017. Previously
published online May 11, 2017.
Abstract: With all of our present knowledge, high techno-
logy diagnostic equipment, electronic databases and
other available supporting resources, detection of fetal
syndromes is still a challenge for healthcare providers
in prenatal as well as in the postnatal period. Prenatal
diagnosis of fetal syndromes is not straightforward, and
it is a difficult puzzle that needs to be assembled and
solved. Detection of one anomaly should always raise a
suspicion of the existence of more anomalies, and can
be a trigger to investigate further and raise awareness of
possible syndromes. Highly specialized software systems
for three- and four-dimensional ultrasound (3D/4D US)
enabled detailed depiction of fetal anatomy and assess-
ment of the dynamics of fetal structural and functional
development in real time. With recent advances in 3D/4D
US technology, antenatal diagnosis of fetal anomalies
and syndromes shifted from the 2nd to the 1st trimester
of pregnancy. It is questionable what can and should be
done after the prenatal diagnosis of fetal syndrome. The
3D and 4D US techniques improved detection accuracy of
fetal abnormalities and syndromes from early pregnancy
onwards. It is not easy to make prenatal diagnosis of fetal
syndromes, so tools which help like online integrated
databases are needed to increase diagnostic precision.
The aim of this paper is to present the possibilities of dif-
ferent US techniques in the detection of some fetal syn-
dromes prenatally.
Keywords: Craniofacial anomalies; fetal syndromes; four-
dimensional ultrasound; high-definition live rendering;
prenatal diagnosis, three-dimensional ultrasound.
Introduction
According to the European Registry of Congenital Mal-
formations (EUROCAT), the prenatal detection rate for
18selected congenital anomalies excluding genetic condi-
tions ranges from 44.8% for clubfoot (talipes equinovarus)
to 98.4% for anencephaly and similar conditions, while all
genetic conditions have been prenatally detected in 72.8%
of cases, with the range from 66.1% for Down syndrome
and 93.6% for Edwards syndrome (Table 1) [1]. The overall
detection rate of all abnormalities is reported to be 34.5%
in the EUROCAT [1].
Data on the prenatal detection rates of some syn-
dromes are missing. A fetal syndrome should always be
searched for and considered if at least two congenital mal-
formations have been detected prenatally. Monogenetic
syndromes have a low prevalence rate, from 0.02 per
10,000 births for all types of acrocephalopolysyndactyly
to 0.96 per 10,000 births for DiGeorge syndrome [1].
With the introduction of ultrasound (US), prenatal
detection of congenital malformations became available.
Yet, there are still unsatisfactory detection rates in eve-
ryday clinical practice. Three-dimensional ultrasound
(3D US) has been claimed by some authors to increase
the detection rates of all malformations, while others are
skeptical about it. Knowledge on the prenatal detection
rate of more than 6000syndromes is still sparse and only
a few hundred and counting can be detected prenatally.
*Corresponding author: Lara Spalldi Barišić, MD, Director of Ian
Donald Inter-University School of Medical Ultrasound, Croatian
Branch, Mlinovi 161A, 10 000 Zagreb, Croatia; and Specialist in
Obstetrics and Gynecology at Private Clinic Veritas d.o.o, Zagreb,
Croatia, Tel.: +385-(98) 462 392, E-mail: spalldi@gmail.com
Milan Stanojević: Ian Donald Inter-University School of Medical
Ultrasound, Zagreb, Croatia; and Department of Obstetrics and
Gynecology, Medical School University of Zagreb, University
Hospital “Sveti Duh” Zagreb, Croatia
Asim Kurjak: Ian Donald Inter-University School of Medical
Ultrasound, Zagreb, Croatia
Selma Porović: Ian Donald Inter-University School of Medical
Ultrasound, Sarajevo, Bosnia and Herzegovina
Ghalia Gaber: Ian Donald Inter-University School of Medical
Ultrasound, Abu Dhabi, UAE
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
652Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound
However, implementing new ideas and knowledge from
scientific research along with taking advantage of pro-
gress in available diagnostic equipment make prenatal
detection much more accurate and precise. With the recent
dynamic and quick development of computer technology,
like 3D high definition live (3D HDlive) silhouette and
flow US technology, there has been an enormous break-
through in US equipment, with remarkable image quality.
Thanks to highly specialized software systems, it is possi-
ble to view fetal anatomy in the smallest detail [2] and the
dynamics of fetal structural and functional development
in real time. Using four-dimensional (4D) technology, one
can get an idea of the functionality of some organs and
systems, for example, the brain or the eye, introducing
new fields of fetal assessment like fetal neurology or fetal
sono-ophthalmology [3]. Some new functional tests have
even been introduced in everyday clinical practice, like
the Kurjak antenatal neurodevelopmental test (KANET),
to assess the function of the fetal brain [4–7], adding
some additional valuable input into the diagnosis of fetal
syndromes [8]. Many authors reported a shift of prenatal
detection of fetal syndromes from the 2nd to the 1st trimes-
ter of pregnancy [3, 8, 9–13].
The aim of this paper is to present and discuss the
possibilities of different US techniques to improve the
detection rates of some fetal syndromes prenatally.
When to suspect a syndrome
prenatally and how to detect it
Common terminology used to describe fetal syndromes
can sometimes be confusing. A wide variety of terms and
synonyms are used. Sometimes, there is a lack of good
definitions of how many major and minor criteria should
be present to diagnose each syndrome. The difference in
prenatal detection rates for each region or country can be
partly explained by differences in screening policies and
follow-up practices, as well as the possible variations in
practitioners’ skills and available equipment [8].
Clinical dysmorphology is a branch of clinical genetics
dedicated to the study of abnormal human development,
with emphasis on syndromes expressed mostly as altera-
tions in body morphology [14, 15]. There are many patho-
physiological mechanisms for fetal maldevelopment,
which can be described as malformation, deformation,
disruption or dysplasia [16]. Malformation is commonly
defined as a single localized poor formation of tissue initi-
ating a sequence of defects (e.g. anencephaly). The recur-
rence risk for malformations generally range from 1% to
5%. Deformation is a result of extrinsic mechanical forces
on otherwise normal tissue, deforming it (e.g. abnormal
faces, pulmonary hypoplasia and limb contractures that
Table 1:Prenatal diagnosis of 18selected congenital anomaly subgroups for registries with complete EUROCAT data from 2010 to 2014 [1].
Malformation Total cases Cases prenatally diagnosed
(% of total cases)
Excluding genetic conditions
All anomalies (excluding genetic conditions) , , (.)
Anencephalus and similar (excluding genetic conditions) (.)
Spina bifida (excluding genetic conditions) (.)
Hydrocephalus (excluding genetic conditions) (.)
Transposition of great vessels (excluding genetic conditions) (.)
Hypoplastic left heart (excluding genetic conditions) (.)
Cleft lip with or without palate (excluding genetic conditions) (.)
Diaphragmatic hernia (excluding genetic conditions) (.)
Gastroschisis (excluding genetic conditions) (.)
Omphalocele (excluding genetic conditions) (.)
Bilateral renal agenesis including Potter syndrome (excluding genetic conditions) (.)
Posterior urethral valve and/or prune belly (excluding genetic conditions) (.)
Limb reduction defects (excluding genetic conditions) (.)
Clubfoot – talipes equinovarus (excluding genetic conditions) (.)
Chromosomal
Chromosomal (.)
Down syndrome (.)
Patau syndrome/trisomy (.)
Edwards syndrome/trisomy (.)
Includes the following registries: Antwerp (Belgium), French West Indies (France), Isle de la Reunion (France), Saxony-Anhalt (Germany),
Cork and Kerry (Ireland), SE Ireland, Emilia Romagna (Italy), Tuscany (Italy), Malta, N Netherlands (NL), S Portugal, Basque Country (Spain),
Valencia Region (Spain), Vaud (Switzerland), Wales (UK), Ukraine.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound 653
result from prolonged oligohydramnios or primary renal
agenesis in Potter syndrome with Potter facies). Disrup-
tion results from an extrinsic insult that destroys normal
tissue, altering the formation of affected structure (e.g.
amniotic band syndrome). If the primary defect is absence
of normal organization of cells into tissue, then we speak
of dysplasia (e.g. achondroplasia) [8, 16].
Any of the mechanisms of fetal maldevelopment can
result in altered morphology of fetal organs and systems,
which can result in the formation of a fetal syndrome if
many organs are involved. The word syndrome originates
from ancient Greek meaning “running together” [17], rep-
resenting a specific pattern of associated signs, symptoms,
dysmorphic features and/or behaviors occurring together
in the same individual [8, 14, 15].
Some fetal syndromes can be detected prenatally while
others cannot; some are expressed prenatally while others
are not. In many cases definitive diagnosis can be made
posnatally, many years later [8]. The differential diagnosis
of fetal syndromes is wide, and there are several available
databases online that can be of assistance in the recogni-
tion of patterns of anomalies as a syndrome, sequence or
association [8]. The most widely used online databases are
Online Mendelian Inheritance in Man (OMIM), Orphanet,
London Dysmorphology Database, Possumweb and the
Phenotip online database. For the sonographer, the most
user-friendly database, especially designed to include all
antenatal sonographic findings (instead of postnatal find-
ings), is the Phenotip online database, while the London
Dysmorphology Database and Possumweb are non-free
databases, constructed to aid in differential diagnosis, with
the inclusion of postnatal findings. There is quick access to
the information, with the possibility to search by ultrasono-
graphic marker, a combination of a few markers or just by the
name of the syndrome. The triggers to investigate even more
carefully for the syndrome could be known family history,
earlier pregnancy with malformed fetus/infant, history of
consanguinity, exposure to some teratogenic drug or other
agents, traveling to high-risk areas and possible exposure
to some infections (Zika virus, TORCH infections) or trauma
[8]. There is also the possibility to include parental markers
if present. Synonyms of the syndromes are included in the
search automatically, which makes it easier and faster.
Clinical application of 3D/4D
ultrasound in the prenatal detection
of fetal syndromes
An optimized and systematic approach (guidelines) to the
evaluation of the fetus by conventional two-dimensional
(2D) US should always be followed to avoid mistakes in
prenatal assessment [8]. When evaluating structures like
the fetal spine or the face, 3D/4D US renders much more
accurate images [18]. Magnetic resonance imaging (MRI)
has comparable image quality with US, which is the most
commonly used modality for pregnancy evaluation. US
provides cost-effective real-time imaging, offers high reso-
lution and is considered safe for the mother and the fetus
[19]. US is superior to any other imaging technology in
pregnancy because of the possibility to be used from the
early 1st trimester [18], with the possibility to assess fetal
movements in almost real-time [18]. Undoubtedly, one of
the best non-invasive diagnostic tools for the detection
and visualization of fetal anomalies and syndromes is US,
particularly 3D/4D US [9]. With recent advances in 3D/4D
technology, antenatal diagnosis of fetal anomalies and
syndromes greatly shifted from the 2nd to the 1st trimester
of pregnancy [9, 11, 18].
Goncalves etal. [20] reviewed 525 articles on 3D/4D
sonography and found that 3D US provides additional
diagnostic information for the diagnosis of facial anom-
alies, especially facial clefts, neural tube defects and
skeletal malformations.
Merz and Welter [21] examined a large group of 3472
fetuses evaluated with detailed 2D and 3D US targeted
for fetal anomalies. The total number of defects was
1012. Comparing the 2D and 3D techniques, 3D US proved
advantageous in 60.8% of the defects, which was related
to the favorable demonstration of targeted areas in differ-
ent views (e.g. multiplanar, surface view) [21, 22].
Only in the last several years have high-frequency
transducers and HDlive technology made major improve-
ments in the quality of US imaging. The 3D HDlive ren-
dering method takes advantage of “shadowing effects”
to improve the visualization of details on the image [23].
Unlike conventional 3D surface rendering that uses a
fixed virtual light source and reflects the light off the skin
surface, HDlive rendering calculates the propagation of
light through the skin and the tissue [23]. Shadows are
created where light has moved through denser tissues.
The virtual light source can be changed and directed
easily from any angle and can be manipulated to enhance
segmentation of tissue structures, define precise outlines
and highlight important clinical details [23]. This tool is
handy when observing surfaces, particularly of the facial
area. Any suspected area or malformation can be investi-
gated and visualized much better than with conventional
2D US. By changing the angle of virtual light, one can
adjust it perfectly to emphasize and get depth perception
in visualizing a region of interest that may be an anomaly.
A translucent effect is gained if the light source is placed
behind the object [23]. Enhanced smoothing is obtained
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
654Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound
by volume-speckle reduction imaging (V-SRI) on quality
multi-planar 3D/4D rendered images by applying volume
(voxel) vs. traditional single slice (pixel) imaging.
HDlive rendering can be successfully applied during
the entire pregnancy [18]. In the 1st trimester, normal and
abnormal embryonal and fetal developments can be fol-
lowed and evaluated in the smallest detail. Early and mid-
trimester anomaly scans can be aided with 3D/4D HDlive
technology in detecting fetal anomalies and syndromes,
as suggested by many studies [10, 18, 24–26]. Only 2years
ago, new applications in 3D US called HDlive silhouette
and HDlive flow were launched. HDlive silhouette found
its clinical significance in imaging simultaneously the
inner morphology through the outer surface in a transpar-
ent fashion. This helps in mapping the exact location and
volume of inner structures, which can be hyperechoic,
such as bone, or hypoechoic, such as a cyst [12]. HDlive
flow adds more spatial resolution to a conventional angio-
gram. With the simultaneous combination of both tech-
niques (HDlive silhouette and flow), one can visualize the
exact location of vascular structures inside the organs and
map the direction of the vascular flow (3D HDlive bidi-
rectional power Doppler). These two novel applications
enabled the visualization of intracorporeal vascularity,
premature forebrain, midbrain and hindbrain, as well as
flow in the brain vessels.
The use of a skin-like color tone in HDlive gave an even
more realistic impression of a live fetus, with impressive
pictorial illustration [3, 7–12, 18, 24–30]. Many of the earlier
mentioned innovations in 3D/4D US applications are par-
ticularly beneficial in the prenatal detection and visualiza-
tion of anomalies of the fetal face and its discreet details.
The fascinating combination of science, research and new
technologies is all together implemented in a new upcom-
ing research program called “Give a face to a syndrome” [8,
31]. Facial Dysmorphology Novel Analysis (FDNA®) is a new
technology that facilitates detection of facial dysmorphic
features and recognizable patterns of human malforma-
tions (postnatal/adult life) to present comprehensive and
up-to-date neurogenetic references available online [8, 31].
Brain anomalies
An important milestone in the prenatal recognition of
normal brain development is the visualisation of corpus
callosum (CC) by improved ultrasound imaging; without
this prenatal assessment was rather difficult. With 3D
surface rendering in the median plane, CC can be visual-
ized with all its segments: genu, body and splenium. Addi-
tionally, vascularization of CC with a 3D sonoangiogram
of the pericallosal artery (PA) (Figure 1) and the anterior
cerebral artery (ACA) became much easier than before [12,
32]. If there is a suspicion or clear prenatal diagnosis of
agenesis of CC (ACC), it is important to search for other fetal
abnormalities or syndromes [trisomy 18, cerebro-costo-
mandibular syndrome, Walker-Warburg syndrome, Pai
syndrome, Fryns syndrome and also fetal varicella zoster
syndrome, fetal cytomegalovirus (CMV) syndrome and the
most recently recognized congenital fetal Zika virus syn-
drome, etc.] [33]. Despite the fact that we are able to recog-
nize some structural anomalies prenatally, the prediction
of the exact extent of the damage and prognosis may still
be a challenge [7, 32].
Congenital heart defects
Congenital heart defects (CHD) are the most common con-
genital anomalies occurring more frequently than chro-
mosomal malformations and spinal defects together. The
incidence is estimated to about 4–13 per 1000 live births,
representing a significant cause of fetal mortality and
morbidity [34].
Prenatal diagnosis of CHD by US is difficult, demand-
ing thorough training and expertise. The detection rate of
CHD is variable and it ranges from 35% to 86% in most
studies [34]. In the past, many attempts were made to
improve the prenatal detection rate of CHD. Four-dimen-
sional US (real-time 3D US) used for fetal cardiac assess-
ment may improve visualization of cardiac anatomy and
allow better evaluation of valvular function [20].
Early evaluation of the fetal heart as well as recog-
nition of several major cardiac abnormalities frequently
coexisting in many fetal syndromes (Down syndrome,
Edwards syndrome, DiGeorge syndrome, tarsal tunnel syn-
drome, etc.) can be obtained by 3D/4D US and improved
by special applications [8, 12, 18, 26]. Two-dimensional US
is still the technique of choice for the prenatal diagnosis of
CHD; however, the last decade has shown some promising
results due to advanced 3D/4D US technology [34], such
as advanced spatio-temporal image correlation (STIC),
volume contrast imaging (VCI) and Omni view. STIC is
a technological development of 3D/4D US developed to
assist the detection of CHD. An automated device is incor-
porated into the ultrasound probe that has the capacity to
perform a slow sweep to acquire a single 3D volume [34].
Acquisition of volume data of the fetal heart and connec-
tions is done (the intraventricular septum, atrioventricu-
lar valves, great vessels’ outflow tracts, aorta and ductal
arch) by allowing multiplanar and surface reconstruction
of the heart anatomy [34]. The sonographer, even when
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound 655
Figure 1:3D angiography (bidirectional power Doppler ultrasound imaging).
(A) Normal fetal intracranial circulation. Notice the pericallosal vascularization.
∗
PA (pericallosal artery),
∗
ACA (anterior cerebral artery),
∗
∗
ACA branches,
∗
∗
SSS (superior sagittal sinus). (B–D) The circle of Willis presented in advanced STIC (spatio-temporal image correlation),
3D HD flow, Glass body rendering mode.
less experienced in fetal echocardiography, can acquire
volume data, which can be digitally stored and analyzed
later or sent to a (fetal echocardiography) expert for
further analysis. For better evaluation, the acquired data
can be also assessed in the cine loop feature [34], played
in slow motion and stopped any time to evaluate cardiac
or vascular structures of interest. This application is also
very helpful in counselling the parents and showing them
where the problem is when CHD is found in the fetus.
Detecting the syndrome from
the sonographer’s point-of-view:
adifficult puzzle to solve
DiGeorge syndrome is the microdeletion of chromosome
22q11.2, the most common human deletion syndrome.
This syndrome includes a wide spectrum of abnormalities
among them; CHD [conotruncal, ventricular septal defect
(VSD), tetralogy of Fallot] in more than 40% of cases,
facial dysmorphysm (hyperthelorism, bulbous nasal tip),
cleft palate, hypoplasia/aplasia of the thymus, malfor-
mation of cortical brain development (poly mycrogyria),
missing ribs, open spina bifida, polydactyly and clubfoot
are the most common (Figure2) [33]. All the above-men-
tioned malformations can be detected prenatally by US.
Beside the heart anomalies, thymic hypoplasia/aplasia
is known to be a typical feature in this condition, and
Chaoui etal. [35] suggested that fetal thymic US can be
an additional parameter in the assessment of fetuses
with CHD. Thymic hypoplasia/aplasia finding appears to
be sensitive (90%) in detecting fetuses with 22q11.2 dele-
tion. When defects are found, prenatal cytogenetic eval-
uation should be offered. A frequently used acronym to
remember the features of the syndrome is CATCH-22 (C:
cardiac defects, A: abnormal faces, T: thymus aplasia/
hypoplasia, C: cleft palate, H: hypocalcemia) [36].
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
656Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound
While evaluating fetal faces, one must consider ethnic
variations and normal differences. For example, an epi-
canthal fold may be normal for people of Asiatic descent
and for some non-Asian infants, but it can be considered
as a dysmorphic feature of syndromes such as Down syn-
drome, Turner syndrome, Noonan syndrome, Williams
syndrome, fetal alcohol syndrome, etc. Different shape
of the nose in different ethnic groups is another example
(Mediterranean, African, Asian, Hispanic and Cauca-
sian). A broad-beaked nose is a feature of Wolf-Hirschhorn
syndrome (Greek warrior helmet syndrome) [33] and a
short-beaked nose of some craniosynostosis-associated
syndromes like Apert syndrome, Pfeiffer syndrome,
Crouson syndrome, etc. [37]. A bulbous nose tip is feature
of DiGeorge syndrome, as mentioned earlier. However, if
there is a syndrome, there will be other associated anoma-
lies too. So even a small deviation from the normal can be
a trigger and clue to look further and raise awareness of
possible syndromes.
Syndromes featuring primarily craniofacial
anomalies
Paramedian cleft lip (CL) or cleft palate (CP) or a combina-
tion of the two (Figure 3) are the most common fetal facial
anomalies and one of the most common fetal anomalies.
They occur between the 8th and 9th gestational week and
can be unilateral or bilateral. If this is an isolated finding
(in less than 50% of cases), the defect can be surgically
repaired with a good postoperative result. Unfortunately, a
majority of the fetuses with CL or CP have high incidence of
chromosomal abnormalities and other associated anoma-
lies as part of syndromes [37]. Carriers of Van der Woude
(VdW) syndrome have facial clefts in 50% of cases. VdW
syndrome has an autosomal dominant mode of inherit-
ance, which accounts for approximately 2% of all cases of
CL and CP [37]. Incomplete unilateral small CL can easily
be missed by conventional 2D US, while 3D HDlive surface
rendering is a better method to detect it. Bilateral CL can
ABCD
Figure 3:Paramedian cleft lip (CL) or cleft palate (CP) or a combination of the two (CL/P).
(A) Prenatal detection of unilateral paramedian right CL/P by 3D HDlive surface rendering in fetus with detected Edwards syndrome (trisomy
18). (B) Postnatal presentation of unilateral paramedian right CL/P. (C) Postnatal presentation of unilateral paramedian left only CL. (D) Post-
natal presentation of bilateral paramedian CL/P.
AB
Figure 2:Similarity in visualisation prenatally and postnatally.
(A) Prenatal 3D surface rendering image of clubfeet. (B) Postnatal image of clubfeet.
Prenatally detected one malformatation, should be trigger to search for possible presence of other abnormalities.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound 657
sometimes also be missed because it does not change the
symmetry of facial appearance [13]. Bilateral complete CL
and CP, on the other hand, are most likely to be detected
because of the protrusion of the inner maxillary segment
under the nose, which is an obvious and unusual mass
when observing a profile of the face [37]. When checking
for CP, 3D HDlive surface and maximum modes are valuable
as well as 3D application of tomographic US imaging (TUI),
enabling to better determine the extent of the cleft [18].
Midline clefts are always severe and usually part of
some sequence such as holoprosencephaly, with gross
Figure 4:Postnatal findings of anophtalmia, median facial cleft and
holoprosencephaly in a fetus with Patau syndrome (trisomy 13).
Figure 5:Prenatal detection of micrognathia with low-set ears by 3D HDlive surface rendering.
(A) In a fetus with detected Pierre- Robin sequence (PRS). (B) In a fetus with Meckel-Gruber syndrome (courtesy of S. Panchal).
facial appearance (cyclopia, midline facial cleft to a
diverse extent, cebocephaly, flat nose). It is a common
feature of some chromosomal syndromes such as Patau
syndrome (trisomy 13) (Figure 4) and Edwards syndrome
(trisomy 18). Trisomy 13 is the most common syndrome
associated with alobar holoprosencephaly and facial
clefts. However, up to 75% of holoprosencephaly cases
have normal karyotype [37].
Mandibular anomalies (agnathia, micrognathia, ret-
rognathia) have been described in various syndromes and
seem to be very frequent, either isolated or coexisting as a
part of the more heterogeneous syndrome.
Two-dimensional US images first indicate an abnor-
mal profile, while with the different 3D applications
(Figure 5), it is possible to explore it in more detail and
obtain the complete impression of its appearance and
possible coexistence of other orofacial anomalies.
Pierre-Robin sequence (PRS) is characterized by a
triad of orofacial anomalies consisting of retrognathia,
glossoptosis and a posterior median soft CP. An osseous
defect of the mandible is rarely found. Mandibular hypo-
plasia is a primary defect that occurs early in gestation
between the 7th and 11th week of gestation and causes the
tongue to be maintained high up in the oral cavity, which
subsequently prevents fusion of the posterior soft palate
[16, 37]. Prenatal diagnosis of micrognathia in PRS by 3D
US can be unveiled in the 1st trimester of pregnancy, as
reported by several authors [13, 38, 39]. Pooh and Kurjak
[13] pictorially presented mandibular hypoplasia and slow
jaw development in a case of PRS during pregnancy. Serial
3D scans can be used to clearly reveal improvement and the
progress of mandibular growth over several weeks [13,37].
The catch-up growth of the mandible occurs during the
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
658Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound
first year of life and the adjusted profile of the child can
be expected between the 3rd and 6th year of life [38–40].
Isolated PRS (without any other associated malformation)
occurs in about 50% of cases; however, in the other half
of the cases, PRS is part of a malformation syndrome. The
clinical expression of the syndrome depends on the exist-
ence and severity of associated anomalies [37]. The nature
of these anomalies is diverse – most commonly, the first
branchial arch anomalies, various chromosomal disorders
(DiGeorge syndrome), collagenopathies or syndromes
associated with toxic agents such as alcohol (fetal alcohol
syndrome), etc. In the review of 115 cases of patient with
PRS, as expected, 54% had PRS as an isolated finding.
The others included syndromes such as Stickler syndrome
(18%), velocardiofacial syndrome (7%), Treacher Collins
syndrome (TCS) (5%), facial and hemifacial microsomia
(3%) and other defined (3.5%) and undefined disorders
(9%) [8, 40]. Facial dysmorphism commonly arises from
a combination of migration and inadequate formation of
facial mesenchyme (especially when associated with dis-
orders of the first and second branchial arches) [41].
Goldenhar syndrome (GS) or oculo-auriculo-vertebral
(OAV) syndrome is the combination of such abnormalities
[37]. It is characterized by a wide spectrum of symptoms,
facial and associated features that may differ in range
and severity from one case to another (Figure 6). A classic
feature of GS is asymmetric (mostly unilateral) hypoplasia
of the face. Fetuses with GS have major anomalies, such
as unilateral mandibular hypoplasia with involvement
of the temporomandibular joint and multiple skin tags
around the ear, ear hypoplasia/aplasia and/or eye malfor-
mations (microphthalmia/anophthalmia) and vertebral
anomalies. Typically, these malformations are unilateral
(70%) and give an asymmetric appearance of the face.
Usually, the right side is more severely affected than the
left [42–44]. There have been some theories about the
origin of this condition. Some authors hypothesized that
the problem could be unilateral disruption of the blood
supply (ischemia) to the 1st and 2nd brachial arches, which
could occur in the timeline between the 4th and 8th weeks
of gestation [44]. However, Wang etal. [45] analyzed data
from a large congenital birth defects registry in Spain
and found a connection between diabetic mothers and
increased risk of their infants being born with OAV syn-
drome. There has been speculation that poorly controlled
maternal diabetes interferes with cephalic neural crest
cell migration, causing this syndrome [45]. The first sono-
graphic clue for the detection of this syndrome (also with
conventional 2D US imaging) can be finding asymmetry of
the face due to hemifacial macrosomia or something small
and very typical as periauricular skin tags (Figure 7).
By using 3D surface rendering, more can be evaluated.
Unilateral craniofacial anomaly underdevelopment of one
side of the body can include brain (cerebellar hemisphere
hypoplasia) [45], eye (micro/anophtalmia), low-set ears
with malformation, face (asymmetry of the soft tissue),
kidney (hydronephrosis), etc. With the application of 3D
HDlive imaging technology, even small details of the face
and other body parts can be visualized in a very realis-
tic way, which can be very helpful while counseling the
parents. The combination of micrognathia with low-set
ears is a common finding in many syndromes. Detection
of bilateral symmetric hypoplasia of the face, preauricular
tags in combination with micrognathia may be part of TCS,
Nager syndrome or Miller syndrome. TCS is a congenital
disorder of craniofacial development caused by mutations
in the TCOF1 gene on chromosome 5q32 [33]. TCS is repre-
sented by bilateral symmetrical otomandibular dysplasia
(Figure8). TCS is often associated with downward slant-
ing of the palpebral fissures. There could be associated
head and neck defects, and abnormalities of the extremi-
ties can be also found. The incidence of TCS is estimated
at 1:50,000 live births per year. The inheritance is autoso-
mal dominant with variation in expressivity. Cranioskel-
etal hypoplasia develops due to an insufficient number
of neural crest cells as a consequence of neuroepithelial
progenitor cell death [46]. The onset of defects occurs very
early in embryogenesis between the 4th and 8th weeks of
Figure 6:Postpartum images of a baby with Goldenhar syndrome.
Note: Hemifacial hypoplasia, external ear deformity, preauricular sinuses and tags.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound 659
gestation. Prenatal diagnosis so far has been reported
mostly in the 2nd trimester of pregnancy [39, 46, 47], but
with more powerful 3D applications and HDlive techno-
logy, there is a possibility to shift the detection of TCS from
the 2nd to the 1st trimester. With the combination of anoma-
lies, suspicion of a syndrome is very essential for inform-
ing the geneticists who can order the gene sequencing
added to the usual amniocentesis (AC) panel to confirm
the diagnosis, which otherwise would be missed [47].
There have been some animal studies featuring chemical
and genetic inhibition of the p53 protein in the attempt to
prevent TCS, but so far, no effective method of prevention
in humans exists [47].
The shape of the skull might sometimes be informa-
tive, for example, a strawberry-shaped head seen in
Figure 7:Prenatal 3D surface rendering image of preauricular tag, postnatal images of external ear deformity, small ipsilateral half of the
face and microphtalmia.
Figure 8:3D surface rendering image of fetus at 19 gestational
weeks with Treacher-Collins syndrome and typical facial dysmor-
phism: bilateral symmetrical otomandibular dysplasia with hypo-
plasia of soft tissues is observed in the malar bone, inferior orbital
rim and cheek (image courtesy of S. Panchal).
Edwards syndrome (trisomy 18), with a flattened occiput
due to hypoplasia of the occipital brain lobes, brainstem
and cerebellum, along with pointed frontal bones with
hypoplasia of the frontal lobes of the brain. A lemon-
shaped head can be seen with neural tube defects and as
a part of some syndromes. A cloverleaf skull is present in
different syndromes characterized by craniosynostosis,
which can be found in Crouzon and Pfeiffer syndrome
and in skeletal dysplasias such as thanatophoric dyspla-
sia type II [37]. This shape of the fetal head develops due
to premature closure of the coronal and lambdoid sutures,
which causes bulging of temporal bones and confluence
of anterior and posterior fontanelles. So, there are two
bulges laterally (temporally) and an expansion superiorly
(the anterior cranial fossa). Depending on the involvement
of specific fetal skull sutures in premature fusion (cranio-
synostosis), different shapes of the head may appear.
Apert syndrome is an autosomal dominant disorder
with a mutation found in the FGFR2 gene, chromosome
10q26.13 [33]. This syndrome has a few characteristic
features that can be depicted while screening for abnor-
malities. Three signs to remember would be strawberry
shaped head, flat face and mitten-like hands [37]. Due to
bicoronal craniosynostosis, there is brachycephaly and
acrocephaly, resulting in a strawberry-shaped head. In
other words, one can detect an abnormal skull with a flat
occiput, high forehead, midfacial hypoplasia (flat face),
hypertelorism of the eyes and eyelid edema by a combi-
nation of conventional 2D imaging with 3D maximum
mode (for bony structures), conventional 3D surface and
3D HDlive surface imaging. Mild ventriculomegaly can be
detected by the 3D inversion mode and the newest appli-
cation of HDlive silhouette imaging. ACC can be an accom-
panying finding best detected with 3D surface rendering
in the median plane with additional 3D sonoangiogram
visualization (3D HDlive bidirectional power Doppler)
of the absent pericallosal artery. Very specific for fetuses
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
660Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound
with the Apert syndrome is defect on the extremities,
called “mitten-like hands/feet”: syndactyly (soft tissue
and osseous) of the 2nd, 3rd and 4th finger in combination
with a broad thumb. Pooh and Kurjak [13] published a
case of a prenatally detected fetus with Apert syndrome
by using 3D sonography. Correlation was made between
prenatal 3D US images of anomalies and identical post-
natal appearance [13, 18]. Three-dimensional US images
can be used to present the parents with the extent of
the abnormalities of the face, skull and extremities [48].
Parents should be counseled about prognosis, possibility
of different degrees of intellectual impairment and risk
of recurrence. When resulting from a de novo mutation,
recurrence risk is improbable, but if one of the parents is a
carrier, the recurrence risk is 50%. There may be an asso-
ciation between advanced paternal age and higher risk of
occurrence of Apert syndrome as a single-gene disorder
[49]. To confirm the diagnosis prenatally, the option of AC
should be offered to the parents.
Frontal bossing may be a typical finding in achondro-
plasia (autosomal dominant condition with rhizomelic
limb shortening) (Figure 9) and Russell-Silver syndrome
(short stature, asymmetric intrauterine growth restriction
of the skeleton with normal size of the head). Asymmetry
of the fetal skull can also be found in the fetus with amni-
otic band syndrome (sequence). Due to rupture in the
amnion, which initiates the process very early in the 1st
trimester of pregnancy, the amniotic band causes a wide
variety and severity of destructive fetal malformations,
depending on fetal parts that come in contact and get
trapped in it. When affecting the skull, asymmetric anen-
cephaly, encephalocele, facial clefting and micrognathia
can be detected. Other abnormalities that are also found
are limb defects (constriction rings, amputation of the
limb or digits, etc.) and anterior abdominal wall defects
(gastroschisis, omphalocele) (Figure 10) [16, 37]. Other
skull abnormalities detected by US are microcephaly and
macrocephaly. Microcephaly indicates a group of disor-
ders characterized by a small head and typically asso-
ciated with abnormal neurological findings and mental
disabilities [37]. Microcephaly usually also implies micro-
encephaly because the head size is commonly determined
by the brain size. Fetuses with prenatally suspected
microcephaly have head circumference (HC) >3standard
deviations (SDs) below the mean for gestational age [50].
Different associated US features depend greatly on the
etiologic factor causing microcephaly. The exact etiology
of most microcephaly cases is still unknown. However, it
is linked to numerous syndromes associated with chro-
mosomal abnormalities like Cornelia de Lange syndrome,
DiGeorge syndrome, Wolf-Hirshhorn syndrome, cri-du-
chat syndrome, trisomy 13 and 9, etc., exposure to some
toxic agents (alcohol, drugs, chlomiphene, methotrexate,
phenylalanine), maternal under-nutrition and certain
maternal infections during pregnancy, such as rubella,
toxoplasmosis, varicella and cytomegalovirus (CMV).
There are reports of a new causation between maternal
infection and Zika virus during pregnancy and adverse
pregnancy outcomes such as microcephaly, other brain
and eye defects and pregnancy loss [51]. Zika congenital
syndrome is generally characterized by cerebral atrophy
that may interfere in formation and neuronal migration
during early cerebral embryogenesis [52]. Other features
of this syndrome are the following: severe microcephaly,
lissencephaly, cataract of the eye, microophtalmia, club-
foot, contractures and arthrogryposis [51–53]. Viruses
Figure 9:3D surface rendering.
(A) 3D skeleton. (B) 3D HDlive surface rendering. (C) 3D HDlive surface rendering of the same fetus at 34 gestational weeks with suspected
achondroplasia. Notice typical facial features such as frontal bossing and depressed nasal bridge.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound 661
such as CMV or Zika have been shown to invade the brain
cells, particularly neural progenitors, infect and destroy
the primary stem cells (the radial glial cells) of the brain;
therefore, there is a lack of future daughter neurons
[54–56]. The severity of the condition may depend on the
timing of infection during pregnancy. Microcephaly is
mostly the result of decreased size of the cerebral cortex.
In addition, infection may cause scars and calcifications
in the brain tissue. Abnormalities such as periventricular
and intraparenchymal calcifications, ventriculomegaly
secondary to cerebral atrophy, cerebellar hypoplasia and
cortical abnormalities are seen and detected much earlier
than microcephaly itself. Besides the standard US screen-
ing, fetal neurosonography as well as KANET should be
ABCD
EFGH
Figure 10:Prenatal detection of omphalocele at 13+3 gestational weeks. Different ultrasound modes and rendering applications are used to
visualize the omphalocele.
(A) Conventional 2D mode. (B–D and E–G) 3D HDlive surface rendering with different angle of illumination. (H) Postnatal presentation of the
baby born at 40 gestational weeks, realistic and same appearance of omphalocele in the prenatal compared to the postnatal period.
Figure 11:Prenatally detected congenital anomalies of the urinary tract.
(A) Unilateral hydronephrosis in fetus at 26 gestational weeks, 3D rendering. (B) Conventional 2D image in fetus at 25 gestational weeks and
obstructed urethra with distention of the bladder and hydronephrosis. (C) Conventional 2D image of fetus with massive distention of the
bladder in Prune-Belly syndrome at 14 gestational weeks.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
662Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound
performed and repeated in the follow-up period until
the delivery. The infection should be confirmed by the
real-time reverse transcription polymerase chain reac-
tion (rRT-PCR) [53]. The most recent follow-up studies
from Brazil have shown that even though some babies are
born with a normal head size, postnatal development of
microcephaly can still occur as well as significant neuro-
logical sequelae also leading to arthrogryposis, a condi-
tion resulting in deformities of joints [52]. In the prenatal
assessment of pregnancies at risk, evaluation with 4D
US and KANET could be included. Prenatal results can
be compared with postnatal results of neonatal neuro-
logical evaluation in the follow-up period during the first
2–3years of life [6–8].
During a routine anomaly scan, abnormalities of
fetal kidneys can be detected. A wide variety of structural
and functional abnormalities can be seen (Figure11).
Dysplastic kidneys with multiple cysts [multcystic dys-
plastic kidneys (MCDK)] that fluctuate in size can be
found in some very severe syndromes. As MCDK are dys-
functional, it could be a lethal condition called Meckel-
Gruber syndrome (Figure 12) with autosomal recessive
inheritance [57], if found bilaterally. Three pathogno-
monic anomalies can be found: occipital encephalocele,
MCDK (Figure13) and polydactyly. Neonates die within
Figure 12:Facial appearance of fetus with Meckel-Gruber syndrome.
(A) 2D conventional image of fetal profile (notice the flat face). (B–E) 3D surface rendering of fetal profile.
Figure 13:Multicystic dysplastic kidney (MCDK) found in fetus at 26 gestational weeks.
(A, B) Conventional 2D images (courtesy RM. Nieto). (C, D) 3D HDlive silhouette images, volume extraction (courtesy RK. Pooh).
Figure 14:3D HDlive surface rendering of normal appearance of
fetal face at 28 gestational weeks.
KANET assessment by 4D. Notice the open eye.
the first few days of life due to pulmonary hypoplasia
and renal failure. Detection of occipital encephalocele
in the 1st trimester is easier due to a better overview and
normal collection of amniotic fluid. Later in pregnancy,
there is progressive oligohydramnios and encephalocele
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound 663
may be missed. Special attention should be paid to eval-
uate both fetal kidneys because normal sonographic
finding of kidneys rules out the lethal Meckel-Gruber
syndrome.
Conclusion
As soon as it becomes achievable to detect congenital
anomalies by prenatal US, there lie questions of what can
and should be done. Many ethical issues arise as well.
Modern medicine faces some problems when having the
possibility to extend the life of the sickest babies with
potentially lethal congenital syndromes. The possibil-
ity to do so does not always justify the opportunity [8].
Generally, the idea is to find the balance between the
benefits and limitations of US imaging. At the same time,
one should be able to optimize the recommendations with
the expectations of the parents of a severely damaged
baby. Given the complexity of the prenatal diagnosis of
syndromes, everything involved around it is so complex.
That includes the postnatal confirmation of the diagnosis,
determination of the prognosis aiming to help the parents
to deal with the sick baby and to indicate the necessity
of complex, lifelong and costly multidisciplinary care of
affected babies.
Taken together, the previously described 3D/4D US
techniques (Figure 14) promise to advance clinicians’
accuracy in detecting fetal abnormalities and syndromes
as early as possible. So far, there have been many advan-
tages of the prenatal detection of fetal syndromes, but
there is also a lot of room for improvement. As the new
3D/4D US technology becomes more available to general
use in everyday practice, one should be well informed and
keep up with emerging new diagnostic possibilities, so
that the number of detected affected fetuses will probably
improve over time. Helping tools such as available online
databases integrate all necessary information for better
diagnostic precision. However, human involvement,
knowledge and rational thinking are still irreplaceable in
making the right diagnosis of fetal syndromes.
Author’s Statement
Conflict of interest: Authors state no conflict of interest.
Material and Methods: Informed consent: Informed
consent has been obtained from all individuals included
in this study.
Ethical approval: The research related to human subject
use has complied with all the relevant national regula-
tions, and institutional policies, and is in accordance
with the tenets of the Helsinki Declaration, and has been
approved by the authors’ institutional review board or
equivalent committee.
References
[1] EUROCAT. Prenatal screening & diagnosis. Prenatal detection
(pd) rates. Available at: http://www.eurocatnetwork.eu/pre-
natalscreeninganddiagnosis/prenatal%20detection(pd)rates.
(Accessed on October 11, 2016).
[2] Kurjak A, Pooh RK, Merce LT, Carrera JM, Salihagic-Kadic A,
Andonotopo W. Structural and functional early human develop-
ment assessed by three-dimensional and four-dimensional
sonography. Fertil Steril. 2005;84:1285–99.
[3] Pooh RK. A New Field of “Fetal Sono-ophthalmology” by 3D
HDlive Silhouette and Flow. Donald School J Ultrasound Obstet
Gynecol. 2015;9:221–2.
[4] Kurjak A, Miskovic B, Stanojevic M, Amiel-Tison C, Ahmed B,
Azumendi G, etal. New scoring system for fetal neurobehavior
assessed by three- and four-dimensional sonography. J Perinat
Med. 2008;36:73–81.
[5] Kurjak A, Abo-Yaqoub S, Stanojevic M, Yigiter AB, Vasilj O, Lebit
D, etal. The potential of 4D sonography in the assessment of
fetal neurobehavior-multicentric study in high-risk pregnan-
cies. J Perinat Med. 2010;38:77–82.
[6] Stanojevic M, Antsaklis P, Kadic AS, Predojevic M, Vladareanu
R, Vladareanu S, etal. Is kurjak antenatal neurodevelopmental
test ready for routine clinical application? Bucharest consen-
sus statement. Donald School J Ultrasound Obstet Gynecol.
2015;9:260–5.
[7] Kurjak A, Barišić LS, Stanojević M, Kadić AS, Porović S. Are we
ready to investigate cognitive function of fetal brain? The role
of advanced four-dimensional sonography. Donald School J
Ultrasound Obstet Gynecol. 2016;10:116–24.
[8] Barišić LS, Kurjak A, Pooh RK, Delić T, Stanojević M, Porović S.
Antenatal detection of fetal syndromes by ultrasound: from a
single piece to a complete puzzle. Donald School J Ultrasound
Obstet Gynecol. 2016;10:63–77.
[9] Pooh RK, Kurjak A. Novel application of three-dimensional
HDlive imaging in prenatal diagnosis from the first trimester. J
Perinat Med. 2015;43:147–58.
[10] Bonilla-Musoles F, Raga F, Castillo JC, Bonilla F Jr, Climent MT,
Caballero O. High definition real-time ultrasound (HDlive) of
embryonic and fetal malformations before week 16. Donald
School J Ultrasound Obstet Gynecol. 2013;7:1–8.
[11] Pooh RK, Kurjak A. 3D/4D sonography moved prenatal
diagnosis of fetal anomalies from the second to the first
trimester of pregnancy. J Matern Fetal Neonatal Med.
2012;25:433–55.
[12] Pooh RK. Novel application of hdlive Silhouette and hdlive
flow: clinical significance of the “see-through fashion” in pre-
natal diagnosis. Donald School J Ultrasound Obstet Gynecol.
2016;10:90–8.
[13] Pooh RK, Kurjak A. Three-dimensional ultrasound in detection
of fetal anomalies. Donald School J Ultrasound Obstet Gynecol.
2016;10:214–34.
[14] Lyons KJ, Crandall MJ, del Campo M. Smith’s recognizable
patterns of human malformation, 7th ed. Philadelphia, PA:
Elsevier Saunders; 2013.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
664Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound
[15] Lanna M, Rustico MA, Pintucci A, Spaccini L, Lalatta F, NicoliniU.
Three-dimensional ultrasound and genetic syndromes. Donald
School J Ultrasound Obstet Gynecol. 2007;1:54–9.
[16] Jones KL. Smith’s recognizable patterns of human malforma-
tion. 5th ed. Philadelphia, PA: Elsevier Saunders; 1997.
[17] Dorland’s Illustrated Medical Dictionary online. Elsevier.
Available at: www.dorlands.com/wsearch.jsp.
[18] Pooh RK, Kurjak A. Donald school atlas of advanced ultrasound
in obstetrics and gynecology. 1st ed. New Delhi: Jaypee Broth-
ers Medical Publishers (P) Ltd; 2015.
[19] Reddy UM, Filly RA, Copel JA. Prenatal imaging: ultrasonog-
raphy and magnetic resonance imaging. Obstet Gynecol.
2008;112:145–57.
[20] Gonçalves LF, Lee W, Espinoza J, Romero R. Three- and
4-dimensional ultrasound in obstetric practice: does it help? J
Ultrasound Med. 2005;24:1599–624.
[21] Merz E, Welter C. Two-dimensional and three-dimensional
ultrasound in the evaluation of normal and abnormal fetal
anatomy in the second and third trimesters in a level III center.
Ultraschall Med. 2005;26:9–16.
[22] Merz E, Abramowicz JS. Three-dimensional/four-dimensional
ultrasound in prenatal diagnosis: is it time for routine use? Clin
Obstet Gynecol. 2012;55:336–51.
[23] Benoit B, Levaillant JM. Voluson GE healthcare technology.
Available at: www.volusonclub.net. Accessed: 10 Dec 2016.
[24] Kagan KO, Pintoffl K, Hoopmann M. First-trimester ultrasound
images using HDlive. Ultrasound Obstet Gynecol. 2011;38:607.
[25] Hata T. HDlive rendering image at 6weeks of gestation. J Med
Ultrason. 2013;40:495–6.
[26] Hata T, Mashima M, Ito M, Uketa E, Mori N, Ishimura M.
Three-dimensional HDlive rendering images of the fetal heart.
Ultrasound Med Biol. 2013;39:1513–7.
[27] Hanaoka U, Tanaka H, Koyano K, Uematsu R, Kanenishi K, Hata
T. HDlive imaging of the face of fetuses with autosomal triso-
mies. J Med Ultrasonics. 2014;41:339–42.
[28] Hata T, Hanaoka U, Mashima M. HDlive rendering image of
cyclopia and a proboscis in a fetus with normal chromosomes
at 32weeks of gestation. J Med Ultrason. 2014;41:109–10.
[29] Tonni G, Castigliano AP, Grisolia G, Lithuania M, Meagher S,
DaSilva Costa F, etal. HDlive in early gestation. J Turk Ger
Gynecol Assoc. 2016;17:110–9.
[30] Pooh RK. Recent advances in 3D ultrasound, silhouette ultra-
sound, and sonoangiogram in fetal neurology. Donald School J
Ultrasound Obstet Gynecol. 2016;10:193–200.
[31] Basel-Vanagaite L, Wolf L, Orin M, Larizza L, Gervasini C, Krantz
ID, etal. Recognition of the Cornelia de Lange syndrome phe-
notype with facial dysmorphology novel analysis. Clin Genet.
2016;89:557–63.
[32] Merz E, Pashaj S. What is known about corpus callosum
prenatally? Donald School J Ultrasound Obstet Gynecol.
2016;10:163–9.
[33] The Phenotip Team. Phenotip tutorial. Available at: http://pheno-
tip.com/possible-syndromes/. (Accessed on September 21, 2016).
[34] Ahmed BI. The new 3D/4D based spatio-temporal imaging cor-
relation (STIC) in fetal echocardiography: a promising tool for
the future. J Matern Fetal Neonatal Med. 2014;27:1163–8.
[35] Chaoui R, Kalache D, Heling KS, Tennstedt C, Bommer CC,
Korner H. Absent or hypoplastic thymus on ultrasound: a
marker for deletion 22q11.2 in fetal cardiac defect. Ultrasound
Obstet Gynecol. 2002;20:546–52.
[36] Wilson DI, Burn J, Scambler P, Goodship J. DiGeorge syndrome:
part of CATCH 22. J Med Genet. 1993;30:852–6.
[37] Benacerraf BR. Ultrasound of fetal syndromes. 2nd ed. London:
Churchill Livingstone; 2008.
[38] Teoh M, Meagher S. First-trimester diagnosis of micrognathia
as a presentation of Pierre Robin syndrome. UltrasoundObstet
Gynecol. 2003;21:616–8.
[39] Tsai MY, Lan KC, Ou CY, Chen JH, Chang SY, Hsu TY. Assessment
of the facial features and chin development of fetuses with use
of serial three-dimensional sonography and the mandibular
size monogram in a Chinese population. Am J Obstet Gynecol.
2004;190:541–6.
[40] Evans AK, Rahbar R, Rogers GF, Mulliken JB, Volk MS. Robin-
sequence: a retrospective review of 115 patients. Int J Pediatr
Otorhinolaryngol. 2006;70:973–80.
[41] Johnson JM, Moonis G, Green GE, Carmody R, Burbank HN.
Syndromes of the first and second branchial arches, part 2:
syndromes. Am J Neuroradiol. 2011;32:230–7.
[42] Castori M, Brancati F, Rinaldi R, Adami L, Mingarelli R, Gramma-
tico P, etal. Antenatal presentation of the oculo-auriculo-verte-
bral spectrum (OAVS). Am J Med Genet A. 2006;140:1573–79.
[43] Miller TD, Metry D. Multiple accessory tragi as a clue to the
diagnosis of the oculo-auriculo-vertebral (Goldenhar) syn-
drome. J Am Acad Dermatol. 2004;50(2 Suppl):S11–13.
[44] Martinelli P, Maurotti GM, Agangi A, Mazzarelli LL, Bifulco
G, Paladini D. Prenatal diagnosis of hemifacial microsomia
and ipsilateral cerebellar hypoplasia in a fetus with ocu-
loauriculovertebral spectrum. Ultrasound Obstet Gynecol.
2004;24:199–201.
[45] Wang R, Martinez-Frias ML, Graham JM Jr. Infants of diabetic
mothers are at increased risk for the oculo-auriculo-vertebral
sequence: a case-based and case-control approach. J Pediatr.
2002;141:611–7.
[46] Paul A, Trainor PA, Dixon J, Dixon MJ. Treacher Collins syn-
drome: etiology, pathogenesis and prevention. Eur J Human
Genetics. 2009;17:275–83.
[47] Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, Rey JP, etal.
Prevention of the neurocristopathy Treacher Collins syndrome
through inhibition of p53 function. Nat Med. 2008;14:125–33.
[48] David AL, Turnbull C, Scott R, Freeman J, Bilardo CM, vanMaarle
M, etal. Diagnosis of Apert syndrome in the second-trimester
using 2D and 3D ultrasound. Prenat Diagn. 2007;27:629–32.
[49] Toriello HV, Meck JM. Statement on guidance for genetic
counseling in advanced paternal age. Genet Med.
2008;10:457–60.
[50] Chervenak FA, Rosenberg J, Brightman RC, Chitkara U, Jeanty P.
A prospective study of the accuracy of ultrasound in predicting
fetal microcephaly. Obstet Gynecol. 1987;69:908–1043.
[51] De Araújo TV, Rodrigues LC, de Alencar Ximenes RA, de Barros
Miranda- Filho D, Montarroyos UR, de Melo AP, etal. Associa-
tion between Zika virus infection and microcephaly in Brazil,
January to May, 2016: preliminary report of a case-control
study. Lancet Infect Dis. 2016;12:1356–63.
[52] van der Linden V, Pessoa A, Dobyns W, Barkovich AJ, van der
Linden HJ, Rolim Filho EL, etal. Description of 13 infants born
during October 2015–January 2016with congenital zika virus
infection without microcephaly at birth, Brazil. MMWR Morb
Mortal Wkly Rep. 2016;65;1343–8.
[53] Melo AS de O, Aguiar RS, Amorim MMR, Tanuri A, Melo FO,
Ribeiro ST, etal. Congenital Zika Virus Infection. JAMA Neurol.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
Barišić etal., Diagnosis of fetal syndromes by 3D/4D ultrasound 665
Published online October 3, 2016. Corrected on October 24,
2016.
[54] Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C,
Bershteyn M, Kriegstein AR. Expression analysis highlights AXL
as a candidate zika virus entry receptor in neural stem cells.
Cell Stem Cell. 2016;18:591–6.
[55] Li C, Xu D, Ye Q, Hong S, Jiang Y, Liu X, etal. Zika virus disrupts
neural progenitor development and leads to microcephaly in
mice. Cell Stem Cell. 2016;19:120–6.
[56] Society for Maternal-Fetal Medicine (SMFM) Publications
Committee. SMFM Statement. Ultrasound screening for fetal
microcephaly following zika virus exposure. Am J Obstet
Gynecol. 2016;214:B2–B4.
[57] Barišić I, Odak LJ, Loane M, Garne E, Wellesley D,
Calzolari E, etal. Prevalence, prenatal diagnosis and
clinical features of oculo-auriculo-vertebral spectrum:
aregistry-based study in Europe. Eur J Human Genetics.
2014;22:1026–33.
Authenticated | akurjak@public.carnet.hr
Download Date | 8/28/17 2:45 PM
