Chapter 21: ULTRASOUND DETECTION OF CHROMOSOMAL ANOMALIES

In Chapter 20 (Fetal Syndromes), several syndromes, the majority of which could be traced to genetic anomalies, were reviewed.* In this chapter, syndromes and associated findings that can be traced to chromosomal anomalies are reviewed. Many standard textbooks^{1,2,3,4,5,6, and 7} and other sources^8,9 have been used to write this chapter; hence, specific points have not been cited; these are considered basic sources and should be part of every library.

Figure 21-1 shows the increase in frequency of aneuploidy with advancing maternal age.^10,11 After 35 years of age, the risk increases steeply, not only for trisomy 21 but also for other aneuploidies in general. Some chromosomal anomalies are increased with the maternal age, and these include trisomies 13, 18, and 21, but not all chromosomal anomalies are increased with maternal age; in particular, triploidy and most of the sex chromosomal aneuploidies do not increase with maternal age.

Fetuses that have structural anomalies often also have chromosomal anomalies (Figure 21-2). Wladimiroff et al.¹² and Palmer et al.¹³ demonstrated that between 10% and 30% of fetuses that have structural anomalies also have chromosomal anomalies. In their studies, approximately half of the fetuses had a trisomy, one-fourth had a monosomy, approximately 10% to 15% had a mosaic, and the remainder had a few triploidies and miscellaneous aneuploidies.

In addition, Nicolaides et al.¹⁴ showed that babies who have more than one anomaly are more likely to have chromosomal anomalies, and the graph from their study clearly demonstrates this association.

Plachot et al.¹⁵ conducted a very interesting study in which eggs fertilized in vitro were used to assess the frequency of chromosomal anomalies in the fertilized eggs. In those experiments, 38% of the fertilized eggs demonstrated an aneuploidy (26% due to aneuploid oocytes, 8% to aneuploid sperm, 2% to polyploidy, and 6% to parthenogenesis). However, in practice, 38% of embryos do not demonstrate aneuploidies because approximately one-fourth of the embryos disappear and are not able to implant and, among those that are implanted, approximately one-half survive into the first trimester. Further, during the first trimester, the majority of these embryos are lost to miscarriages, and the number of aneuploidies decreases to approximately 1% in the second and third trimesters.

The usual aneuploid findings include biochemical alterations, structural anomalies, and growth restriction, which are reviewed in the following section. When a fetus is suspected to have an aneuploidy, a karyotype is obtained by chorionic villus sampling, amniocentesis, or fetal blood sampling. Echocardiography was performed previously on these fetuses, but echocardiography is presently preferred as part of the normal examination.

Triple Screen

Biochemical alterations are commonly evaluated with a test called the triple screen. This is a maternal blood test in which maternal serum values are assessed and expressed as a multiple of the median. The triple screen tests three components: α-fetoprotein, beta–human chorionic gonadotropin (α-hCG), and unconjugated estriol. Abnormal combinations of these three values have predictive value in the detection of trisomies 21 and 18 (Figure 21-3).

There are other markers that are being investigated, for instance, free α-hCG, α-hCG, and the pregnancy-associated plasma protein A. Other investigators are also investigating urine tests versus blood tests. Thus, some studies may describe quadruple tests rather than triple tests or some other combination. Approximately 5% of triple screen tests are positive, 95% of which are falsely positive.¹⁶ The triple screen test detects trisomy 21 in approximately 60% of pregnancies in women younger than 35 years and in almost 100% of pregnancies in women older than 35 years, trisomy 18 in 40%, neural tube defects in 85%, and abdominal wall defects in 75%. Thus, this simple blood test can reveal valuable information with regard to the pregnancy. An important question that referring clinicians and patients will have is, To what degree does a normal ultrasound decrease the risk of the triple screen? Unfortunately, there is no consistent data in the literature; Nyberg et al.¹⁷ reported a decrease in risk of approximately 45%, whereas Bahado-Singh et al.¹⁸ reported a decrease of approximately 800%. As physicians, we use the Nyberg value when speaking with our patients; therefore, a risk of 1 in 180 decreases to 1 in 270.

A chromosome is a linear structure with a short arm p, a centromere that attaches the short arm and long arm, and a long arm q, which follows the letter p in the alphabet (Figure 21-4).

A cell that contains the normal number of sets of chromosomes is called euploid. Therefore, in the gamete (ovum or sperm), which contain 23 chromosomes, a cell with one set of chromosomes is called haploid. Other cells in the body contain two sets of chromosome, and these cells are called diploid.

Chromosomes are displayed in a karyotype by order of decreasing size, with the small arm p on top and the longer arm q on the bottom. The sex chromosomes are displayed as the last pair in a karyotype. The other 21 pairs of chromosomes are called autosomes.

Fluorescence in situ hybridization is a technique by which chromosomes are recognized by being labeled with fluorescent probes. This technique allows very rapids results, usually within hours rather than days for amniocentesis, but it provides information concerning only selected portions of chromosomes.

Mitosis

One of the important forms of cell division is mitosis, which results in two daughter cells that are identical to the parent cell. The cell contains DNA that organizes itself into chromatids before division. Each cell contains one chromosome from the mother and one chromosome from the father, and these are called homologue chromosomes. In human cells, there are 23 pairs of chromosomes and thus 46 chromosomes. In the early stage of cell division, the chromatids replicate into identical copies called sister chromatids. The sister chromatids then separate from each other and migrate into each daughter cell. At the end of the division, two cells identical to the parent cell are produced.

Meiosis

Meiosis is the other form of cell division that occurs in the germ cells and results in two daughter cells containing half of the genetic material of the parent cell. The difference between meiosis and mitosis is that, during the first phase of the meiosis, the gametocytes (either the oocyte or the spermatocyte) divide into secondary gametocytes that contain undivided chromosomes. During the first phase of meiosis, the homologue chromosomes pair and exchange segments during two events called synapsis and recombination, so that segments of one chromosome are transferred onto the homologue chromosome. In contrast, during the first phase of meiosis, the sister chromatids do not separate but migrate toward the daughter cells, so that each daughter cell receives one chromosome and each chromosome is a double chromatid chromosome. In the second phase of meiosis, the two secondary gametocytes that were just produced divide, and each daughter cell receives one chromatid from the parent cell. Thus, at the end of the second division of meiosis, four cells are produced, which may be four spermatids, which are equal in size, or one mature ovum and three polar bodies, which are unequal in size.

Chromosomal Anomalies

Aneuploidy

A cell that contains an uneven number of chromosomes is called aneuploid. A common example is trisomy, which presents with an extra chromosome. Another example is monosomy, a condition in which a chromosome is absent. Monosomy is less common than trisomy because the absence of a chromosome is more lethal than the presence of an extra one unless the missing chromosome is a sex chromosome.

When a cell contains three sets of chromosomes, it is called triploid. The most common form of triploidy results from the fertilization of a normal egg by two normal sperm, a condition called dispermy. Less frequently, an abnormal sperm that contains two sets of chromosomes can fertilize a normal egg, or a normal sperm can fertilize an abnormal egg that contains two sets of chromosomes. A cell that contains four sets of chromosomes is called tetraploid.

Inversion

An inversion results from a double break in an arm of a chromosome, with the segment between the two breaks being reinserted upside-down (Figure 21-5). This condition is usually fairly benign. For instance, the notation INV(11) (q13-q21) represents an inversion of the segment between band 13 and band 22 of the long arm of chromosome 11.

Isochromosomes

An isochromosome results from an aberrant equatorial rather than a longitudinal division of the sister chromatid. One chromosome receives both short (p) arms, and another receives both long (q) arms (Figure 21-6).

Uniparental Disomy

Uniparental disomy is a condition that results from gametocytes with an abnormal number of chromosomes. The association of a normal gamete with a disomic gamete will produce a trisomic embryo, and all the cells of that embryo will be trisomic. The union of a normal gamete with a nullisomic gamete will produce a monosomy. The union of two nullisomic gametes will produce an embryo with a double monosomy, and such embryos are not expected to survive. The association of a disomic gamete with a nullisomic gamete or, more commonly, the rescue of a trisomic gamete by loss of a chromosome may produce a gamete that has two chromosomes, the normal number, but both homologue chromosomes of a certain pair come from one parent rather than each homologue coming from different parents.

Deletions

There are two forms of deletions. Terminal deletions result from loss of terminal material in the chromosome, and interstitial deletions result from loss of the middle material.

Duplications

Duplications result from an unequal transfer between sister chromatid during synapsis and recombination, so that one arm receives more material than it should, leading to partial trisomy or monosomy of the affected segments (Figure 22-7).

Ring Chromosome

A ring chromosome is produced by the fusion, usually with loss of the distal material, of the small arm with the long arm.

Reciprocal Translocation

A reciprocal translocation results from exchange of material between two nonhomologous chromosomes; instead of these two chromosomes being part of a pair, they are part of different pairs (eg, 1 and 9; Figure 21-8). If a reciprocal translocation of the distal end of chromosomes 1 and 9 has occurred, the parent may transfer a set of perfectly normal chromosomes to the child, a balanced set in which the right amount of material is transmitted on the wrong set of chromosomes, or an imbalanced set with duplication of one portion of a chromosome and deletion of the equivalent portion of the other chromosome.

Robertsonian Translocation

The fusion of two acrocentric chromosomes, which are chromosomes with very short p arms, results in a composite chromosome in which the long arms of both original chromosomes are retained (Figure 21-9). This is called a Robertsonian translocation in honor of the entomologist who, at the beginning of the 20th century, described the phenomenon in insects. It occurs with the acrocentric chromosomes, which are chromosomes 13, 14, 15, 21, and 22.

Dominant and Recessive Alleles

For each pair of chromosomes, one is inherited from the mother and one from the father, and these are called homologue chromosomes. Similar genes exist on homologue chromosomes and they are called alleles. When both alleles are identical, the individual is called homozygous. When both alleles are different, the individual is referred to as heterozygous.

When both alleles are different and the altered or "mutant" allele is expressed, the disorder is said to be dominant. When both alleles are different and the function of the normal allele masks the expression of the altered or "mutant" allele, the disorder is said to be recessive. Both alleles of a recessive disorder must be altered or "mutant" for the disorder to be manifest.

Autosomal Dominant

Knowledge of the transmission of autosomal dominant and recessive disorders is an important topic for those who perform prenatal diagnoses by ultrasound. Autosomal dominant disorders are usually manifested in the heterozygous form. They affect males and females equally. They have variable degree of expression, and may have an age-dependent expression. Autosomal dominant disorders are usually due to the production of a defective protein or developmental morphogenesis. One allele codes for the correct protein, and the mutant allele codes for the defective protein.

Figure 21-10 illustrates what would happen in an autosomal dominant disorder. As an example, assume that the father is carrier of the gene and, because this is an autosomal dominant disorder, that the father is affected. Half of his children will have the abnormal gene and half of his children will have the normal gene. The mother transmits normal genes to all of her children. Therefore, 50% of the children will have the abnormal gene and be affected and half of the children will be normal.

In a less common scenario, both parents are affected by the autosomal dominant disorder, and an example is the union of two parents with achondroplasia (Figure 21-11). In this case, the father will transmit the abnormal gene to half of his children, as will the mother. Therefore, half of the children will be affected. One-fourth of the children will receive the abnormal gene from both the mother and the father and thus will be homozygous for the abnormal gene, and this is often a lethal condition. In the example of parents with achondroplasia, this will result in a fetus that has a condition similar to achondrogenesis. One-fourth of the children will receive the normal gene from both father and mother and will be perfectly normal.

Autosomal Recessive

An autosomal recessive disorder is usually manifested only in the homozygous form, i.e., in babies that have the abnormal gene from both the mother and the father. The mother and the father usually are not affected by the disorder. It affects males and females equally. Autosomal recessive disorders are usually due to the omission of an enzyme, factor, or receptor. If only one parent has the abnormal gene, half the offspring will inherit the gene and not be affected but have the same carrier status as that of the father. Figure 21-11 also illustrates this point, but the shading would represent the carrier rather than the affected member.

If both parents carry the recessive gene, half of the children will inherit the abnormal gene from either the father or the mother and will simply be carrier. One-fourth will inherit the normal gene from both parents and thus be normal and not be carriers. One-fourth of the children will be homozygous, i.e., they have inherited the abnormal gene from both the father and mother and will express the disorder. Figure 21-11 can be used to illustrate an autosomal recessive disorder, in which case the shading represents the carrier, and the offspring with both abnormal alleles would be the only one to express the disorder completely.

X-Linked Transmission

Thus far, we have dealt with autosomal anomalies. At this point, it is worth noting the anomalies associated with the sex chromosomes, in particular the X-linked disorders. X-linked disorders can be dominant or recessive in heterozygous females and are usually manifested in males who are called hemizygous because they have only one chromosome. In X-linked dominant disorders, if the mother is affected, half of the children will be affected, and this is the usual transmission; however, if the father is affected, then all of his daughters but none of his sons will be affected. Let us begin with an X-linked dominant disorders in which the mother is affected. Because the father does not have the abnormal gene, he will transmit only normal genes to his children. The mother will transmit the affected X chromosome to half of her children. There is nothing unusual aside from the fact that the X chromosome is affected. The situation is more unusual when the father carries the abnormal gene, in which case the father is affected because he has inherited a dominant disorder. The father will transmit his abnormal X chromosome to all his daughters but will not transmit the X chromosome to his sons (he only passes the Y chromosome to his sons). Therefore, all the daughters but none of the sons of the affected father will be affected.

In X-linked recessive disorders, it is usually only the males that are affected, and they are affected from their carrier mother. If the mother is affected, half of the sons will be affected, and half of the daughters will be carriers. If the father is affected, all the sons will be normal, and all the daughters will be carriers. In the unusual case in which both the mother and the father have an abnormal X-linked recessive disorder, the father has only one X chromosome and thus will be affected, whereas the mother is only a carrier. Therefore, 50% of the daughters will be affected, 50% of the daughters will be carriers, and 50% of the sons will be affected.

Although most aneuploid fetuses are recognized in the first trimester, they usually present as failed pregnancies and impending miscarriages. Nevertheless, several observations should raise the suspicion of aneuploidy during the first trimester.

Nuchal Edema

A small black space under the skin of the fetus behind the neck is called a nuchal lucency between 10 and 14 weeks and a nuchal fold between 15 and 22 weeks (Figure 21-12). This is different from cystic hygroma, in which a major amount of fluid accumulates under the skin behind the neck. A nuchal lucency is usually considered abnormal if it is greater than 2.5 mm between 10 and 14 weeks (upper limit of 2 mm for embryos with a crown–rump length of 35 mm and 2.5 mm for embryos with a crown–rump length of 85 mm).¹⁹ In practice, however, this difference is not significant and 3 mm is a good cutoff value. The easiest way to obtain the measurement is to perform a transvaginal examination and obtain a view of the back of the neck of the fetus.

The calipers should be placed on the white lines surrounding the nuchal lucency. The suspicion is that the nuchal lucency is due to overperfusion of the cephalic end of the fetus due to narrowing of the isthmus, which increases the size of the aorta over the ductus and increases the perfusion of the cephalic end.²⁰ Further, these embryos often present with some early cardiac failure, which is manifested by an abnormal ductus venosus tracing.²¹ Overall, approximately 30% of fetuses that have a nuchal lucency will have an aneuploidy, and the most common aneuploidies are trisomies 21 and 18 and monosomy X. Several studies have also demonstrated that the risk of aneuploidy increases with the thickness of the nuchal lucency.^{22,23, and 24} In fetuses in which the karyotype is normal despite the nuchal lucency, the nuchal lucency can also be a marker for a nonchromosomal disorder in approximately 4% of cases. Such disorders include Noonan's syndrome, cystic hygroma, hydrops, omphalocele, obstructive uropathy, genetic syndromes, and many others that are constantly being described. There is also a tendency for fetuses with a thick nuchal lucency to have a poor outcome and decreased survival rate compared with those with a thin nuchal fold. In general, the nuchal lucency spontaneously regresses and is rarely seen after 20 weeks.

Tight Amnion

When the amnion is too close to the fetus, e.g., when the gestational sac is occupied predominantly by the extraamniotic coelom or when the amniotic cavity is tightly wrapped around the fetus, that fetus is often at risk for trisomy 16 or triploidy (Figure 21-13).

Two-Vessel Cord

The presence of a two-vessel cord can be a marker for aneuploidy. This is not typically sought in the first trimester but, as Figure 21-14 demonstrates, the finding can be recognized in a 10-week fetus.

One would look for a two-vessel cord if the fetus has other findings such as a thick nuchal lucency. Between 0.2% and 1% of pregnancies present with a two-vessel cord. Of these, approximately 1% to 10% have an aneuploidy, including trisomies 18 and 13, triploidy, and monosomy X.

Yolk Sac Anomalies

Levi and colleagues have published several studies in which they demonstrate that an irregular yolk sac and a yolk sac that is too large are predictors of pregnancies that will spontaneously abort during the first trimester.^{25,26, and 27}

Major Structural Anomalies

The presence of certain major anomalies should also prompt a karyotypic analysis. Figures 21–15,21–16, and 21–17 show three fetuses at 9 and 10 weeks. One appeared to have an omphalocele (greater than the normal physiologic herniation of the guts²⁸) and had trisomy 18, the other had a large obstructed bladder and a small omphalocele and had trisomy 13, and the other had alobar holoprosencephaly and trisomy 18.

Thus, in the presence of major anomalies during the first trimester, a karyotype is indicated.

Shapeless Embryo

A shapeless embryo is an embryo with no distinctive head and body at a time when these findings should be recognized. This can be a sign of various trisomies, usually very lethal trisomies such as 8 and 16, and triploidy.

In this section, the sonographic markers that can be used in second- and third-trimester fetuses are reviewed.

Central Nervous System

Ventriculomegaly is a common finding that occurs in 5 to 25 per 10,000 deliveries (Figure 21-18). The normal measurement of the atrium should be less than 10 mm at any time during gestation. When it is between 10 and 15 mm (the gray zone), it is suspicious for aneuploidy; when it is greater than 15 mm, it is more likely to represent hydrocephalus. Approximately 15% of fetuses with ventriculomegaly will have an aneuploidy, only 2% if the hydrocephalus is isolated, but 17% if other findings are noted. Ventriculomegaly is not a predictor of a particular type of aneuploidy.

Choroid plexus cysts (CPCs) occur in 1% of the normal population (Figure 21-19). According to the literature, approximately 30% to 60% of fetuses with trisomy 18 have CPCs. Further, approximately 97% of fetuses that have trisomy 18 and CPCs have associated anomalies.

The issue of whether an amniocentesis should be performed for fetuses with CPC has been debated. The following example may decide the debate.²⁹ Assume a population of 1 million fetuses. Because the incidence of CPC is 1% in midtrimester fetuses, among 1 million fetuses 10,000 will have CPC and be normal. Because the incidence of trisomy 18 is 3 per 10,000, 300 fetuses will have trisomy 18. Because the prevalence of CPC in trisomy 18 is 30%, the fetuses with trisomy 18 will be comprise 100 cases of CPCs. Because the sensitivity of ultrasound in detecting trisomy 18 is 75%, of those 100 fetuses that have trisomy 18 and CPCs, 25 would be missed by a normal ultrasound alone. Therefore, 25 fetuses with trisomy 18 and CPCs would be missed out of 10,075 fetuses that have CPC and correctly identified as either normal or having trisomy 18. This is roughly a miss of 1 in 400 fetuses with only CPC and trisomy 18, and this is the reason that performing amniocentesis in fetuses that have only CPC and no other finding is probably not worthwhile because, to detect that fetus with trisomy 18, one would have to perform amniocentesis in 400 normal fetuses. If one assumes that the risk of miscarriage after amniocentesis is 1 in 200 or even 1 in 400, amniocentesis would endanger the lives of 1 to 2 normal fetuses to detect 1 fetus with trisomy 18, whose outcome is dismal in any case.

Dysgenesis of the corpus callosum may be an isolated finding of little significance but may also be associated with trisomies 13 and 18, in which case it is rarely an isolated finding. Ultrasound findings include widening of the interhemispheric fissure, the teardrop-shaped lateral ventricles, and colpocephaly (Figure 21-20).

The presence of an enlarged cisterna magna or a Dandy–Walker malformation, either with a blocked fourth ventricle or a communicating fourth ventricle, may also be an indicator of aneuploidy. Isolated Dandy–Walker cysts do not indicate great risk; however, when associated anomalies are present, the risk increase to approximately 50%, predominantly for trisomies 13 and trisomy 18.

Holoprosencephaly occurs in 1 per 10,000 deliveries. Fetuses with holoprosencephaly have a higher risk of aneuploidies than do those with simple ventriculomegaly. Approximately one-third will have an aneuploidy, if holoprosencephaly is isolated; if other anomalies are noted, almost 40% will have an aneuploidy. Thus, this is a very significant finding, and trisomies 13 and 18 will be the most likely aneuploidies.

Microcephaly occurs in 10 per 10,000 deliveries. This is a difficult diagnosis to make. The commonly used criteria include a biparietal diameter (BPD) below the first percentile or a head perimeter greater to femur length below the 2.5 percentile.^30,31 The BPD is a difficult criterion to use the because it is not much affected by microcephaly. What is affected is the size of the cranial vault in relation to the size of the face, which is easier to determine in a sagittal view of the head. Twenty percent of fetuses with microcephaly have an aneuploidy.

Head and Neck

Facial clefts occur in 14 per 10,000 deliveries, and they are associated with several aneuploidies such as trisomies 13 and 18, but others such as 4p syndrome may also have clefts.

Micrognathia is a nonspecific finding but may associated with trisomies 18 and 13 and triploidy. This finding is easier to determine in a sagittal view of the face. Figures 21-21, and 21-22 show two normal sagittal views of the profile; note the position of the chin in relation to the middle section, which indicates a fetus with trisomy 18, on both the ultrasound image and the postdelivery image.

Macroglossia is the presence of a tongue that is too large and is a finding typical of trisomy 21 and Beckwith–Wiedeman syndrome. Normally, the tongue should not pass the alveolar ridge of the teeth, but in cases of macroglossia the tongue extends pass the tooth buds (Figures 21-23, and 21-24).

A nuchal fold is usually considered abnormal if it is greater than 6 mm between 15 and 22 weeks. Although the measurement can be obtained in a sagittal section of the hand and neck, it is more typically obtained in the axial section of the head through the cerebellum. Even an isolated nuchal fold is a significant finding, mainly as a predictor for trisomy 21.

Cystic hygroma is a very common finding, occurring in 0.5% of all spontaneous abortions. It is also associated with hydrops in 40% to 100% of cases, with congenital heart defect in 0% to 92% of cases, and with aneuploidy in 46 to 90% of cases. Cystic hygroma can be localized in the back of the neck or may extend farther down the back of the embryo or fetus (Figure 21-25).

Ears that are too small or too round or have a malformed helix may be associated with trisomies 13, 18, and 21; monosomy X; and several other translocations. Therefore, in the proper context, the finding of an abnormal ear may suggest the need for a karyotype.

Microphthalmia is a condition in which the eyes that too small, and it is often associated with hypotelorism. Microphthalmia is associated with several aneuploidies. In Figure 21-26, the eyes are also a bit more echogenic than they would normally appear.

A cataract, which is an opacification of the lens of the eye, is a finding that may be associated with aneuploidy. It is associated with other conditions such as TORCH infections, but it may also be associated with aneuploidy. The way to observe a cataract is to make a section through the eye and observe echoes of low-level intensity inside the lens.

The finding of hypotelorism should suggest that the fetus has cyclopia and proboscis, which are typical of holoprosencephaly and thus are associated with trisomy 13. Hypotelorism is a decrease of the interocular distance, and fetuses will have an interocular distance less than one-third the binocular distance.

Wormian bones, described by Olaus Worm, a Danish anatomist living in the 16th century, are little bones that occur in the fontanels and sutures (Figure 21-27). They are also called Inca bones. They may occur in several disorders including trisomy 21, cleidocranial dysplasia, osteogenesis imperfecta, hypothyroidism, pycknodysostosis, and progeria.

Hypoplasia of the nose is a typical finding in trisomy 18. A low nasal bridge is a common finding in many aneuploidies, but it is also common in other conditions such as skeletal dysplasias (Figure 21-28). The portion that is hypoplastic is the nasal spine; and when it is too small, it appears as if the nose base is too low. This is seen by ultrasound as a continuous dark echo between the eyes of the fetus.

Cardiovascular Anomalies

Cardiac anomalies are very common: 85 per 10,000 newborns will have a cardiac anomaly. However, among fetuses with an aneuploidy, the association is even more dramatic: 99% of fetuses with trisomy 18 have a cardiac anomaly, 90% trisomy 13, and 50% trisomy 21. Therefore, there is a great association between the finding of a cardiac anomaly and an aneuploidy. Overall, 29% of fetuses with a cardiac anomaly also have an aneuploidy, and 16% of fetuses that have an isolated cardiac anomaly have an aneuploidy; and when the cardiac anomaly is associated with other anomalies, 66% of these fetuses will have an aneuploidy. Overall, the finding of a cardiac anomaly is related more to trisomies 18 and 21 because they are so common and less to the other aneuploidies (Figure 21-29).

Echogenic Focus in the Heart

Brown et al. were the first to describe the association between echogenic foci and trisomy 21.³² Subsequent studies have demonstrated that approximately 5% of midtrimester pregnancies have an echogenic foci in the heart. Different investigators have reported an association of 0% to 3% with trisomy 21.^{33,34,35,36,37,38, and 39} The issue of one or more echogenic foci or whether the foci are on the right or left side is more predictive of aneuploidy has not been settled at the current time. Figures 21-30, and 21-31 show an echogenic focus in a normal fetus and a fetus with trisomy 21, respectively; there are no criteria for distinguishing the echogenic foci of normal fetuses from those of fetuses with aneuploidies.

The presence of a small layer of pericardial fluid is a common finding (Figure 21-32). Up to 2 mm is usually considered normal⁴⁰; when the layer is greater than 2 mm, one can consider a pericardial effusion. Pericardial effusions are associated with some aneuploidies, in particular trisomy 21, and with TORCH infections.

Hydrops is a fairly common finding at delivery, 10 per 10,000, and 12% to 16% of nonimmune hydrops may be associated with aneuploidy.

Chest

Most of the other findings that are present in the chest are discussed in sections concerning the heart, gastrointestinal, and skeletal systems. Approximately 5% of fetuses with a pleural effusion will have an aneuploidy, usually trisomies 21 and 13 and monosomy X.

Two-Vessel Cord

Between 0.2% and 1% of pregnancies present with a two-vessel cord (Figure 21-33). Among these, approximately 1% to 10% have an aneuploidy, including trisomies 18 and 13, triploidy, and monosomy X.^{41,42,43,44,45,46,47,48,49,50,51, and 52}

Cord Cysts

Although most cord cysts are benign, they may be present in fetuses with aneuploidy, in particular trisomies 13 and 18 (Figure 21-34).

Swiss-Cheese Placenta

The typical appearance of a Swiss-cheese placenta is that of a placenta that contains innumerable, small, round vesicles that are quite different from bleeding or blood accumulated in the cotyledons (Figure 21-35). These are much smaller and much rounder. The Swiss-cheese placenta is very typical of triploidy, but it may also occur in trisomy 18.

Gastrointestinal Findings

Duodenal Atresia

Duodenal atresia occurs in 1 per 10,000 deliveries (Figure 21-36). It is due to a failure of the recanalization of the gut distal to the ampulla of Vater. Because of the obstruction, the proximal portion the duodenum distends, which creates, with the distended stomach, the appearance of a double bubble. Another consequence of the obstruction is that content does not pass through the proximal jejunum and thus the jejunum thins down; this condition is called a disused jejunum.

Forty percent of fetuses that have an isolated duodenal atresia will have an aneuploidy; however, if other associated anomalies are present, the percentage rises to 66. Duodenal atresia is mostly a marker for trisomy 21.

Esophageal Atresia or Tracheoesophageal Fistulas

Esophageal atresia or tracheoesophageal fistulas occur in 2 per 10,000 deliveries. The ultrasound diagnosis is fairly straightforward: the stomach too small for its gestational age and there is an increase in amniotic fluid in the third trimester. A stomach that is too small is not much larger than the gallbladder. However, there are many conditions that present with the same findings. Esophageal atresia or tracheoesophageal fistulas are classified into five groups (Figure 21-37). A small stomach will be present only in cases of types B and C, and more than 95% of fetuses have an associated fistula. Therefore, the absence of a stomach is rare on ultrasound, and polyhydramnios develops only in the third trimester.

A recent study has addressed the association of tracheoesophageal fistula and aneuploidy.⁵³ In the presence of esophageal atresia combined with tracheoesophageal fistula, 7% of these fetuses will have an aneuploidy. If there is only a tracheoesophageal fistula, the number differs between 3% and 10%. However, in cases of pure esophageal atresia without associated tracheoesophageal fistula, 20% to 25% of these fetuses will have an aneuploidy and the most likely one is trisomy 18 (Figure 21-38).

Omphalocele

Omphaloceles occur in 1 per 10,000 deliveries, and 20 to 60% of these fetuses will have an aneuploidy (Figure 21-39). The risk of aneuploidy increases if the fetus has either oligohydramnios or polyhydramnios. Nyberg et al. demonstrated that the risk of aneuploidy is 16% if the omphalocele contains the liver and bowel and increases to 66% if only bowel is present.⁵⁴ Thirteen percent of fetuses that have just an omphalocele have an aneuploidy, but with an associated anomaly the risk increases to 46%. Trisomies 18 and 13 are the most likely aneuploidies.

Diaphragmatic hernia occurs in 3 to 4 per 10,000 deliveries. This is a fairly easy diagnosis by ultrasound because the position of the stomach alongside the heart is characteristic (Figure 21-40). Although an isolated diaphragmatic hernia is seldom associated with aneuploidy, the presence of a diaphragmatic hernia and associated anomalies is associated with aneuploidy in approximately 30% of cases, and the most likely aneuploidy is trisomy 18.

Hyperechoic bowel is a common finding and occurs in approximately 0.5% of pregnancies during the second trimester. To be considered hyperechoic, the bowel has to be whiter than the other abdominal structures and it is usually as white as bone but without the shadowing. The reason for this occurrence is unknown; it may be a normal variant, it may represent swallowed blood that persists undigested in the gut of the fetus, later in gestation it may represent either meconium ileus or meconium peritonitis (this is rarely the case early in the second trimester), it may represent varicella infection, or it may be a marker for trisomy 21.

The difficulty with the echogenic bowel is that this is a poorly defined criteria (Figure 21-41). In addition, there is marked a variability between ultrasound manufacturers and between transducers. Some scanners can demonstrate an echogenic bowel, whereas others cannot.

To Karyotype or not to Karyotype?

We do not consider a hyperechoic bowel with no associated findings a justification for amniocentesis. The indication, when it exists, is usually related to other findings, and the hyperechoic bowel rarely affects the decision one way or another. Some investigators disagree and recommend amniocentesis on the sole finding of hyperechoic bowel,^{55,56,57,58,59, and 60} whereas others do not recommend karyotyping.^{61,62, and 63}

Malrotation of the bowel is another nonspecific finding that may be part of many aneuploidies.^{64,65,66,67,68,69,70, and 71}

Bowel Obstructions

Although bowel obstructions are seldom associated with aneuploidies, approximately 1% of fetuses with trisomy 21 will present with bowel obstruction.^72,73

Urinary Tract Anomalies

Urinary tract anomalies are common and occurred in 20 to 30 per 10,000 deliveries. The presence of mild hydronephrosis (greater than 4 mm) is suggestive in some cases of trisomy 21 (Figure 21-42). When the hydronephrosis is moderate to severe, it may be associated with trisomy 13 or 18. Multicystic dysplasia is also associated with trisomies 13 and 18, as is renal agenesis.

The risk of aneuploidy seldom depends on the type of urinary tract anomaly, by whether the anomaly is unilateral or bilateral, or by the level of amniotic fluid. When associated anomalies are present, only 25% of these fetuses will have an aneuploidy.

Genital Findings

Ambiguous genitalia or clitoromegaly (Figure 21-43) is common in triploidy and in many other sex chromosomal anomalies such as XXY, XXYY, XYYY. They may also be present in trisomy 18, 4p deletion, and many other conditions.

Skeletal Findings

In this section, the many skeletal findings that could be markers for aneuploidies are reviewed. These include shortening of the limbs, clinodactyly, syndactyly, simian crease, radial ray aplasia, clubfoot, rockerbottom foot, and sandal gap. In addition, other skeletal findings such as 11 pairs of ribs, hypoplasia of the clavicle, double ossification center of the manubrium, and wide angle of the iliac wings are reviewed.

Limb Shortening

It has long been known that children with Down's syndrome have shorter limbs than do normal children. In their study population, Benacceraf et al. observed a cutoff limit of 91% of the expected size of the femur in relation to the BPD, a sensitivity of 68% and a specificity of 98% in detecting fetuses with trisomy 21.⁷⁴ These rates were not confirmed in other studies,^75,76 although the trend clearly exists and has been extended to the finding of a short humerus.⁷⁷

Brachymesophalangia of the fifth digit results from a too-small middle phalanx of the fifth digit, which occurs in 68% of cases with trisomy 21 (Figure 21-44). Benacceraf et al. studied the predictive value of this finding and found that, if the middle phalanx of the fifth digit is less than 70% of the middle phalanx of the fourth digit, there is a 70% chance of trisomy 21.^78,79 Although few would make major clinical decisions based on this finding, a hypoplastic middle phalanx is an important observation. Another anomaly commonly associated with brachymesophalangia is clinodactyly, in which the distal end of the fifth finger is bent toward the hand because of the deformed and hypoplastic middle phalanx.

A clenched fist is a typical finding of triploidy and trisomy 18 (Figure 21-45). The overlapping of the finger gives the impression of a clenched fist that does not change during the examination. The typical finding is the overlapping of the third digit by the second digit and of the fourth digit by the fifth digit.

Simian Crease

There are two normal transverse palmar creases: the proximal palmar crease and the distal palmar crease. In fetuses that do not open and close their hands often enough during early gestation, only one crease, called the simian crease, develops (Figure 21-46).⁸⁰ Simian creases are present in 4% of the normal population in one hand and in 1% of the normal population in both hands. These creases are interesting because they are present in 45% of the fetuses with trisomy 21.^3,81 They also occur in cases of trisomies 18 and 13 and in many conditions associated with decreased flexion of the hands such as skeletal dysplasias. Although searching for a simian crease prenatally may seem very difficult, this is in fact fairly easy to do under the right conditions (amniotic fluid and semi-open hand).

What is the risk of trisomy 21 when a simian crease is found? To answer that question, assume a population of 10,000 fetuses. Because 4% of the normal population has a simian crease, there will be 400 cases. Further, because trisomy 21 occurs at a rate of 13 per 10,000 and because 45% of fetuses with trisomy 21 have a simian crease, 6 of those 13 fetuses will have a simian crease. Therefore, the number of simian creases will be 406 (400 plus 6), and the likelihood of trisomy 21 when a simian crease is found is 6 of 406, which is roughly 1.5%.

Radial ray aplasia is a typical finding in trisomy 18, with very few differential diagnoses such as Holt–Oram syndrome and thrombocytopenia aplasia of the radius syndrome. The spectrum of radial ray aplasia includes absence of the radius, absence of the radius and thumb, or absence of the radius and the whole hand (Figure 21-47).

Another finding of trisomy 21 is elevation of the first toe. This can be seen by ultrasound because the first toe is no longer in the same plane as the other toes (Figure 21-48). In a sagittal section, one can see the angle between the big toe and the rest of the foot.⁸²

A rockerbottom foot is a foot that has a convex rather than a concave sole because of malpositioning of the calcaneus and talus. It is typically associated with trisomy 18.

A sandal gap is a slight interspace between the first and second toes, and this is a risk factor for trisomy 21 (Figure 21-49).⁸³

Findings Related to Anomalies of the Skull and Skull Shape

Brachycephaly is a deformity of the head in which the skull appears too round, and this is manifested by a short occipitofrontal distance (Figure 21-50). This is measured by the cephalic index, which is the ratio of the biparietal diameter to the occipital frontal diameter, and normal values should be between 75% and 85%. If the cephalic index is greater than 85%, the fetus has brachycephaly (Figure 21-51). If the head is too flat from side to side, the condition is referred to as scaphocephaly, a finding in fetuses that have in utero crowding or premature rupture of the membranes, for instance. This finding is not related to aneuploidy. Brachycephaly is a reliable indicator in children with trisomy 21 but a less reliable criterion in fetuses.

A strawberry head is a deformed head with narrowing of the frontal region and flattening of the occipital region. This is a marker for trisomy 18, and it has not been found without other associated anomalies (Figure 21-52).

Eleven Pairs of Ribs

The presence of 11 pairs of ribs may be an indicator of aneuploidy. Five percent of the normal population has 11 pairs of ribs. This finding is interesting because it occurs in one-third of fetuses with trisomy 21 and in fetuses with trisomy 18. It is also present in some skeletal dysplasias such as camptomelic dysplasia and cleidocranial dysplasia.^{83,84, and 85} Counting 11 pairs of ribs used to be very tedious: one used to have to take a single section that would include all pairs of ribs and not omit any. With the advent of the cineloop, it has become easier to take a sweep through the rib cage and then to go back and forth through the ribs in each frame. With the introduction of three-dimensional ultrasound, counting ribs has become even easier because a single reconstruction demonstrates all the ribs (Figure 21-53).

Hypoplasia of the clavicle is a common finding in trisomy 18 (Figure 21-54). The length of the clavicle, expressed in millimeters, should be approximately equal to the gestational age, expressed in weeks. Therefore, a 22-week fetus should have a clavicle that measures approximately 22 mm.

Iliac Wing Angle

Borg et al. recently demonstrated that the increase in the angle between the iliac wings, which has been a staple of the radiologic diagnosis of trisomy 21 for many years, can also be recognized prenatally by ultrasound (Figure 21-55).⁸⁶ In their nomogram, in an axial view of the pelvis, the normal angle between the iliac wings should be smaller than 70° ±15. In their studies, fetuses with trisomy 21 had iliac wing angles larger than 100° ±10.

Adouble ossification center of the manubrium is another marker for aneuploidy (Figure 21-56). One would look for two ossification centers in a craniocaudal alignment, which distinguishes the ossification center of the manubrium from the ossification centers of the sternebrae, which are side by side (Figure 21-57). Ossification of the manubrium starts in the fifth month of pregnancy. The manubrium first appears as a hypoechoic center and then it becomes hyperechoic as it ossifies. A double ossification center of the manubrium is present in 10% of the normal population, but it is also present in 33% to 80% of cases with trisomy 21 and in 25% of cases with monosomy X.

Growth Restriction

Fewer than 1% of fetuses that suffer from intrauterine growth restriction (IUGR) have an aneuploidy. Growth restriction is most typical of triploidy and trisomies 13 and 18. The association between IUGR and aneuploidy is more likely if the IUGR is detected in the second trimester. A very typical finding of triploidy is a very large disproportion between the head and the abdomen, in which the size abdomen is much smaller than the size of the head.

Schneider and Nicolaides¹ developed a very elaborate and well-conceived scoring system that considers the age of the patient and the different findings, and the risk factor is presented to the patient in the form of 1 in XXX. The interested reader is referred to their work, which contains numerous tables.

The scoring systems that Benacerraf et al. designed uses minor and major criteria.^{87,88, and 89} Major criteria include major anomalies (such as endocardial cushion defect and omphaloceles), a nuchal fold, a short femur, a short humerus, pyelectasis greater than 4 mm, or a maternal age older than 40 years. The minor criteria include echogenic bowel, echogenic cardiac focus, or a maternal age between 35 and 40 years. Major criteria have a score of 2 and minor criteria a score of 1. In their population, a score greater than 2 is associated with a 75% risk of trisomy 21, with only a 5% to 10% false positive rate. This scoring system is useful because it is simple to use and does not requires tables; however, it only predicts for trisomy 21.

Our scoring system is even simpler. If the fetus has major anomalies such as an endocardial cushion defect, omphalocele, or any other anomalies with an intrinsic risk greater than 1% in association with aneuploidy, we offer amniocentesis. If the fetus has only one small anomaly, such as an echogenic focus in the heart, CPC, and pyelectasis, the triple screen is normal, and the mother is younger than 35 years, then we typically do not recommend an amniocentesis unless the patient is very anxious about the finding. Most of these patients do not have amniocentesis. In the occasional fetus with two small findings, such as a single umbilical artery, CPC, pyelectasis, a simian crease, maternal age older than 35 years, abnormal triple screen, or any of the small findings in combination, we tend to recommend a karyotype because these fetuses are not very common, and the likelihood of aneuploidy is probably greater than 1% in this group.

An occasional finding with normal amniocentesis is a fetus with multiple anomalies. There are some syndromes that may resemble aneuploidies such as Smith–Lemli–Optiz syndrome, Meckel's syndrome, iniencephaly, the cardiosplenic syndromes, and the TORCH infections. These should occasionally be included in the differential diagnosis of aneuploidies.

Synonyms

Down's syndrome, Mongolism (do not use!).

Definition

Multiple malformation syndromes, with a trisomy for all of or a large part of chromosome 21.³

Prevalence

Every 13 per 10,000 live births, with a maternal age effect.

Etiology

Presence of an extra chromosome 21 or a long arm including the q22.1 band in all or some (mosaic) cells¹:

• 93% are free trisomies due to meiotic nondisjunction in one parent; 60% are maternal during the first meiotic division and 20% are paternal nondisjunction during the first or second meiotic division

• 5% are Roberstsonian translocations (14/21, 21/21, or 21/22) either de novo or parental

• 2% are mosaic (postzygotic event) and have a variable phenotype

Pathogenesis

Unknown; increases with advancing maternal age.

Differential Diagnosis

Multiple malformation syndromes, including severe IUGR and polyhydramnios, and congenital heart disease such as trisomies 18 and 13, Smith–Lemli–Optiz, or individual anomalies.

Associated Anomalies

Central Nervous System

• Mild ventriculomegaly (less than 15 mm)

Face, Neck, and Skull

• Flattened face, 90%

• Nuchal fold

• Nuchal translucency

• Oblique palpebral fissure, 80%

• Flat occiput, 78%

• Brachycephaly, 75%

• High arch palate, 70%

• Low nasal bridge, 60%

• Ear anomalies, 50%

• Epicanthal fold, 40%

• Cataract, 3%

• Low-set ears

• Macroglossia

• Small nose

• Mild microcephaly

Cardiovascular (40% To 60%)

• Endocardial cushion defect

• Ventricular septal defect

• Atrial septal defect

• Aberrant subclavian artery

• Tetralogy of Fallot (pericardial effusion)

Gastrointestinal

• Duodenal atresia, 30%

• Tracheoesophageal fistula

• Omphalocele

• Pyloric stenosis

• Annular pancreas

• Hirschprung's disease

• Imperforate anus

• "Bright bowel"

Urinary Tract

• Mild pyelectasis

Reproductive Tract

• Small penis

Skeletal

• Short limbs, 70%

• Short finger, 70%

• Abnormal iliac wing angle, 67%

• Brachymesophalangia, 62%

• Clinodactyly, 50%

• Simian crease, 50%

• Sandal gap, 45%

• Plantar crease between first and second toes, 28%

• Single flexion crease of fifth phalangeal joint, 20%

• 11 Pairs of ribs

• Instability of atlas–axis joint

• Double ossification of the manubrium

• Funnel or pigeon breast

• Hip anomalies

Other Findings and Anomalies

• Hypotonia, 20% to 80%

• Goiter

• Leukemia, 1%

Prognosis

Approximately two-thirds of fetuses with trisomy 21 die before delivery. Approximately one-third of survivors die during the first year, and half die before the age of 4 years. The life expectancy of the remaining survivors is brief. Mental retardation (moderate to severe) is the rule, but in some mosaic cases intelligence may be almost normal. There is decreased muscle tone. Some anomalies will need corrective surgery (heart defects, duodenal atresia).

Recurrence Risk

For free trisomy in young mothers, the risk is 1% to 2%; the risk in older mothers depends on the maternal age. With Robertsonian translocation, all offspring are either mono- or trisomic for 14/21 or 21/22; the risk from the mother is 16% and the risk from the father is 5%. For the proband's offspring, the risk is 50%.

Management

When ultrasound findings are consistent with trisomy 21, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term.

Synonyms

Edwards' syndrome, trisomy E.

Definition

Multiple malformation syndromes with a trisomy for all of or a large part of chromosome 18.

Prevalence

Every 3 per 10,000 live births, with a maternal age effect.

Etiology

Parental nondisjunction, rarely parental translocation. Approximately 80% of parents have a straight trisomy, another 10% are mosaics, whereas the rest either are double trisomies for another chromosome or have a translocation. Pericentric inversion in chromosomes has been described to recombine during meiosis and cause unbalanced offspring phenotypically similar to those fetuses with trisomy 18.

Pathogenesis

Trisomy 18 results from a faulty chromosomal distribution, which is mostly likely to occur in the older gravida age. Advanced maternal age is a risk factor, and the parental origin of an extra chromosome is maternal age in 96% of cases in whom chromosomal origin could be determined.

Differential Diagnosis

Multiple malformation syndromes, which include severe IUGR and polyhydramnios, and congenital heart disease such as, trisomy 13, triploidy, Pena–Shokeir syndrome should also be included in the differential diagnosis.

Prognosis

Although trisomy 18 is less common than trisomy 21, it is more lethal: 96% of liveborn infants with trisomy 18 die in the first month, 50% within 2 months, and only 10% survive the first year and are profoundly mentally retarded. Approximately 68% of the fetuses with an in utero diagnosis of trisomy 18 die before delivery.

Recurrence Risk

For full trisomy 18, the recurrence risk is lower than the 1% for full trisomy 21 syndrome. A carrier of pericentric inversion in chromosome 18 may produce affected offspring in 6% of pregnancies and carrier offspring in 53% of such pregnancies.

Management

When ultrasound findings are consistent with trisomy 18, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term. Tocolysis for preterm labor and cesarean section should be avoided.

Associated Anomalies

Central Nervous System

• Meningomyelocele, 16%

• Arnold–Chiari malformation, 13%

• Abnormal gyration, 13%

• Heterotopics, 13%

• Abnormal olivary nuclei, 10%

• Arachnoid cyst, 3%

• Hypoplastic cerebellar vermis, 3%

• Alobar holoprosencephaly, 3%

Face, NNeck, and Skull

• Low-set ears, 58%

• Micrognathia, 48%

• Small face, 35%

• Abnormal ears, 35%

• Small eyes, 26%

• Small mouth, 16%

• Microcephaly, 16%

• Large anterior fontanelle, 13%

• Hypertelorism, 6%

• Choanal atresia, 6%

• Preauricular tag, 6%

• High arcade palate, 6%

• Cleft palate, 3%

• Small anterior fontanelle, 3%

• Third fontanelle, 3%

• Low hair line, 3%

Cardiovascular

• Ventricular septal defect, 81%

• Polyvalvular dysplasia, 65%

• Bicuspid aortic valve, 45%

• Bicuspid pulmonary valve, 42%

• Coarctation of the aorta, 35%

• Atrial septal defect, 10%

• Endocardial cushion defect, 10%

• Mitral atresia, 6%

• Double right ventricle, 6%

• Dextrocardia, 6%

• Transposition of great vessels, 6%

• Retroesophageal subclavian vein, 6%

• Tetralogy of Fallot, 3%

• Hypolastic left ventricle, 3%

• Common atrium, 3%

• Anomalous pulmonary venous return, 6%

• Single coronary ostium, 3%

Gastrointestinal

• Omphalocele, 29%

• Meckel's diverticulum, 26%

• Malrotation of intestine, 23%

• Diaphragmatic hernia, 19%

• Ectopic pancreas, 16%

• Tracheoesophageal fistula, 10%

• Diaphragmatic hernia, 10%

• Ectopic gastric tissue, 6%

• Ileal atresia, 3%

• Imperforate anus, 3%

• Absent gallbladder, 3%

• Absent appendix, 3%

• Inguinal hernia, 3%

• Anomalies of the pancreas, 6%

• Accessory spleen, 3%

Urinary Tract

• Horseshoe kidney, 23%

• Hydroureter, 16%

• Duplicated ureter, 13%

• Renal microcysts, 6%

• Renal cystic dysplasia, 6%

• Bladder diverticulum, 3%

• Bladder outlet obstruction, 3%

Reproductive Tract

• Cryptorchidism, 26%

• Dysplastic ovaries, 16%

• Bicornuate uterus, 10%

• Hypospadias, 3%

• Septate uterus, 3%

• Abnormal external genitalia, 3%

Skeletal

• Overlapping fingers, 71%

• Rockerbottom feet, 39%

• Clubfeet, 32%

• Single palmar crease, 23%

• Hypoplastic nails, 19%

• Short sternum, 13%

• Clinodactyly, 13%

• Syndactyly, 10%

• Abnormal ribs, 10%

• Hip dislocation, 6%

• Deviation of hands, 6%

• Small pelvis, 6%

• Hemivertebrae, 3%

• Redundant skin, 3%

• Cleft in hand, 3%

• Small great toe, 3%

Other Findings and Anomalies

• Body: IUGR, 87%; thin body habitus, 13%; hydrops, 10%; cystic hygroma, 3%; redundant skin, 3%

• Respiratory system: pulmonary hypoplasia, 58%.

• Other findings: extramedullary hematopoiesis, 23%; adrenal hypoplasia, 23%

• Placenta and cord: two-vessel cord, 29%; polyhydramnios, 29%; villitis, 13%; chorioamnionitis, 6%, trophoblastic inclusions, 3%

Synonyms

Patau's syndrome and D trisomy.

Definition

Multiple malformation syndromes with trisomy for all of or a large part of chromosome 13.

Etiology

Presence of an extra chromosome 13 or part of the long arm (proximal segment 13pter[q14] or distal segment 13q14[qter]). The majority is free trisomy due to meiotic nondisjunction in one parent. A few are mosaic (postzygotic event) and have a variable phenotype. The rare Robertsonian translocations (13/14, 13/15) are either de novo or parental.

Pathogenesis

Unknown; increases with advancing maternal age.

Differential Diagnosis

Multiple malformation syndromes, which include severe IUGR, polyhydramnios, and congenital heart disease such as trisomy 18, or individual anomalies.

Prognosis

Most fetuses with trisomy 13 die before delivery or are stillborn. Of those that survive, 80% die during the first month and 95% before 6 months.

Recurrence Risk

The risk for the trisomy is not increased; for Robertsonian translocation, the risk is 2%.

Management

When ultrasound findings are consistent with trisomy 13, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term.

Associated Anomalies

Central Nervous System

• Holoprosencephaly

• Deafness

• Dysgenesis of the corpus callosum

• Hydrocephaly

• Cerebellar hypoplasia

• Meningomyelocele

Face, Neck, and Skull

• Cleft lip and palate, 60% to 80%

• Hypo- and hypertelorism

• Anophthalmia

• Microphthalmia

• Retinal dysplasia

• Cataract

• Corneal opacities

• Intraocular cartilage

• Microcephaly

• Wide sutures and fontanelles

• Abnormal ears

• Nuchal fold

• Cleft tongue

• Absence of the philtrum

• Micrognathia

Cardiovascular (80%)

• Ventricular septal defect, 50% to 60%

• Atrial septal defect, 40% to 50%

• Dextroposition, 20% to 50%

• Coarctation

• Anomalous pulmonary venous return

• Overriding aorta

• Pulmonary stenosis

• Hypoplasia aorta

• Mitral atresia

• Aortic atresia bicuspid aortic valve

Gastrointestinal (50% To 80%)

• Umbilical hernia

• Omphalocele

• Heterotopic pancreas

• Malrotation, 20% to 30%

• Diaphragmatic hernia

• Elongated gallbladder

• Accessory spleen

Urinary Tract

• Mild pyelectasis

Reproductive Tract (80%)

• Cystic kidneys, 40% to 50%

• Hydronephrosis, 10% to 20%

• Horseshoe kidney

• Multiple renal arteries

• Duplication of the renal pelvis, 10% to 20%

Reproductive Tract (50% To 100%)

• Cryptorchidism

• Hypospadias

• Abnormal scrotum

• Bicornuate uterus, 50% to 80%

Skeletal

• Simian crease

• Clenched fist

• Camptodactyly

• Syndactyly

• Polydactyly

• Club-hand with ulnar deviation

• Radial aplasia

• Sandal gap

• Club-feet

• Elevation of the big toe, 10% to 50%

• 11 pairs of ribs

• Abnormal iliac wings

Other Findings and Anomalies

• Two-vessel cord

• Situs inversus

• IUGR

Synonyms

Warkanys syndrome.

Definition

Predominantly final malformations syndrome with a trisomy for all of or a large part of chromosome 8.

Prevalence

Fewer than 100 cases have been reported.

Etiology

Presence of an extra chromosome 8 or part of the short arm.

Pathogenesis

Unknown.

Differential Diagnosis

Other aneuploidies.

Prognosis

The survival rates are better than with other trisomies; some reasonably healthy adults exist.

Recurrence Risk

Unknown.

Management

When ultrasound findings are consistent with trisomy 8, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term.

Associated Anomalies

Central Nervous System

• Agenesis of the corpus callosum

• Hydrocephalus

Face, Neck, and Skull

• Everted lips

• Large dysplastic ears

• Prominent forehead

• Broad nose

• Microphthalmia

• Cataract

Cardiovascular (40% to 60%)

• Ventricular septal defect

• Atrial septal defect

• Great vessel anomalies

Gastrointestinal

• Diaphragmatic hernia

• Esophageal atresia

• Absence of the gallbladder

Urinary Tract

• Hydronephrosis

• Reflux

Reproductive Tract

• Cryptorchidism

Skeletal

• Vertebral anomalies (hemivertebrae, spina bifida, kyphoscoliosis)

• Joint contractures

• Abnormal metacarpals and metatarsals

• Simian crease

• Deep longitudinal plantar crease

Other Findings and Anomalies

• Associated malignancy

• May be related to advanced parental age

Synonyms

None.

Definition

Trisomy for all of or a large part of chromosome 9. Most cases are mosaic, with 2% to 97% abnormal cells.

Prevalence

Fewer than 30 cases have been reported.

Etiology

Not associated with parental age.

Pathogenesis

Unknown.

Differential Diagnosis

Other aneuploidies.

Prognosis

Very lethal trisomy; most newborns die and very few survive beyond 4 months.

Recurrence Risk

Unknown.

Management

When ultrasound findings are consistent with trisomy 9, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term. Tocolysis for preterm labor and cesarean section should be avoided.

Associated Anomalies

Central Nervous System

• Dysgenesis of the corpus callosum

Face, Neck, and Skull

• Abnormal and low-set ears

• Micrognathia

• Small palpebral fissure

• Microcephaly

• Broad nose

• Wide sutures: craniosynostosis

• Cleft and high arched palate

• Short neck

Cardiovascular

• Atrial or ventricular septal defect

• Persistent left superior vena cava

• Single umbilical artery

Gastrointestinal

• Malrotation

• Diaphragmatic hernia

• Omphalocele, 29%

Reproductive Tract

• Cryptorchidism

• Small penis

• Hypoplastic scrotum

Skeletal

• Hypoplastic bones

• Hand anomalies (abnormal fingers, overlapping, hypoplastic phalanges)

• Simian crease

• Rockerbottom feet

• Deep palmar furrow

Other Findings and Anomalies

• IUGR

Synonyms

Monosomy 4p, partial deletion of chromosome 4, and Wolf's syndrome.

Definition

Absence of part of the short arm of chromosome 4; 87% of cases are due to de novo deletions (predominantly paternal in origin) and 13% are inherited from parents with balanced translocations (predominantly maternal).

Prevalence

More than 100 cases have been reported.

Etiology

Abnormal chromosome breakage during synapsis and recombination.

Pathogenesis

Unknown.

Differential Diagnosis

Other aneuploidies, in particular trisomy 13.

Prognosis

Lethal; most newborns die and very few surviving beyond 1 year.

Recurrence risk

Unknown.

Management

When ultrasound findings are consistent with partial deletion of chromosome 4, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term. Tocolysis for preterm labor and cesarean section should be avoided.

Associated Anomalies

Central Nervous System

• Absence of the cavum septum pelludidum

• Interventricular cysts

• Unspecified

Cardiovascular (80%)

• Atrial septal defect

• Unspecified

Gastrointestinal (50% To 80%)

• Malrotation

• Unspecified

Urinary Tract

• Hypoplastic kidney

• Reflux

• Various

Reproductive Tract

• Hypospadias

Skeletal

• Simian crease

• Scoliosis

• Abnormal ossification of the sternum

• Unspecified

Other Findings and Anomalies

• IUGR

• Decreased fetal movements

• Weak cry after birth

Synonyms

Incomplete molar gestation, partial triploid mole.

Definition

Presence of three sets of chromosomes, resulting in focal hydropic swelling of chorionic villi with throphoblastic hyperplasia and identifiable embryonic or fetal tissues.

Prevalence

In 1% of conceptuses but in 0.1 to 1 per 10,000 pregnancies.

Etiology

Abnormal fertilization.

Pathogenesis

Fertilization of a normal (haploid) ovum by two normal (haploid) sperm or fertilization of a normal ovum by an abnormal (diploid) sperm. All configurations (XXX; XXY; XYY) have been found.

Differential Diagnosis

Twin gestation with one fertilized ovum undergoing molar degeneration and hydropic changes in a missed abortion.

Prognosis

Most die in utero during the first trimester or early in the second trimester; if born alive, infants die within a few hours.

Recurrence Risk

Unknown, but probably none.

Management

When ultrasound findings are consistent with triploidy, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term. Tocolysis for preterm labor and cesarean section should be avoided.

Associated Anomalies

Central Nervous System

• Relative macrocephaly

• Agenesis of corpus callosum

• Dandy–Walker malformation

• Holoprosencephaly

• Arnold–Chiari malformation

• Spina bifida

• Meningomyelocele

• Hydrocephalus

• Central and cerebellar hypoplasia

Face, Neck, and Skull

• Cleft lip

• Low-set ears

• Micrognathia

• Hypertelorism

• Cystic hygroma

Cardiovascular (40% To 60%)

• Ventricular septal defect

• Atrial septal defect

• Many others

Gastrointestinal

• Omphalocele

• Unspecified

Urinary Tract

• Hydronephrosis

• Dysgenesis of kidneys

• Multicystic kidneys

Reproductive Tract

• Hypospadias

• Ambiguity of external genitalia

• Cryptorchidism

Skeletal

• Skeletal dysplasias

• Syndactyly of third and fourth toes and fingers

• Short hallux

• Clubfoot

• Rockerbottom foot

• Unspecified

Other Findings and Anomalies

• IUGR

• Decreased fetal movement

• Lung hypoplasia

Synonyms

Turner's syndrome and 45,X0.

Definition

Absence of one X chromosome, either in all cells or as a mosaic (45,X0 or 46,XX). Absence of the short arm results in the Turner phenotype. Absence of the short arm up to Xp11 or of the long arm up to Xq21 results in gonadal dysgenesis.

Prevalence

Every 2 per 10,000 live births.

Etiology

Complete monosomy (57%), presence of an abnormal X chromosome (ring chromosome, 10%; isochromosome, 17%), or mosaic with 46,XX or 46,XY. Mosaic 45X0 or 46,XY may span the range between phenotypical Turner's syndrome, ambiguous genitalia, and hermaphroditic and almost normal male genitalia.

Pathogenesis

Meiotic nondisjunction during gametogenesis (complete monosomy) or mitotic error. The missing X is of paternal origin. Risk does not increase with advancing maternal age.

Differential Diagnosis

Hydrops fetalis.

Prognosis

Most (95%) die in utero; those who survive may have a normal life span but be infertile (99%) or have early menopause.

Recurrence Risk

Not known, but probably low.

Management

When ultrasound findings are consistent with monosomy X, prenatal karyotyping should be undertaken. Pregnancy termination can be offered before viability. No alterations of prenatal care are necessary should the pregnancy be allowed to go to term. Tocolysis for preterm labor and cesarean section should be avoided.

Associated Anomalies

Central Nervous System

• Nothing in particular

Face, Neck, and Skull

• Cystic hygroma, above 80%

• Ear anomalies, 80%

• Short neck, 80%

• Narrow palate, 80%

• Micrognathia, above 70%

• Increased nuchal thickness, 50%

• Short metacarpal of the fourth digit, 50%

• Short metatarsal of the fourth digit, 50%

• Hypertelorism

Cardiovascular (40% To 60%)

• Bicuspid aorta valve

• Coarctation of the aorta

• Dilatation of the aorta

• Hypoplastic left heart syndrome

• Cardiac anomalies are more likely if there is a nuchal thickening³⁵

Gastrointestinal

• Nothing in particular

Urinary Tract

• Horseshoe kidneys

• Duplicated renal pelvis

Reproductive Tract

• Nothing in particular prenatally

• Primary or secondary amenorrhea at puberty

Skeletal

• Simian crease

• Cubitus valgus (not detected prenatally)

• Short stature (probably not detected prenatally)

Other Findings and Anomalies

• Broad chest

• Pectus excavatum

• IUGR