Genetic Evaluation of Fetal Sonographic Abnormalities


Structural malformations, many of which can be diagnosed antenatally, are present in approximately 2%–3% of live births. Fetuses with structural malformations are at increased risk for an underlying genetic disorder, even in the setting of a normal karyotype. The clinical prognosis is highly variable depending on the presence of a genetic syndrome, the specific type of anomaly that is present, as well as whether the anomaly is isolated or part of a spectrum of malformations involving other organ systems.

What Is the Role of Ultrasound in Identifying Fetal Anomalies?

Fetal assessment by ultrasound is a standard component of prenatal care. The American College of Obstetricians and Gynecologists (ACOG) recommends that all obstetric patients be offered ultrasound evaluation at least once during pregnancy. The average number of ultrasounds performed in the United States has increased from 1.5 per pregnancy in 1995 to between four and five scans in low-risk patients in 2011.

Screening for congenital anomalies by ultrasound is the primary indication for second-trimester anatomic imaging and has been demonstrated to improve the detection of major fetal anomalies before 24 weeks (RR 3.46 [95% CI: 1.67–7.14]). Factors that influence detection rates include the setting in which the ultrasound is performed (community based vs. tertiary care), the fetal gestational age at the time of the study, and technical imaging challenges such as obesity. Adherence to a systematic imaging protocol improves prenatal diagnosis of anomalies. In pregnancies where a malformation is identified and termination is chosen, there is over 98% confirmation of the primary diagnosis.

What Is the Difference Between a Standard and Detailed Anatomic Scan?

The American Institute of Ultrasound in Medicine (AIUM) and ACOG distinguish between standard second-trimester examinations and detailed examinations. A standard examination is utilized to evaluate fetal anatomy in a population at low risk for congenital anomalies. A more comprehensive or detailed obstetrical ultrasound examination is performed for women at increased risk for a congenital malformation based on medical history, results of laboratory evaluations, or concerns identified on a standard obstetrical ultrasound examination. Detailed fetal anatomic imaging is performed by a provider with additional training and expertise in obstetrical imaging and dysmorphology assessment. It is important to recognize that despite optimal imaging and diagnostic testing, there is a residual risk of an undetected abnormality. Additionally, false-positive findings may occur. These may be structural anomalies that are suspected but not confirmed after birth, “markers” of aneuploidy (see Chapter 10 ) or conditions such as ventriculoseptal defects or mild ventriculomegaly that may resolve during the course of pregnancy.

What Is the Impact of Gestational Age in Identifying Fetal Anomalies?

The Late First-Trimester Scan: 11 0 –13 Weeks

A late first-trimester ultrasound is performed primarily to measure the nuchal translucency (NT) as a component of first-trimester risk assessment for aneuploidy (see Chapter 8 ). Although a thickened nuchal translucency confers an increased risk of aneuploidy, it is also a marker for increased risk of structural anomalies and other genetic conditions. Imaging the fetus at this gestational age provides the first opportunity to perform an anatomic assessment of the fetus. Although this is not currently standard practice in the United States, it is feasible by dedicated sonographers and sonologists.

Estimates of detection rates for major anomalies between 11 weeks 0 days and 13 weeks 6 days vary from 18% to 84%, with most authors reporting a sensitivity of approximately 50% for major anomalies. The detection rate depends on the anatomic area that is being evaluated.

A systematic review of 78,002 fetuses that underwent ultrasound examination between 11–14 weeks found that the detection rate of nuchal defects was 92%, whereas only 34% of limb, face, and genitourinary tract anomalies were detected. In addition, there was a higher detection rate in fetuses evaluated between 13 and 14 weeks than those examined between 11 and 12 weeks. Detection rates are higher in those with multiple abnormalities compared with a single finding, and in high-risk populations (61%) compared with low-risk populations (32%). The adherence to an imaging protocol improves detection rates as does the use of transvaginal imaging. With experience and recognition of additional markers, detection rates may improve.

Some anomalies, such as anencephaly, alobar holoprosencephaly, body stalk anomalies, omphalocele, and major disruption of fetal contour, should almost always be detected during this gestational age window. Others, such as cardiac defects, spina bifida, and facial clefts, are more challenging to diagnose. Finally, some anomalies, such as those involving the corpus callosum and congenital lung malformations, are not detectable at this early gestational age, partly because of timing of embryologic development. As with all obstetrical imaging, the natural history of some diagnosed abnormalities may not be fully understood or may change with advancing gestation.

The early anatomic evaluation of the fetus allows patients to consider the implications of the condition detected and pursue expert consultation and diagnostic testing. Detection of structural anomalies between 11 and 14 weeks allows those patients who choose to terminate to do so at an earlier gestational age, when the procedure is safer. For those who continue their pregnancy, a follow-up ultrasound examination at 18–22 weeks is necessary to better elucidate the abnormality.

It is important that patients understand that a “normal” first-trimester ultrasound does not exclude all major or lethal anomalies and this imaging window does not replace the standard second-trimester anatomic assessment of the fetus.

Second-Trimester Anatomic Survey

The gold standard for prenatal anomaly screening by ultrasound in the United States is an ultrasound examination performed between 18 and 22 weeks of gestation. Anatomic imaging should be performed in accordance with a contemporary imaging protocol. This may be a standard scan performed in patients at “low risk” for congenital anomalies or a detailed scan in those who are at “increased risk.”

The majority of literature on routine screening for congenital anomalies in unselected populations was performed several decades ago with wide variations in reported detection rate of anomalies. The Eurofetus study, performed in 61 obstetric centers between 1990 and 1993 reported a prenatal detection of 61.4% of fetuses with an anomaly and 56.2% of all malformations. The detection of major anomalies was 73.7% compared with 45.7% of minor anomalies. Overall, 55% of major anomalies were detected before 24 weeks. The sensitivity of anomaly detection was 88.3% for the central nervous system and 84.8% for the genitourinary tract, as compared with 38.8% for the heart and great vessels.

In more contemporary literature evaluating first and second-trimester anatomic imaging, approximately 75%–95% of structural malformations may be suspected or detected. Detection rates will vary with the population studied, the follow-up available, the experience and skill of the imager, the imaging protocol utilized, and imaging conditions such as obesity, which may preclude an optimal anatomic evaluation.

Third-Trimester Scans

Routine ultrasound in the third trimester is not currently standard practice. However, there are certain anomalies that are not usually diagnosed until this advanced gestational age, such as microcephaly, lissencephaly, or achondroplasia ( Fig. 11.1A and B ). The contribution of a third-trimester scan was demonstrated in a prospective study of 8074 fetuses who had previously had a normal first and second-trimester ultrasound and were reexamined between 28 and 32 weeks. At the third-trimester ultrasound, an additional 15% of the total anomalies were diagnosed despite two prior normal ultrasounds. The anomalies diagnosed in the third trimester were primarily urogenital, cardiovascular, and central nervous system anomalies. Overall, 90% of anomalies in the cohort were detected prenatally, whereas 10% were not detected until after birth.

FIG. 11.1

Achondroplasia. (A) Second-trimester fetal anatomic evaluation demonstrating normal morphology and biometry. (B) The same fetus imaged at 39 weeks shows severe shortening of the long bones and a trident hand raising the suspicion of achondroplasia, which was confirmed with genetic testing after birth.

What Is the Importance of a Systematic Ultrasound Evaluation Using Pattern Recognition?

If a fetal anomaly is identified, it is incumbent on the sonologist to formulate a differential diagnosis. The sonologist must be a detective, using a deliberate stepwise approach of observation and deductive reasoning. With pattern recognition of genetic syndromes in mind, a structured systematic and thoughtful evaluation of other organ systems, looking for sentinel features, will allow the sonologist to narrow the differential diagnosis.

As an example, a required anatomic component of the standard fetal ultrasound includes evaluation of the upper lip. Facial clefts are relatively prevalent, occurring in about 15 per 10,000 live births in the United States. Contemporary reports suggest that approximately 69%–80% of cleft lip with or without cleft palate is diagnosed before 24 weeks’ gestation. In nearly two-thirds of fetuses in which a cleft lip is identified, there will be an associated cleft palate. Cleft palate without a disrupted lip is most often not diagnosed prenatally. In 77% of cases, a facial cleft is an isolated finding; however, in 16% of cases, they are associated with malformations in other organ systems and approximately 7% of cases occur as part of a recognized genetic syndrome.

Once a facial cleft is identified, it is critical to determine the extent of the clefting. How much of the lip does it involve? Does it extend to the nares or even up the face to the orbits? Does it involve the palate? Is it unilateral, bilateral, or central? The risk of associated anomalies increases with more severe degrees of clefting.

There are numerous chromosomal abnormalities and genetic syndromes associated with facial clefting, and an attempt to uncover sentinel features by detailed anatomic evaluation will narrow the differential diagnosis of a potentially nonisolated condition. If the fetus has a central or median cleft, an examination of the central nervous system and cardiac anatomy should be performed. Additionally, the hands should be evaluated for postaxial polydactyly, which would lead to a suspicion of trisomy 13, or if a facial cleft is associated with choroid plexus cysts and clenched hands, trisomy 18 would be suspected ( Fig. 11.2 ). If the median cleft is associated with polysyndactyly or a bifid hallux, one must consider oro-facial-digital syndrome as an etiology. If the cleft is associated with ectrodactyly of the hands (split or cleft hand), ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome would be the most likely diagnosis. Facial clefting may be associated with skeletal dysplasias, and an evaluation of the ribs, long bones, and hands may lead to a suggestion of Roberts syndrome or Majewski syndrome. If the anatomic evaluation reveals that the cleft does not follow an expected embryologic sequence and other asymmetric defects such as transverse limb defects are present, the sonologist should look for evidence of amniotic bands. In some rare cases, the cleft may extend up the face and involve the orbits (Tessier cleft). Even in cases of presumed isolated clefting, family history is important to potentially differentiate a sporadic event from the autosomal dominant Van der Woude syndrome. Once a facial cleft is identified and the differential diagnosis narrowed, genetic counseling and diagnostic testing is recommended.

FIG. 11.2

3D surface rendering of a second-trimester fetus with trisomy 18 demonstrating a facial cleft and persistently clenched hands. This fetus also had choroid plexus cysts and a major cardiac defect.

What Is the Role of Pattern Recognition in Common Aneuploidy Syndromes?

Each of the common autosomal trisomies presents with a relatively distinct constellation of findings that allows a tentative prenatal diagnosis based on imaging. Detailed anatomic assessment with attention to pattern recognition including evaluation of the fetal hands helps narrow the suspected diagnosis. Other chromosomal anomalies that may be encountered, such as monosomy X and triploidy, also have distinct features that often can be recognized on prenatal sonographic evaluation. These conditions may be diagnosed by karyotype.

Trisomy 21 (Down Syndrome)

Trisomy 21 is the most common chromosomal abnormality resulting in a live birth, occurring in approximately 1 in 700 pregnancies. Prenatal sonography evaluating the nuchal translucency and/or second-trimester “markers” of aneuploidy in conjunction with standard analyte screening can identify at least 85%–90% of affected fetuses. Sonography alone is useful in identifying 50%–80% of affected fetuses based on “markers” and to a lesser extent structural anomalies. Please see Chapter 10 for further discussion of ultrasound markers of aneuploidy. Approximately 20%–30% of fetuses with trisomy 21 will have a structural malformation. The major structural anomalies identified in fetuses with trisomy 21 include cardiac anomalies such as atrioventricular canal defects, tetralogy of Fallot, and ventriculoseptal defects. Noncardiac abnormalities include mild ventriculomegaly, duodenal atresia, and esophageal atresia. Fetuses with trisomy 21 may also have abnormal fluid collections, such as a pericardial or pleural effusions, or nonimmune hydrops.

Trisomy 18 (Edwards Syndrome)

Trisomy 18 is the second most common autosomal trisomy in live-born infants, occurring in 1 in 3134 pregnancies. Fetuses with trisomy 18 have multiple congenital abnormalities that are identifiable by prenatal sonography, resulting in a detection rate of 98%–100% by imagers using protocols that involve a detailed evaluation of the fetal heart and hands. Lower detection rates are reported before 18 weeks’ gestation.

Structural abnormalities of the central nervous system that are often identified in affected fetuses include neural tube defects, agenesis of the corpus callosum, and posterior fossa abnormalities, including cerebellar hypoplasia. Other anomalies that may be seen in affected fetuses are micrognathia, omphalocele, diaphragmatic hernia, and cystic renal dysplasia. Examination of the extremities, particularly the fetal hands, is critical in making a presumptive diagnosis of trisomy 18, as fetuses with this condition may have radial ray defects (usually unilateral). The sentinel features of this syndrome are clenched hands and overlapping index fingers, which are identified in 95% of affected fetuses ( Fig. 11.2 ). Other abnormalities of the extremities include clubbed and rocker-bottom feet.

Fetal growth restriction is seen in 50% of affected fetuses in the second trimester, and the unusual combination of intrauterine growth restriction and polyhydramnios in the third trimester is highly suspicious for this condition. Although choroid plexus cysts are seen in 50% of fetuses with trisomy 18, they are rarely (if ever) seen as an isolated finding in affected fetuses. Similarly, a strawberry-shaped skull or a single umbilical artery may be seen in affected fetuses but again, not characteristically, as an isolated finding. Survival with trisomy 18 is limited, with many fetuses dying before birth and few surviving past the first year of life. Those that do survive have significant developmental and medical challenges. In pregnancies where prenatal cytogenetic confirmation is obtained, termination rates are 84%. In those that are live-born, survival to 5 years is 12%.

Trisomy 13 (Patau Syndrome)

Trisomy 13 is also seen in live-born infants, although less commonly than trisomy 18 or 21, occurring in 1 in 7000 pregnancies. It is associated with severe intellectual disability and numerous congenital anomalies. Prenatal detection by ultrasound is 90%–100% in the second trimester. Abnormal findings include holoprosencephaly, agenesis of the corpus callosum, cerebellar malformations, and neural tube defects. Affected individuals will often have severe craniofacial defects such as hypotelorism, micro- or anophthalmia, midface hypoplasia, and proboscis ( Fig. 11.3 ). Bilateral cleft lip and palate and midline clefts are common. Affected fetuses also often have major congenital heart defects. Omphalocele and enlarged echogenic kidneys may be associated with this syndrome, and postaxial polydactyly also suggests the diagnosis of trisomy 13 when associated with other major anomalies. Fetal growth restriction is common. Many affected fetuses die in utero and in those that are live-born, survival to 5 years is less than 10%. In pregnancies where prenatal cytogenetic confirmation is obtained, termination rates are 89%.

FIG. 11.3

3D surface rendering of the face in a fetus with trisomy 13 demonstrating a single orbit (“O” arrow) and a proboscis (“P”arrow).

Monosomy X (Turner Syndrome)

Monosomy X occurs due to complete or partial absence of the X chromosome. The prevalence in live-born females is reported as 1 in 2000; however, the majority of affected fetuses are spontaneously aborted. The classic features of 45,X on second-trimester sonography are a female fetus with a large septated cystic hygroma involving the posterior and lateral neck with skin thickening and lymphedema that may extend down the trunk. Abnormal fluid collections characteristic of nonimmune hydrops may be seen. Cardiovascular abnormalities are identified in 10%–40% of fetuses, most commonly left-sided cardiac anomalies such as coarctation of the aorta or hypoplastic left heart syndrome. Renal malformations including a horseshoe kidney and collecting system malformations have been identified in approximately 25%–40% of cases. Prenatal detection by ultrasound is reported to be in 68% overall, and sonographic findings are evident in 92% of those with complete monosomy X and 56% of those with mosaicism for monosomy X. In some cases, prenatal detection is in the later third-trimester because of the recognition of congenital cardiac anomalies. In cases where the diagnosis of monosomy X is associated with congenital anomalies, termination rates of 78% are reported.


In triploidy, there is a complete extra set of haploid chromosomes as a consequence of fertilization of a diploid ovum (digynic) or fertilization by two sperm (dispermy) or a diploid sperm (diandric). Triploidy is reported to occur in 1%–3% of clinically recognized pregnancies, and most fetuses with this condition are spontaneously aborted by midpregnancy. Two distinct phenotypes have been reported and sonographically identified in 80% of fetuses with this condition. Fetuses with diandric triploidy tend to have enlarged cystic placentas and may have symmetrical growth restriction ( Fig. 11.4A ). Those with digynic triploidy have a small placenta and severe fetal growth restriction with relative macrocephaly and oligohydramnios ( Fig. 11.4B ).

FIG. 11.4

(A) Anterior thick cystic placenta fetus with triploidy at 13 weeks’ gestation. (B) 3D surface rendering of the body of a different fetus with triploidy at 13 weeks. The fetus is growth restricted and has a large head compared with the small size of the body.

Sonographic abnormalities are identified in 85%–92% of second-trimester fetuses with triploidy. Massalska et al. reported on the sonographic findings of 67 fetuses with triploidy by karyotype and noted structural anomalies in 60% of affected fetuses. The majority of structural anomalies reported in this condition are not unique and include abnormalities of the central nervous system, including ventriculomegaly, neural tube defects, and abnormalities of the posterior fossa. Fetuses also may have major congenital heart anomalies and craniofacial deformities. Abnormalities of the placenta are seen in 25% of affected fetuses, and fetal growth restriction is almost universal, with characteristic features including severe early growth restriction with relative macrocephaly. A sentinel hand feature of this condition is syndactyly of the third and fourth fingers. Fetal survival to birth is very rare. Early prenatal diagnosis is important as the presence of this condition is associated with maternal complications including severe hyperemesis and early-onset preeclampsia.

What Is the Role of Pattern Recognition in Other Genetic Syndromes?

Although sonographically one may suspect a condition based on a constellation of findings, genetic counseling or consultation with a geneticist is critical to narrowing the differential diagnosis and choosing the optimal testing strategy.

22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

The 22q11.2 deletion syndrome is caused by a hemizygous (only one copy of the 22q region) deletion on the chromosomal region of 22q11.2 and is associated with broad phenotypic variability. Before the identification of the genetic deletion, different groupings of overlapping and similar conditions had a variety of different names, including DiGeorge syndrome, velocardiofacial (Shprintzen) syndrome, and others, which are now known collectively as 22q11.2 deletion syndrome.

The syndrome is characterized by variable phenotypic findings that range from mild to severe. The most common findings are related to cardiac abnormalities, reported in 45%–74% of affected individuals. Noncardiac findings include cleft palate or palatal insufficiency, thymic hypoplasia with immune deficiency, and parathyroid hypoplasia with hypocalcemia. Developmental and language delay, autism spectrum disorder, and an increase in schizophrenia are associated with this syndrome. Specific deletions in genes within the region known as TBX1 may be related to physical features of the syndrome, whereas deletion in the COMT gene is suspected to play a role in the increased risk of neuropsychiatric and behavior issues.

The prevalence is approximately 1 in 4000 births, although it may be underdiagnosed because of mild features. Prenatal detection has been reported based on thickened nuchal translucency in the first trimester; it is the most common pathogenic copy number variant reported in fetuses with normal karyotype and abnormal microarray findings.

In the second trimester, prenatal suspicion of 22q11.2 deletion syndrome is largely based on the detection of cardiac abnormalities, most commonly conotruncal abnormalities such as tetralogy of Fallot and truncus arteriosus. These major anomalies can be detected by standard sonographic assessment of the fetal heart, which includes evaluation of the great vessels. Subtle cardiac findings such as right-sided and interrupted aortic arch are also associated with this syndrome but require a more detailed evaluation of the fetal heart. The presence of a congenital heart defect is the most common indication for genetic testing in affected individuals. In a registry-based series of prenatally detected cases of 22q11.2 deletion in France, 84% of affected individuals had a congenital heart defect; in 62%, the cardiac defect was an isolated finding. Evaluation of the thymus for hypoplasia/aplasia may improve the detection of this condition and is optimally visualized in the three-vessel trachea view. However, this is challenging with less than 10% identified in a recent prenatal series.

Other prenatal abnormalities potentially detectable by ultrasound include cleft palate, which may be suspected by the presence of micrognathia. Evaluation of the face for evidence of hypertelorism and a broad nasal bridge may contribute to the suspicion of this syndrome. Renal anomalies may also be identified by prenatal sonography. In prenatally diagnosed cases, these features are often associated with other abnormalities, most notably congenital heart defects.

Routine prenatal karyotype is usually normal, given the small size of the microdeletion, and is not useful for detecting this condition. The primary diagnostic study should be a microarray based on family history, abnormal ultrasound findings, or a positive cell-free DNA test. The use of FISH (fluorescent in situ hybridization) as an initial test is not recommended as other microdeletions associated with congenital heart defects may be present; therefore, chromosomal microarray is recommended in cases of fetal congenital heart defects. The use of FISH as an initial test is not recommended because smaller deletions may be missed. Testing by FISH may be used in cases in which an affected parent is known to have a 22q11.2 deletion. Preimplantation genetic evaluation is possible for families in which a pathogenic variant has been identified. Although cell-free DNA screening for 22q11 is commercially available, it is not recommended by professional societies because its sensitivity and positive predictive value are unknown.

Noonan Syndrome

Noonan syndrome (NS) is an autosomal dominant disorder (de novo mutation is common) with a prevalence of 1 in 1000 to 1 in 2500. Postnatally, the condition is characterized by distinctive facial features including a broad forehead and hypertelorism, right-sided cardiac defects, hypertrophic cardiomyopathy, musculoskeletal abnormalities, short stature, and intellectual disability. Noonan syndrome can be recognized using clinical criteria, and although affected individuals have normal chromosomes, molecular genetic testing reveals a pathogenic variant in over 75% of cases. Individuals with Noonan syndrome may have a pathogenic variant in the PTPN11 , SOS1, MAP2K1, RAF1, RIT1, and KRAS genes.

Prenatal sonographic signs associated with NS are nonspecific but are often related to lymphatic dysplasia. Affected individuals may have a thickened nuchal translucency, nuchal jugular lymphatic sacs, cystic hygromas, and/or pleural effusions. The prenatal lymphatic features do not predict adverse postnatal outcomses, although structural anomalies are associated with developmental delay and hematologic abnormalities.

Other prenatal sonographic findings include hypertelorism, hemivertebrae, right-sided heart defects such as pulmonary stenosis, hypertrophic cardiomyopathy, hydrops, and polyhydramnios. Prenatal sonography has been poor in detection of cardiac anomalies in fetuses with Noonan syndrome. A recent study of 50 patients with NS reported cardiac defects in 87%; however, less than 10% were identified prenatally.

NS is the most common single-gene disorder in patients with an increased NT and normal karyotype. Approximately 7%–10% of fetuses with an increased NT and normal karyotype have NS identified by gene sequencing. In the absence of abnormal karyotype, NS should be considered if prenatal ultrasound demonstrates an abnormality in lymphatic development such as cystic hygroma, thickened NT, ascites, or pleural effusions as well as those with congenital heart defects.

Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome in which the hallmark features include macroglossia and omphalocele, although there is wide clinical heterogeneity. The condition is associated with an increased risk of embryonal malignancy such as Wilms tumor. BWS has an estimated incidence of 1 in 14,000 and usually occurs sporadically, although familial transmission occurs in 15% of cases. There is an increased frequency in monozygotic twins, and assisted reproductive technologies are associated with a 10-fold increased risk of BWS.

The structural findings seen in some affected individuals with BWS are amenable to prenatal imaging. Sonographically, BWS has been associated with an increased nuchal translucency measurement and omphalocele. Detection of omphalocele is excellent in the 11–14 weekswindow. In a prenatal series of isolated omphalocele without other major structural anomalies or autosomal trisomy, 20% of fetuses were demonstrated to have BWS ( Fig. 11.5 ). Placental mesenchymal dysplasia in which the placenta appears enlarged and hydropic with multiple cysts (similar to a molar appearance) has been associated with BWS.

FIG. 11.5

Axial image through the umbilical cord insertion into the fetal abdomen demonstrating a bowel containing omphalocele (arrow) in a fetus with Beckwith-Wiedemann syndrome.

Macroglossia is a hallmark feature of BWS and can often be detected by prenatal sonography, although in some cases it may not be apparent until later in gestation or even after birth ( Fig. 11.6 ). When present, macroglossia may lead to disordered swallowing and polyhydramnios. The generalized overgrowth of the fetus results in a large abdominal circumference because of the combination of nephromegaly (large kidneys with normal architecture) and hepatomegaly, contributing to the diagnosis of macrosomia, although the growth pattern may vary by molecular subtype.

FIG. 11.6

3D surface rendering of the fetal face in the third trimester showing macroglossia, a finding may be seen in some fetuses with Beckwith Wiedemann syndrome.

As with other conditions, the possibility of a syndromic etiology should be considered when a structural abnormality is detected. If an omphalocele is identified prenatally, a detailed anatomic scan should be performed to exclude other structural anomalies suggestive of an autosomal trisomy (cardiac defects, clenched hands, postaxial polydactyly). If the karyotype is normal or the omphalocele is seemingly isolated, the sonologist should consider BWS and carefully examine the fetal face for macroglossia and size of the internal organs for organomegaly.

BWS is caused by alterations in the imprinted genes on chromosome 11p15.5, which may be identified in 80% of affected individuals. A number of different mechanisms including loss or gain in methylation and paternal uniparental disomy have been reported. Genetic testing may be performed by chorionic villus sampling or amniocentesis, although amniocentesis may be more reliable because of variation in methylation of chorionic villi. Genetic testing approaches can include DNA methylation studies, chromosomal microarray, single-gene testing, copy number analysis for sequences within 11p15.5, karyotype, and use of multigene panels that include genes in the BWS critical region.

CHARGE Syndrome

CHARGE syndrome is an autosomal dominant condition characterized by multiple congenital malformations; this disorder is primarily reported in children and adults, and the phenotype in these individuals is not necessarily reflective of the antenatal presentation. The prevalence of CHARGE is 1 in 8500 to 15,000 live births. The majority of cases are de novo.

The acronym recognizes a cluster of findings that may be seen in affected individuals, including C oloboma of the eye, H eart defects, Choanal A tresia, Growth R estriction, G enital malformations, and E ar abnormalities. Other anomalies that have been described in association with CHARGE include orofacial clefts and trachea-esophageal malformations. The condition is variably expressed so that not all affected individuals will have the same features, and the severity of findings also differs. Findings such as heart defects and genital malformations overlap with other syndromes.

Identifying a prenatal constellation of structural abnormalities leading to a presumptive diagnosis of CHARGE syndrome is challenging, underscoring the importance of a meticulous detailed ultrasound by a provider experienced in evaluating dysmorphic fetuses. A study of 40 fetuses (38 of whom terminated) with abnormal sonographic features and a CHD7 variant consistent with CHARGE sequence reflects the most severe end of the CHARGE spectrum. Features that may be identified on prenatal ultrasound include major congenital cardiac abnormalities, abnormalities of the central nervous system, orofacial clefts, esophageal abnormalities, and abnormal genitalia. However, these anomalies are not specific to CHARGE. Microophthalmia raises the suspicion of CHARGE in a fetus with a nonspecific major congenital abnormality. The evaluation of the nose is of diagnostic importance, as the finding of abnormal nares raises the suspicion for choanal atresia, especially if associated with polyhydramnios. Arhinencephaly, which is complete absence of the olfactory tract formation, and abnormalities of the semicircular canals should raise the suspicion of CHARGE. An abnormal shape to the external ear is a constant feature of CHARGE in the fetus. The external ear appearance can be evaluated with prenatal ultrasound imaging, utilizing color Doppler and 3D imaging. Evaluation of the inner ear and olfactory sulcus using MRI in the prenatal diagnosis of CHARGE has been reported.

CHARGE syndrome is caused by a mutation in the chromodomain helicase DNA-binding protein-7 (CHD7) gene on chromosome 8. Postnatal diagnosis of CHARGE syndrome is based on a combination of major and minor diagnostic criteria. Molecular testing for CHD7 will confirm the diagnosis in the majority of cases. The CHD7 variant is found in 90%–95% of affected individuals and mostly occurs de novo. Some individuals with a CHARGE phenotype may have a 22q11.2 deletion or other cytogenetic abnormalities. In contrast, 10%–20% individuals with a clinical diagnosis will not have an identified abnormal gene sequence. Prenatal suspicion for CHARGE is made in the presence of multiple congenital anomalies that overlap with other syndromes. Prenatal diagnostic testing may include CVS or amniocentesis. Workup may include karyotype and microarray analysis that will help exclude other syndromes with overlapping features. If chromosomal microarray analysis is nondiagnostic, CHD7 gene sequencing is recommended. If gene sequencing is negative, deletion/duplication analysis can be performed. If the CHD7 analysis is nondiagnostic, whole-exome sequencing may be considered.

Smith-Lemli-Opitz Syndrome

SLOS is an autosomal recessive disorder caused by a variant in the DHCR7 gene, which encodes the enzyme 7-dehydrocholesterol reductase (7-DHC). Affected individuals have elevated serum 7-DHC levels and low levels of serum cholesterol. Many fetuses with SLOS die in utero resulting in a live birth incidence of 1 in 20,000 to 60,000.

The disorder results in multiple structural malformations, although the phenotypic spectrum is broad. Affected individuals may have congenital heart defects, micrognathia and cleft palate, upturned nares, and ptosis. Other anomalies characteristic of SLOS include abnormalities of the extremities, such as postaxial polydactyly and syndactyly of second and third toes, as well as abnormal genitalia. Growth restriction, microcephaly, and developmental delay, which may range from mild to severe, are common in affected individuals.

Sonographically, SLOS has been associated with an increased nuchal translucency measurement, although this is a nonspecific finding. Prenatal anatomic imaging may detect cardiac abnormalities, most notably atrioventricular canal defects and septal defects. Additional abnormalities reported with SLOS include holoprosencephaly, agenesis of the corpus callosum and cerebellar hypoplasia, hypertelorism, and micrognathia. These major anomalies are not unique to SLOS but should prompt the sonologist to evaluate the genitals, looking for hypospadias or ambiguous genitalia. Correlation with known karyotype is useful in cases where the genitalia appears female. Evaluation of the distal extremities to detect postaxial polydactyly and 2–3 syndactyly of the toes may increase the suspicion of SLOS. Growth restriction has been reported to be present in 30% of affected fetuses between 20 and 22 weeks and in 70% between 30 and 34 weeks. The combination of growth restriction and genital anomalies should prompt consideration of the diagnosis of SLOS. Microcephaly, although a common postnatal finding, may not be present at the time anatomic imaging is performed, and antenatal detection of microcephaly in SLOS has been poor. Although affected fetuses may be noted to have some of the features noted above on prenatal ultrasound, it is also possible for an affected fetus to have a normal fetal ultrasound evaluation.

A low maternal serum unconjugated estriol concentration on second-trimester maternal serum screening for aneuploidy in a fetus should raise suspicion of SLOS in a fetus with a normal karyotype. Steroid measurement in maternal urine may be useful in diagnosis of SLOS. In addition, amniotic fluid and chorionic villi contain high levels of 7-DHC in affected fetuses. Mutation analysis from amniotic fluid or chorionic villi can be used for prenatal diagnosis if a proband in the family has previously been identified with a DHCR7 gene mutation. For pregnancies with no family history of SLOS, where the diagnosis is suspected based on ultrasound findings, abnormal maternal serum screening, or both, measurement of 7-DHC levels in amniotic fluid or tissue obtained from CVS is an alternative to sequence analysis of the DHCR7 gene.


VACTERL sequence includes V ertebral, A nal atresia, C ardiac, T racheoesophageal fistula with E sophageal atresia, R enal anomalies, and L imb defects (primarily radial ray). At least three features should be present to consider this diagnosis as well as the absence of other conditions. In 90% of cases, VACTERL is sporadic although there is a small subset of patients with a first-degree relative with similar anomalies, suggesting that there may be an inherited component. VACTERL occurs in approximately 1 in 10,000 to 1:40,000 live births.

VACTERL may be suspected on prenatal sonography, although some clinical features are difficult to identify on routine prenatal ultrasound. In a registry-based study of 19 cases of VACTERL, approximately 50% were identified by prenatal sonography and cases detected prenatally had more malformations than those diagnosed postnatally ( Fig. 11.7A and B ). Renal, limb, and vertebral anomalies are the most amenable to prenatal diagnosis. Renal anomalies associated with VACTERL include renal agenesis (unilateral or bilateral), cystic or dysplastic kidneys as well as renal fusion abnormalities. Major limb anomalies are also amenable to prenatal detection; however, an astute sonologist must be aware to look for more subtle abnormalities such as isolated thumb anomalies.

Jan 5, 2020 | Posted by in PEDIATRICS | Comments Off on Genetic Evaluation of Fetal Sonographic Abnormalities

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