**Normal and Abnormal Fetal Face**

Israel Goldstein and Zeev Wiener

*Rambam Health Care Campus, Haifa Israel* 

### **1. Introduction**

84 Prenatal Diagnosis – Morphology Scan and Invasive Methods

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hemihypertrophy, shortness of stature, and elevated urinary gonadotropins.

During the early stages of embryogenesis, genetic factors play the predominant role in the development of the fetal face. In later stages, environmental influences increase in importance. Facial malformation may be the result of chromosomal aberrations as well as teratogenic factors. Therefore, facial dysmorphism can provide important clues that suggest chromosomal or genetic abnormalities. The post-natal diagnosis of facial dysmorphism is a well-known pediatric diagnosis, primarily based on pattern diagnosis related to the appearance of one or a combination of facial features, such as low-set ears, hypohypertelorism, small orbits, micrognathia, retrognatia, and more. Some of these features are detectable prenatally (Benacerraf, 1998). More than 250 syndromes are associated with disproportional growth of abnormal features of the fetal face (Smith & Jones, 1988).


Table 1. Indications for ultrasound examination of the fetal face (Pilu et al., 1986)

Sonographic assessment of the fetal face is part of the routine anatomic survey. Recently, three-dimensional ultrasound (3D) images of the fetus can be also obtained. However, twodimensional ultrasonographic images are more easily, rapidly, efficiently, and accurately obtained. Imaging of the fetal face is possible in most ultrasound examinations beyond 12 weeks of gestation.

This chapter describes normal structural development and the sonographic approach to evaluation of the fetal face. Clinical applications are discussed in relation to perinatal management.

#### **2. Fetal face profile**

Sonographic imaging of the fetal face can provide information for the antenatal diagnosis of fetuses with various congenital syndromes and chromosomal aberrations, many of which are known to be associated with facial malformations. Deviation from the normal

Normal and Abnormal Fetal Face 87

Fig. 2. Sonographic picture of the fetal face. Typical facial concavities and protrusions are presented. The calipers measured between the upper philtrum to the mouth (upper picture),

and between the mouth to the chin (lower picture).

proportions of the fetal face profile might be one of the 'soft sonographic signs' that can provide important clues that suggests congenital syndromes (Benacerraf, 1998).

Visualization of the curvature of the forehead is important to rule out a flat forehead, such as microcephaly, or bossing of the forehead, such as craniosynostosis (Goldstein et al., 1988). Visualization of the bridge of the nose could rule out Apert or Carpenter syndromes (Smith & Jones, 1988). Visualization of normal prominent lips can rule out cleft lip (Benacerraf, 1998). Finally, a normal jaw appearance is important to rule out microganthia or prognathia (Sivan et al., 1997).

Evaluation of the fetal face structures is suggested on the coronal and mid-sagittal views. The fetal face profile appearance should be obtained, while an imaginary line is passed through the nasion (bridge of the nose) and the gnathion (lower protrusion of the chin). This imaginary line is vertical to the maxillary bone. In this view, the following structures can be identified: the bridge and tip of the nose, the philtrum (area between the nose and the upper lip), upper and lower lips, and chin (Goldstein et al., 2010).

Fig. 1. **A** describes the distance from the tip of the nose to the mouth (line between the lips), **B** from the mouth to the chin, **a** describes the distances from the upper philtrum and the mouth**, b** from the mouth and the upper concavity of the chin.

The ratios between the following distances are independent of the gestational age and are almost constant: the distances between the tip of the nose and the mouth, and the distance from the mouth to the gnathion. In addition, a constant ratio was found between the upper philtrum and the mouth and from the mouth to the upper concavity of the chin (Goldstein et al., 2010).

proportions of the fetal face profile might be one of the 'soft sonographic signs' that can

Visualization of the curvature of the forehead is important to rule out a flat forehead, such as microcephaly, or bossing of the forehead, such as craniosynostosis (Goldstein et al., 1988). Visualization of the bridge of the nose could rule out Apert or Carpenter syndromes (Smith & Jones, 1988). Visualization of normal prominent lips can rule out cleft lip (Benacerraf, 1998). Finally, a normal jaw appearance is important to rule out microganthia or prognathia

Evaluation of the fetal face structures is suggested on the coronal and mid-sagittal views. The fetal face profile appearance should be obtained, while an imaginary line is passed through the nasion (bridge of the nose) and the gnathion (lower protrusion of the chin). This imaginary line is vertical to the maxillary bone. In this view, the following structures can be identified: the bridge and tip of the nose, the philtrum (area between the nose and the upper

Fig. 1. **A** describes the distance from the tip of the nose to the mouth (line between the lips), **B** from the mouth to the chin, **a** describes the distances from the upper philtrum and the

The ratios between the following distances are independent of the gestational age and are almost constant: the distances between the tip of the nose and the mouth, and the distance from the mouth to the gnathion. In addition, a constant ratio was found between the upper philtrum and the mouth and from the mouth to the upper concavity of the chin (Goldstein

mouth**, b** from the mouth and the upper concavity of the chin.

provide important clues that suggests congenital syndromes (Benacerraf, 1998).

lip), upper and lower lips, and chin (Goldstein et al., 2010).

(Sivan et al., 1997).

et al., 2010).

Fig. 2. Sonographic picture of the fetal face. Typical facial concavities and protrusions are presented. The calipers measured between the upper philtrum to the mouth (upper picture), and between the mouth to the chin (lower picture).

Normal and Abnormal Fetal Face 89

**GA [weeks] FLD [cm] mean±2SD TFLD [cm] mean±2SD**  15 1.4 0.4 3.2 0.4 16 1.4 0.4 3.2 0.4 17 1.6 0.2 3.6 0.6 18 1.6 0.2 3.7 0.6 19 1.7 0.2 3.8 0.4 20 1.7 0.2 4.1 0.4 21 1.8 0.4 4.1 0.4 22 1.8 0.4 4.6 0.4 23 1.8 0.4 4.6 0.4 24 1.9 0.2 4.7 0.4 25 2.2 0.4 5.1 0.6 26 2.3 0.4 5.2 0.6 27 2.5 0.6 5.6 0.8 28 2.8 0.2 5.7 0.4 29 2.7 0.2 6.1 0.4 30 2.8 0.6 6.2 1.2 31 2.9 0.4 6.2 0.8 32 3.0 0.6 6.4 0.8 33 3.1 0.6 6.5 0.6 34 3.2 0.2 6.7 0.6 35 3.2 0.4 6.9 0.6 36 3.2 0.4 7.0 0.4 37 3.4 0.4 7.2 0.6 38 3.5 0.4 7.3 0.8 39 3.7 0.6 7.5 0.8 40 4.0 0.6 7.7 0.8 Table 2. Measurements of the mean±2SD of the frontal lobe distance and thalamic frontal lobe distance versus gestational age (Goldstein et al., 1988) (GA = gestational age, FLD =

Fig. 5. A flat forehead in neonates with microcephaly

frontal lobe distance, TFLD = thalamic frontal lobe distance)

Fig. 3. 3D pictures of the fetal face. Mimics of face: a. kiss, b: open mouth and tongue, c: whistling, d: whistling, e: bye-bye

### **3. The forehead**

Visualization of the curvature of the forehead is important to rule out a flat forehead (Figure 4). Investigators agree that microcephaly is associated with a decreased size of the frontal fossa and flattening of the frontal bone. Therefore, determination of the normal dimensions of the anterior cranial fossa and the frontal lobe of the fetal brain can provide normative

Fig. 4. Schematic picture of the anterior lobe on sagittal and axial planes

Fig. 3. 3D pictures of the fetal face. Mimics of face: a. kiss, b: open mouth and tongue, c:

Fig. 4. Schematic picture of the anterior lobe on sagittal and axial planes

Visualization of the curvature of the forehead is important to rule out a flat forehead (Figure 4). Investigators agree that microcephaly is associated with a decreased size of the frontal fossa and flattening of the frontal bone. Therefore, determination of the normal dimensions of the anterior cranial fossa and the frontal lobe of the fetal brain can provide normative

whistling, d: whistling, e: bye-bye

**3. The forehead** 

Fig. 5. A flat forehead in neonates with microcephaly


Table 2. Measurements of the mean±2SD of the frontal lobe distance and thalamic frontal lobe distance versus gestational age (Goldstein et al., 1988) (GA = gestational age, FLD = frontal lobe distance, TFLD = thalamic frontal lobe distance)

Normal and Abnormal Fetal Face 91

possible improvement in screening for trisomy 21 by examining the fetal nasal bone with ultrasound at 11-14 weeks of gestation (Cicero et al., 2001). The nasal bone was absent in 43 of 59 (73%) trisomy 21 fetuses, and in three of 603 (0.5%) chromosomally normal fetuses.

Smallness of fetal nose, often attributed to hypoplasia, is a common finding during postnatal

14-15 5.5 7.2 7.6 8.3 10.2 16-17 6.5 7.3 7.9 8.5 10.5 18-19 8.5 8.9 10.0 10.5 11.0 20-21 10.2 11.0 12.0 12.0 13.0 22 13.0 13.0 14.0 15.0 15.0 23 13.0 13.0 14.0 15.0 15.0 24 13.0 14.1 15.0 16.0 16.0 25 14.2 15.0 16.3 17.0 17.0 26 14.1 15.0 16.3 17.4 18.4 27 13.4 15.4 17.2 18.4 19.0 28 15.1 16.9 17.6 18.2 20.2 29-30 16.5 17.4 18.1 19.2 20.6 31-32 16.6 17.9 19.6 20.7 21.4 33-34 17.4 19.1 20.5 21.4 23.1 35-37 17.6 20.0 20.5 22.0 23.3 38-40 17.4 17.9 18.9 20.5 23.4

**10 25 50 75 90**

**10 25 50 75 90**

examination of fetuses or neonates with trisomy 21 (Smith & Jones, 1988)

**GA [weeks] Centiles**

Table 6. The fetal nose width (mm) (Goldstein et al., 1997)

Table 7. The fetal nostril distance (mm) (Goldstein et al., 1997)

**GA [weeks] Centiles**

14-15 3.3 3.6 4.2 4.7 5.4 16-17 3.5 3.9 4.4 4.8 5.9 18-19 4.0 4.4 .6 5.0 5.8 20-21 4.2 5.0 5.0 5.7 6.0 22 5.0 5.0 6.0 6.4 7.0 23 5.0 5.6 6.0 7.0 7.0 24 5.8 6.0 6.2 7.3 7.9 25 5.9 6.0 6.4 7.0 7.7 26 5.1 6.2 7.7 8.0 9.0 27 6.4 6.8 7.8 8.4 9.4 28 6.4 7.0 7.9 8.6 9.4 29-30 5.4 7.0 7.0 8.2 9.6 31-32 4.6 7.4 7.9 9.2 10.7 33-34 5.4 6.4 8.1 9.0 9.7 35-37 5.8 6.6 8.5 9.6 10.2 38-40 6.0 6.8 8.5 9.5 10.5

**5. The nostrils** 

data against which fetuses suspected to have microcephaly or any other lesion affecting the anterior fossa can be evaluated. A dysmorphic sign with a high frequency appears to be a flat facial profile in neonates with trisomy 21 (Smith & Jones, 1988). Table 2 describes the normal dimensions of the frontal lobe of the fetal brain (Goldstein et al., 1988).

#### **4. The nasal bone**

Smallness of the nose is a common finding at postnatal examination of fetuses or neonates with trisomy 21, but also with more than 40 other genetic conditions. Measurements of the nasal bone were performed on a mid-sagittal profile in normal singleton fetuses at 14-34 weeks' gestation. It was found that the length of the nasal bones increased from 4 mm at 14 weeks to 12 mm at 35 weeks' gestation (Guis et al., 1995). Investigators examined the


Table 3. Mean, standard deviation (SD), mean+2SD and mean-2SD for length of the nasal bones (mm) throughout gestation (Guis et al., 1995)


Table 4. Fetal nasal bone length (mm), 11-20 weeks' gestation (Cuick et al., 2004)


Table 5. Nomogram of fetal nasal bone length at 11-13 gestational weeks in fetuses (Sivri et al., 2006)

possible improvement in screening for trisomy 21 by examining the fetal nasal bone with ultrasound at 11-14 weeks of gestation (Cicero et al., 2001). The nasal bone was absent in 43 of 59 (73%) trisomy 21 fetuses, and in three of 603 (0.5%) chromosomally normal fetuses.

### **5. The nostrils**

90 Prenatal Diagnosis – Morphology Scan and Invasive Methods

data against which fetuses suspected to have microcephaly or any other lesion affecting the anterior fossa can be evaluated. A dysmorphic sign with a high frequency appears to be a flat facial profile in neonates with trisomy 21 (Smith & Jones, 1988). Table 2 describes the

Smallness of the nose is a common finding at postnatal examination of fetuses or neonates with trisomy 21, but also with more than 40 other genetic conditions. Measurements of the nasal bone were performed on a mid-sagittal profile in normal singleton fetuses at 14-34 weeks' gestation. It was found that the length of the nasal bones increased from 4 mm at 14 weeks to 12 mm at 35 weeks' gestation (Guis et al., 1995). Investigators examined the

**Gestation [weeks] Mean SD** 14 4.183 0.431 16 5.213 1.062 18 6.308 0.654 20 7.621 0.953 22 8.239 1.102 24 9.362 1.300 26 9.744 1.277 28 10.72 1.459 30 11.348 1.513 32 11.580 1.795 34 12.285 2.372 Table 3. Mean, standard deviation (SD), mean+2SD and mean-2SD for length of the nasal

**Gestation [weeks] Mean [mm] SD [mm]** 11-11.9 1.7 0.5 12-12.9 2.0 0.5 13-13.9 2.3 0.5 14-14.9 3.4 0.7 15-15.9 3.3 0.8 16-16.9 4.4 0.7 17-17.9 5.0 0.7 18-18.9 5.5 0.9 19-19.9 5.7 0.1 20-20.9 6.2 0.1 Table 4. Fetal nasal bone length (mm), 11-20 weeks' gestation (Cuick et al., 2004)

> **Gestation [weeks] Mean [mm] SD [mm]** 11-11+6 1.69 0.26 12-12+6 2.11 0.37 13-13+6 2.34 0.39 14-14+6 2.94 0.48

Table 5. Nomogram of fetal nasal bone length at 11-13 gestational weeks in fetuses (Sivri et

bones (mm) throughout gestation (Guis et al., 1995)

normal dimensions of the frontal lobe of the fetal brain (Goldstein et al., 1988).

**4. The nasal bone** 

al., 2006)

Smallness of fetal nose, often attributed to hypoplasia, is a common finding during postnatal examination of fetuses or neonates with trisomy 21 (Smith & Jones, 1988)


Table 6. The fetal nose width (mm) (Goldstein et al., 1997)


Table 7. The fetal nostril distance (mm) (Goldstein et al., 1997)

Normal and Abnormal Fetal Face 93

**10 25 50 75 90** 

**10 25 50 75 90** 

**N Mean 95% CI Centiles** 

14 10 5.2 4.8-5.7 4.5 5.0 5.3 5.7 90 15 26 6.1 5.9-6.3 5.4 5.5 6.2 6.5 6.7 16 25 6.6 6.3-6.9 5.8 6.2 6.5 7.0 7.6 17-18 19 7.3 6.7-7.8 6.2 6.5 6.7 9.0 9.0 19-20 23 9.8 9.3-10.2 8.6 9.0 10.0 10.1 11.3 21 19 10.5 10.0-10.9 9.4 9.9 10.0 11.0 12.0 22 26 10.4 10.0-10.7 9.5 9.6 10.5 11.0 11.3 23 21 10.7 10.4-11.1 9.6 10.0 10.5 11.4 11.5 24 19 11.6 11.3-11.8 10.7 11.0 11.5 12.0 12.5. 25 13 11.2 11.4-12.4 10.3 11.0 12.2 12.5 12.8 26 16 12.7 12.0-13.4 11.0 11.0 12.7 13.8 14.5 27 14 13.0 12.4-13.5 11.9 12.0 12.9 13.4 14.8 28 21 13.0 12.7-13.3 21.1 12.0 13.1 13.3 14.1 29 23 13.9 13.4-14.4 12.6 13.0 13.7 14.6 15.7 30-31 24 14.2 13.8-14.5 13.3 13.0 13.9 14.7 15.4 32-33 24 14.4 13.7-15.1 12.2 13.0 14.1 14.8 17.5 34-36 26 15.8 15.4-16.2 14.6 15.0 15.7 16.5 16.9 Table 8. The fetal orbital diameter (mm) (Goldstein et al., 1998) GA = gestational age; CI =

**n Mean 95% CI Centiles** 

14 10 2.5 23.3-2.7 2.1 2.4 2.5 2.7 2.9 15 26 2.9 2.9-3.0 2.7 2.8 2.9 3.1 3.2 16 25 2.9 2.8-3.0 2.7 2.8 2.9 3.1 3.2 17-18 19 3.3 3.0-3.6 2.8 2.9 3.0 3.3 5.0 19-20 23 4.1 4.0-4.3 3.6 4.0 4.0 4.3 5.0 21 19 4.4 4.1-4.6 3.7 3.9 4.0 5.0 5.0 22 26 4.4 4.2-4.7 3.9 4.0 4.3 5.0 5.0 23 21 4.6 4.3-4.8 3.8 4.0 5.0 5.0 5.0 24 19 4.6 4.4-4.8 4.0 4.3 4.6 5.0 5.0 25 13 4.8 4.6-5.0 4.2 4.6 5.0 5.1 5.2 26 16 5.0 4.8-5.2 4.4 4.8 5.1 5.2 5.5 27 14 5.0 5.0-5.2 4.5 5.0 5.2 5.2 5.5 28 21 5.1 5.0-5.2 4.5 5.0 5.2 5.2 5.5 29 23 5.3 5.1-5.5 4.6 5.2 5.2 5.5 5.9 30-31 24 5.3 5.2-5.5 4.8 5.1 5.5 5.5 5.7 32-33 24 5.6 5.4-5.8 4.8 5.2 5.5 5.9 6.2 34-36 26 5.8 5.6-6.0 5.4 5.5 5.7 6.0 6.5 Table 9. Diameter of orbital lens (mm) (Goldstein et al., 1998) GA = gestational age; CI =

**GA [weeks]** 

confidence interval

confidence interval)

**GA [weeks]** 

### **6. The fetal eyes**

The earliest sonographic visualization of the fetal orbit and lens has been considered to be in the beginning of the second trimester of pregnancy. On ultrasound, the orbits appear as echolucent circles in the face of the fetus, and the lens can be easily identified inside these structures. Imaging of these structures, which is possible on virtually all ultrasound examinations beyond the first trimester, is important because deviation in the relative size of the orbit and the lens can be associated with congenital malformations. The fetal orbits and lens eyes are best visualized by scanning the fetal face in coronal and axial planes. The fetal orbits should appear as two symmetrical structures on both sides of the fetal nose. Both lenses are depicted on the coronal or axial plane of the eye as circular hyperechogenic rings and with hypoechogenic areas inside the ring.

The coronal planes of the fetal face are the most important in the evaluation of the fetal orbits. Figure 6a shows the the outer orbital distance small hands, and Fig 6b the inner orbital distace the small arrows. The calipers measuring the outer orbital from the lateral mid-echogenicity to the lateral mid-echogenicity, and the calipers measuring the inner orbital distace from the middle mid-echogenicity to the middle mid-echogenicity of the orbits.

Fig. 6a. Coronal plane of the fetal orbits – small hands showing the outer orbital diameter measurement

Fig. 6b. Coronal plane of the fetal orbits – small arrows showing the inner orbital diameter measurement

The earliest sonographic visualization of the fetal orbit and lens has been considered to be in the beginning of the second trimester of pregnancy. On ultrasound, the orbits appear as echolucent circles in the face of the fetus, and the lens can be easily identified inside these structures. Imaging of these structures, which is possible on virtually all ultrasound examinations beyond the first trimester, is important because deviation in the relative size of the orbit and the lens can be associated with congenital malformations. The fetal orbits and lens eyes are best visualized by scanning the fetal face in coronal and axial planes. The fetal orbits should appear as two symmetrical structures on both sides of the fetal nose. Both lenses are depicted on the coronal or axial plane of the eye as circular hyperechogenic rings

The coronal planes of the fetal face are the most important in the evaluation of the fetal orbits. Figure 6a shows the the outer orbital distance small hands, and Fig 6b the inner orbital distace the small arrows. The calipers measuring the outer orbital from the lateral mid-echogenicity to the lateral mid-echogenicity, and the calipers measuring the inner orbital distace from the

Fig. 6a. Coronal plane of the fetal orbits – small hands showing the outer orbital diameter

Fig. 6b. Coronal plane of the fetal orbits – small arrows showing the inner orbital diameter

**6. The fetal eyes** 

measurement

measurement

and with hypoechogenic areas inside the ring.

middle mid-echogenicity to the middle mid-echogenicity of the orbits.


Table 8. The fetal orbital diameter (mm) (Goldstein et al., 1998) GA = gestational age; CI = confidence interval


Table 9. Diameter of orbital lens (mm) (Goldstein et al., 1998) GA = gestational age; CI = confidence interval)

Normal and Abnormal Fetal Face 95

Fig. 7. Axial scan of a fetus at 25.3 weeks of gestation showing severe hypotelorism

**BPD [cm] Weeks' gestation IOD [cm] OOD [cm]**  1.9 11.6 0.5 1.3 2.0 11.6 0.5 1.4 2.1 12.1 0.6 1.5 2.2 12.6 0.6 1.6 2.3 12.6 0.6 1.7 2.4 13.1 0.7 1.7 2.5 13.6 0.7 1.8 2.6 13.6 0.7 1.9 2.7 14.1 0.8 2.0 2.8 14.6 0.8 2.1 2.9 14.6 0.8 2.1 3.0 15.0 0.9 2.2 3.1 15.5 0.9 2.3 3.2 15.5 0.9 2.4 3.3 16.0 1.0 2.5 3.4 16.5 1.0 2.5 3.5 16.5 1.0 2.6 3.6 17.0 1.0 2.7 3.7 17.5 1.1 2.7 3.8 17.9 1.1 2.8 4.0 18.4 1.2 3.0 4.2 18.9 1.2 3.1 4.3 19.4 1.2 3.2 4.4 19.4 1.3 3.2 4.5 19.9 1.3 3.3 4.6 20.4 1.3 3.4 4.7 20.4 1.3 3.4 4.8 20.9 1.4 3.5 4.9 21.3 1.4 3.6 5.0 21.3 1.4 3.6

#### **6.1 Hypotelorism**

Hypotelorism is a condition pertaining to abnormally close eyes.


Table 10. The outer orbital diameter (OOD) and inner orbital diameter (IOD), GA = gestational age (Jeanty et al., 1984)

**5th 50th 95th 5th 50th 95th**

Hypotelorism is a condition pertaining to abnormally close eyes.

**GA [weeks] OOD [mm] IOD [mm]** 

Table 10. The outer orbital diameter (OOD) and inner orbital diameter (IOD), GA =

gestational age (Jeanty et al., 1984)

**6.1 Hypotelorism** 

Fig. 7. Axial scan of a fetus at 25.3 weeks of gestation showing severe hypotelorism


Normal and Abnormal Fetal Face 97

Hypertelorism is an abnormally increased distance between two organs or body parts, usually referring to an increased distance between the eyes (orbital hypertelorism), seen in a

Vilaret, Weyers-Tier, ocular vertebral syndrome

Chromosome 15-p-proximal partial trisomy syndrome

Chromosome 14 p-proximal partial trisomy syndrome

Craniosynostosis-medical aplasia syndrome

Microphthalmus Autosomal recessive or autosomal dominant Intrauterine infection

Chromosomal aberration

Chromosome 13 trisomy

Acrocephalosyndactyly

Auditory canal atresia Basal nevus syndrome

Campomelic dysplasia

Coffin-Lowry syndrome Cranio-carpo tarsal dysplasia Cranio-facial dysostosis

Branchio-skeleto-genital syndrome Broad thumb-hallux syndrome

Cerebro-hepato-renal syndrome Chromosome 18 p- syndrome Chromosome 5 p- syndrome Chromosome 4 p- syndrome

Acrodystasis

Holoprosencephaly Meckel syndrome

Associated with gingival fibromatosis

Radiation

X-linked

Ocular hypotelorism Chromosome 5 p-syndrome

Ocular hypetelorism Aarshog syndrome

Depigmentation

**6.2 Hypertelorism** 

variety of syndromes (Table 12).

**Malformation Syndromes** 

Anophthalmus Trisomy 13


Table 11. Predicted BPD and weeks' gestation from the inner orbital diameter (IOD) and outer orbital diameter (OOD) (Mayden et al., 1982)

#### **6.2 Hypertelorism**

96 Prenatal Diagnosis – Morphology Scan and Invasive Methods

**BPD [cm] Weeks' gestation IOD [cm] OOD [cm]**  5.1 21.8 1.4 3.7 5.2 22.3 1.4 3.8 5.3 22.3 1.5 3.8 5.4 22.8 1.5 3.9 5.5 23.9 1.5 4.0 5.6 23.3 1.5 4.0 5.7 23.8 1.5 4.1 5.8 24.3 1.6 4.1 5.9 24.3 1.6 4.2 6.0 24.7 1.6 4.3 6.1 25.2 1.6 4.3 6.2 25.2 1.6 4.4 6.3 25.7 1.7 4.4 6.4 26.2 1.7 4.5 6.5 26.2 1.7 4.5 6.6 26.7 1.7 4.6 6.7 27.2 1.7 4.6 6.8 27.6 1.7 4.7 6.9 28.1 1.7 4.7 7.0 28.6 1.8 4.8 7.1 29.1 1.8 4.8 7.3 29.6 1.8 4.9 7.4 30.0 1.8 5.0 7.5 30.6 1..8 5.0 7.6 31.0 1.8 5.1 7.7 31.5 1.8 5.1 7.8 32.0 1.8 5.2 7.9 32.5 1.9 5.2 8.0 33.0 1.9 5.3 8.2 33.5 1.9 5.4 8.3 34.0 1.9 5.4 8.4 34.4 1.9 5.4 8.5 35.0 1.9 5.5 8.6 35.4 1.9 5.5 8.8 35.9 1.9 5.6 8.9 36.4 1.9 5.6 9.0 36.9 1.9 5.7 9.1 37.3 1.9 5.7 9.2 37.8 1.9 5.8 9.3 38.3 1.9 5.8 9.4 38.8 1.9 5.8 9.6 39.3 1.9 5.8 9.7 39.8 1.9 5.9 Table 11. Predicted BPD and weeks' gestation from the inner orbital diameter (IOD) and

outer orbital diameter (OOD) (Mayden et al., 1982)

Hypertelorism is an abnormally increased distance between two organs or body parts, usually referring to an increased distance between the eyes (orbital hypertelorism), seen in a variety of syndromes (Table 12).


Normal and Abnormal Fetal Face 99

Cyclopia is an anomaly characterized by a single orbital fossa, with fusion of bulbs, eyelids and lacrimal apparatus to a variable degree. Usually there is a single eye or partially divided eye in a single orbit and arhinia with proboscis. A normal nose is absent and a proboscis structure originating from the nasal root may be seen (Bergsma, 1979). The differential diagnosis in these cases includes ethmocephaly (extreme hypotelorism, arhinia and blinded proboscis located between the eyes) and ceboephaly (hypotelorism and a single nostril nose, without midline cleft). In ethmocephaly, the nasal bones, maxilla and nasal septum and turbinate are missing and lacrimal and palatine bones are united (Goldstein et al., 2003;

Fig. 8. Axial and sagittal scans of a fetus at 25.3 weeks of gestation show prominent forehead

Fig. 9. Ethmocephaly – postmortem demonstrating hypotelorism and proboscis

**6.3 Cyclopia** 

McGahan et al., 1990).

and proboscis


Table 12. Syndromes associated with fetal ocular malformation (Bergsma, 1979)

#### **6.3 Cyclopia**

98 Prenatal Diagnosis – Morphology Scan and Invasive Methods

Deafness myopia cataract and saddle nose

Hypertelorism–hypospadias syndrome

Iris coloboma and canal atresia syndrome

Hypertelorism microtia facial clefting and conductive deafness

Ocular and facial anomalies with proteinuria and deafness

Cranio-metaphyseal dysplasia Cranio-oculodental syndrome

Ehlers-Danlos syndrome Fetal hydantoin syndrome Fetal warfarin syndrome

G syndrome

Cleft lip

Bifid nose

Deafness

Larsen syndrome

Meckel syndrome Median cleft syndrome Noonan syndrome

Glioma of the nose

Multiple lentigines syndrome

Nose and nasal septum defects

Posterior atresia of the nose

Wolf-Hirschhorn syndrome Waardenburg syndrome Cri du chat syndrome DiGeorge syndrome Loeys-Dietz syndrome Morquio syndrome Hurler's syndrome

Table 12. Syndromes associated with fetal ocular malformation (Bergsma, 1979)

Oculo-dento osseous dysplasia Opitz-Kaveggia FG syndrome Oto-palatodigital syndrome Bilateral renal agenesis Roberts syndrome Robinow syndrome Sclerosteosis Thymic agenesis Apert syndrome LEOPARD syndrome Crouzon syndrome

Marden-Walker syndrome

**Malformation Syndromes** 

Cyclopia is an anomaly characterized by a single orbital fossa, with fusion of bulbs, eyelids and lacrimal apparatus to a variable degree. Usually there is a single eye or partially divided eye in a single orbit and arhinia with proboscis. A normal nose is absent and a proboscis structure originating from the nasal root may be seen (Bergsma, 1979). The differential diagnosis in these cases includes ethmocephaly (extreme hypotelorism, arhinia and blinded proboscis located between the eyes) and ceboephaly (hypotelorism and a single nostril nose, without midline cleft). In ethmocephaly, the nasal bones, maxilla and nasal septum and turbinate are missing and lacrimal and palatine bones are united (Goldstein et al., 2003; McGahan et al., 1990).

Fig. 8. Axial and sagittal scans of a fetus at 25.3 weeks of gestation show prominent forehead and proboscis

Fig. 9. Ethmocephaly – postmortem demonstrating hypotelorism and proboscis

Normal and Abnormal Fetal Face 101

Imaging of the maxillary bone is possible in most ultrasound examinations and is important, because deviations in maxillary bone development can also be associated with a malformed face. The relationship between the maxillary, zygomatic and palatine bones provides a capacity for rapid movement of the fetal face. The etiology of hypoplasia of the maxillary bone may, in some cases, form part of well-established structural abnormalities in the fetus

Table 13. Fetal ear length (Yeo et al., 1998)

**8. The maxillary bone** 

#### **6.4 Cataracts**

A cataract is an opacity of the lens and accounts for 10% of the blindness seen in preschool age children in Western countries. Fetal cataracts may occur in association with infectious diseases, chromosomal anomalies or systemic syndromes.

Fig. 10. Sonographic pictures of fetal cataracts at 15 weeks of gestation. Coronal views of echogenic lens.

#### **7. The ear**

Abnormally small ears have been noted to be one of the findings in newborn and infants with trisomy 21 and other aneuploidies. Ears in these infants are often described as small, low-set, and malformed. Short ear length has been found to be the most consistent clinical characteristic in making the diagnosis of Downs' syndrome (Aase et al., 1973). Sonographically, a short fetal ear length may be a parameter in predicting fetal aneouploidy (Chitkara et al., 2002). Sonographic studies have suggested that short ear length measurements might be a useful predictor of fetal anomalies (Awwad et al., 1994; Lettieri et al., 1993; Shimizu et al., 1997; Yeo et al., 1998).

Investigators had suggested that the fetal ear length may be a useful measurement in prediction of aneuploidy in patients at high risk for fetal chromosomal abnormalities (Awwad et al., 1994; Lettieri et al., 1993; Shimizu et al., 1997; Yeo et al., 1998). However, it remains to be determined whether this measurement alone, or in combination with other aneuploidy markers, will prove to be a useful predictor of aneuploidy in a population of women at low risk for fetal chromosomal abnormalty.

A cataract is an opacity of the lens and accounts for 10% of the blindness seen in preschool age children in Western countries. Fetal cataracts may occur in association with infectious

Fig. 10. Sonographic pictures of fetal cataracts at 15 weeks of gestation. Coronal views of

Abnormally small ears have been noted to be one of the findings in newborn and infants with trisomy 21 and other aneuploidies. Ears in these infants are often described as small, low-set, and malformed. Short ear length has been found to be the most consistent clinical characteristic in making the diagnosis of Downs' syndrome (Aase et al., 1973). Sonographically, a short fetal ear length may be a parameter in predicting fetal aneouploidy (Chitkara et al., 2002). Sonographic studies have suggested that short ear length measurements might be a useful predictor of fetal anomalies (Awwad et al., 1994; Lettieri et

Investigators had suggested that the fetal ear length may be a useful measurement in prediction of aneuploidy in patients at high risk for fetal chromosomal abnormalities (Awwad et al., 1994; Lettieri et al., 1993; Shimizu et al., 1997; Yeo et al., 1998). However, it remains to be determined whether this measurement alone, or in combination with other aneuploidy markers, will prove to be a useful predictor of aneuploidy in a population of

diseases, chromosomal anomalies or systemic syndromes.

**6.4 Cataracts** 

echogenic lens.

al., 1993; Shimizu et al., 1997; Yeo et al., 1998).

women at low risk for fetal chromosomal abnormalty.

**7. The ear** 


Table 13. Fetal ear length (Yeo et al., 1998)

#### **8. The maxillary bone**

Imaging of the maxillary bone is possible in most ultrasound examinations and is important, because deviations in maxillary bone development can also be associated with a malformed face. The relationship between the maxillary, zygomatic and palatine bones provides a capacity for rapid movement of the fetal face. The etiology of hypoplasia of the maxillary bone may, in some cases, form part of well-established structural abnormalities in the fetus

Normal and Abnormal Fetal Face 103

populations (Chen et al., 2011). These authors previously studied the FMF angle in fetuses with trisomy 21 in the first trimester and found significant differences in the FMF angle between normal fetuses and fetuses with trisomy 21 in the Chinese population (Chen et al.,

Fetal macroglossia and microglossia are associated with several chromosomal defects. Table

Table 15. Tongue circumference (mm) by gestational age (weeks) and the 95% confidence

Cleft lip and palate is a common facial anomaly, with an incidence of 1 in 1000 live births. The incidence in fetuses is much higher, and many of these also have other malformations. Cleft palate alone occurs in about 1 of 2,500 white births. Cleft lip is more common in males, and cleft palate is more common in females. Cleft lip is one or more splits (clefts) in the upper lip. Cleft lip can range from a small indentation in the lip to a split in the lip that may extend up into one or both nostrils. Cleft lip develops in about the sixth to eighth week of gestation, when structures in the upper jaw do not fuse properly and the upper lip does not completely merge. Sometimes the nasal cavity, palate, and upper teeth are also affected in an opening in the roof of the mouth that develops when the cleft palate bones and tissues do not completely join during fetal growth, sometime between the 7th and 12th weeks of gestation. The severity and type of cleft palate vary according to where the cleft occurs on the palate and whether all the layers of the palate are affected. A mild form of cleft palate may not be visible because tissue covers the cleft. A complete cleft palate involves all layers of tissue of the soft palate, extends to and includes the hard palate, and may continue to the lip and nose. Sometimes problems associated with cleft palate also include deformities of the

nasal cavities and/or the partition separating them (septum).

15 describes the tongue circumference between 14 and 26 weeks of gestation.

2009).

**9. The tongue** 

interval (Achiron et al., 1997)

**10. Cleft lips & palate** 

such as choanal atresia, or genetic syndromes such as Marfan's syndrome. Sonographically, early prenatal detection of the maxillary bone is possible at 14 week of gestation. Hypoplasia of the maxillary bone can appear as an incidental finding. Table 14 depicts nomograms of the maxillary bone length.

Fig. 11. Sonographic picture of the maxillary bone


Table 14. Maxillary bone length across gestational age (Goldstein et al., 2005)

The frontomaxillary facial (FMF) angle was studied in the first trimester in a Chinese population, demonstrating that the FMF angle decreases with fetal CRL increases. Similarity in the normal values of the FMF angle was found between the Chinese and Caucasian populations (Chen et al., 2011). These authors previously studied the FMF angle in fetuses with trisomy 21 in the first trimester and found significant differences in the FMF angle between normal fetuses and fetuses with trisomy 21 in the Chinese population (Chen et al., 2009).

#### **9. The tongue**

102 Prenatal Diagnosis – Morphology Scan and Invasive Methods

such as choanal atresia, or genetic syndromes such as Marfan's syndrome. Sonographically, early prenatal detection of the maxillary bone is possible at 14 week of gestation. Hypoplasia of the maxillary bone can appear as an incidental finding. Table 14 depicts nomograms of

the maxillary bone length.

Fig. 11. Sonographic picture of the maxillary bone

Table 14. Maxillary bone length across gestational age (Goldstein et al., 2005)

The frontomaxillary facial (FMF) angle was studied in the first trimester in a Chinese population, demonstrating that the FMF angle decreases with fetal CRL increases. Similarity in the normal values of the FMF angle was found between the Chinese and Caucasian Fetal macroglossia and microglossia are associated with several chromosomal defects. Table 15 describes the tongue circumference between 14 and 26 weeks of gestation.


Table 15. Tongue circumference (mm) by gestational age (weeks) and the 95% confidence interval (Achiron et al., 1997)

#### **10. Cleft lips & palate**

Cleft lip and palate is a common facial anomaly, with an incidence of 1 in 1000 live births. The incidence in fetuses is much higher, and many of these also have other malformations. Cleft palate alone occurs in about 1 of 2,500 white births. Cleft lip is more common in males, and cleft palate is more common in females. Cleft lip is one or more splits (clefts) in the upper lip. Cleft lip can range from a small indentation in the lip to a split in the lip that may extend up into one or both nostrils. Cleft lip develops in about the sixth to eighth week of gestation, when structures in the upper jaw do not fuse properly and the upper lip does not completely merge. Sometimes the nasal cavity, palate, and upper teeth are also affected in an opening in the roof of the mouth that develops when the cleft palate bones and tissues do not completely join during fetal growth, sometime between the 7th and 12th weeks of gestation. The severity and type of cleft palate vary according to where the cleft occurs on the palate and whether all the layers of the palate are affected. A mild form of cleft palate may not be visible because tissue covers the cleft. A complete cleft palate involves all layers of tissue of the soft palate, extends to and includes the hard palate, and may continue to the lip and nose. Sometimes problems associated with cleft palate also include deformities of the nasal cavities and/or the partition separating them (septum).

Normal and Abnormal Fetal Face 105

Ultrasonography can be used to identify clefting in the lip and primary palate (alveolar ridge). The ultrasound detecting rates of facial clefting have been reported as low as 21-30% using two-dimensional ultrasound (Crane et al., 1994). Accurate characterization of the fetal clefting is an important aspect of ultrasound diagnosis. Three-dimensional ultrasound may be useful in defining the location and extent of facial clefting *in utero* (Johnson et al., 2000). Although three-dimensional images of the fetal alveolar ridge can be obtained, twodimensional sonographic images are obtained more easily, rapidly and accurately

Fig. 14. Sonographic pictures of cleft palate (15 & 23 weeks of gestation)

Gestation [weeks] Mean [mm] ±SD [mm] 14 -15 10.5 1.3 16 11.7 1.1 17 16.6 2.5 18 17.5 1.1 19 18.0 1.1 20 18.5 1.1 21 18.5 2.1 22 19.9 1.7 23 20.5 1.9 24 21.3 2.7 25 22.8 1.9 26 23.6 2.6 27-28 23.6 2.1 29 25.5 2.2 30 26.3 2.5 31 26.5 2.1 32 26.7 2.0

Table 16. Normal values of the fetal alveolar ridge width (Goldstein et al., 1999)

Abnormal size of the chin, micrognathia and macrognathia, and abnormal length of the philtrum (short or long) are morphological features in numerous syndromes. Micrognathia is a common finding in many chromosome aberrations and dysmorphic syndromes (Gulla

**11. The chin: Microganthia-retroganthia or prognathia** 

(Goldstein et al., 1999).

An ultrasound detection of cleft lip and palate may be seen as early as 14 to 16 weeks of gestation. Cleft palate and cleft lip may occur independent of each other or at the same time. The hard palate is the front part of the roof of the mouth, and the soft palate is the back part of the roof of the mouth. This description may include whether the uvulais affected. The latter is impossible to detect prenatally. Cleft lip is classified according to its location and severity. Unilateral cleft lip affects one side of the mouth; bilateral cleft lip affects both sides of the mouth. A complete cleft lip is a deep split in the upper lip extending into one or both sides of the nose; an incomplete cleft lip affects only one side of the upper lip. It may appear as a slight indentation or as a deep notch.

Fig. 12. Sonographic picture of normal primary palate (The alveolar ridge)

Fig. 13. Sonographic pictures of cleft lip

An ultrasound detection of cleft lip and palate may be seen as early as 14 to 16 weeks of gestation. Cleft palate and cleft lip may occur independent of each other or at the same time. The hard palate is the front part of the roof of the mouth, and the soft palate is the back part of the roof of the mouth. This description may include whether the uvulais affected. The latter is impossible to detect prenatally. Cleft lip is classified according to its location and severity. Unilateral cleft lip affects one side of the mouth; bilateral cleft lip affects both sides of the mouth. A complete cleft lip is a deep split in the upper lip extending into one or both sides of the nose; an incomplete cleft lip affects only one side of the upper lip. It may appear

Fig. 12. Sonographic picture of normal primary palate (The alveolar ridge)

as a slight indentation or as a deep notch.

Fig. 13. Sonographic pictures of cleft lip

Ultrasonography can be used to identify clefting in the lip and primary palate (alveolar ridge). The ultrasound detecting rates of facial clefting have been reported as low as 21-30% using two-dimensional ultrasound (Crane et al., 1994). Accurate characterization of the fetal clefting is an important aspect of ultrasound diagnosis. Three-dimensional ultrasound may be useful in defining the location and extent of facial clefting *in utero* (Johnson et al., 2000). Although three-dimensional images of the fetal alveolar ridge can be obtained, twodimensional sonographic images are obtained more easily, rapidly and accurately (Goldstein et al., 1999).

Fig. 14. Sonographic pictures of cleft palate (15 & 23 weeks of gestation)


Table 16. Normal values of the fetal alveolar ridge width (Goldstein et al., 1999)

#### **11. The chin: Microganthia-retroganthia or prognathia**

Abnormal size of the chin, micrognathia and macrognathia, and abnormal length of the philtrum (short or long) are morphological features in numerous syndromes. Micrognathia is a common finding in many chromosome aberrations and dysmorphic syndromes (Gulla

Normal and Abnormal Fetal Face 107

 Fig. 16. Sagittal scan and postmortem of a fetus at 16 weeks of gestation shows prominent

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Table 17. Chin length (Sivan et al., 1997)

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Fig. 15. Chin length measured between the lower lip and the apex of the chin (Sivan et al., 1977)

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Table 17. Chin length (Sivan et al., 1997)

Fig. 16. Sagittal scan and postmortem of a fetus at 16 weeks of gestation shows prominent forehead and retrognathia

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**7** 

**Current Issues Regarding Prenatal Diagnosis of** 

It has long been established that there is a relationship between hypercholesterolemia and cardiovascular disease in adulthood. However, only in the 90s, the biological consequence of low levels of cholesterol for mitotic cells was highlighted, with the description of the devastating effect of hypocholesterolemia on fetal development. This was supported by the discovery of a group of metabolic diseases caused by mutations in genes coding for enzymes involved in endogenous synthesis of cholesterol. This group is still growing as new diseases, phenotypes and mutated genes are being described by researchers. Despite the fact that they share some common clinical features - including abnormal morphogenesis and growth retardation - these inherited metabolic diseases are still poorly recognized in daily

Cholesterol is an essential lipid found in all mammalian cells. It can modulate the activity of the Hedgehog proteins, which act as morphogens that regulate the precise patterning of many embryonic structures [Gofflot et al., 2003]. Furthermore, cholesterol is a key component of lipid-rafts, which have a structural role in cellular membranes and myelin sheets and it is a precursor molecule for sterol-based compounds, including bile acids, oxysterols, neurosteroids, glucocorticoids, mineralocorticoids, and sex hormones like estrogen and testosterone [Correa-Cerro et al., 2005]. Due to the panoply of biological functions of the sterols, a decrease of its availability during pregnancy has major consequences to the fetus, severely impairing his development [Cardoso et al., 2005a].

Dietary cholesterol is absorbed from bile salt micelles, with fatty acids and phospholipids, at the proximal part of the small intestine, in a process which involves Nieman-Pick C1-Like1 protein (NPC1L1). This protein contains a sterol sensing domain (SSD) and is located in the

**2. Intestinal cholesterol absorption, transport and metabolism** 

**1. Introduction** 

obstetric clinical practice.

**Inborn Errors of Cholesterol Biosynthesis** 

*2Institute for Molecular and Cell Biology, University of Porto, Porto* 

*4Life and Health Sciences Research Institute, School of Health Sciences,* 

Maria Luís Cardoso1,2, Mafalda Barbosa3,4, Ana Maria Fortuna3 and Franklim Marques1,2 *1Faculty of Pharmacy, University of Porto, Porto* 

> *3Medical Genetics Centre Jacinto Magalhães, National Health Institute Ricardo Jorge Porto*

> > *University of Minho, Braga*

*Portugal* 

Yeo L., Guzman E.R., Day-Salvatore D., Vintzileos A.M. & Walters C. (1998). Prenatal detection of fetal aneuploidy using sonographic ear length. *American Journal of Obstetrics & Gynecology*, Vol.178:S141.
