Catherine Fredouille
CHAPTER CONTENTS
The karyotype is unknown
The karyotype is known to be normal
When a cardiac anomaly has been discovered, the ultrasound (US) specialist must concentrate on finding associated morphological anomalies in order to better orient the diagnosis. This research can be guided by the type of cardiopathy.
In the absence of a known karyotype, we first look for markers associated with chromosomal anomalies. The practice of finding an early abnormal karyotype in case of first-trimester heart examination for increased risk factors has changed our possibilities in this area as explained in Chapter 5.
It is now usual to practice morphological US in the context of a known normal karyotype practiced because of an increased NT,1 which is why we extend our research to US markers of certain genetic syndromes and associations. With this in mind, besides concentrating on those organs normally examined through morphological US, we can extend our research towards specific signs, which are rarer but whose discovery will modify the prognosis.
!!! Attention !!!
Attention should be paid to the limitations of an US examination: it may display certain dysmorphic elements poorly and will never reveal the possibility of mental retardation.
Two possibilities exist
The Karyotype Is Unknown
We first consider a situation that occurs for the patient who did not have—or refused—an early US investigation and/or the investigation of serum markers (as in a twin pregnancy). This is also true in the case where the initial results happened to be normal. In all such cases, the discovery of a cardiac anomaly during US at a gestational age of 22 weeks—or even 32 weeks—requires us first to look for those signs associated with the principal chromosomal abnormalities.
Even when this morphological study is negative, when we are faced with the discovery of a cardiopathy, we must systematically propose the determination of the karyotype. This should be associated with an investigation of 22q11 chromosomal deletion if it is a conotruncal cardiopathy (CTC).
Warning signs of chromosomal anomalies2
In order of frequency, these are as follows.
Trisomy 21 (T21; Down syndrome)
This occurs in 1 in 700 pregnancies (Fig. 7.1).
FIGURE 7.1 Fetus with trisomy 21.
Despite the increase in the early diagnosis of this pathology, certain women—voluntarily or otherwise—have not had early tests for this condition. In questioning the patient, we should seek out elements to help direct our research: an old or very young maternal age; an inadequate dating for the US; serum markers not performed.
The type of cardiopathy can point us in the right direction. It is often primarily a cardiopathy of the atrioventricular septal defect (AVSD) spectrum, whether complete AVSD (Figs 7.2 and 7.3) to linear insertion of atrioventricular valves (LIAVV) without defect (Figs 7.4 and 7.5);3,4 trisomy 21 should also be considered with tetralogy of Fallot.
FIGURE 7.2 Anatomic thoracic four-chamber view: complete AVSD. The interventricular septum (IVS) is short and thick.
FIGURE 7.3 An apical incidence of a complete AVSD. The common leaflet is linear.
FIGURE 7.4 Apical four-chamber view of a LIAVV without defect. There is no offsetting.
FIGURE 7.5 Apical anatomic four-chamber view of a LIAVV without defect. The needle is under the septal tricuspid leaflet which is not stuck to the IVS.
The examination looks for extracardiac anomalies or malformations:5 a flat profile with shortening or even the absence of the fetal nasal bone (NB) and a filling of the small nasofrontal space; small ears; a thick nape of the neck or nuchal thickening (Fig. 7.6); a brachy- and even an amesophalangy of the fifth digit (Fig. 7.7); and a spacing of the big toe (Fig. 7.8). All these characteristics are more evocative than images of a pyelectasis, a suspicion of esophageal atresia (Fig. 7.9), or a unique umbilical artery (UUA).
FIGURE 7.6 Trisomy 21 (T21) showing the thick neck (nuchal thickening).
FIGURE 7.7 Brachymesophalangy of the fifth digit.
FIGURE 7.8 Spread of the large toe.
FIGURE 7.9 Proximal part of esophagus in esophageal atresia.
Trisomy 18 (T18; Edwards syndrome)
This occurs in 1 in 1800 pregnancies.
Trisomy 18 is more often associated with outlet cardiopathies; it is first considered when the cardiopathy (Fig. 7.10)6 is associated with intrauterine retarded growth (IURG) (Fig. 7.11). Nearly always present, IURG should not always be attributed to a possible coexistent vascular pathology.
FIGURE 7.10 Open heart positioned vertically. The probe is in an outlet VSD in a T18 fetus.
FIGURE 7.11 Week 27 of a T18 pregnancy. The fetus has the development of only 24 weeks demonstrating IURG. Notice the dysmorphia, the clenched hands, and the club-foot.
The discovery of clenched hands (Figs 7.12 and 7.13) (with the impossibility of obtaining an image with the hands open), an aplasia of the radial ray responsible for “boot hands”, a small exomphalos, spina bifida, or a diaphragmatic hernia all lead us to this diagnosis. But as in all chromosomal anomalies there exist minor forms of this pathology which support the principle of systematically asking for a karyotype faced with any and all cardiopathies.
FIGURE 7.12 Macroscopic view of clenched hands.
FIGURE 7.13 Ultrasound view of clenched hands.
Trisomy 13 (T13; Patau syndrome)
This occurs in 1 in 5000 pregnancies.
The pathognomonic triad of a labiopalatine cleft (Fig. 7.14), holoprosencephaly (Fig. 7.15), and hexadactyly (Figs 7.16 and 7.17) is not always seen together. In the absence of all of these signs the diagnosis can be directed by the type of cardiopathy: frequency of the AVSD or a common arterial trunk (CAT) with displastic valves (hyperechogenic).
FIGURE 7.14 Labiopalatine cleft in a T13 fetus.
FIGURE 7.15 A lobar holoprosencephaly in a T13 fetus. Notice the microphthalmos, the unique naris, and the small mouth. This demonstrates the saying that the “face reflects the brain”.
FIGURE 7.16 Macroscopic view of hexadactyly in a T13 fetus.
FIGURE 7.17 Ultrasound view of hexadactyly in a T13 fetus.
Next to these three frequent anomalies—whose minor forms we should be aware of—two other anomalies seldom go unnoticed at 12 gestational weeks. More than NT (Fig. 7.18), we often have to deal with a hygroma with anasarca in Turner's syndrome or a very early IUGR in triploidy.
FIGURE 7.18 Nuchal translucency.
Turner syndrome
Turner syndrome (Fig. 7.19) is with a karyotype primarily of 45X0. Its early diagnosis is frequently made when faced with a hygroma which can be differentiated from an augmentation of the NT at 12 gestational weeks. This could be a description of hydrops with anasarca. The diagnosis of the characteristic cardiopathy will only be made in fetal pathology; it is a stenosis of the horizontal section of the aorta7 in a female fetus (Fig. 7.20). Approximately 95% of pregnancies with a fetus having 45X0 are spontaneously interrupted and stillborn.
FIGURE 7.19 Turner syndrome showing Bonnevie–Ullrich syndrome (hygroma, anasarca, and generalized edema) with primarily a 45X0 karyotype.
FIGURE 7.20 Fetal heart–lung block (HLB) showing horizontal aortic arch stenosis, which is typical of Turner's syndrome. Notice the left persistent caval vein.
Triploidy
This is a pathology8 that is often proposed when we see an early, major form of IURG, and which is frequently taken to be an error of dating at the beginning of pregnancy. We note that there is often a disproportion between the head and the body, thin members with a large head (Fig. 7.21). In certain forms, we equally observe a highly suggestive fetus–placenta disequilibrium. Here, associated with a severe type of CTC in the form of a tetralogy of Fallot (Fig. 7.22), we see syndactyly III–IV (Fig. 7.23), characteristic, but difficult to see on US.
FIGURE 7.21 Triploid fetus with large head and thin limbs.
FIGURE 7.22 Severe form of tetralogy of Fallot in a triploid fetus.
FIGURE 7.23 III–IV typical syndactyly.
The Karyotype Is Known To Be Normal
This situation is becoming more frequent.9 Attention should be paid to two elements.
First, the karyotype can be made using a culture from different cells (biopsy of the trophoblast, cells from the amniotic liquid, or fetal blood) which can produce discordance in the results, for example by disregarding a tetrasomy 12p10 in a fetus appearing quite similar to Fryns syndrome (Figs 7.24 and 7.25). (If the karyotype seems to be normal in fetal blood, the tetrasomy appears only when requested on an investigation of the amniotic fluid.)
FIGURE 7.24 Fetus having a normal karyotype in fetal blood suspected of having Fryns syndrome.
FIGURE 7.25 The same fetus as in Figure 6.24 with the viscera showing a diaphragmatic hernia. A new karyotype carried out using the amniotic fluid showed a 12p tetrasomy.
In addition, certain minor pathologies of the karyotype11 can only be suspected after a re-examination of the initial karyotype, made after the discovery of a cardiopathy. Finally, an indication for specific research such as exploring a 4p deletion, for instance (Fig. 7.26), or even the possibility of a new karyotype, can be considered.
FIGURE 7.26 A fetus with 4p deletion having a profile “like a Greek helmet”.
Second, the “standard” karyotype only explores the chromosomal pathologies of number. The discovery of a CTC leads us to request a complementary research in the 22q11 chromosomal deletion. This deletion will primarily be found in cases of IAA of the B type (Fig. 7.27), or with a pulmonary atresia with opened septum (PA with OS) with aortic–pulmonary collaterals (main aorta–pulmonary collateral arteries: MAPCA), or even a CTC with a right aortic arch (Fig. 7.28) and/or the absence of the ductus arteriosus (DA). We equally find other anomalies: hypo- to athymism; cleft palate or cleft lips; or frequent renal anomalies (in 29% of the cases),12 which can rapidly hamper the examination by creating oligohydramnios. The dysmorphism (Fig. 7.29) is difficult to appreciate, except in those instances where there is a cleft. As for a thymic hypoplasia, it is easier to appreciate on the fetal–pathologic examination (Fig. 7.30) than with US.13
FIGURE 7.27 Anterior view of a HLB IAA type B in a 22q11 deletion.
FIGURE 7.28 Posterior view of a HLB: right descending aorta with MAPCA under the probe in a 22q11 deletion.
FIGURE 7.29 Light dysmorphia in a 22q11 deletion.
FIGURE 7.30 Thymus aplasia in a 22q11 deletion.
When we are sure of the absence of any chromosomal anomalies, then all associated markers, no matter how minor, should alert us to the possibility of a polymalformation syndrome, which radically modifies the prognosis.14
Protocols when faced with a curable cardiopathy are very different depending on whether it is (or is not) part of a syndrome or association.
A cardiopathy associated with IURG, especially in the case where the NT is abnormal and the fetal karyotype is normal, leads to the following considerations.
Fetal alcohol syndrome15
Fetal alcohol syndrome must be considered when the practitioner is faced with a specific fetal profile: a long, smooth, and curved philtrum (Fig. 7.31), sometimes associated to a IURG, a microcephaly or a corpus callosum agenesis. The mental prognosis is highly negative; the social and familial context can fool you.
FIGURE 7.31 Profile of a fetus with fetal alcohol syndrome: long, smooth, and curved philtrum.
Smith–Lemli–Opitz syndrome (SLOS)
This condition is an autosomal recessive (AR) syndrome. In searching for other signs that can be detectable by US,16 other than IURG, sexual ambiguity should be examined in a fetus having a karyotype 46XY where the external sex is ambiguous, even feminine (Fig. 7.32). Look for anomalies of the extremities (Fig. 7.33), which are easier to see than dysmorphia (Fig. 7.34), where certain elements such as a short, wide neck are the consequence of an elevated NT.
FIGURE 7.32 Hypogenitalism in a fetus with a 46XY karyotype.
FIGURE 7.33 The feet of a fetus with Smith–Lemli–Opitz syndrome (SLOS).
FIGURE 7.34 External view of a SLOS fetus 46XY: sex reversal, dysmorphia with a short, thick neck, and abnormalities of the limbs.
The diagnosis of SLOS is possible by the analysis of cholesterol precursors in the amniotic fluid.17or the DHCR7 gene.18 We should consider requesting it when faced with the association of a cardiopathy, IURG, hypogenitalism, and extremity anomalies. The interest in confirming this diagnosis is that SLOS is an AR syndrome, recurring once every four times, and we could practice this bioassay analysis at the beginning of the following pregnancy.
The CHARGE association
CHARGE stands for:
Coloboma, which is not detectable by US
Heart (Fig. 7.35), for cardiac malformation
FIGURE 7.35 CHARGE association: small VSD.
Atresia choanae, which can cause hydramnios (Fig. 7.36)
FIGURE 7.36 CHARGE association: the cleft.
Retarded growth (often postnatal)
Genitals, e.g., hypospadias in a boy
Ears, anomalies of (Fig. 7.37); the external ears are asymmetric with the absence of the semicircular canals.
FIGURE 7.37 CHARGE association: the abnormal ear.
A diagnosis of CHARGE should be considered when we are faced with any curable cardiopathy, especially if associated with a sign such as a cleft lip and/or palate (Fig. 7.38), because of the severity of mental retardation, which is always present in this pathology.
FIGURE 7.38 CHARGE association: hydramnios with UUA.
The verification of the presence of the upper semicircular canals is possible during morphological US at a gestational age of 22 weeks, on a plane that is close to that of the biparietal diameter (Fig. 7.39). The upper canals appear as two small echogenic lines situated a third posterior to the insertion of the tentorium cerebelli (Figs 7.39 and 7.40). Another different view allows us to visualize the three canals (Fig. 7.41); however, this becomes impossible by the third trimester due to the ossification of the petrous part of the temporal bone.
FIGURE 7.39 Macroscopic view of the upper semicircular canal (arrows).
FIGURE 7.40 Ultrasound (at a gestation of 22 weeks) of the upper semicircular canal (arrows).
FIGURE 7.41 Another incidence of the semicircular canal.
A molecular analysis of the CHD7 gene 19 is able to confirm the diagnosis.
Cornelia de Lange syndrome20
This syndrome—also called de Lange syndrome or Brachmann–de Lange syndrome—should be considered if there are limb anomalies of the first order (Fig. 7.42) (going from an oligodactyly to a phocomely). The most characteristic element, dysmorphism with synophrys, is not detectable by US. We must nonetheless consider this syndrome when faced with the association of IURG with hypogenitalism and anomalies of the limb especially in the cubital ray.
FIGURE 7.42 External view of Cornelia de Lange syndrome.
Cardiopathies associated with skeletal anomalies
In carefully examining the spine, all the way to the sacrum (Fig. 7.43), the straightness and/or shortness of the lumbosacral spine could be an indirect sign of an anal imperforation. This crippling pathology is one of the key elements in the VACTERL association (Fig. 7.44).21 This acronym stands for the association of at least three of the following components:
FIGURE 7.43 Spine in profile showing the straightness and shortness of the sacrum in a VACTERL association with an imperforate anus.
FIGURE 7.44 Fetus with VACTERL. Note the deformations of Potter's facies that resulted from the lack of amniotic fluid due to renal agenesis.
Vertebral anomalies (hemivertebrae (Fig. 7.45) and, at the same level, esophageal atresia and/or a sacrum anomaly)
FIGURE 7.45 Vertebral anomalies at the same level as a tracheo–esophageal (T–E) fistula.
Anal imperforation
Cardiac anomalies
Tracheo–esophageal (T–E) fistula with the upper part of esophagus (Fig. 7.46; see also Fig. 7.9), which is responsible for a variable excess of amniotic fluid
FIGURE 7.46 Posterior view of a HLB with a T-E fistula.
Esophageal atresia
Radial aplasia or Renal anomalies
Limb anomalies (when “R” illustrates the renal anomaly).
This association,22 where cardiopathy presents in almost 50% of cases, is generally sporadic. It appears to be AR when associated with a ventricular dilatation, which is why examining the cephalic pole is extremely important here.
Long bones
Certain chondrodysplasias are associated with cardiopathies. The biometry of the long bones, and the aspect of the ribs should be examined with care because any bone impairment can be both late and discrete. In Ellis–van Creveld syndrome23 (Fig. 7.47), the cardiopathy, which often takes the form of a UA with an AVSD, could perhaps be primary. We look for hexadactyly (Figs 7.48 and 7.49), which is present in this syndrome.
FIGURE 7.47 Ellis–van Creveld syndrome: radiography showing short long bones and ribs.
FIGURE 7.48 Ellis–van Creveld syndrome: hexadactyly.
FIGURE 7.49 Ellis–van Creveld syndrome (the same fetus as in Figure 6.48): hexadactyly.
The study of the limbs and extremities is of the utmost importance. Certain major forms, such as complete aplasias of the radial ray, certain VACTERL association anomalies, or major anomalies in certain syndromes such as Cornelia de Lange could be detected early. In these cases, the most subtle forms will remain difficult to discern if we do not rigorously attempt to visualize the two hands open counting all five fingers per hand. The frequent hexadactyly in SLOS, which is practically a constant in Ellis–van Creveld syndrome, should suggest a syndrome diagnosis when discovered in the fetal–pathologic examination.
Cardiopathies associated with cephalic anomalies
The appreciation of a fetal dysmorphia, key to a pediatric diagnosis, is unclear in classic US; 3D US now opens new perspectives in this field. Using US, we first begin by examining the following:
• Profile. The nasal bones (NB),20 their shortness (normal is 7 mm at 22 gestational weeks) is a warning; their absence is suspicious, testifying to a dysmorphic rule. A retrognathism is often an indirect sign of a cleft palate which we must try to confirm (Figs 7.50 and 7.51). It is often difficult to define the impression of dysmorphia explicitly, but we must try to refine this description. (One example would be the philtrum of fetal alcohol syndrome, where the mental prognosis is so negative.)
FIGURE 7.50 Normal palate.
FIGURE 7.51 Labio-duplication (green arrows) of the uvula (red arrows) in complete cleft palate.
• Researching an atresia choanae (the “A” in CHARGE) which can be seen simply by looking for transnasal flow on Doppler imaging in the context of hydramnios.
• Face. Investigation of a labial cleft, often associated with a cardiopathy.
• Biparietal diameter views and sagittal views of the brain should allow us to perform the most complete possible cerebral assessment. Here we systematically investigate for a corpus callosum pathology, cerebellar vermix, or indirect signs of defaults in the closing of the neural tube. These are investigated, especially in VACTERL, in order to find if there is a dilatation of the ventricle. This association, considered sporadic, is in fact AR in cases associated with VACTERL with hydrocephaly.
• Verification of the semicircular canals (see above).
• Examination of the ears becomes more pertinent in 3D when we understand the importance of this examination in light of a facial dysmorphia. An example is the constant asymmetry of the ears in the CHARGE association (see Fig. 7.37).19
Cardiopathy associated with visceral anomalies
We should think of a visceroatrial heterotaxia (VAH) when faced with a situs anomaly associated with a complex cardiopathy with a normal karyotype, but also when there are signs of minor cardiac problems. If this has not already been done, it is important to verify the position of the abdominal organs diligently (median liver, the stomach). In this family of VAH, the situs is variable.24 It is rarely recognized, in the case of a complete situs inversus, if we do not systematically verify the laterality when the stomach and the apex are on the same side. The cardiopathy is often complex, and associated with anomalies of the pulmonary or systemic venous return, a unique atrium, an AVSD or a unique ventricle with transposed vessels, and a PA with OS. We must examine with care the abdominal and thoracic vessels looking for the absence of IVC and azygos venous return (a left isomerism), or a TAPVR (a right isomerism).
A diaphragmatic hernia with the presence of intrathoracic abdominal viscera should lead us to look for other signs associated with Fryns syndrome. The IURG is often late, but the distal phalanges are always short, and facial dysmorphia is considered where there is a cleft and/or the absence of NB. In Cornelia de Lange syndrome, on the other hand, the anomalies of the superior limbs (more affecting the cubital ray), like the wings of a bird, are easier to find than a dysmorphia.
On the level of the digestive tubes, the anomalies are understood through signs that are more indirect. A stomach can be poorly visualized, or not visualized at all in the case of a T–E fistula. Now, certain techniques allow the US diagnosis of atresia of the esophagus25 (see Figs 7.9 and 7.46) and the fistula.
At the level of the kidneys an oligoamnios, which can often evolve into an anamnios, hampers the examination of the heart and other organs. This should lead us to consider renal malformations (after verification of the absence of a 22 q11 deletion) which are frequent conditions of polymalformation syndromes.
The external genital organ examination (EGO) is of particular interest. In syndrome pathologies, the EGO, especially in male fetuses, can show a hypoplasia in CHARGE or discordance, i.e., hypoplasia, even feminine (see Fig. 7.32), in a fetus with 46XY in SLOS, and in Cornelia de Lange syndrome.
The verification of the architecture of the fetal heart—the primary objective of the US specialist—should always be completed by an attentive and thorough verification of the fetal morphology. It is crucial to do everything necessary to eliminate—as much as possible—the risk of associated malformations before sending the fetus affected by a cardiopathy to the pediatric cardiology team.
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