CHAPTER 9 • The Fetal Face and Neck
NTRODUCTION
Visualization of the fetal face and neck in early gestation is an important aspect of the
ultrasound examination as it has been incorporated in the first-trimester fetal risk
assessment for aneuploidy (Chapters 1 and 5). A midsagittal plane of the fetus is part of
nuchal translucency (NT) measurement and is also used to assess for the presence or
absence of nasal bones. A more detailed assessment of the fetal face and neck in the
first trimester allows for the diagnosis of a number of abnormalities with high
associations, including aneuploidy and genetic syndromes. In this chapter, we present a
systematic approach to the evaluation of the fetal face and neck and discuss in detail
major facial and neck abnormalities that can be diagnosed in the first trimester. The
posterior fossa in the brain, which is also visualized in the midsagittal plane of the
fetus, is separately discussed in Chapter 8 on central nervous system (CNS) anomalies.
EMBRYOLOGY
Embryologic development of the fetal face and neck is a complex process, which
involves coordination of multiple tissues including ectoderm, neural crest, mesoderm,
and endoderm with involvement of six pairs of pharyngeal arches. The pharyngeal
arches play a dominant role in building the face and neck, including its skeletal,
muscular, vascular, and nerve structures.
The first evidence of facial development is seen during the third week of
embryogenesis with the formation of the oropharyngeal (oral) membrane, which lies at
the opening of the foregut and represents the future oral cavity. During the fourth to
seventh week of embryogenesis, five facial swellings or processes merge and fuse to
form the facial structures. These facial processes include one frontonasal process,
arising from crest cells, and two maxillary and mandibular processes, arising from the
first pharyngeal arch (Fig. 9.1). The frontonasal process gives rise to two medial and
two lateral nasal processes. Table 9.1 and Figures 9.1 and 9.2 list the various
contributions of facial processes to the development of facial structures. Fusion and•••••
merging of the medial nasal and maxillary processes form the primary palate, and the
secondary palate is formed by fusion of the maxillary processes, which completes facial
development by the 12th week of embryogenesis. Facial growth continues during the
fetal period with changes in proportions and features of facial structures. Detailed
embryologic development of the face and neck is beyond the scope of this book. Failure
of development or fusion of facial processes contributes to the majority of facial
abnormalities, including clefting, which is discussed later in this chapter.
Figure 9.1: Schematic drawings of the development of the mouth and nose in
the early sixth week (A) and in the late seventh week (B) of embryogenesis.
The two medial and two lateral nasal processes fuse in the middle along with
the lateral maxillary and mandibular processes to form the nose, as shown in A,
and mouth, as shown in B. The primary palate is formed by the medial nasal
and maxillary processes, whereas the secondary palate is formed by the fusion
of the maxillary processes. The colors of nose, maxilla, and mandible in A and
B show the process contributing to embryogenesis. See text for more details.
Table 9.1 • Contributions of Embryologic Facial Prominences to Facial
Structures
Frontonasal: Forehead, dorsum of nose
Lateral nasal: Lateral aspects of nose
Medial nasal: Septum of nose
Maxillary: Upper cheek, most of upper lip and secondary palate
Mandibular: Lower cheek, chin, and lower lipThe pharyngeal arches contribute to the development of the neck. The third
pharyngeal arch forms the skeletal structures of the hyoid bone. The parathyroid glands
and the laryngeal cartilages are formed by fusion of the fourth and sixth pharyngeal
arches. The thyroid gland originates around the 24th day of embryogenesis from the
primitive pharynx and neural crest cells, forming the median and lateral thyroid,
respectively. The median thyroid becomes the main thyroid gland. The thyroid descends
in the neck until it reaches the front of the trachea in the seventh week of embryogenesis.
The thyroid gland is the first endocrine organ to develop, and it starts producing thyroid
hormones by the 12th week of menstrual age.
Figure 9.2: Formation of the lower face at 10 weeks of embryogenesis. Note
that the face is completely formed, and note the contribution of various
processes to the formation of the face. See Figure 9.1 for corresponding colors
and text for details.
NORMAL SONOGRAPHIC ANATOMY
The systematic visualization of the face and neck includes multiple approaches from the
midsagittal, coronal, and axial planes. The midsagittal approach allows for the
visualization of the facial profile and NT, and the coronal and axial planes allow for
visualization of other facial and neck features. Several brain anatomic structures, such
as the thalamus, brain stem, fourth ventricle, lateral ventricles, and choroid plexuses,
can also be demonstrated in the midsagittal and parasagittal views of the head and face1
and are discussed in detail in Chapters 5 and 8. We will hereby describe normal
sonographic features of the face and neck in each anatomic plane.
Sagittal PlanesThe midsagittal plane of the fetal head (Figs. 9.3 and 9.4), demonstrating the fetal
profile in the first trimester, enables the assessment of the forehead, nose with nasal
bone, mouth with maxilla, mandible anteriorly, and NT posteriorly. In the first trimester,
the fetal head appears slightly larger in proportion to the body than later on in gestation,
and in this midsagittal view the forehead shows some normal-appearing “frontal
bossing” (Figs. 9.3 and 9.4). At this stage of early gestation, the metopic suture is still
wide and the frontal bones are not seen in the midsagittal view. The perpendicular
insonation to the nasal structures in the midsagittal plane of the face enables clear
visualization of facial structures. The midsagittal plane landmarks are important in
order to correctly identify the nasal bone on midsagittal scanning, with the
demonstration of the “equal sign” formed by the nasal bone inferiorly and the nasal skin
superiorly (Figs. 9.4, 9.5A, 9.6, and 1.1). The maxilla is recognized in the midsagittal
plane as a continuous ossified region in the face (Figs. 9.4 to 9.6). In the midsagittal
plane, the anterior part of the mandible is seen as an echogenic dot under the anterior
maxilla (Fig. 9.6A). In parasagittal views, a larger part of the mandible can be seen
(Fig. 9.6C) as well as the maxillary process between the nasal bone and the maxilla
(Fig. 9.6B). Several facial measurements in the midsagittal view have been proposed in
the literature.2–8 The significance of abnormal facial measurements and anatomic
markers is discussed later in this chapter.
In the posterior aspect of the midsagittal view, the neck with NT is also
demonstrated. A detailed discussion of NT measurement (Figs. 9.3 and 9.4) and its
significance is presented in Chapters 1 and 6. Conditions associated with a thickened
NT and cystic hygroma are discussed at the end of this chapter.
Coronal Planes
A frontal coronal view of the bony face in the first trimester reveals both orbits and
eyes and their relationships to the nasal bridge and maxilla (Fig. 9.7) (see Chapter 5).
The position, size, and shape of the eyes and orbits are generally assessed in a
subjective manner. A coronal view of the face demonstrates the anterior maxilla
(alveolar ridge) (Fig. 9.7). The retronasal triangle is imaged in an oblique plane,
between the coronal and axial planes of the face, in the region of the nose and maxilla
(Fig. 9.7B)9 (see Chapter 5 and Fig. 5.9). An oblique plane between the maxilla and the
mandible normally reveals a mandibular gap (Fig. 9.7B).10 Good visualization of facial
structures is typically performed from a 3D surface rendering of the face, ideally
obtained transvaginally.Figure 9.3: Schematic drawing of the midsagittal plane of the fetal head
showing the fetal facial profile and displaying important anatomic structures
evaluated by the first-trimester ultrasound, including forehead, nasal bone,
maxilla, mouth, mandible, midline central nervous system structures, and nuchal
translucency. See corresponding ultrasound in Figure 9.4 and text for details.Figure 9.4: Midsagittal ultrasound plane of the fetal head at 13 weeks of
gestation showing the profile with the forehead (1), nose with nasal bone (2),
mouth (3), maxilla (4), and chin with mandible (5). The posterior aspect of the
profile plane displays the nuchal translucency (6) and different anatomic
structures of the midline brain to include the thalamus (7), brain stem (8), fourth
ventricle as intracranial translucency (9), choroid plexus of the fourth ventricle
(10), the developing cisterna magna (11), and the occipital bone (12). See
Figure 9.3 for the corresponding schematic drawing.
Axial Planes
In the experience of the authors, the systematic visualization of the axial planes of the
face is of secondary importance to the midsagittal and coronal planes (Chapter 5). As
performed in the second trimester, multiple axial planes obtained in the first trimester
from cranial to caudal enable the demonstration of orbits, nasal bridge with nasal bones,
the maxilla, and the mandible (Fig. 9.8) (Chapter 5) . The fetal lips cannot be well
identified on transabdominal scanning in the first trimester, and, when needed, imaging
of these structures can be obtained transvaginally with high-resolution transducers.
Three-Dimensional Ultrasound of the Fetal Face
Similar to the use of three-dimensional (3D) ultrasound in surface mode of the fetal face
in the second and third trimesters of pregnancy, 3D ultrasound in the first trimester (Fig.
9.9) provides additional information to the 2D midsagittal (profile), frontal, and axial
facial views.11 When fetal abnormalities are suspected in the first trimester, 3D
ultrasound of the fetal face in surface mode enables a detailed view of facial features,
including the forehead, eyes, nose, mouth, chin, and ears (Figs. 9.9 to 9.11). Threedimensional ultrasound of the fetal face can often be obtained by transabdominal
acquisition, but when an abnormality is suspected the transvaginal approach provides
for more details and higher resolution. Figures 9.9 to 9.11 show examples of normal
and abnormal fetal faces on 3D ultrasound in the first trimester of pregnancy. Threedimensional ultrasound can also be used in multiplanar display with reconstruction of
planes for the specific evaluation of target anatomic regions (Figs. 9.12 to 9.14) such as
the bony face or the palate in the evaluation of facial anomalies (see later). For more
details on the use of 3D ultrasound in the first trimester, refer to Chapter 3 in this book
and a recent book on the clinical use of 3D in prenatal medicine.11
Figure 9.5: Transvaginal ultrasound of the midsagittal plane of the fetal face in
two fetuses (A and B) at 13 weeks of gestation. In fetus A, the ultrasound
beam is perpendicular to the long axis of the face and clearly displays the nose
with nasal bone, the maxilla, and chin with mandible. Note in A the tongue
between the maxilla and mandible. In fetus B, the ultrasound beam is inferior
below the chin and shows the posterior aspect of the mouth region with the
tongue, hard and soft palate, and the pharynx.Figure 9.6: Midsagittal (A) and two parasagittal views (B and C) of the fetal
face in the same fetus at 13 weeks of gestation showing the nasal bone (1),
maxilla (2), and mandible (3). In A, obtained at the midsagittal view, the maxilla
is seen (2), but the processus maxillaris (broken arrow) is not seen. In A also,
the tip of the mandible is seen (3), but the mandibular body (short arrow) is not
seen. B is a slight tilt to a parasagittal plane, where the processus maxillaris
(asterisk) and the body of the mandible (two arrows) start to be seen. A more
angulated parasagittal view is seen in C, showing the bony face with the
processus maxillaris (asterisk) between nasal bone (1) and maxilla (2) and the
lateral aspect of the mandible (3) with the body, the ramus, and the condylar
joint (short arrows).Figure 9.7: Coronal planes in two fetuses (A and B) at 12 weeks of gestation,
obtained at the frontal aspects of the bony face. In fetus A, the coronal plane is
at the level of the orbits and shows the two eyes (1) with orbits and lenses,
between the maxillary processes (2), the nasal bones (3), and the anterior
aspect of the maxilla (4) with the alveolar ridge. In fetus B, the plane is oblique
and demonstrates the retronasal triangle (see text for details), which is formed
by the nasal bones superiorly (3), the frontal processes of the maxilla laterally
(2), and the alveolar ridge (primary palate) inferiorly (4). This coronal section
(B) is posterior to the tip of the mandible, and therefore the two lateral bodies
of the mandible are seen (5) with a normal gap between, called the mandibular
gap. The presence of micrognathia results in disappearance of the mandibular
gap in the retronasal triangle plane. See Figure 9.14 to help understand the
anatomic facial location of the retronasal triangle plane.Figure 9.8: Axial views of the fetal face at the level of the orbits in two fetuses
at 13 weeks’ gestation in transabdominal (A) and transvaginal approach (B).
Note that the eyes (1), maxillary processes (2), and nasal bones (3) are seen
in this plane. In the transvaginal approach (B), the lenses in the eyes (1) and
two separate nasal bones (3) are also seen.Figure 9.9: Three-dimensional ultrasound images in surface mode of the
normal fetal face obtained in six fetuses (A–F) by the transvaginal approach.
Note the physiologic frontal bossing and the clear anatomic regions of
forehead, eyes, nose, mouth, chin, and ears. Compare with Figures 9.10 and
9.11 obtained in abnormal fetuses.Figure 9.10: Three-dimensional ultrasound images in surface mode of the
abnormal fetal face obtained in three fetuses (A–C) by the transvaginal
approach. Fetus A has acrania/exencephaly (1); fetus B has trisomy 13 with
holoprosencephaly, hypotelorism, and cebocephaly (2) (small nose with one
nostril); and fetus C has trisomy 13 with proboscis (3).
Figure 9.11: Three-dimensional ultrasound images in surface mode of the
abnormal fetal face obtained in three fetuses (A–C) by the transvaginal
approach. Fetus A has trisomy 13 with micrognathia (1), fetus B has trisomy 18
with abnormal profile and dysplastic ears (2), and fetus C has a syndromic
condition with associated facial cleft (3).Figure 9.12: Three-dimensional ultrasound of a normal fetal face obtained
transvaginally at 12 weeks of gestation and shown in tomographic display. Note
the anatomic details assessed in the midsagittal and parasagittal views.Figure 9.13: Three-dimensional ultrasound volume of the fetal face acquired
transvaginally at 12 weeks of gestation and displayed in tomographic mode. In
the reference image (upper left), the midsagittal plane is shown and the
corresponding tomographic coronal planes are displayed with plane A at the
level of the eyes (1), plane B at the level of the maxilla (3), and plane C at the
level of the tongue (4). The maxillary processes (2) and the pharynx (5) are
also shown in A and C, respectively. Acquisition of a three-dimensional volume
of the fetal head in early gestation allows for detailed assessment of facial
anatomy.
BIOMETRIC MEASUREMENTS OF THE FACE
Several biometric measurements are currently published for the assessment of facial
features in the second and third trimesters, and some of these are proposed for use in the
first-trimester ultrasound screening. These measurements include diameters, ratios, and
angles, primarily performed in the midsagittal plane of the fetal profile. They are used
mainly in the first trimester in screening for aneuploidies or in the detection of facial
clefts and micrognathia. Some of these measurements are discussed in the following
sections.
Nasal Bone LengthReference ranges for nasal bone length in the fetus were reported in the second and third
trimesters of pregnancy, and nasal bone has been described to be absent or short in
fetuses with trisomy 21.12 This observation was adapted to aneuploidy screening at 11
to 14 weeks of gestation, and Cicero et al.2 demonstrated that nasal bones are
hypoplastic or not ossified in the first trimester in the majority of fetuses with trisomy
212 (Figs. 9.15 and 6.1), and in other aneuploidies and syndromic conditions (Figs. 6.6,
6.8, 6.33, and 6.35).13 Assessment of the nasal bone is also used to improve the
efficiency of the combined first-trimester screening for Down syndrome.13,14 Table 1.2
in Chapter 1 summarizes the essential criteria for an accurate nasal bone assessment in
the first trimester.
Prenasal Thickness
The observation that the skin of the forehead, called the “prenasal thickness,” is
increased in the second trimester in fetuses with trisomy 2115,16 has led to the use of this
marker in the first trimester of pregnancy as well (Fig. 9.16).5,8,17 To reduce the falsepositive rate of prenasal thickness measurement, the ratio of the prenasal thickness to
nasal bone length was proposed5 (Fig. 9.16). In normal fetuses, the prenasal thickness is
small and the nasal bone is relatively long, resulting in a ratio of approximately 0.6.5 In
trisomy 21 fetuses in the first trimester, the prenasal thickness increases, whereas the
nasal bone length decreases, resulting in a ratio >0.8.5Figure 9.14: Three-dimensional ultrasound volume of the fetal face acquired
transvaginally at 12 weeks of gestation and displayed in tomographic mode. In
this figure, only two planes are displayed: plane A, showing a midsagittal plane
of the head with facial profile, and plane B, obtained as the corresponding
coronal plane at the level of the yellow line. Note that plane B shows the
retronasal triangle view with the mandibular gap. See Figure 9.7 for details.Figure 9.15: Midsagittal views of the fetal face showing the measurement of
the nasal bone length in a normal fetus (A) and in a fetus with trisomy 21 (B). In
more than half of the fetuses with trisomy 21, the nasal bone is either
completely nonossified or, as in this case, poorly ossified, resulting in a short
and thin appearance. Long arrows point to the nose tip and short arrows to the
nasal skin. Nuchal translucency measurement is also seen (asterisk). Compare
with Figure 1.3 in Chapter 1 and with Fig. 9.16.Figure 9.16: Midsagittal views of the fetal face showing the measurement of
the prenasal thickness in a normal fetus (A) and in a fetus with trisomy 21 (B).
Prenasal thickness was adapted from the second trimester, where fetuses with
trisomy 21 showed increased prenasal thickness. The prenasal thickness
(white line) is measured as shown in A and B. Note the presence of increased
prenasal thickness in fetus B with trisomy 21. In order to reduce the falsepositive rate, the ratio of the prenasal thickness (white line) to nasal bone
length (yellow line) was introduced. In normal fetuses, the ratio is smaller than
0.6 and is increased in trisomy 21. Note in A that the white line is shorter than
the yellow line, whereas in B it is vice versa. Nuchal translucency measurement
is also seen (asterisk).
Maxillary Length
Fetuses with trisomy 21 have a flat profile due to midfacial hypoplasia, leading to the
known feature of a protruding tongue. Measuring the maxillary length between 11 and 14
weeks of gestation is proposed as a method to quantify midfacial hypoplasia.3 The
measurement is performed in a slightly parasagittal view of the facial profile and
includes the mandibular joint.3 Maxillary length is short in fetuses with trisomy 21.3
Midfacial hypoplasia can also be assessed by the use of the frontomaxillary facial
angle, which indirectly includes the maxilla.18 The frontomaxillary facial angle is
discussed in the next section.Frontomaxillary Facial Angle
The frontomaxillary facial (FMF) angle is the angle between the maxilla and forehead
and in normal fetuses is quantified at 85° (±10°) (Fig. 9.17A).18 A wide FMF angle is
reported in fetuses with trisomy 214,19 (Fig. 9.17B), whereas a narrow FMF angle is
noted in fetuses with open spina bifida (Fig. 9.18).20 Abnormal FMF angles are also
reported in fetuses with trisomy 18 with midfacial hypoplasia and micrognathia21 and in
fetuses with trisomy 13 in association with holoprosencephaly.22 Caution should be
used, however, in the evaluation of the FMF angle because slightly oblique views will
introduce false-positive and negative results. Measurement of the FMF angle using 3D
multiplanar rendering has been shown to improve its accuracy.18,23 The wide FMF angle
in fetuses with aneuploidies is likely due to the short maxilla, whereas in spina bifida
the narrow angle is probably due to the small flat head owing to the posterior shift of the
brain and decreased fluid in the ventricles. Another facial angle is the maxilla–nasion–
mandible (MNM) angle and uses the nasion as reference point of the intersection of the
frontal and nasal bones.8,24 The MNM angle is defined as the angle between the
maxilla–nasion line and the mandible–nasion line in the midsagittal plane of the face
and can be used to identify fetuses at high risk for aneuploidies, micrognathia, and
clefts.8
Prefrontal Space Distance
Prefrontal space distance (PSD) is obtained by drawing a line from the anterior aspect
of both the mandible and maxilla and extended toward the fetal forehead (Fig. 9.19).6,7
The PSD is calculated by the distance of the prenasal skin to this extended line (Fig.
9.19). The distance can have positive or negative values.6 PSD is abnormal in fetuses
with aneuploidies, such as trisomies 21, 18, and 13,6 as well as in fetuses with
micrognathia and clefts7 (Fig. 9.19).Figure 9.17: Midsagittal views of the fetal face showing the measurement of
the fronto-maxillary-facial (FMF) angle in a normal fetus (A) and in a fetus with
trisomy 21 (B). The FMF angle is measured in the midsagittal view of the face
between the maxilla and the forehead, as shown in A and B. In the normal fetus
(A), the angle is approximately 85° (yellow lines), whereas in the fetus with
trisomy 21 (B), the angle is wider than 85° (red lines). Nuchal translucency
measurement is also seen in fetus B. See also Figure 9.18.Figure 9.18: Midsagittal views of the fetal face showing the measurement of
the fronto-maxillary-facial (FMF) angle in two fetuses (A and B) with open
spina bifida. The FMF angle is typically smaller in fetuses with spina bifida due
to a smaller head and decreased fluid in the ventricles, resulting in a flat face.
Note the thickened brain stem (asterisk) and the almost-absent fluid in the
intracranial translucency (IT).Figure 9.19: Midsagittal views of the fetal face showing the measurement of
the prefrontal space distance in a normal fetus (A), in a fetus with cleft lip and
palate (B), and in a fetus with micrognathia (C). The prefrontal space distance
(PSD) is the distance between the forehead and a line drawn from the anterior
aspect of maxilla (1) and mandible (2). In the normal fetus (A), the PSD is quite
short. In the presence of a facial cleft (fetus B), there is a protrusion of the
maxilla (asterisk), and the PSD is increased. In the presence of micrognathia
(fetus C), the mandible is posteriorly shifted (arrow), leading to an increased
PSD as well. Note in fetus B the presence of an interrupted maxilla, called
maxillary gap, a midsagittal view sign for the presence of cleft lip and palate.
Orbit Size and Distances
To the best of our knowledge, no charts currently exist on the size of the orbit and the
interorbital distances in the first trimester of pregnancy, and such measurements are not
obtained routinely. Recently, a paper reported on the interlens distance, starting at 12
weeks of gestation.25
FETAL FACIAL ABNORMALITIES IN ANEUPLOIDIES
AND IN CNS MALFORMATIONS
Fetal Profile in Aneuploidies
Trisomy 21 fetuses typically show an abnormal facial flat profile with an absent or
hypoplastic nasal bone (Fig. 9.15), a short maxilla, an increased FMF angle (Fig. 9.17),
and a thickened prenasal thickness (Fig. 9.16). Similar facial appearance can also be
found in trisomy 18 fetuses, in addition to retrognathia and facial clefts. Trisomy 13fetuses show severe facial anomalies due to their association with holoprosencephaly
(Fig. 9.20) and/or with facial clefts. Ultrasound markers of aneuploidies, including
facial abnormalities in the first trimester, are discussed in detail in Chapter 6.
Holoprosencephaly
Lobar and semilobar holoprosencephaly is often associated with facial abnormalities
such as cyclopia, hypotelorism, proboscis, cebocephaly, agnathia-holoprosencephaly,
nasal hypoplasia, and facial clefts.26 In most cases, the profile is severely abnormal, in
addition to the abnormal head shape and brain. Figures 9.10 and 9.20 show abnormal
profiles in fetuses with alobar holoprosencephaly. Holoprosencephaly is discussed in
detail in Chapter 8.
Acrania/Anencephaly/Exencephaly
In acrania/anencephaly/exencephaly, the profile and the frontal view of the face have
characteristic abnormalities with the presence of large eyes and small face. Facial
profile views in Figure 9.21 show different aspects of the forehead region in acrania.
Abnormalities in facial profiles in anencephaly/exencephaly are discussed in detail in
Chapter 8.
Figure 9.20: Midsagittal views of the fetal face in three fetuses (A–C) with
alobar holoprosencephaly at 11, 12, and 13 weeks of gestation, respectively.
In fetus A, no normal facial structures are identifiable, and a proboscis (1) can
be seen in the midline. In fetus B, cebocephaly with an abnormal nose (2) is
seen (compare with 3D image in Fig. 9.10). In fetus C, no maxilla (3) is seen in
this midsagittal plane due to the presence of a large midline cleft.Figure 9.21: Midsagittal views of the fetal face in three fetuses with
acrania/exencephaly at 10 (A), 12 (B), and 11 (C) weeks of gestation,
respectively. Note the various aspects of acrania/exencephaly on ultrasound in
early gestation. No normal-looking forehead can be seen, and the nasal region
is abnormal as well.
Open Spina Bifida
Open spina bifida is associated with reduced cerebrospinal fluid in the head, which
results in a small head, with a small biparietal diameter (BPD) measurement.27 The
cerebrospinal fluid leakage leads to a flat forehead and a reduced FMF angle by about
10° in 90% of the cases.20 Figures 9.18A and B show facial profiles with flat
foreheads in two fetuses with open spina bifida in the first trimester of pregnancy.
Epignathus
Epignathus is an oropharyngeal teratoma, generally originating from the oral cavity. Its
origin can be the sphenoid bone, the palate, the tongue, or the pharynx.28,29 The growth
is usually out of the oral cavity,28 but epignathus can also grow into the brain and face.29
Reports of this very rare anomaly are generally from fetuses diagnosed in the second or
third trimester, but similar to teratomas of other locations (see Chapter 14), its
appearance can also be evident in the first trimester as well (Fig. 9.22). The typical
appearance is a protrusion in the mouth region of irregular shape with a mixture of
hyperechoic tissue with few cystic structures. If the protrusion is small, it can mimic
bilateral facial clefting, but a detailed ultrasound reveals the irregular shape in
epignathus, which is atypical for a cleft. Figure 9.22 shows an epignathus, evident in the
midsagittal profile view of the face at 13 weeks of gestation.Figure 9.22: Midsagittal view of the face at 12 weeks of gestation in a fetus
with epignathus. B represents a magnified view of A. Note the solid character
of the tumor (arrows) arising from the fetal mouth. Nasal bone (1) and the
maxilla (2) are identified in the midline.
Frontal Cephalocele
As discussed in Chapter 8, most cephaloceles arise from the occipital region.
Cephaloceles can also arise from the parietal or frontal regions of the head.30 The
frontal cephalocele, also called frontoethmoidal or anterior cephalocele, is less
common than other cephalocele types. In the study by Sepulveda et al.30 only 3 (9%) out
of 25 cases of cephaloceles were frontal in location. The frontal cephalocele can be a
meningocele with normal intracranial anatomy or an encephalocele with brain tissue
protruding through the defect with resulting intracranial changes. In the first trimester,
amniotic band syndrome should be considered a possible etiology when a frontal or
parietal cephalocele is suspected (see Chapter 8) . Differential diagnosis of frontal
cephalocele includes the presence of proboscis in holoprosencephaly, nasal glioma, or
teratoma. In holoprosencephaly, additional facial and intracerebral characteristic signs
are present, which help to differentiate proboscis from cephalocele. Prognosis of frontal
cephalocele cannot be predicted in the first trimester, but the earlier in gestation that
frontal cephaloceles are detected, the worse is the prognosis. Figure 9.23 shows a fetus
at 11 weeks of gestation with a frontal cephalocele.
Posterior Fossa DisordersPosterior fossa disorders with cerebellar abnormalities, increased fluid in the fourth
ventricle, and/or compressed or abnormal kinking of the brain stem can be found in
several conditions, including aneuploidies, syndromic conditions as Walker–Warburg
syndrome, Joubert syndrome, or Dandy–Walker malformation, and as a normal variant
with persistent Blake pouch cyst (see Chapter 8) . Posterior fossa disorders are
commonly seen in trisomies 18 and 13 or triploidy (Fig. 9.24). When Walker–Warburg
syndrome is suspected, the eyes can be affected, and a targeted first-trimester
transvaginal ultrasound examination of the eyes and lenses may show abnormalities that
can be consistent with the diagnosis.31 The presence of a prior history of Walker–
Warburg syndrome is important as it targets the ultrasound examination in the first
trimester. It is important to note, however, that the absence of cataract in the first
trimester cannot rule out Walker–Warburg syndrome given that cataract may not be
evident until later on in pregnancy.
FETAL FACIAL ABNORMALITIES
Cleft Lip and Palate
Definition
Cleft lip and palate (CLP) is one of the most common congenital defects, with an
incidence of 1/700 to 1/1,000 live births.32,33 Given the high prevalence of CLP,
imaging of the upper lip and philtrum is currently part of the basic obstetric ultrasound
examination in the second trimester.34 Among CLP cases, about a third affect the lip
only, and two-thirds involve the lip and palate.35 CLP can be either isolated or
associated with a wide range of chromosomal anomalies and genetic syndromes. A
family history of CLP is found in about one-third of patients with nonsyndromic CLP,
and with recent genetic advancements, several novel loci that are significantly
associated with CLP have been identified.36 CLP occurs more frequently in males
(male/female = 1.70), especially among isolated cases.35 There are different
classifications of facial clefts,35,37,38 and it is often difficult to collect all needed details
for a precise classification of CLP in the first trimester of pregnancy. Prenatally, and
especially in the first trimester, we recommend Nyberg’s classification (Fig. 9.25) of
CLP, with type 1 being the isolated cleft lip, type 2 with unilateral (or mediolateral)
CLP, type 3 with bilateral CLP, type 4 with midline (or median) CLP, and type 5 with
complete facial clefts, which is primarily seen in amniotic band syndrome.38Figure 9.23: Fetus at 11 weeks of gestation with an anterior cephalocele,
shown in a midsagittal 2D plane of the head in A and in three-dimensional
ultrasound in surface mode in B. The completely cystic aspect of the defect
suggests the diagnosis of cephalocele.Figure 9.24: Midsagittal views of the fetal head in four fetuses (A–D) with
posterior fossa dilation (asterisks) at 12, 12, 14, and 13 weeks of gestation,
respectively. Fetus A has trisomy 18 with absent nasal bone and a cleft lip and
palate recognized by the maxillary gap. Fetus B has trisomy 13 with
micrognathia (arrow). Fetuses C and D had no abnormal facial findings in the
profile views, and follow-up ultrasound examinations confirmed Dandy–Walker
malformations in both.
Figure 9.25: Schematic drawings of typical cleft lips and palates (CLP)
observed by ultrasound in early gestation. CLP can be unilateral (mediolateral),
either on the left or on the right side (A). CLP can also be bilateral (B) with a
pseudomass in the middle or midline, as shown in C. See text for details.
Ultrasound Findings
The diagnosis of isolated CLP is often difficult in the first trimester, primarily related tothe small size of facial structures.39–41 Indeed, most cases of isolated CLP are not
detected during the first-trimester ultrasound examination.42,43 In the large study of
Syngelaki et al.42 (see Table 5.2 in Chapter 5), only 1 out of 20 fetuses (5%) with
nonaneuploid clefts was detected in the first trimester, whereas in another recent study
from two specialized referral centers, the detection rate of isolated clefts in early
gestation was 24%.43 The planes used for detecting CLP in the first trimester are similar
to those used in the second-trimester ultrasound, but the visualization of the nose–lip
region is not practical in the first trimester due to the low resolution and small size of
these structures. For the identification of a CLP in the first trimester, we therefore
recommend either an axial view of the maxilla or a more coronal oblique view of the
retronasal triangle (Fig. 9.7).9 In addition, in an ultrasound screening setting, our
reported sign, called “maxillary gap sign” (Figs. 9.26 to 9.32) is fairly simple and can
suspect the presence of CLP, which needs to be confirmed in an axial plane of the
maxilla or in the retronasal triangle view (Figs. 9.26 to 9.32). The maxillary gap sign is
discussed in more detail later on in this section. The retronasal triangle (RNT) view,
suggested by Sepulveda et al.,9 is an oblique view of nose and anterior maxilla (Fig.
9.7) and is formed by the two nasal bones superiorly, the frontal processes of the
maxilla laterally, and the alveolar ridge (primary palate) inferiorly9 (Fig. 9.7). The
RNT is obtained from the midsagittal view of the fetal face by rotating the transducer
90° with a slight tilt to bring the frontal processes of the maxilla and primary palate into
the same plane.44 The presence of CLP is reflected by a defect in the primary palate
seen on the RNT view (Fig. 9.28A). In a prospective study using 3D ultrasound, the
identification of CLP by visualization of the RNT in the first trimester has been shown
to have a sensitivity of 87.5% and a specificity of 99.9%,45 but it is still unknown if
such a sensitivity can be reached with 2D screening ultrasound examinations. In difficult
cases, 3D ultrasound can help in the display of the face and the RNT plane and thus
plays an important role in confirming the presence of CLP in early gestation (Fig.
9.11).11,39,45,46 The RNT is probably the best view to detect or rule out CLP in the first
trimester, but this additional plane is not always easy to obtain and is not part of
screening ultrasound examinations. As previously stated and in our opinion, improved
detection of CLP in the first trimester can be achieved if a sonographic marker can be
integrated into the screening ultrasound. For this purpose, Chaoui et al.43 reported on the
first trimester presence of a maxillary gap in the midsagittal plane of the fetus as a clue
for CLP (Fig. 9.26).43 This finding is significant in the sense that the midsagittal plane of
the fetus is routinely obtained for the assessment of NT, nasal bone, and posterior fossa.
The maxillary gap is observed in 96% of nonisolated CLP and more than 65% of
isolated CLP.43 However, a small maxillary gap can be seen in 5% to 7% of normal
fetuses and in this setting represents a false-positive diagnosis.7,43 A possible reason forthe presence of a small maxillary gap in normal fetuses is probably related to delayed
ossification of the maxilla at 11 to 13 weeks of gestation. Indeed, a large maxillary gap
of greater than 1.5 mm or complete absence of the maxilla in the midsagittal plane (Figs.
9.26 to 9.32) was seen in 69% of nonisolated CLP, in 35% of isolated CLP, and in none
of the normal fetuses.43 It is important to note, however, that the presence of a maxillary
gap is a marker for CLP and the diagnosis has to be confirmed in the axial or frontal
views with direct observation of the facial cleft. Furthermore, bilateral facial clefts
typically show a premaxillary protrusion,47 which can be easily seen in the midsagittal
view of the face as a mass anterior to the mouth and nose region (Figs. 9.29 and 9.30).
A more objective assessment is achieved by measuring the PSD7 (Fig. 9.19) or the
maxilla–nasion–mandible angle8 as previously described in the Biometric
Measurements of the Face section. With such measurements, cases with retrognathia
associated with CLP can also be detected, and this is discussed in the next section.
Figure 9.26: Schematic drawing of the midsagittal view of the fetal face (A)
along with the corresponding ultrasound image (B) demonstrating the maxillary
gap (white arrows) in a fetus with cleft lip and palate. Compare with the
schematic drawing of a normal fetus in Figure 9.3. In this midsagittal view
plane, the entire maxilla should be seen. The size and location of the maxillary
gap vary according to the size and type of clefts. Compare with Figures 9.27 to
9.31.Figure 9.27: Axial (A) and midsagittal (B) views of the face at 13 weeks of
gestation in a fetus with a unilateral cleft lip and palate. The cleft lip and palate
is demonstrated in the axial view (A) (open arrow). Note the presence of a
maxillary gap in the midsagittal view of the face (B). The following facial
structures are seen: nasal bone (1), mandible (2), and maxilla (3). In this fetus,
the cleft was isolated, and the child was successfully operated on postnatally.Figure 9.28: Retronasal triangle (A) and midsagittal (B) views of the face at 13
weeks of gestation in a fetus with bilateral cleft lip and palate. The bilateral
clefts are demonstrated in the retronasal triangle view (A) (open arrows). Note
the presence of a large maxillary gap in the midsagittal view of the face (B).
Also note the presence of a protrusion of a pseudomass (asterisks) in A and B,
as is commonly seen in most fetuses with bilateral clefts in the first trimester.
This fetus also had trisomy 18.Figure 9.29: Coronal (A) and midsagittal (B) views of the face at 13 weeks of
gestation in a fetus with a midline cleft. The midline cleft is demonstrated in the
coronal view (A) (open arrows). Note the almost complete absence of the
maxilla in the midsagittal view of the face (B). In this fetus, holoprosencephaly
was present along with trisomy 13.Figure 9.30: Schematic drawing of the midsagittal view of the fetal face (A)
along with the corresponding axial (B) and sagittal (C) ultrasound images
demonstrating the maxillary gap (white arrow in A, labeled in C) in a fetus with
bilateral cleft lip and palate and trisomy 13. Note the presence in B and C of a
protrusion of a pseudomass (asterisks) anterior to the maxillary region. The
profile (C) is obviously abnormal in such cases. In this case, the maxillary gap
is recognized (white arrow in A, labeled in C) as an interruption of the maxilla in
its anterior part. Depending on the angle of insonation, the position of the gap
may vary. In such cases, a strict midsagittal view may visualize the nasal
septum and mimic a maxilla, but a slight parasagittal view reveals the maxillary
gap.Figure 9.31: Schematic drawing of the midsagittal view of the fetal face (A)
along with midsagittal views in two fetuses (B and C) with bilateral clefts and
no obvious protrusion. Note the presence of a large maxillary gap in both
fetuses. In such cases, the prefrontal space distance (see Fig. 9.19) will not be
abnormal. Fetus B had trisomy 18, and fetus C had a syndromic condition. In
both fetuses, the maxillary gap is recognized in the midsagittal view.Figure 9.32: Ultrasound images of a fetus diagnosed with CHARGE syndrome.
In the first trimester at 13 weeks of gestation, the following findings were
noted: A, midsagittal view of the face showing a protrusion (asterisk) and a
maxillary gap (MG) suggestive of the presence of a facial cleft. The bilateral
facial clefts (arrows) along with the protrusion (asterisks) are demonstrated in
an axial view of the maxilla in B on a convex transducer and in C on the linear
transducer. D: An aberrant right subclavian artery (ARSA) with an otherwise
normal heart (four-chamber view shown in E). Amniocentesis at 16 weeks of
gestation revealed a normal karyotype and microarray. At 28 weeks of
gestation, a perimembranous ventricular septal defect (not shown) in addition to
the presence of a dysplastic ear (F) was noted, which led us to target
molecular genetic testing for CHARGE syndrome, and a mutation on the CHD7
gene was detected.
Associated Malformations
CLP can be an isolated finding or associated with more than 100 genetic syndromes and
aneuploidies48 (see Chapter 6 and Table 9.2). In a large study involving 5,449 cases of
CLP from the EUROCAT network in 14 European countries, a total of 3,860 CLP cases(70.8%) occurred as isolated anomalies, and 1,589 (29.2%) were associated with other
defects such as multiple congenital anomalies of unknown origin and chromosomal and
recognized syndromes.35 Associated malformations were more frequent in infants who
had CLP (34.0%) than in infants with cleft lip only (20.8%). This study confirmed that
musculoskeletal, cardiovascular, and central nervous system defects are frequently
associated with CLP.35 The association of CLP with anomalies is highly dependent on
the anatomic type of the cleft.38,49 In a large study of 500 cases of CLP, Gillham et al.49
found that unilateral CLP had 9.8%, bilateral CLP 25%, and median (or midline) CLP
100% association with other anomalies. Another study from a tertiary referral fetal
center analyzed data from 70 fetuses with facial clefts and similarly found that all
fetuses with midline clefts had associated anomalies.50 In this study, however, the
associated anomalies in the two other groups were higher, being 48% of fetuses with
unilateral clefts and 72% with bilateral clefts, than in other studies.50 Therefore, once a
CLP is detected, detailed first-trimester ultrasound is recommended, looking for
additional structural anomalies including facial, intracerebral, cardiac, and skeletal
anomalies. Interestingly, almost all midline CLP, along with bilateral CLP but without
premaxillary protrusion, are associated with intracerebral anomalies and
aneuploidies.49–51 On the other hand, CLP in combination with cardiac anomalies
should raise the suspicion of deletion 22q11, deletion 4p− (Wolf–Hirschhorn
syndrome), or CHARGE syndrome (Fig. 9.32). The presence of a CLP in the mother or
father of an affected fetus should raise suspicion for an autosomal-dominant condition,
such as Van der Woude syndrome. When a CLP is identified in the first trimester in our
centers, we perform a detailed first-trimester ultrasound examination looking for
additional abnormalities and offer the patient invasive diagnostic genetic testing for
karyotype and microarray testing. A follow-up 2D and 3D ultrasound in the early
second trimester is also performed for evaluation of fetal anatomy. Table 9.2 lists few
of the numerous conditions associated with CLP.
Table 9.2 • Common Syndromic Conditions in Facial Clefts
Numerical aneuploidies (trisomy 13, 18, triploidy, etc.)
Deletions and duplications (4p−, 22q11, 18p−, etc.)
CHARGE syndrome
Ectrodactyly–ectodermal dysplasia cleft (EEC) syndrome
Frontonasal dysplasia
Fryns syndrome
Goldenhar syndromeGorlin syndrome
Holoprosencephaly autosomal-dominant syndromes
Kallmann syndrome
Nager syndrome
Pierre Robin syndrome
Roberts syndrome
Treacher Collins syndrome
VACTERL sequence
van der Woude syndrome
Micrognathia
Definition
Micrognathia is the term used to describe a rare facial malformation that is
characterized by a small, underdeveloped mandible. Retrognathia is a term used to
describe a mandible that is receded in relation to the maxilla and is commonly present
in association with the presence of micrognathia. Prenatally, both are commonly found
concurrently and the terms are used interchangeably. In this chapter, we will use the
term micrognathia to describe this condition because only severe findings may be
detected in the first trimester.
Ultrasound Findings
The presence of micrognathia is initially suspected in the midsagittal plane of the fetal
face in the first trimester by noting that the mandible is not at the same level as the
maxilla, but rather recessed posteriorly (Fig. 9.33). Unlike in normal facial anatomy, in
the presence of micrognathia, a line drawn from the mandible toward the maxilla will
not intersect the forehead (Fig. 9.19),7,10 and this can be quantified by the FMF angle,21
the PSD (Fig. 9.19),7 or the MNM angle.8 Often in the first trimester, the chin may
appear impressively small in suspected micrognathia, but in follow-up ultrasound
examination in the second and third trimesters, proportionate growth occurs and the fetal
profile will look less abnormal (Fig. 9.34). In isolated cases, therefore, the severity of
micrognathia cannot be predicted from the sole appearance of the profile view. An
interesting observation is the assessment of the chin region in the coronal plane
displayed by the RNT. In the normal fetus, facial anatomy of the RNT in the first
trimester displays a characteristic gap between the right and left bodies of the mandible,
referred to as the mandibular gap (Fig. 9.35).10 This mandibular gap can be measured
from the midpoint of the echogenic edge of one mandibular bone to the other and
appears to increase linearly with increasing CRL.10 Sepulveda et al.10 observed that the
absence of the mandibular gap or failure to identify the mandible in the RNT view ishighly suggestive of micrognathia (Fig. 9.35). The absence of a mandibular gap in the
coronal view of the face in the first trimester should therefore prompt the examiner to
perform a detailed ultrasound in order to confirm micrognathia and to assess for the
presence of other anomalies. Typically, micrognathia leads to a small mouth space, and
in these cases the tongue is shifted backward to what is called glossoptosis, which is
almost always combined with a cleft of the posterior palate. Such a condition has
already been reported in the early second trimester52 and in our observation can also be
seen in the first trimester. In suspected cases of micrognathia, we recommend a
transvaginal ultrasound to visualize, if technically feasible, the posterior palate region
(Fig. 9.5), as described by Wilhelm and Borgers,53 for the demonstration of amniotic
fluid in the pharynx, which is absent in micrognathia with glossoptosis. Since
micrognathia is associated with many syndromic conditions (Fig. 9.36), the face, ears,
and brain should be examined in detail in 2D and 3D ultrasound (Fig. 9.37).
Figure 9.33: Schematic drawing of the midsagittal plane of the face (A) along
with the corresponding midsagittal (B) ultrasound image of a fetus with
micrognathia (white arrows). Compare with the schematic drawing of a normal
fetus in Figure 9.3. Note that the mandibular tip does not reach the anterior
aspect of the maxilla in A and B, but rather reaches the midportion of it.
Micrognathia can be isolated as in the context of Pierre Robin sequence but
also can be part of numerous syndromic conditions. Compare with Figures 9.34
to 9.37. See text for details.Figure 9.34: Facial growth and development in a fetus with micrognathia in
Pierre Robin sequence, shown at 12 (A), 16 (B), 20 (C), and 26 (D) weeks of
gestation and in three-dimensional ultrasound in surface mode at 26 weeks of
gestation (E). White arrows point to the mandibles. Note that the micrognathia
appears very pronounced (severe) in the first trimester (A), but with the growth
of the mandible the profile appears less abnormal in the second (B–E) and third
trimesters. In this case, micrognathia was isolated, and a cleft palate was
repaired after birth.Figure 9.35: Schematic drawing of the midsagittal plane of the fetal face (A, D)
along with the corresponding midsagittal (B, E) and retronasal triangle (C, F)
ultrasound views in a normal fetus (A–C) and in a fetus with micrognathia (D–
F). Note in the normal fetus that the tip of the mandible (red arrow) reaches
under the anterior aspect of the maxilla (asterisk), as shown in A and B. In the
normal fetus, the retronasal triangle (C) demonstrates the normal mandibular
gap. In the fetus with micrognathia (D–F), the chin is receded behind the line
(red arrow) (E), and no mandibular gap is noted in the retronasal triangle view,
as shown in F. See text for details.
Associated Malformations
Micrognathia can be an isolated finding as in Pierre Robin sequence, commonly with a
cleft palate and glossoptosis, but can also be associated with other chromosomal
abnormalities, including trisomies 18 and 13, triploidy, and numerous genetic
syndromes.8,54,55 Notably, the association of micrognathia with Pierre Robin sequence is
well known and can be diagnosed in the first trimester56 as shown in Figure 9.35. Lowset ears can be a marker for the possible association of micrognathia with syndromicconditions. The absence of a mandible or maxilla is observed in agnathia and is
associated with otocephaly, a severe lethal condition.26,57 In addition to these
conditions, Goldenhaar syndrome and Treacher Collins syndrome should be considered.
Prenatal management of the first-trimester diagnosis of micrognathia is similar to that of
CLP.
Anomalies of the Eyes
Anomalies of eyes and orbits are rarely detected in the first trimester except in the
presence of other fetal anomalies or in a prior family history of such conditions (Figs.
9.38 to 9.40). Anomalies of eyes and orbits are typically found in association with
alobar holoprosencephaly, as in the presence of proboscis for instance (Figs. 9.10 and
9.39). Abnormal orbits, such as in hypotelorism or hypertelorism, are often subjectively
assessed in the first trimester (Figs. 9.38 to 9.40), especially in syndromic conditions
with facial dysmorphism. In general, trisomies 13 and 18 are the most common
conditions detected in such cases (Figs. 9.38 and 9.39). Isolated anophthalmia is very
rare, and microphthalmia can also be recognized when other fetal anomalies are
present. Isolated microphthalmia or cataract can be difficult to diagnose at this early
stage, as the anomaly itself may not be apparent in the first trimester of pregnancy. Fetal
cataracts reported in the first trimester of pregnancy are commonly recurrent cases or
present in suspected syndromes such as Walker–Warburg syndrome 31 or Warburg micro
syndrome with microcephaly, which becomes apparent in the late second trimester. In
high-risk patients, direct visualization of orbits and lenses with transvaginal ultrasound
increases the reliability of demonstrating normal eyes and orbits. When suspected, a
repeat ultrasound in the second trimester with the transvaginal approach, if feasible,
will help to confirm or rule out abnormalities of eyes and orbits.Figure 9.36: Midsagittal views of the face in two fetuses with trisomy 13 and
micrognathia (white arrows) at 14 (A) and 12 (B) weeks of gestation,
respectively. Note in fetus B the presence of dilated posterior fossa (asterisk).
Figure 9.37 shows the 3D rendering of the face in fetus B.
Figure 9.37: Three-dimensional ultrasound in surface mode of a fetus with
trisomy 13 at 12 weeks of gestation (same as in Fig. 9.36B). Note the small,
receded mandible (micrognathia) along with a thickened nuchal translucency
(asterisk).Figure 9.38: Axial views of the head at the level of the eyes in three abnormal
fetuses. Fetus A has marked hypotelorism in association with
holoprosencephaly and trisomy 13. Fetus B has hypotelorism in association
with holoprosencephaly with normal chromosomes but with PIGF mutation.
Fetus C has hypertelorism and abnormal orbital shape in association with
trisomy 13 and odd facial features. Compare with normal orbital anatomy in
Figure 9.8.
Figure 9.39: Axial views (A and B) of the head at the level of the eyes in a
fetus with trisomy 13, holoprosencephaly, pseudocyclopia, and proboscis at 13
weeks of gestation. A: The plane at the level of the eyes with the almost fused
eyes and no orbits. B: Is a more cranial plane showing the proboscis.Figure 9.40: Three-dimensional ultrasound in tomographic mode obtained from
a facial profile in a normal fetus (A) and in a fetus with holoprosencephaly (B).
Corresponding coronal views of the fetal face, showing the eyes are displayed
in the lower images. Note the normal distance of the eyes (white lines) in the
normal face in A, and narrowing of the orbits called hypotelorism in B.
FETAL NECK ABNORMALITIESCystic Hygroma
Definition
Cystic hygroma is a congenital abnormality involving the vascular lymphatic system in
the fetus and is characterized by the presence of fluid-filled cystic spaces in the soft
tissue, commonly in the posterolateral aspects of the neck or in other locations in the
body (Figs. 9.41 to 9.44). Pathogenesis of cystic hygroma is thought to result from the
abnormal connection between the lymphatic and vascular systems, primarily from
failure of development of the communication between the jugular lymphatic sac and the
jugular vein.58 This may lead to progressive lymphedema and fetal hydrops. On
occasion, however, a communication is established between the lymphatic and the
vascular systems, resulting in resolution of the swelling. Cystic hygroma can be
multiseptated and is thus classified as septated or nonseptated (Figs. 9.42 and 9.43). In
some cases, a thick septum can be seen in the midline, corresponding to the presence of
the nuchal ligament.58 The prevalence of cystic hygroma is reported at 1:285 of firsttrimester pregnancies.59 There is currently a controversy on whether cystic hygroma is
an entity that is distinct from an enlarged NT, because septations can be seen in both
conditions.60 Irrespective of the designation of nuchal swelling as NT or cystic
hygroma, the association of this finding with fetal anatomic and genetic abnormalities
should be considered in pregnancy management.
Figure 9.41: Midsagittal view of the fetus at 13 weeks of gestation showing a
thickened nuchal translucency (NT) (asterisk). When the NT is septated, the
diagnosis of cystic hygroma is made in some settings. The presence of NTseptations is best assessed in the axial views.
Figure 9.42: Midsagittal (A), coronal (B), and axial (C) views in a fetus with
cystic hygroma and Turner syndrome at 13 weeks of gestation. Note the
presence of NT thickening of 16 mm shown in A and NT septations (asterisk)
shown in B and C.Figure 9.43: Axial views of the fetal head in two fetuses with cystic hygromas
at 13 (A) and 12 (B) weeks of gestation, respectively. Note the presence of
septations in both fetuses, and also note that the fluid within the septations
(asterisk) is clear in A and echogenic, jelly-like in B.
Ultrasound Findings
The presence of cystic masses on ultrasound in the posterolateral aspect of the fetal
neck is suggestive of cystic hygroma. This is easily seen on an axial view of the neck
(Figs. 9.42 and 9.43) and when extensive, cystic hygroma can be seen in the sagittal
plane that is obtained for NT measurement (Figs. 9.41 and 9.42). The demonstration of
the presence of septations is best done in the axial plane of the neck and upper chest
(Fig. 9.44). A thick septum is commonly seen in the posterior midline neck region
corresponding to the nuchal ligament (Fig. 9.43). When multiple septations are present,
the ultrasound appearance resembles a honeycomb. Nonseptated cystic hygroma is seen
as cystic spaces on either side of the fetal neck, representing dilated cervical
lymphatics. Given the common association with other fetal malformations and
chromosomal abnormalities, a comprehensive evaluation of the fetus by detailed
ultrasound is warranted when a cystic hygroma is diagnosed in the first trimester.
Associated Malformations
Cystic hygroma is associated with other fetal anatomic abnormalities in 60% of cases.
Associated abnormalities commonly include cardiac, genitourinary, skeletal, and central
nervous systems, and the majority can be seen on the first-trimester ultrasound.
Chromosomal abnormalities are common, with trisomy 21 and Turner syndrome
representing the two most common associated chromosomal findings, reported in morethan 50% of cases.59 A typical syndromic condition to be considered is the presence of
Noonan syndrome (Fig. 9.45). Amniotic fluid abnormalities are common, but they are
noted in the second and third trimesters of pregnancy. Generalized hydrops is also
common and carries a poor prognosis.61 The outcome is usually good when cystic
hygroma resolves prenatally in the presence of a normal karyotype.
Figure 9.44: Midsagittal view at 11 weeks (A) and axial view at 17 weeks (B)
in a fetus with thickened nuchal translucency (NT), diagnosed at 11 weeks, as
shown in A (asterisk). In this fetus, nuchal edema persisted into the second
trimester (B).Figure 9.45: Ultrasound images obtained from a dichorionic twin fetus at 12
weeks of gestation in a 40-year-old pregnant woman presenting for genetic
screening. Note in A and B the presence of an enlarged nuchal translucency
(asterisks), measuring 7.4 mm. C and D: A normal four-chamber view and a
normal three-vessel-trachea view, respectively. Mild urinary tract dilation is
shown in E. Chorionic villous sampling revealed normal karyotype, but due to
the ultrasound findings, molecular genetic examination for Noonan syndrome
confirmed a mutation of the PTPN11 gene, shown in 50% of affected cases.
Increased NT with Normal Karyotype
The relationship of an increased NT with chromosomal anomalies, especially Down
syndrome, is currently well established. The detection of an increased NT currently
leads to genetic counseling and options for additional screening workup, or invasive
diagnostic testing. The presence of a thickened NT with normal karyotype represents amajor challenge to counseling and for additional workup. Further management in that
setting has been debated in the literature since the late 1990s.62–69 The presence of a
thickened NT is associated with aneuploidies (Fig. 9.46), and a thickened NT with a
normal karyotype is associated with a wide spectrum of major and minor fetal
anomalies, including genetic syndromes (Fig. 9.47) and an increased risk of in utero
fetal demise (Fig. 9.48).14,65,66,69,70 The risk of abnormal neurodevelopmental delay is
currently unclear, and controversial observations are reported.65 Despite normal
ultrasound findings and a normal karyotype in the setting of a thickened NT, the birth of
a “healthy” child without malformations decreases with increasing NT thickness (Fig.
9.49). In this section, we present essential points and current literature related to this
topic.
Figure 9.46: Relationship between nuchal translucency thickness (x axis) and
prevalence of chromosomal defects (y axis). (Graph is based on data from
Souka AP, von Kaisenberg CS, Hyett JA, et al. Increased nuchal translucency
with normal karyotype. Am J Obstet Gynecol. 2005;192:1005–1021.)
Pathophysiology of Increased NT
Understanding the pathophysiology of increased neck fluid in fetuses with thickened NT
is important as it allows for establishing associations with various abnormal fetal
conditions.14,65 This task, however, has not been proven to be easy, and it appears that a
thickened NT can result from various conditions. A thickened NT can be caused by
chromosomal anomalies, but can also be due to functional and structural cardiac
abnormalities; disturbances in the lymphatic system; disturbances in the collagen
metabolism; mechanical causes such as intrathoracic compression, infection, metabolicand hematologic disorders; or a combination of some of these and others. The main
types of anomalies associated with an increased NT in addition to aneuploidies71 (Fig.
9.46) include cardiac defects72 (Fig. 11.7 in Chapter 11), major malformations (Fig.
9.47) with specific syndromes (e.g., Noonan syndrome) (Fig. 9.45),68,73 skeletal
dysplasia,74 syndromic and nonsyndromic diaphragmatic hernias, and complex
syndromic conditions affecting brain, kidneys, and other organs.65,66 The association of
a thickened NT with these abnormalities increases with the NT thickness (Fig. 9.47).
Figure 9.47: Relationship between nuchal translucency thickness (x axis) and
prevalence of major anomalies (y axis). (Graph is based on data from Souka
AP, von Kaisenberg CS, Hyett JA, et al. Increased nuchal translucency with
normal karyotype. Am J Obstet Gynecol. 2005;192:1005–1021.)Figure 9.48: Relationship between nuchal translucency thickness (x axis) and
prevalence of fetal deaths (y axis). (Graph is based on data from Souka AP,
von Kaisenberg CS, Hyett JA, et al. Increased nuchal translucency with normal
karyotype. Am J Obstet Gynecol. 2005;192:1005–1021.)
Figure 9.49: Relationship between nuchal translucency thickness (x axis) and
prevalence of live birth of a child with no major anomalies (y axis). (Graph is
based on data from Souka AP, von Kaisenberg CS, Hyett JA, et al. Increased
nuchal translucency with normal karyotype. Am J Obstet Gynecol.2005;192:1005–1021.)
Congenital Cardiac Defects
The observation of Hyett et al.72 that in fetuses with a thickened NT the prevalence of a
cardiac anomaly is increased has been confirmed by other studies. A direct correlation
exists between the size of the NT and the associated risk for cardiac defects (Fig. 11.7
in Chapter 11). In our centers, a thickened NT is an indication for an early ultrasound
cardiac examination, even before performing an invasive procedure. A follow-up fetal
echocardiogram is also performed at 16 to 22 weeks of gestation. Please refer to
Chapter 11 for a detailed discussion of the evaluation of the fetal heart in the first
trimester.
Other Structural Anomalies and Genetic Syndromes
The list of reported structural anomalies and genetic syndromes in association with a
thickened NT is quite long66 (see Table 9.3). However, it is still unclear whether in all
reported cases the relationship is causal or accidental.65 Fetal anomalies such as
omphalocele and diaphragmatic hernia, isolated or syndromic, are highly associated
with a thickened NT (see case with Fryns syndrome in Fig. 10.20 in Chapter 10). Many
syndromes are listed in series reporting on outcome of fetuses with thickened NT and
normal chromosomes. It is, however, difficult to prove a causative relationship or a
strong association between specific genetic syndromes and thickened NT because most
syndromes have extremely low prevalence in the population.65 In one study, genetic
syndromes and single gene disorders were found in 12.7% of fetuses with thickened
NT.63 Noonan syndrome is currently accepted as the only molecular genetic condition
with a clear association with a thickened NT in the first trimester (Fig. 9.45),68
especially if nuchal edema persists into the second trimester. Skeletal dysplasias also
have a strong association with thickened NT. In the list of first-trimester skeletal
dysplasias reported by Khalil et al.,74 most cases were associated with a thickened NT
(see also Chapter 15 on skeletal anomalies). Table 9.3 summarizes some anomalies
reported in the literature with a thickened NT.66
Table 9.3 • Some Fetal Abnormalities in Fetuses with Increased Nuchal
Translucency Thickness
Anomalies of CNS,
Head and Neck
Thoracic and
Abdominal
Anomalies
Skeletal Anomalies Genetic and
Metabolic Diseases
Acrania/anencephaly Ambiguous
genitalia Achondrogenesis B syencdkrwoimthe–Wiedemann
Agenesis of the Body stalkcorpus callosum anomaly Achondroplasia CHARGE syndrome
Agnathia/micrognathia
Cardiac
anomalies (all
possible)
Asphyxiating thoracic
dystrophy
Congenital
lymphedema
Craniosynostosis Cloacal
exstrophy
Blomstrand
osteochondrodysplasia
Cornelia de Lange
syndrome
Cystic hygroma
Congenital
adrenal
hyperplasia
Campomelic dysplasia Deficiency of the
immune system
Neck lipoma
Congenital
nephrotic
syndrome
Cleidocranial dysplasia DiGeorge syndrome
Dandy–Walker
malformation
Cystic
adenomatoid
malformation
Hypochondroplasia EEC syndrome
Diastematomyelia Diaphragmatic
hernia Hypophosphatasia F deeftoarlmakaitnioensia sequence
Encephalocele Duodenal
atresia
Jarcho–Levin
syndrome
Fetal anemia (different
etiologies)
Facial cleft Esophageal
atresia Kyphoscoliosis GM1 gangliosidosis
Fowler syndrome Exomphalos Limb reduction defect Mucopolysaccharidosis
type VII
Holoprosencephaly Fryns
syndrome
Nance–Sweeney
syndrome Myotonic dystrophy
Hydrolethalus
syndrome Gastroschisis O imspteerofgeecn taesis N enecoenpahtaallompyaothcylonic
Iniencephaly HydronephrosisRoberts syndrome Noonan syndrome
Joubert syndrome Hypospadias Robinow syndrome Perlman syndrome
Macrocephaly Meckel–Gruber
syndrome
Short-rib polydactyly
syndrome
Severe developmental
delay of unknown
origin
Microcephaly Megacystis Sirenomelia Smith–Lemli–Opitz
syndromeMicrophthalmia
Multicystic
dysplastic
kidneys
Talipes equinovarus Spinal muscular
atrophy (SMA) type 1
Spina bifida
Polycystic
kidneys,
infantile
Thanatophoric
dwarfism Stickler syndrome
Treacher Collins
syndrome
Small bowel
obstruction VACTER association Syndrome unspecified
Trigonocephaly C Vitamin D–resistant
rickets
Ventriculomegaly Zellweger syndrome
Modified from Souka AP, von Kaisenberg CS, Hyett JA, et al. Increased
nuchal translucency with normal karyotype. Am J Obstet Gynecol.
2005;192:1005–1021. (Copyright Elsevier Ltd, with permission.)
Additional Genetic Evaluation
Comparative Genomic Hybridization Array
In a recent meta-analysis, an abnormal comparative genomic hybridization array (CGH)
or microarray is present in about 5% of a thickened NT, with a range reaching 10% in
some studies.69 Offering CGH to pregnancies with a thickened NT thus appears to be
warranted.
Monogenic Diseases
There are several studies reporting on the high prevalence of Noonan syndrome in
fetuses with thickened NT,68,73 especially when the thickened NT has persisted into the
second trimester.73 In one series of 120 fetuses, eight were shown to have Noonan
syndrome.68 Preliminary observations of a relationship between increased NT and the
presence of spinal muscular atrophy (SMA-Type 1) was not confirmed on subsequent
evaluation.68 It is possible that in the future, whole genomic sequencing may be offered
in these conditions, but the value of this approach has to be proven in large studies
before wide implementation.
Management and Follow-up of Thickened NT
Once a fetus is identified with a thickened NT, we recommend a detailed first-trimester
ultrasound examination, including a transvaginal ultrasound if feasible. The components
of the detailed first-trimester ultrasound examination are presented in Chapter 5. A
follow-up ultrasound examination at 16 weeks of gestation is also warranted in order to
reassess fetal anatomy.75 Evaluation of the nuchal fold in the second trimester is also
important because outcome is improved if the nuchal fold is normal (Fig. 9.49). A1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
detailed second-trimester ultrasound examination at 18 to 22 weeks of gestation along
with a fetal echocardiogram is also recommended. This approach will detect the
majority of major malformations and syndromic conditions, many of which can be
detected in the first and early second ultrasound examinations.
R E F E R E N C E S
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