Diagnosis of fetal syndromes by three- and four-dimensional ultrasound: is there any improvement?

Brain anomalies

An important milestone in the prenatal recognition of normal brain development is the visualisation of corpus callosum (CC) by improved ultrasound imaging; without this prenatal assessment was rather difficult. With 3D surface rendering in the median plane, CC can be visualized with all its segments: genu, body and splenium. Additionally, vascularization of CC with a 3D sonoangiogram of the pericallosal artery (PA) (Figure 1) and the anterior cerebral artery (ACA) became much easier than before [12], [32]. If there is a suspicion or clear prenatal diagnosis of agenesis of CC (ACC), it is important to search for other fetal abnormalities or syndromes [trisomy 18, cerebro-costo-mandibular syndrome, Walker-Warburg syndrome, Pai syndrome, Fryns syndrome and also fetal varicella zoster syndrome, fetal cytomegalovirus (CMV) syndrome and the most recently recognized congenital fetal Zika virus syndrome, etc.] [33]. Despite the fact that we are able to recognize some structural anomalies prenatally, the prediction of the exact extent of the damage and prognosis may still be a challenge [7], [32].

Figure 1:

3D angiography (bidirectional power Doppler ultrasound imaging).

(A) Normal fetal intracranial circulation. Notice the pericallosal vascularization. PA (pericallosal artery), ACA (anterior cerebral artery), ACA branches, SSS (superior sagittal sinus). (B–D) The circle of Willis presented in advanced STIC (spatio-temporal image correlation), 3D HD flow, Glass body rendering mode.

Congenital heart defects

Congenital heart defects (CHD) are the most common congenital anomalies occurring more frequently than chromosomal malformations and spinal defects together. The incidence is estimated to about 4–13 per 1000 live births, representing a significant cause of fetal mortality and morbidity [34].

Prenatal diagnosis of CHD by US is difficult, demanding thorough training and expertise. The detection rate of CHD is variable and it ranges from 35% to 86% in most studies [34]. In the past, many attempts were made to improve the prenatal detection rate of CHD. Four-dimensional US (real-time 3D US) used for fetal cardiac assessment may improve visualization of cardiac anatomy and allow better evaluation of valvular function [20].

Early evaluation of the fetal heart as well as recognition of several major cardiac abnormalities frequently coexisting in many fetal syndromes (Down syndrome, Edwards syndrome, DiGeorge syndrome, tarsal tunnel syndrome, etc.) can be obtained by 3D/4D US and improved by special applications [8], [12], [18], [26]. Two-dimensional US is still the technique of choice for the prenatal diagnosis of CHD; however, the last decade has shown some promising results due to advanced 3D/4D US technology [34], such as advanced spatio-temporal image correlation (STIC), volume contrast imaging (VCI) and Omni view. STIC is a technological development of 3D/4D US developed to assist the detection of CHD. An automated device is incorporated into the ultrasound probe that has the capacity to perform a slow sweep to acquire a single 3D volume [34]. Acquisition of volume data of the fetal heart and connections is done (the intraventricular septum, atrioventricular valves, great vessels’ outflow tracts, aorta and ductal arch) by allowing multiplanar and surface reconstruction of the heart anatomy [34]. The sonographer, even when less experienced in fetal echocardiography, can acquire volume data, which can be digitally stored and analyzed later or sent to a (fetal echocardiography) expert for further analysis. For better evaluation, the acquired data can be also assessed in the cine loop feature [34], played in slow motion and stopped any time to evaluate cardiac or vascular structures of interest. This application is also very helpful in counselling the parents and showing them where the problem is when CHD is found in the fetus.

Syndromes featuring primarily craniofacial anomalies

Paramedian cleft lip (CL) or cleft palate (CP) or a combination of the two (Figure 3) are the most common fetal facial anomalies and one of the most common fetal anomalies. They occur between the 8^th and 9^th gestational week and can be unilateral or bilateral. If this is an isolated finding (in less than 50% of cases), the defect can be surgically repaired with a good postoperative result. Unfortunately, a majority of the fetuses with CL or CP have high incidence of chromosomal abnormalities and other associated anomalies as part of syndromes [37]. Carriers of Van der Woude (VdW) syndrome have facial clefts in 50% of cases. VdW syndrome has an autosomal dominant mode of inheritance, which accounts for approximately 2% of all cases of CL and CP [37]. Incomplete unilateral small CL can easily be missed by conventional 2D US, while 3D HDlive surface rendering is a better method to detect it. Bilateral CL can sometimes also be missed because it does not change the symmetry of facial appearance [13]. Bilateral complete CL and CP, on the other hand, are most likely to be detected because of the protrusion of the inner maxillary segment under the nose, which is an obvious and unusual mass when observing a profile of the face [37]. When checking for CP, 3D HDlive surface and maximum modes are valuable as well as 3D application of tomographic US imaging (TUI), enabling to better determine the extent of the cleft [18].

Figure 3:

Paramedian cleft lip (CL) or cleft palate (CP) or a combination of the two (CL/P).

(A) Prenatal detection of unilateral paramedian right CL/P by 3D HDlive surface rendering in fetus with detected Edwards syndrome (trisomy 18). (B) Postnatal presentation of unilateral paramedian right CL/P. (C) Postnatal presentation of unilateral paramedian left only CL. (D) Postnatal presentation of bilateral paramedian CL/P.

Midline clefts are always severe and usually part of some sequence such as holoprosencephaly, with gross facial appearance (cyclopia, midline facial cleft to a diverse extent, cebocephaly, flat nose). It is a common feature of some chromosomal syndromes such as Patau syndrome (trisomy 13) (Figure 4) and Edwards syndrome (trisomy 18). Trisomy 13 is the most common syndrome associated with alobar holoprosencephaly and facial clefts. However, up to 75% of holoprosencephaly cases have normal karyotype [37].

Figure 4:

Postnatal findings of anophtalmia, median facial cleft and holoprosencephaly in a fetus with Patau syndrome (trisomy 13).

Mandibular anomalies (agnathia, micrognathia, retrognathia) have been described in various syndromes and seem to be very frequent, either isolated or coexisting as a part of the more heterogeneous syndrome.

Two-dimensional US images first indicate an abnormal profile, while with the different 3D applications (Figure 5), it is possible to explore it in more detail and obtain the complete impression of its appearance and possible coexistence of other orofacial anomalies.

Figure 5:

Prenatal detection of micrognathia with low-set ears by 3D HDlive surface rendering.

(A) In a fetus with detected Pierre- Robin sequence (PRS). (B) In a fetus with Meckel-Gruber syndrome (courtesy of S. Panchal).

Pierre-Robin sequence (PRS) is characterized by a triad of orofacial anomalies consisting of retrognathia, glossoptosis and a posterior median soft CP. An osseous defect of the mandible is rarely found. Mandibular hypoplasia is a primary defect that occurs early in gestation between the 7^thand 11^thweek of gestation and causes the tongue to be maintained high up in the oral cavity, which subsequently prevents fusion of the posterior soft palate [16], [37]. Prenatal diagnosis of micrognathia in PRS by 3D US can be unveiled in the 1^st trimester of pregnancy, as reported by several authors [13], [38], [39]. Pooh and Kurjak [13] pictorially presented mandibular hypoplasia and slow jaw development in a case of PRS during pregnancy. Serial 3D scans can be used to clearly reveal improvement and the progress of mandibular growth over several weeks [13], [37]. The catch-up growth of the mandible occurs during the first year of life and the adjusted profile of the child can be expected between the 3rd and 6th year of life [38], [39], [40]. Isolated PRS (without any other associated malformation) occurs in about 50% of cases; however, in the other half of the cases, PRS is part of a malformation syndrome. The clinical expression of the syndrome depends on the existence and severity of associated anomalies [37]. The nature of these anomalies is diverse – most commonly, the first branchial arch anomalies, various chromosomal disorders (DiGeorge syndrome), collagenopathies or syndromes associated with toxic agents such as alcohol (fetal alcohol syndrome), etc. In the review of 115 cases of patient with PRS, as expected, 54% had PRS as an isolated finding. The others included syndromes such as Stickler syndrome (18%), velocardiofacial syndrome (7%), Treacher Collins syndrome (TCS) (5%), facial and hemifacial microsomia (3%) and other defined (3.5%) and undefined disorders (9%) [8], [40]. Facial dysmorphism commonly arises from a combination of migration and inadequate formation of facial mesenchyme (especially when associated with disorders of the first and second branchial arches) [41].

Goldenhar syndrome (GS) or oculo-auriculo-vertebral (OAV) syndrome is the combination of such abnormalities [37]. It is characterized by a wide spectrum of symptoms, facial and associated features that may differ in range and severity from one case to another (Figure 6). A classic feature of GS is asymmetric (mostly unilateral) hypoplasia of the face. Fetuses with GS have major anomalies, such as unilateral mandibular hypoplasia with involvement of the temporomandibular joint and multiple skin tags around the ear, ear hypoplasia/aplasia and/or eye malformations (microphthalmia/anophthalmia) and vertebral anomalies. Typically, these malformations are unilateral (70%) and give an asymmetric appearance of the face. Usually, the right side is more severely affected than the left [42], [43], [44]. There have been some theories about the origin of this condition. Some authors hypothesized that the problem could be unilateral disruption of the blood supply (ischemia) to the 1^st and 2^ndbrachial arches, which could occur in the timeline between the 4^th and 8^th weeks of gestation [44]. However, Wang et al. [45] analyzed data from a large congenital birth defects registry in Spain and found a connection between diabetic mothers and increased risk of their infants being born with OAV syndrome. There has been speculation that poorly controlled maternal diabetes interferes with cephalic neural crest cell migration, causing this syndrome [45]. The first sonographic clue for the detection of this syndrome (also with conventional 2D US imaging) can be finding asymmetry of the face due to hemifacial macrosomia or something small and very typical as periauricular skin tags (Figure 7).

Figure 6:

Postpartum images of a baby with Goldenhar syndrome.

Note: Hemifacial hypoplasia, external ear deformity, preauricular sinuses and tags.

Figure 7:

Prenatal 3D surface rendering image of preauricular tag, postnatal images of external ear deformity, small ipsilateral half of the face and microphtalmia.

By using 3D surface rendering, more can be evaluated. Unilateral craniofacial anomaly underdevelopment of one side of the body can include brain (cerebellar hemisphere hypoplasia) [45], eye (micro/anophtalmia), low-set ears with malformation, face (asymmetry of the soft tissue), kidney (hydronephrosis), etc. With the application of 3D HDlive imaging technology, even small details of the face and other body parts can be visualized in a very realistic way, which can be very helpful while counseling the parents. The combination of micrognathia with low-set ears is a common finding in many syndromes. Detection of bilateral symmetric hypoplasia of the face, preauricular tags in combination with micrognathia may be part of TCS, Nager syndrome or Miller syndrome. TCS is a congenital disorder of craniofacial development caused by mutations in the TCOF1 gene on chromosome 5q32 [33]. TCS is represented by bilateral symmetrical otomandibular dysplasia (Figure 8). TCS is often associated with downward slanting of the palpebral fissures. There could be associated head and neck defects, and abnormalities of the extremities can be also found. The incidence of TCS is estimated at 1:50,000 live births per year. The inheritance is autosomal dominant with variation in expressivity. Cranioskeletal hypoplasia develops due to an insufficient number of neural crest cells as a consequence of neuroepithelial progenitor cell death [46]. The onset of defects occurs very early in embryogenesis between the 4^th and 8^th weeks of gestation. Prenatal diagnosis so far has been reported mostly in the 2^nd trimester of pregnancy [39], [46], [47], but with more powerful 3D applications and HDlive technology, there is a possibility to shift the detection of TCS from the 2^nd to the 1^sttrimester. With the combination of anomalies, suspicion of a syndrome is very essential for informing the geneticists who can order the gene sequencing added to the usual amniocentesis (AC) panel to confirm the diagnosis, which otherwise would be missed [47]. There have been some animal studies featuring chemical and genetic inhibition of the p53 protein in the attempt to prevent TCS, but so far, no effective method of prevention in humans exists [47].

Figure 8:

3D surface rendering image of fetus at 19 gestational weeks with Treacher-Collins syndrome and typical facial dysmorphism: bilateral symmetrical otomandibular dysplasia with hypoplasia of soft tissues is observed in the malar bone, inferior orbital rim and cheek (image courtesy of S. Panchal).

The shape of the skull might sometimes be informative, for example, a strawberry-shaped head seen in Edwards syndrome (trisomy 18), with a flattened occiput due to hypoplasia of the occipital brain lobes, brainstem and cerebellum, along with pointed frontal bones with hypoplasia of the frontal lobes of the brain. A lemon-shaped head can be seen with neural tube defects and as a part of some syndromes. A cloverleaf skull is present in different syndromes characterized by craniosynostosis, which can be found in Crouzon and Pfeiffer syndrome and in skeletal dysplasias such as thanatophoric dysplasia type II [37]. This shape of the fetal head develops due to premature closure of the coronal and lambdoid sutures, which causes bulging of temporal bones and confluence of anterior and posterior fontanelles. So, there are two bulges laterally (temporally) and an expansion superiorly (the anterior cranial fossa). Depending on the involvement of specific fetal skull sutures in premature fusion (craniosynostosis), different shapes of the head may appear.

Apert syndrome is an autosomal dominant disorder with a mutation found in the FGFR2 gene, chromosome 10q26.13 [33]. This syndrome has a few characteristic features that can be depicted while screening for abnormalities. Three signs to remember would be strawberry shaped head, flat face and mitten-like hands [37]. Due to bicoronal craniosynostosis, there is brachycephaly and acrocephaly, resulting in a strawberry-shaped head. In other words, one can detect an abnormal skull with a flat occiput, high forehead, midfacial hypoplasia (flat face), hypertelorism of the eyes and eyelid edema by a combination of conventional 2D imaging with 3D maximum mode (for bony structures), conventional 3D surface and 3D HDlive surface imaging. Mild ventriculomegaly can be detected by the 3D inversion mode and the newest application of HDlive silhouette imaging. ACC can be an accompanying finding best detected with 3D surface rendering in the median plane with additional 3D sonoangiogram visualization (3D HDlive bidirectional power Doppler) of the absent pericallosal artery. Very specific for fetuses with the Apert syndrome is defect on the extremities, called “mitten-like hands/feet”: syndactyly (soft tissue and osseous) of the 2^nd, 3^rd and 4^thfinger in combination with a broad thumb. Pooh and Kurjak [13] published a case of a prenatally detected fetus with Apert syndrome by using 3D sonography. Correlation was made between prenatal 3D US images of anomalies and identical postnatal appearance [13], [18]. Three-dimensional US images can be used to present the parents with the extent of the abnormalities of the face, skull and extremities [48]. Parents should be counseled about prognosis, possibility of different degrees of intellectual impairment and risk of recurrence. When resulting from a de novo mutation, recurrence risk is improbable, but if one of the parents is a carrier, the recurrence risk is 50%. There may be an association between advanced paternal age and higher risk of occurrence of Apert syndrome as a single-gene disorder [49]. To confirm the diagnosis prenatally, the option of AC should be offered to the parents.

Frontal bossing may be a typical finding in achondroplasia (autosomal dominant condition with rhizomelic limb shortening) (Figure 9) and Russell-Silver syndrome (short stature, asymmetric intrauterine growth restriction of the skeleton with normal size of the head). Asymmetry of the fetal skull can also be found in the fetus with amniotic band syndrome (sequence). Due to rupture in the amnion, which initiates the process very early in the 1^st trimester of pregnancy, the amniotic band causes a wide variety and severity of destructive fetal malformations, depending on fetal parts that come in contact and get trapped in it. When affecting the skull, asymmetric anencephaly, encephalocele, facial clefting and micrognathia can be detected. Other abnormalities that are also found are limb defects (constriction rings, amputation of the limb or digits, etc.) and anterior abdominal wall defects (gastroschisis, omphalocele) (Figure 10) [16], [37]. Other skull abnormalities detected by US are microcephaly and macrocephaly. Microcephaly indicates a group of disorders characterized by a small head and typically associated with abnormal neurological findings and mental disabilities [37]. Microcephaly usually also implies microencephaly because the head size is commonly determined by the brain size. Fetuses with prenatally suspected microcephaly have head circumference (HC) >3 standard deviations (SDs) below the mean for gestational age [50]. Different associated US features depend greatly on the etiologic factor causing microcephaly. The exact etiology of most microcephaly cases is still unknown. However, it is linked to numerous syndromes associated with chromosomal abnormalities like Cornelia de Lange syndrome, DiGeorge syndrome, Wolf-Hirshhorn syndrome, cri-du-chat syndrome, trisomy 13 and 9, etc., exposure to some toxic agents (alcohol, drugs, chlomiphene, methotrexate, phenylalanine), maternal under-nutrition and certain maternal infections during pregnancy, such as rubella, toxoplasmosis, varicella and cytomegalovirus (CMV). There are reports of a new causation between maternal infection and Zika virus during pregnancy and adverse pregnancy outcomes such as microcephaly, other brain and eye defects and pregnancy loss [51]. Zika congenital syndrome is generally characterized by cerebral atrophy that may interfere in formation and neuronal migration during early cerebral embryogenesis [52]. Other features of this syndrome are the following: severe microcephaly, lissencephaly, cataract of the eye, microophtalmia, clubfoot, contractures and arthrogryposis [51], [52], [53]. Viruses such as CMV or Zika have been shown to invade the brain cells, particularly neural progenitors, infect and destroy the primary stem cells (the radial glial cells) of the brain; therefore, there is a lack of future daughter neurons [54], [55], [56]. The severity of the condition may depend on the timing of infection during pregnancy. Microcephaly is mostly the result of decreased size of the cerebral cortex. In addition, infection may cause scars and calcifications in the brain tissue. Abnormalities such as periventricular and intraparenchymal calcifications, ventriculomegaly secondary to cerebral atrophy, cerebellar hypoplasia and cortical abnormalities are seen and detected much earlier than microcephaly itself. Besides the standard US screening, fetal neurosonography as well as KANET should be performed and repeated in the follow-up period until the delivery. The infection should be confirmed by the real-time reverse transcription polymerase chain reaction (rRT-PCR) [53]. The most recent follow-up studies from Brazil have shown that even though some babies are born with a normal head size, postnatal development of microcephaly can still occur as well as significant neurological sequelae also leading to arthrogryposis, a condition resulting in deformities of joints [52]. In the prenatal assessment of pregnancies at risk, evaluation with 4D US and KANET could be included. Prenatal results can be compared with postnatal results of neonatal neurological evaluation in the follow-up period during the first 2–3 years of life [6], [7], [8].

Figure 9:

3D surface rendering.

(A) 3D skeleton. (B) 3D HDlive surface rendering. (C) 3D HDlive surface rendering of the same fetus at 34 gestational weeks with suspected achondroplasia. Notice typical facial features such as frontal bossing and depressed nasal bridge.

Figure 10:

Prenatal detection of omphalocele at 13+3 gestational weeks. Different ultrasound modes and rendering applications are used to visualize the omphalocele.

(A) Conventional 2D mode. (B–D and E–G) 3D HDlive surface rendering with different angle of illumination. (H) Postnatal presentation of the baby born at 40 gestational weeks, realistic and same appearance of omphalocele in the prenatal compared to the postnatal period.

During a routine anomaly scan, abnormalities of fetal kidneys can be detected. A wide variety of structural and functional abnormalities can be seen (Figure 11). Dysplastic kidneys with multiple cysts [multcystic dysplastic kidneys (MCDK)] that fluctuate in size can be found in some very severe syndromes. As MCDK are dysfunctional, it could be a lethal condition called Meckel-Gruber syndrome (Figure 12) with autosomal recessive inheritance [57], if found bilaterally. Three pathognomonic anomalies can be found: occipital encephalocele, MCDK (Figure 13) and polydactyly. Neonates die within the first few days of life due to pulmonary hypoplasia and renal failure. Detection of occipital encephalocele in the 1^st trimester is easier due to a better overview and normal collection of amniotic fluid. Later in pregnancy, there is progressive oligohydramnios and encephalocele may be missed. Special attention should be paid to evaluate both fetal kidneys because normal sonographic finding of kidneys rules out the lethal Meckel-Gruber syndrome.

Figure 11:

Prenatally detected congenital anomalies of the urinary tract.

(A) Unilateral hydronephrosis in fetus at 26 gestational weeks, 3D rendering. (B) Conventional 2D image in fetus at 25 gestational weeks and obstructed urethra with distention of the bladder and hydronephrosis. (C) Conventional 2D image of fetus with massive distention of the bladder in Prune-Belly syndrome at 14 gestational weeks.

Figure 12:

Facial appearance of fetus with Meckel-Gruber syndrome.

(A) 2D conventional image of fetal profile (notice the flat face). (B–E) 3D surface rendering of fetal profile.

Figure 13:

Multicystic dysplastic kidney (MCDK) found in fetus at 26 gestational weeks.

(A, B) Conventional 2D images (courtesy RM. Nieto). (C, D) 3D HDlive silhouette images, volume extraction (courtesy RK. Pooh).