Key Terms
Screening test: usually non-invasive tests that are designed to identify people with an increased risk for a certain condition before they realize they have it. Nuchal translucency thickness, first trimester screening, quad screening, sequential screening, integrated screening, and maternal cell-free DNA provide risk estimates for trisomy 21 for low risk patients.
Diagnostic test: test aimed at providing certainty about a specific diagnosis in an individual suspected to have the condition. Example: a fetal karyotype obtained by amniocentesis conclusively diagnoses or excludes trisomy 21 in a patient at risk based on screening tests (e.g. nuchal translucency thickness or cell-free DNA screening).
Phenotype: constellation of observable characteristics or traits of an individual.
Karyotype: number and appearance of chromosomes in the cell nucleus displayed as a systematized arrangement of chromosome pairs in descending order of size.
Fluorescent in situ hybridization (FISH): molecular cytogenetic technique that uses fluorescent probes that identify specific DNA sequences on chromosomes. The test provides a quick method to determine the number of copies of a particular chromosome without the need to produce a karyotype.
Chromosomal microarray: method to identify submicroscopic deletions and duplications (copy number variants or CNVs) across the genome via molecular methods.
Variant of uncertain significance (VOUS): allele or variant of a gene whose significance to health is unknown.
Congenital anomalies are typically organized by organ system. This is an excellent method that allows similar disorders to be grouped together. However, the multisystem chromosomal anomalies and syndromes do not fit neatly into this organ organizational method. Usually the most striking finding or the most unusual finding is the one that leads to inclusion into one or another group.
In the following pages, we will review the phenotypic features of several chromosomal anomalies and syndromes that should be familiar to those performing obstetrical ultrasonography. These disorders have been selected either because they are fairly characteristic or common, or because their recognition may have an impact for genetic counseling and pregnancy management. From the outset, we would like to state that this review cannot be exhaustive, as there are entire books (eg, the Birth Defects Encyclopedia with approximately 2000 described syndromes)1 and websites (eg, Online Mendelian Inheritance in Man [OMIM], created in December 1995 and, as of today, beyond the 18,000-syndrome landmark)2 dedicated to this subject.
Another important aspect of prenatal diagnosis of syndromes and chromosomal anomalies is that a final prenatal diagnosis based on phenotypic features alone is usually not be possible. Indeed, an accurate diagnosis is often achieved only after appropriate prenatal genetic testing and/or after careful examination of the child after birth. The term “appropriate” is used here to emphasize that no single test is currently available that is capable of providing a final diagnosis or of excluding every genetic abnormality in a fetus diagnosed with multiple malformations. Therefore, genetic counselling by a professional who is up-to-date with the wide scope and ever changing landscape of complex genetic testing cannot be overemphasized. It is also important to bear in mind that different syndromes often have significant overlap of phenotypic features. This requires that those who provide prenatal imaging services be cognizant of providing not only the most likely diagnosis, but also a reasonable list of pertinent differential diagnoses for each case. We also strongly believe that management of these rather complex and emotionally charged cases is best served by a formal consultation with a multidisciplinary team, using a multidisciplinary conference format.3 In this format, all images, genetic tests, and pertinent aspects of the prenatal and family history are reviewed and discussed by the members of the multidisciplinary team before the group formally meets with the parents to present a consensual approach and answer all questions. The core multidisciplinary team is composed, at a minimum, of the patient’s obstetrician, a maternal-fetal medicine specialist, a genetic counselor and a social worker. Depending on the nature of each particular case, other professionals frequently participate in the sessions, including pediatric radiologists, neonatologists, pediatric cardiologists, pediatric surgeons, pediatric urologists, orthopedic and plastic surgeons.
When anomalies are observed by ultrasound, genetic screening and diagnostic testing options may be considered. Referral to a genetic counselor is prudent to allow patients to consider the benefits and limitations of screening or testing given the type of anomalies and the relative certainty of the ultrasound findings. The goal of genetic counseling in this setting is to help the patient and family make an informed decision, among the options available to them.
Prenatal testing for the detection of chromosomal anomalies falls into two basic categories: (1) screening and (2) diagnostic tests. Screening tests are noninvasive and provide risk estimates, generally for a few conditions, whereas diagnostic tests are commonly invasive and aim at providing certainty about the presence of a particular disorder.4 The classic screening option is multiple marker screening with or without nuchal translucency measurement.5-7 As most anomalies are detected at the time of, or after, this measurement, this screen is typically of limited value in the setting of ultrasound anomalies. More recently, cell-free DNA screening has become available.8 The options for this screen include aneuploidy screening alone or in conjunction with specific microdeletions. Additionally, cell-free DNA to screen for microdeletions and microduplications across the genome is now available.9,10 Cell-free DNA screening has high sensitivity and specificity for detection of Down syndrome and trisomy 18. However, since many of the conditions potentially detectable through microdeletion and microduplication screening have a relatively low prevalence, the positive predictive value for these is low, and the sensitivity and specificity of these tests is currently unknown. It is important for patients to know that multiple marker screening and cell-free DNA are screening tests, rather than diagnostic tests. Patients who have a positive screen are offered an invasive procedure (chorionic villus sampling [CVS] or amniocentesis) for diagnostic testing.
With an isolated soft finding on ultrasound, either screening or diagnostic testing may be considered. With multiple soft findings or with one or more fetal anomalies, diagnostic testing is favored. Diagnostic testing is available via CVS in the first trimester, or amniocentesis in the second or third trimester. Classically, routine karyotyping is performed to evaluate for aneuploidy and microscopically evident deletions or duplications of chromosomal material. The patient with a normal ultrasound or one with a soft marker, and who may or may not have a screening test positive for aneuploidy, is a candidate for routine karyotyping.
Chromosomal microarray analysis (CMA), also referred to as array comparative genomic hybridization (array CGH) or single nucleotide polymorphism (SNP) array has come into favor as a method of finding submicroscopic deletions and duplications (called copy number variants or CNVs) across the genome via molecular methods. For patients with abnormal ultrasound findings and normal karyotype, approximately 6% to 8% have abnormal CMA results.11,12 In a joint statement, both the American College of Obstetrics and Gynecology (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have recommended CMA over routine karyotyping when one or more structural anomalies are noted on prenatal ultrasound.13 While CMA has many advantages, it cannot detect balanced chromosomal rearrangements, mosaicism (ie, more than one cell population), or triploidy. While there is increasing data on phenotype associations with various CNVs, variants of uncertain significance (VOUS) may be reported; these can add anxiety to already stressful situations. With increasing experience in recent years, VOUS have decreased in likelihood to approximately 1% as more of them can be defined as “likely benign” or “likely pathogenic.”10 Parental blood samples may be needed to understand the significance of a given variant.
When anomalies raise suspicion for a specific diagnosis, routine karyotyping and CMA will typically not be helpful. Based on the constellation of findings, individual genes or possibly panels of genes may be tested through molecular methods to help determine the etiology. Sometimes the ultrasound determination of severity is more useful to families than genetic testing when the differential diagnosis is broad. For example, there are over 400 different skeletal dysplasias which have a multitude of etiologies. Some are inherited as Mendelian traits in an autosomal dominant, autosomal recessive, or X-linked pattern, some occur as a result of imprinting, some as a result of somatic mosaicism (postconception errors), and others as a result of prenatal teratogen exposure. A molecular defect has been identified in more than one-half of skeletal dysplasias.14 Prenatal molecular testing for a skeletal dysplasia that occurs sporadically (no prior family history) is typically not of great use to the family as it can be a lengthy process and typically will not change care, especially if the skeletal dysplasia appears to be lethal.15 Accurate diagnosis of skeletal dysplasias, and of other conditions not due to a chromosome abnormality, often occurs postnatally through genetic and/or pathologic evaluation.16
Whole exome sequencing (WES) and similar tests are starting to be incorporated into prenatal practice. WES involves genome-wide sequencing, often of just the protein-coding regions. While it is increasingly being used in the pediatric and adult populations, some current concerns include a long turnaround time, high false-positive and false-negative rates, VOUS, and secondary findings which may be unacceptable to families. Therefore, more data are needed to make this a useful test in prenatal practice.16,17
The ultimate goal of prenatal testing is to provide an answer to families in the form of an etiology for the ultrasound findings. It is important to give a range of prognosis, and to try to provide the recurrence risk for future pregnancies. If there is a risk of recurrence, the goal is to find the specific molecular or chromosomal abnormality to be able to offer options of prenatal diagnosis or preimplantation genetic diagnosis in future pregnancies.
In the following pages, we will provide a brief overview of structural abnormalities that can be visualized by ultrasonography in fetuses affected by chromosomal anomalies. As noted previously, ultrasound can neither provide a definitive diagnosis of a chromosomal anomaly nor rule it out without genetic testing. Therefore, although a constellation of findings may strongly suggest a specific condition (eg, increased nuchal fold, atrioventricular canal, and duodenal atresia in the same fetus strongly suggest trisomy 21), the diagnosis is not definitive until confirmed by genetic testing.
Synonyms: Down syndrome.
Definition: Multiple malformation syndrome, with trisomy for all or a large part of chromosome 21.18
Prevalence: One in 750 to 1 in 1000 live births, with a maternal age effect (15-29 years, 1 in 1500; 30-34 years, 1 in 800; 35-39 years, 1 in 270; 40-44 years, 1 in 100; and over 45 years, 1 in 50).18,19
Etiology: Presence of an extra chromosome 21 (full trisomy 21, 94%), trisomy 21/normal mosaicism (2.4%), and translocation (most commonly involving chromosomes 14 and 21, 3.3%).18,19
Central Nervous System (CNS)
Mild ventriculomegaly (<15 mm) (Figure 24-1)
Face, Neck, and Skull
Flattened face, 90%
Increased nuchal translucency between 11 and 14 weeks (Figure 24-2)
Increased nuchal fold (≥6 mm between 16 and 20 weeks) (Figure 24-3)
Oblique palpebral fissure, 80%
Flat occiput, 78%
Brachycephaly, 75%
High arched palate, 70%
Low nasal bridge, 60%
Ear anomalies, 50%
Epicanthal fold, 40%
Cataract, 3%
Low-set ears
Macroglossia
Absent or hypoplastic nasal bones (Figures 24-4A and B)
Mild microcephaly
Cardiovascular (40%-60%)
Endocardial cushion defect (Figure 24-5)
Ventricular septal defect
Atrial septal defect
Tetralogy of Fallot
Pericardial effusion
Aberrant right subclavian artery (ARSA)
Gastrointestinal
Duodenal atresia, 30% (Figures 24-6A and B)
Tracheoesophageal fistula
Omphalocele (Figure 24-7)
Pyloric stenosis
Annular pancreas
Hirschprung’s disease
Imperforate anus
Hyperechogenic bowel (Figure 24-8)
Urinary Tract
Mild pyelectasis
Reproductive Tract
Small penis
Skeletal
Short limbs, 70%
Short fingers, 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 rib pairs
Double ossification centers for the manubrium
Funnel or pigeon breast
Hip anomalies
Other Findings and Anomalies
Hypotonia, 20% to 80%
Goiter
Leukemia, 1%
Differential Diagnosis: Multiple malformation syndromes that include fetal growth restriction (FGR), polyhydramnios, and congenital heart malformations such as trisomies 18 and 13, and Smith–Lemli–Opitz syndrome.
Prognosis: Over three-quarters of pregnancies with trisomy 21 miscarry. The spontaneous loss rate for diagnoses made at 10 weeks is about 43%, dropping to approximately 23% if the diagnosis is made at 16 weeks. Down syndrome is the most common cause of intellectual disability, with severity ranging from mild to profound. Ninety-six percent of those without and 80% of those with a heart defect survive the first year of life.28 Life expectancy is approximately 55 to 60 years. Some anomalies, such as atrioventricular septal defects and gastrointestinal anomalies require surgical correction. Regarding long-term complications, 11% develop Alzheimer’s disease by the age of 50 and 77% by age 70. Ten percent may develop seizures. The lifetime risk of leukemia is estimated at 2%.19,28,29
Recurrence Risk: For full trisomy in young mothers, the recurrence risk is estimated at 1% to 2%. The risk for older mothers depends on maternal age. In cases of Robertsonian translocation, the empiric risks are 10% for the offspring of female carriers and 2% for the offspring of male carriers.30
Synonyms: Edwards syndrome.
Definition: Multiple malformation syndrome with trisomy for all of or a large part of chromosome 18.
Prevalence: Second most common autosomal trisomy after trisomy 21, with an estimated prevalence between 1:3000 and 1:8000, with a maternal age effect.18,31
Etiology: Nondisjunction during meiosis, rarely parental translocation. Approximately 80% of patients have a straight trisomy, 10% are mosaics, and the rest are either double trisomies for another chromosome or have a translocation. Advanced gestational age is a risk factor, and the parental origin of the extra chromosome is maternal in 96% of cases in which chromosomal origin can be determined.
CNS
Choroid plexus cysts, 51% (Figure 24-9)
Small cerebellum (<10% percentile), 45%
Meningomyelocele, 16%
Arnold–Chiari malformation, 13%
Abnormal gyration, 13%
Heterotopia, 13%
Abnormal olivary nuclei, 10%
Arachnoid cyst, 3%
Hypoplastic cerebellar vermis, 3%
Alobar holoprosencephaly, 3%
Face, Neck, and Skull
Strawberry-shaped cranium
Low-set ears, 58%
Micrognathia, 48%
Small face, 35%
Abnormal ears, 35%
Small eyes, 26%
Small mouth, 16%
Microcephaly, 16%
Large anterior fontanel, 13%
Hypertelorism, 6%
Choanal atresia, 6%
Preauricular tag, 6%
High arched palate, 6%
Cleft palate, 3%
Small anterior fontanel, 3%
Third fontanel, 3%
Low hair line, 3%
Cardiovascular
Ventricular septal defect, 81% (Figure 24-10)
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 outlet right ventricle, 6%
Dextrocardia, 6%
Transposition of great vessels, 6%
Retroesophageal subclavian vein, 6%
Tetralogy of Fallot, 3%
Hypoplastic 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% (Figure 24-11)
Rockerbottom feet, 39%
Clubfeet, 32%
Abnormal wrist position, 27%
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: FGR, 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%
Differential Diagnosis: Multiple malformation syndromes, which include severe FGR, polyhydramnios, and congenital heart disease such as, trisomy 13, triploidy, and Pena–Shokeir syndrome.
Prognosis: Although trisomy 18 is less common than trisomy 21, it is more lethal. Approximately two-thirds of the fetuses with an in utero diagnosis of trisomy 18 die before delivery,34,35 about 42% die in the first week of life, and 90% die by the age of 6 months. Three percent to 6% of liveborn infants may be still alive at one year of age.32
Recurrence risk: For full trisomy 18, the recurrence risk is approximately 1%.30
Synonyms: Patau syndrome.
Definition: Multiple malformation syndrome with trisomy for all of or a large part of chromosome 13.
Prevalence: One in 20,000 live births.30
Etiology: Primary nondisjunction for the majority of cases, with a maternal age effect. Robertsonian translocations are responsible for less than 20% of the cases (invariably chromosomes 13 and 14 joining at their centromeric regions).
Phenotypic characteristics18,36-38:
CNS
Holoprosencephaly (Figure 24-12)
Deafness
Dysgenesis of the corpus callosum
Hydrocephaly
Cerebellar hypoplasia
Meningomyelocele
Face, Neck, and Skull
Cleft lip and palate, 60% to 80% (Figure 24-13)
Hypo- and hypertelorism
Anophthalmia
Cyclopia
Proboscis
Microphthalmia
Retinal dysplasia
Cataract
Corneal opacities
Intraocular cartilage
Microcephaly (see Figure 24-12)
Wide sutures and fontanels
Abnormal ears
Nuchal fold
Cleft tongue
Absence of the philtrum
Micrognathia
Cardiovascular (80%)
Ventricular septal defect, 50% to 60% (see Figure 24-10)
Atrial septal defect, 40% to 50%
Dextroposition, 20% to 50%
Coarctation of the aorta
Anomalous pulmonary venous return
Overriding aorta
Pulmonary stenosis
Hypoplasia aorta
Mitral atresia
Aortic atresia
Bicuspid aortic valve
Gastrointestinal (50%-80%)
Umbilical hernia
Omphalocele
Heterotopic pancreas
Intestinal malrotation, 20% to 30%
Diaphragmatic hernia
Elongated gallbladder
Accessory spleen
Urinary Tract
Mild pyelectasis
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%-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 umbilical cord
Situs inversus
FGR
Figure 24-12.
Three-dimensional ultrasound multiplanar displays of a fetus with alobar holoprosencephaly in the axial, coronal, and sagittal planes. Note the small head in relationship to the size of the face in the sagittal profile giving the gestalt of a small craniofacial ratio, which is typically seen in microcephaly.
Differential Diagnosis: Multiple malformation syndromes characterized by severe FGR, polyhydramnios, congenital heart defects, and/or renal anomalies, such as trisomy 18, Smith-Lemli-Opitz syndrome, and Meckel-Gruber syndrome.
Prognosis: Approximately two-thirds of fetuses with trisomy 13 die before delivery or are stillborn.34,35 Of those who survive, median survival is 7 days, approximately 50% die during the first month, 95% die within the first year, and only a few survive past 3 years.30
Recurrence Risk: For parents with Robertsonian translocations the risk is 1% to 2%. For primary trisomies, the recurrence risk is not increased.30
Synonyms: Incomplete molar gestation, partial triploid mole.
Definition: Lethal chromosome abnormality characterized by an extra set of chromosomes, resulting in focal hydropic swelling of chorionic villi with trophoblastic hyperplasia and identifiable embryonic or fetal tissues.
Prevalence: Two percent of aborted conceptuses, but only 1 in 10,000 to 1 in 100,000 pregnancies.18
Etiology: Extra set of chromosomes is paternally derived in 69% of cases, either caused by dispermy or double fertilization. Approximately 60% of the cases are XXY and the remainder XXX. Older maternal age is not a risk factor for triploidy.18
Phenotypic Features18:
The phenotype depends on the parental source of the extra chromosome set. Those with an abnormal hydropic placenta (partial mole) have an extra set of paternal chromosomes. For those with an extra set of maternal chromosomes, the fetus is usually small and growth restricted, and the placenta is small and noncystic.39
Large Placenta with Hydatidiform Changes (>50%) (Figure 24-12)
Early Asymmetric FGR (>50%)
Skeletal
Syndactyly of third and fourth toes and fingers (>50%)
Short hallux
Clubfoot (>50%)
Rockerbottom foot
CNS
Relative macrocephaly
Agenesis of the corpus callosum
Dandy-Walker malformation
Holoprosencephaly (>50%)
Arnold-Chiari malformation
Spina bifida
Myelomeningocele
Hydrocephalus (>50%)
Central and cerebellar hypoplasia
Face, Neck, and Skull
Cleft lip
Low-set ears (>50%)
Micrognathia (>50%)
Hypertelorism (>50%)
Cystic hygroma
Cardiovascular (40%-60%)
Ventricular septal defect
Atrial septal defect
Many others
Gastrointestinal
Omphalocele
Intestinal malrotation
Urinary Tract (>50%)
Hydronephrosis
Dysgenesis of kidneys
Multicystic kidneys
Reproductive Tract (>50%)
Hypospadias
Ambiguous genitalia
Cryptorchidism
Other Findings and Anomalies
Decreased fetal movement
Lung hypoplasia
Differential Diagnosis: Twin gestation with one fertilized ovum undergoing molar degeneration and hydropic changes in a missed abortion.
Prognosis: The immense majority of fetuses with full triploidy are stillborn or die in the early neonatal period. There are no recorded survivors beyond 10.5 months.30
Recurrence Risk: No data to indicate an increased recurrence risk.
Synonyms: Monosomy X, Ullrich-Turner syndrome.
Definition: Chromosomal disorder of female patients, described by Turner in 1938, characterized by the absence of one sex chromosome (45, XO) in approximately 50% of the cases, with remaining occurring due to mosaicism.18,30 The majority of cases diagnosed prenatally have a 45,X0 karyotype (~90%).40
Prevalence: Approximately 1 in 2500 liveborn birth females. The incidence in all pregnancies, however, is considered much higher because Turner syndrome accounts for one-fourth of the spontaneous abortions caused by chromosomal anomalies.18,19,30,31
Etiology: Absence of one sex chromosome, in general the paternal chromosome, which occurs sporadically in most cases. Advanced maternal age is not associated with this aneuploidy.18
Phenotypic Features18,40:
Neck
Cystic hygroma—most frequent prenatal feature (~60%) (Figure 24-15)
Webbed neck
Short neck
Lymphedema
Dorsum of the hands and feet
Hydrops (~20%)
Cardiovascular (~8%)
Coarctation of the aorta
Bicuspid aortic valve
Renal (~3%)
Horseshoe kidney
Genital
Ovarian dysgenesis in 90%
Musculoskeletal
Short cervical spine
Short stature
Other
CNS anomalies
FGR
Umbilical cord cysts
Differential Diagnosis: Hydrops fetalis.
Prognosis: Intrauterine demise occurs in many cases, generally caused by hydrops, which is the major intrauterine complication.34,35 Among survivors, the prognosis will depend on the severity of the associated anomalies. Gonadal dysgenesis and small stature are the most consistent features. Congenital lymphedema usually improves during early childhood, leaving residual puffiness in the dorsum of the fingers and toes. Mean final height is 143 cm, approximately 20 cm less than the general female population. Causes of potential morbidity in adult life include an increased risk for dissection of the aorta, diabetes mellitus, hypertension, ischemic heart disease, and stroke. Although overall IQ is generally normal, performance IQ tends to be lower than verbal IQ. Cases of mosaicism tend to have a better prognosis and, in some cases, discrete manifestations the syndrome remain undiagnosed for many years.18,19,30,31
Recurrence Risk: Considering that Turner syndrome is a sporadic event in the majority of cases, chances of recurrence are extremely low, although not precisely known.
Synonyms: Monosomy 4p, partial deletion of chromosome 4, Wolf-Hirschhorn syndrome.
Definition: Absence of part of the short arm of chromosome 4.
Prevalence: One in 50,000 to 1 in 20,000, with a female:male ratio of 2:1.41-43
Etiology: Abnormal chromosome breakage during synapsis and recombination. The deletion proximal breakpoint varies from 4p15.2 to 4p16.3.42 Approximately 50% to 60% of cases are due to de novo deletions, and approximately 40% to 45% have an unbalanced translocation (either de novo or inherited from a parent with a balanced rearrangement) involving both a deletion of 4p and a partial trisomy of a different chromosome.
CNS
Microcephaly (90%)
Brain abnormalities (80%)
Corpus callosum dysgenesis (55%) (Figure 24-16)
Absence of the cavum septi pellucidi
Ventriculomegaly (33%)
Cortical/subcortical atrophy (29%)
Delayed myelination (15%)
Cystic cerebral lesions
Cerebellar hypoplasia (0.04%)
Schizencephaly (0.02%)
Craniofacial Anomalies
Characteristic facies – “Greek warrior helmet” (100%) (Figure 24-17)
Prominent glabella
Wide nasal bridge with beaked nose
High forehead
Hypertelorism
Short philtrum
Downturned corners of the mouth
Micrognathia
Facial clefting (30%)
Posterior midline scalp defects
Webbed neck
Cardiovascular (50%)
Atrial septal defect
Pulmonic stenosis
Ventricular septal defect
PDA
Aortic insufficiency
Gastrointestinal (50%-80%)
Intestinal malrotation
Chest
Diaphragmatic hernia
Urinary Tract (25%)
Hypoplastic kidney
Reflux
Reproductive Tract
Hypospadias
Skeletal (60%-70%)
Simian crease
Kyphosis/scoliosis
Abnormal ossification of the sternum
Clubfeet
Split hand
Other Findings and Anomalies
Prenatal and postnatal FGR (80%)
Generalized hypotonia (100%)
Global developmental delay (100%)
Seizures (93%)
Single umbilical artery
Decreased fetal movements
Weak cry after birth
Hearing loss (40%)
Figure 24-16.
A: Midline sagittal view of the fetal brain by fetal MRI shows a formed corpus callosum (arrowheads) and the cingulate gyrus (*s) immediately above it. B: Complete agenesis of the corpus callosum showing sulci radiating from the roof of the third ventricle given absence of the corpus callosum and cingulate gyrus (radiating gyral pattern).
Figure 24-17.
Facial profile by fetal MRI at 25 weeks (A) show prefrontal edema (arrowhead) and a flat facial profile (“Greek warrior helmet”). Micrognathia (arrow) is also noted. Another fetus with similar features depicted by 3DUS (B). C: Postnatal image showing prefrontal edema and hypertelorism. (B and C, Reproduced with permission from TheFetus.net.)
Prenatal Diagnosis: Prenatal diagnosis has been reported several times based on cytogenetic evaluation after the observation of FGR associated with several of the anomalies described above (microcephaly, brain anomalies, prefrontal forehead edema [“Greek warrior helmet”], cleft lip, renal anomalies, and hypospadias).45-51
Differential Diagnosis: Seckel syndrome, CHARGE syndrome, Smith-Lemli-Opitz syndrome (SLOS), Opitz G/BBB syndrome, Malpuech syndrome, Lowry MacLean syndrome, Williams syndrome, classic Rett syndrome, Angelman syndrome, Smith-Magenis syndrome.44
Prognosis: The life expectancy for children with 4p- syndrome is thought to be higher than once thought. The mortality rate reported from a study of 159 cases published in 2001 was 27.8%, with 63.9% of deaths occurring during the first year of life. Overall mortality in the first year was estimated at 21%. After the age of 2 years, mortality fell dramatically, with a median survival for cases with de novo deletions surpassing 34 years and a median survival for cases caused by translocations of over 18 years. Larger deletions carried a higher risk of death compared to small deletions (51.5% vs 9.7%). Causes of death included birth anoxia, withdrawal of treatment after premature delivery, congenital heart disease, dysplastic kidneys and renal hypoplasia, diaphragmatic hernia, pulmonary hypoplasia, lower respiratory tract infection complicated by seizures and aspiration, and sudden unexplained death.43
Prognosis for surviving individuals is related to the presence and severity of the phenotypic abnormalities listed previously. A study of 87 patients by Battaglia et al42 reported global developmental delay for all cases, ability to walk independently or with support for 45%, and ability to dress/undress and perform simple household tasks for 18% of affected children. Cognitive impairment was severe for 65%, moderate for 25%, and mild for 10% of the cases. Follow-up of their patients over a period of 23 years showed slow but constant evolution in all areas over time. Major medical concerns included seizures, feeding difficulty requiring gastrostomy for 50% of the cases, orthopedic abnormalities, and hearing impairment.
Recurrence Risk: Depends on the mechanism of origin for the deletion. Recurrence risk is negligible for a de novo deletion. The risk is increased if one of the parents carries a balanced translocation.44
Synonyms: 22q11.2DS encompasses phenotypes previously described as DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), some cases of Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies).
Definition: contiguous gene deletion syndrome of the DiGeorge chromosome region (DGCR).52-54
Prevalence: U.S. incidence is estimated at 1/3800 – 1/6000, but is likely greater given that it has broad variability.55
Etiology: 22q11.2DS is diagnosed in individuals with a submicroscopic deletion of 22q11.2 detected by FISH (for deletions larger than 40 kb), or by CMA or MLPA (Multiplex Ligation-dependent Probe Amplication) (for deletions smaller than 40 kb).56
Phenotype: There is marked inter- and intrafamilial variability with the 22q11.2DS. As noted above, 22q11.2DS encompasses phenotypes previously described as DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), some cases of Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies).
Imaging findings: 22q11.2DS is suspected in individuals with a range of findings, including:56
Frequent
Congenital heart disease, especially conotruncal anomalies (74%)
Palate abnormality, especially velopharyngeal insufficiency (69%)
Hypocalcemia (17–60%)
Immune deficiency due to thymic hypoplasia (77%)
Learning difficulties (especially non-verbal, with verbal IQ greater than performance IQ) (70-90%)
Characteristic facial features, which can include auricular abnormalities, nasal anomalies, “hooded eyelids”, hypertelorism, cleft lip and palate, asymmetric crying facies, craniosynostosis, long face, malar flatness
Less Frequent
Severe dysphagia (about 36% with severe feeding difficulties)
Autoimmune disease (thrombocytopenia, juvenile rheumatoid arthritis, Grave’s disease, vitiligo)
Hearing loss (sensorineural and conductive)
Psychiatric illness (60% of adults)
Autism (20% of children)
Other Important Structural Defects May Include
Skeletal: polydactyly, hemivertebrae, craniosynostosis
Genitourinary: renal agenesis, hydronephrosis, kidney anomalies, hypospadias, absent uterus
Laryngotracheoesophageal: vascular rings
Ophthalmologic: coloboma, anophthalmia, strabismus
Central nervous system: neural tube defects, tethered cord, seizures
Gastrointestinal: imperforate anus, congenital diaphragmatic hernia, malrotation, Hirschsprung disease
Skin: Preauricular tags/pits
Individuals with 22q.11DS are also at increased risk for neoplasms, such as hepatoblastoma, renal cell carcinoma, Wilms tumor, and neuroblastoma.56
Prenatal Diagnosis: should be offered if a patient presents with a positive family history and/or in case of prenatal imaging findings that are more strongly associated with the condition, such as congenital heart disease, cleft palate, polydactyly, congenital diaphragmatic hernia, renal anomalies, and polyhydramnios.
The acronym TORCH, originally coined to represent Toxoplasmosis, Other (syphilis), Rubella, Cytomegalovirus (CMV), and Herpes simplex virus now comprises additional well-described infectious agents that are associated with congenital infections leading to stillbirth and increased perinatal morbidity and mortality, with a larger burden to developing countries, such as hepatitis C virus, human immunodeficiency virus (HIV), varicella, and parvovirus B19.57 The newest TORCH agent is the Zika virus, which has been linked to a 20-fold increase in the incidence of microcephaly in endemic regions of Brazil.58 TORCH infections are described in the following pages, highlighting the most characteristic prenatal imaging findings for each disorder.
Definition: Cytomegalovirus (CMV) is a large DNA virus of the human herpes family. The virus causes a mild infection or a mononucleosis-type illness in healthy young adults and a mild to severe congenital infection if transmitted to the fetus.59,60
Incidence: The incidence of congenital CMV infection is estimated at 0.2% to 2.2% of all live births. Primary maternal infection carries a risk of vertical transmission of approximately 40%. Approximately 10% to 15% of liveborn infants have symptomatic disease at the time of birth and/or later, and 25% develop sequelae by age 2. The risk of vertical transmission with reactivation of CMV infection during pregnancy is estimated at 1% to 3%. Less than 1% of these fetuses are symptomatic at birth and, among these, approximately 8% have sequelae by age 2. Although the possibility of congenital infection is highest for maternal CMV infection occurring in the third trimester, first trimester infection carries a higher risk.59-62
Ultrasonographic Abnormalities Associated with CMV Infection: The 3 most frequent ultrasonographic findings are hyperechogenic bowel, microcephaly, and cerebral calcifications.62 However, when scanning fetuses at risk for CMV infection, the reader should pay particular attention to the developing periventricular white matter of second trimester fetuses as the intermediate zone may show increased echogenicity and heterogeneity, both of which have been reported to predate the development of microcephaly, ventriculomegaly, and intracranial calcifications.63 The intermediate zone is a visible migration layer identifiable as a slightly hyperechogenic halo by ultrasound or slightly hypointense area on T2-weighted fetal MRI sequences located between the ventricular zone and the subplate (Figure 24-18). The intermediate zone and subplate are the precursors of the neonatal white matter.63,64
Figure 24-18.
A. Fetal MRI at 20 weeks depicting the normal lamination pattern of the brain during migration. Four of the 7 histologically known transient laminar compartments of the brain are seen from deep to superficial planes: VZ, ventricular zone (germinal matrix); IZ, intermediate zone; SP, subplate; CP, cortical plate. B. Corresponding ultrasonographic image obatined by transvaginal ultrasound at the same gestational age. The 7 histological laminar compartments seen during neuronal migration are: i. ventricular zone or germinal matrix; ii. periventricular fiber rich zone; iii. subventricular cellular zone; iv. intermediate zone (“fetal white matter”); v. subplate zone; vi. cortical plate; and vii. marginal zone.63,64
The following is a comprehensive list of imaging findings associated with congenital CMV infection62,65-69:
Gastrointestinal
Hyperechogenic bowel (4.5%-13%) (see Figure 24-8)
Ascites (8.7%)
Hepatomegaly (4.3%)
Hepatic calcifications (1.4%)
CNS
Microcephaly (14.5%)
Ventriculomegaly (4.5%-11.6%)
Increased echogenicity surrounding the lateral ventricles (Figure 24-19)
Periventricular calcifications (0.6%-17.4%)
Cortical gyral abnormalities (agyria, pachygyria, diffuse polymicrogyria, focal polymicrogyria)
Cerebellar hypoplasia
Periventricular pseudocysts (Figure 24-20)
Ventricular adhesions
Lenticulostriate vasculopathy (Figure 24-21)
Abnormal MRI findings (with increasing degree of severity)70:
T2-weighted hyperintense signal in the parieto-occipital periventricular white matter
T2-weighted hyperintense signal in the temporal periventricular white matter
Cysts and or septa in the temporal and/or occipital lobe
Migration disorders, cerebellar hypoplasia, microcephaly
Eyes
Chorioretinitis (echogenic lining to the vitreous body)
Cardiac
Pericardial effusion (7.2%)
Renal
Hyperechogenic kidneys (4.3%)
Placenta and Amniotic Fluid
Placentomegaly or placental calcification (4.3%)
Oligohydramnios
General
FGR (1.9%-13%)
Hydrops (0.6%)
Figure 24-21.
Head ultrasound of the same neonate as in Figure 24-19B showing hyperechogenic linear structures in the thalamus (arrows) consistent with mineralized lenticulostriate vessels (lenticulostriate vasculopathy).
Diagnosis: Maternal seroconversion is characterized by the presence of IgG and IgM antibodies with low IgG avidity. IgG avidity measures the strength of antibody biding to a target antigen. Low avidity index (<30%) is an accurate indicator of primary infection in the preceding 3 to 4 months. In contrast, high avidity excludes primary infection within the preceding 3 months.71 Once maternal seroconversion is diagnosed, fetal CMV infection can be confirmed by detection of CMV-DNA by polymerase chain reaction (PCR) in amniotic fluid samples obtained after 21 weeks and at least 6 weeks after the estimated onset of infection (because of fetal renal immaturity <21 weeks and delay in transplacental passage of the virus). A negative PCR for CMV by amniocentesis has a specificity of 97% to 100%.62,72
Differential Diagnosis:
Hyperechogenic fetal bowel: aneuploidies, particularly Down syndrome (~3%-5%, probably lower if no other anomalies present), CMV infection (~2%), cystic fibrosis (~2%). Hyperechogenic fetal bowel is an independent risk factor for FGR and intrauterine fetal demise after excluding the conditions listed previously.73-75 Fetal deglutition of blood products may also cause hyperechogenic fetal bowel.76
Brain abnormalities: other TORCH infections (particularly toxoplasmosis and Zika virus infection) and pseudo-TORCH syndromes (eg, Aicardi-Goutières).
Ascites and hydrops: all congenital infections and all causes of hydrops.
Prognosis: Approximately 50% to 70% of the 10% to 15% of infants who present with symptomatic cytomegalovirus infection at birth (hepatosplenomegaly, jaundice, petechiae, microcephaly, and lethargy) have abnormal neuroimaging findings such as intracranial calcifications, ventricular dilatation, cysts, and lenticulostriate vasculopathy. Approximately 50% may develop late neurologic sequelae, including cerebral palsy, seizures, developmental delay, cognitive impairment, vision loss, and sensorineural deafness. Mortality rate for symptomatic newborns is estimated as less than 5%. Of infants lacking symptoms at birth, approximately 10% may develop late sequelae such as sensorineural hearing loss.61,77 For cases prospectively followed after maternal seroconversion, the risk of neurologic disabilities or hearing loss is substantially higher when: (1) seroconversion occurs during the first trimester when compared to the second trimester (19.7% vs 5.6%, p = 0.01), and (2) when ultrasound and/or MRI imaging findings are present (25% for first trimester and 16% for second trimester seroconversions). The presence of temporal lesions on fetal MRI, such as cysts and septae, has been associated with 55% of sensorineural hearing loss and 25% of neurological impairment postnatally.57,72 In contrast, when both ultrasound and MRI imaging studies are normal, the frequency of sequelae decreases to 15.6% for first trimester and 2.0% for second trimester maternal seroconversions, respectively. Isolated FGR does not seem to be associated with increased risk of sequelae.
Definition: Congenital rubella syndrome is a malformation syndrome resulting from primary maternal infection and transplacental transmission of the rubella virus, an RNA togavirus. The congenital syndrome is characterized by deafness, cognitive impairment, congenital cataract, heart defects, and other structural anomalies that may be found with variable frequency and severity. Acute maternal rubella infection is associated with approximately 80% to 100% vertical transmission during the first trimester, approximately 60% between 13 and 17 weeks, and approximately 25% between 18 and 24 weeks. Vertical transmission rates rise to 95% during the third trimester.57,78,79
Ultrasonographic Abnormalities Associated with Congenital Rubella Syndrome: The most frequent sonographic findings are cardiac malformations (in particular, septal defects), eye defects (cataracts, microphthalmia, and retinopathy), microcephaly, hepatomegaly, splenomegaly, and FGR. Deafness and cognitive impairment are expected after birth.
A comprehensive literature review of the fetal and neonatal abnormalities seen in congenital rubella infection have been recently published by Yazigi et al.80 The authors analyzed case reports and series with a least one case of congenital rubella syndrome reported between 1991 and 2014, as well as the French National Reference Center for Rubella between 2011 and 2014. For cases diagnosed after birth, the literature search spanned from 1941 to 2014. The following prenatal abnormalities have been identified in the 32 reported cases with confirmed first trimester congenital infection:
Amniotic Fluid Abnormalities (40.6%, 13/32 cases)
Oligohydramnios (25%)
Polyhydramnios (12.5%)
FGR (34.3%)
Heart (34.3%, 11/32)
Ventricular septal defect (9.4%)
Atrial septal defect (6.3%)
Aortic stenosis (3.1%)
Total anomalous pulmonary venous return (3.1%)
Tricuspid regurgitation (3.1%)
Mitral valve abnormality (3.1%)
Cardiomegaly (3.1%)
Brain (12.5%, 7/32)
Dandy-Walker spectrum (6.3%)
Cerebellar vermis agenesis (3.1%)
Hydrocephalus (3.1%)
Ventriculomegaly (3.1%)
Anencephaly (3.1%)
Periventricular calcifications (3.1%)
Eye
Cataract (3.1%) (Figure 24-22)
Microphthalmia (3.1%)
Gastrointestinal (12.5%, 4/32)
Hepatosplenomegaly (6.3%)
Hyperechogenic bowel (3.1%)
Ascites (3.1%)
Musculoskeletal (6.3%)
Micrognathia (3.1%)
Short femur (3.1%)
Placenta and Umbilical Cord (18.8%, 6/32)
Placentomegaly (15.7%)
Single umbilical artery (3.1%)
For cases diagnosed after birth (n = 1109), cataracts were observed in 37%, chorioretinitis in 28%, microphthalmia in 6.5%, retinopathy in 4%, and glaucoma in 4%. The most frequent congenital heart defects were patent ductus arteriosus (39%), pulmonic stenosis (28%), septal defects (23%), tetralogy of Fallot (2%), aortic stenosis (1%), and fewer cases of coarctation of the aorta, transposition of the great arteries, Ebstein’s anomaly, and pulmonary artery coarctation. The most frequent brain abnormalities were microcephaly (78.5%), hydrocephalus (7.5%), cerebral calcification (4.7%), and a few cases of anencephaly, cerebellar vermis agenesis, and dysgenesis of the corpus callosum. Genitourinary disorders were seen in 40 of the 1109 cases, including vesicoureteral reflux, renal agenesis, hydronephrosis, hypospadias, ectopic testicles, inguinal hernia, and hydrocele. Other anomalies seen postnatally included hepatosplenomegaly, purpura, thrombocytopenia, long bone anomalies, and micrognathia. Hearing loss was present in 19% of the children born with congenital rubella syndrome.
Incidence: Not precisely known. Administration of rubella vaccine has significantly reduced the incidence of maternal infection, although reinfection after vaccination is possible.
Diagnosis: Serological diagnosis is based on the detection of IgG, IgM, and IgG avidity antibodies. IgM appears approximately 5 days after the onset of maternal rash and persists for approximately 6 weeks. Low IgG avidity confirms a more recent infection. The confirmation of fetal infection can be made by isolating rubella viral RNA from amniotic fluid samples by PCR, 6 to 8 weeks after maternal infection, to avoid false-negative results.
Differential Diagnosis: The differential diagnosis is broad, including all conditions manifesting in utero with congenital hepatomegaly and/or cataract. The list includes congenital infections (TORCH), fetal anemia, fetal liver tumors, chondrodysplasia punctata, Neu-Laxova syndrome, Smith-Lemli-Opitz syndrome, and Walker-Warburg syndrome.78,79
Prognosis: Intrauterine death may occur. Postnatal impact of the intrauterine infection varies from absence of any defect to all the anomalies mentioned previously with variable severity. Delayed manifestations include diabetes mellitus, hypertension, panencephalitis, and behavioral disorders.57
Prevention: Women found to be susceptible during pregnancy should be offered vaccination postpartum and before discharge from the hospital. These women should be counselled to avoid pregnancy for 28 days after vaccination.57 Breastfeeding is not a contraindication to receiving the rubella vaccine.
Definition: Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii. Toxoplasmosis is normally asymptomatic in immunocompetent individuals. Acute infection during pregnancy, if transmitted to the fetus, can cause severe illness, including cognitive impairment, blindness, and epilepsy.81,82
Incidence: Approximately 400 to 4000 cases of congenital toxoplasmosis are estimated to occur each year in the United States. Of the 750 deaths attributed to toxoplasmosis each year, 375 (50%) are believed to be caused by eating contaminated meat, making toxoplasmosis the third leading cause of food-borne deaths. The incidence of toxoplasmosis infection during pregnancy ranges from 1 to 4 per 10,000. Women infected with Toxoplasma gondii before conception, with rare exceptions, do not transmit the infection to their fetuses.83 Fetal infection is estimated to occur in 29% of the cases (95% CI 25%-33%), with transmission rates of 6% (95% CI 3%-9%), 40% (95% CI 33%-47%), and 72% (95% CI 60%-81%) for maternal infection occurring during the first, second, and third trimesters, respectively.84 Mothers with chronic infection may transmit the disease after reactivation, usually secondary to immunological dysfunction.83
Ultrasonographic Anomalies: Fetuses infected in the first trimester are much more likely to show clinical signs of infection.84 An inflammatory response to the parasite is thought to cause or contribute to the congenital abnormalities seen with the disease.85 The classic triad of signs suggestive of congenital toxoplasmosis includes chorioretinitis, hydrocephalus (Figure 24-23), and intracranial calcifications (Figure 24-24). Additional abnormalities included FGR, ascites, hepatosplenomegaly, microcephaly, and ventriculomegaly.
Diagnosis: Serological diagnosis is based on the detection of IgG, IgM, and IgG avidity antibodies. Toxoplasma gondii can be detected by amniocentesis using PCR.86
Differential Diagnosis: Other TORCH infections.
Prognosis: Approximately 75% of congenitally infected newborns are asymptomatic.
Common but nonspecific postnatal manifestations include anemia, thrombocytopenia, seizures, jaundice, and hepatosplenomegaly. Many children develop learning and visual disabilities later in life.57
Prevention: Toxoplasmosis infection can be prevented in large part by cooking meat to a safe temperature and peeling or thoroughly washing fruits and vegetables before eating; pregnant women should avoid changing cat litter or, if no one else is available to change the cat litter, should use gloves and then wash hands thoroughly.87
Definition: The varicella zoster virus (VZV) is a member of the herpesvirus family that causes varicella (chickenpox) and herpes zoster (shingles). Although approximately 90% of women of childbearing age are expected to be immune to the virus, primary maternal infection during pregnancy may result in significant fetal, neonatal, and maternal morbidity and mortaility.88 The risk of neonatal varicella is highest following maternal acute infection manifesting clinically between 5 days before and 2 days after delivery. In utero transmission is rare (<2%); however, it may occur in case of maternal infection between 8 and 20 weeks, leading to congenital varicella syndrome.89
Incidence: Estimated as 1 in 10,000 to 5 in 10,000 pregnancies in the United States.90,91 The rate of congenital transmission of VZV following primary maternal infection is thought to be less than 2%.89
Congenital Varicella Syndrome: Congenital varicella syndrome is an uncommon condition characterized by limb abnormalities (hypoplasia, atrophy, and paresis; 46%-72%); cutaneous scars in a dermatomal pattern (~70%); ocular abnormalities (44%-52%); optic nerve atrophy, cataracts, chorioretinitis, microphthalmia, and nystagmus (46%-72%); neurological abnormalities (microcephaly, hydrocephalus, seizures, Horner’s syndrome, and cognitive impairment (48%-62%); gastrointestinal anomalies (atretic or stenotic bowel, gastroesophageal reflux); genitourinary anomalies; cardiovascular anomalies; and FGR.88,92,93
Sonographic Signs of Fetal Disease: Include fetal demise, FGR, musculoskeletal abnormalities such as club feet and abnormal position of the hands (caused by both necrosis and denervation of the affected tissue; Figure 24-25), limitation of limb extension due to cicatrices formation and cutaneous scars (Figure 24-26), limb hypoplasia, chorioretinitis, congenital cataracts, microphthalmia, hydrops, polyhydramnios, hyperechogenic hepatic foci, cerebral anomalies such as ventriculomegaly or atrophy, and microcephaly, disseminated foci of necrosis and microcalcifications, encephalitis, and echogenic bowel in the second trimester.76,94,95
Figure 24-25.
Newborn with varicella infection. Fetal face at autopsy (26 weeks). Note the collapsed cranium, intact skin (very little maceration), disproportionate necrosis of the ocular globes, and flattened midface. (Reproduced with permission from Lebel RR, Fernandez BB, Gibson L. Varicella zoster; brain disruption. The Fetus. 1992;2(3):1-4.)
Diagnosis: Based on classic clinical manifestations. Culture, fluorescent antigen staining, or PCR testing for VZV DNA can be performed on fluid obtained from vesicles or scrapings from the lesions. Congenital infection may be detected by PCR analysis of amniotic fluid performed at least 1 month after maternal infection in order to avoid false-negatives.
Differential Diagnosis: Other viral infections, vascular accidents, and amniotic band syndrome.
Prognosis: Maternal infection during the second or third trimester (except if it occurs within 5 days before or 2 days after delivery) is usually associated with good prognosis. The severity of fetal involvement varies from dermatologic lesions to lethal disseminated disease. Limited scarring tends to have good prognosis. Fetal brain disruptions, or severe maternal varicella with development of lethal maternal pneumonia and/or encephalitis, have an extremely high risk for fetal demise.96 Neonatal varicella has a variable clinical course ranging from a mild illness resembling chickenpox to a disseminated infection complicated by pneumonia, hepatitis, and meningoencephalitis. Mortality rate for neonatal varicella ranges between 7% and 30%.88
Prevention: Serological testing and vaccination should be offered to women of child-bearing age, and they should be questioned about immunity to varicella before conception. Susceptible pregnant patients should be counseled to avoid contact with individuals who have chickenpox. If exposure occurs, varicella-zoster immune globulin (VZIG) should be administered within 96 hours in an attempt to prevent maternal infection. Susceptible neonates should also receive VZIG.89
Definition: The Zika virus is an arthropod-borne single-stranded RNA arbovirus of the family Flaviviridae transmitted by Aedes mosquitoes, which also transmit dengue fever and chikungunya. Clinical signs and symptoms occur in approximately 20% of infected individuals and include: (1) low-grade fever; (2) maculopapular pruritic rash; (3) nonpurulent conjunctivitis; and (4) arthralgia, most commonly involving the small joints of the hands and feet. Less common clinical manifestations include myalgia, asthenia, headache, retro-orbital pain, abdominal pain, nausea, diarrhea, mucus membranes ulcerations, thrombocytopenia and palatal petechiae. Symptoms are usually mild and resolve within 2 to 7 days, with immunity to reinfection acquired after the primary infection. However, neurotropism has been demonstrated both in vitro and in vivo, and the following neurologic complications have been seen in association with Zika virus infection: congenital microcephaly, Guillain-Barré syndrome, brain ischemia, myelitis, and meningoencephalitis.97-98
Transmission: Human transmission may occur following: (1) bite by an infected mosquito (primary mode of transmission), (2) maternal-fetal transmission, (3) sexual intercourse (including vaginal, anal, and oral), (4) blood transfusion, (5) organ transplantation, and (6) laboratory exposure. The incubation period following a mosquito bite is 2 to 14 days.97
Congenital Infection: Vertical transmission may occur by transplacental passage or at the time of delivery.98,99 The exact rate of vertical transmission is unknown at this time; however, 29% of women with a positive test for Zika virus infection attending a clinic in Brazil presented fetal abnormalities detectable by ultrasonography, including placental insufficiency, FGR, and CNS anomalies.100
Microcephaly
Ventriculomegaly
Global hypogyria
Hydranencephaly
Hydrops
FGR
Fetal loss
Ocular anomalies (common), including pigmentary and hemorrhagic retinopathy, chorioretinal atrophy, abnormal vascular development, and optic nerve abnormalities. Although theoretically more difficult to diagnose prenatally, Oliveira Melo et al101 reported fetal cataracts, intraocular calcifications, and microphthalmia in a case of congenital Zika virus infection.
Fetal brain anomalies appear to be associated with maternal infection occurring in the first or second trimester.99 Current recommendations by the Centers for Disease Control (CDC), Society for Maternal-Fetal Medicine (SMFM), and the American College of Obstetrics and Gynecology (ACOG) include obtaining a baseline ultrasound 3 to 4 weeks after symptoms or exposure, followed by serial ultrasonography every 3 to 4 weeks for the duration of pregnancy to search for microcephaly, intracranial calcifications, and/or other fetal anomalies. These recommendations apply to all women who have been exposed to Zika Virus, regardless of clinical symptoms or the results of laboratory tests.103 Fetal MRI, given its increased sensitivity to diagnose CNS anomalies compared to ultrasonography, should be considered as an adjunctive imaging modality in confirmed cases or cases with positive or suspected intracranial abnormalities by ultrasound.99
Postnatally acquired Zika virus infection appears to have a mild course, similar to that in adults.97
Diagnosis: Zika virus RNA has been detected in the following body fluids97:
Blood, usually within a few days to a week after infection (please note that Zika virus RNA has been detected in maternal blood as far as 10 weeks after symptom onset);
Urine, for at least 2 weeks after infection;
Semen, up to 62 days after the onset of fever.104
The diagnosis is suspected in case of rash and/or fever, plus arthralgia and/or arthritis and/or nonpurulent/hyperemic conjunctivitis in an individual with possible exposure to the virus (either residence in or travel to an area where mosquito-borne Zika virus infection has been reported or by unprotected sexual contact with a partner who meets these criteria). The diagnosis is considered probable in the presence of IgM antibody against Zika virus and relevant epidemiologic exposure. The diagnosis is confirmed by detection of viral RNA or antigen in serum or other body fluids, or by detection of Zika IgM antibody in combination with a positive Zika virus plaque-reduction neutralization test (PRNT).
Differential Diagnosis: Other congenital TORCH infections, particularly CMV and toxoplasmosis, and pseudo-TORCH syndromes (eg, Aicardi-Goutières—see the following section).
Prevention: At the time of this writing, no vaccine is available against the Zika virus. Personal protective measures are directed mainly at the prevention of mosquito bites (long sleeves and pants, repellent, staying indoors as feasible). Infected/exposed individuals should abstain from sexual activity or use barrier protection while active mosquito transmission persists. Men who have a pregnant partner should absent from unprotected sex for the duration of the pregnancy. Zika virus infection is currently not considered a deterrent to breastfeeding.98,99
In this chapter, we discuss the phenotypic features of several syndromes that do not fall into the category of skeletal dysplasias, as these have been already discussed in Chapter 23. Several of the most common genetic syndromes that may be recognized by prenatal ultrasonography are listed in alphabetical order.
Synonyms: Agenesis of corpus callosum with chorioretinal abnormality.
OMIM Number: 304050105
Inheritance: X-linked dominant with early embryonic lethality for hemizygous males. Therefore, the syndrome affects females or 47,XXY males.106 A single case of Aicardi syndrome affecting a 46,XY male has been previously reported.107 All cases represent new mutations.
Prevalence: Two in 100,000 to 15 in 100,000 girls.108
Etiology: No gene or candidate region in the X chromosome has been definitively identified.109
Phenotypic Features: The classic triad consists of callosal agenesis, infantile spasms (usually flexion spasms), and chorioretinal lacunae.110 Neuroimaging features include agenesis of the corpus callosum (95% of the cases, more often complete), intracranial cysts (95%), cerebellar abnormalities (95%), polymicrogyria and periventricular heterotopia (100%), and enlarged cisterna magna (55%).106,111 Costovertebral defects (hemivertebrae, scoliosis, absent or malformed ribs) are seen in approximately one-third of the cases.111 Facial anomalies occur in approximately 50%, including prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows. Microphthalmia has been reported in 25% of the cases. Cleft lip and palate may also occur.112 The incidence of tumors, particularly choroid plexus papillomas, has also been reported as increased.109
Diagnosis: The diagnosis is clinical. After birth, the pathognomonic feature is the chorioretinal lacunae identified by ophthalmologic examination, corroborated by brain MRI and skeletal findings.109
Prenatal Diagnosis: Prenatal diagnosis has been reported using ultrasound and fetal MRI.113-117 Aicardi syndrome should be suspected in any case of callosal dysgenesis affecting a female fetus. A diligent search for the aforementioned associated anomalies should be carried out. Fetal MRI best characterizes the migration abnormalities (polymicrogyria and periventricular heterotopia), which are a constant feature of Aicardi syndrome.115 Vertebral and rib abnormalities can be easily seen by three-dimensional ultrasonography. Figure 24-27 shows a case of Aicardi syndrome characterized by agenesis of the corpus callosum with interhemispheric cyst, microphthalmia, and multiple vertebral anomalies.117
Figure 24-27.
Three-dimensional US of the fetal brain and spine. A-C: Axial (A), coronal (B), and sagittal (C) reformats of the brain in a 20-week fetus show a pointed and splayed appearance of the anterior horns of the lateral ventricles, absence of the cavum septi pellucidi, elevated third ventricle (arrowhead), tear-drop lateral ventricles, and an interhemispheric cyst (*). Note that these findings are mainly appreciated on (A) and that the reconstructed sagittal view (C) does not show features that would confirm the diagnosis of corpus callosum dysgenesis because of the image degradation on the reformatted elevation plane. D: Three-dimensional rendered US image of the fetal spine shows scoliosis associated with multiple segmentation anomalies. E: Axial reformat of the fetal face at the level of the orbits shows right microphthalmia (arrowhead). The constellation of findings led to prenatal diagnosis of Aicardi syndrome. (Reproduced with permission from Gonçalves LF. Three-dimensional ultrasound of the fetus: how does it help? Pediatr Radiol. 2016 Feb;46(2):177-189.)
Differential Diagnosis: Isolated or other syndromic forms of agenesis of the corpus callosum (eg, fetal alcohol syndrome, midline craniofacial dysgenesis).118
Prognosis: Moderate to severe global developmental delay and intellectual disability, with seizures developing before the age of 3 months for many of the affected patients. Survival is variable with mean age of death of 8.3 years (median is estimated at 18.5 years).109
Synonyms: Familial infantile encephalopathy with intracranial calcification and chronic cerebrospinal fluid lymphocytosis, Cree encephalitis, pseudotoxoplasmosis syndrome.119
OMIM Number: 225750119
Inheritance: Autosomal recessive (most frequently). De novo autosomal dominant forms exist.119
Prevalence: Unknown.
Etiology: Caused by homozygous, heterozygous or compound mutation in the 3-prime repair exonuclease (TREX1) (22%), ribonuclease H2 subunit B (RNASEH2B) (38%), RNASEH2C (14%), RNASEH2A (6%), SAM domain- and HD domain-containing protein 1(SAMHD1) (12.5%), and adenosine deaminase RNA-specific (ADAR) (7.5%) genes.120
Phenotypic Features: Similar to in utero viral infection. Usually manifests after the first few weeks of life after a period of apparently normal development with a clinical picture similar to a congenital infection, characterized by encephalopathy, hepatosplenomegaly, elevated liver enzymes and thrombocytopenia. Some neonates may already show symptoms at birth. Imaging findings include calcifications in the basal ganglia (globus pallidus, putamen, caudate nucleus, and thalamus), dentate nucleus of the cerebellum, paraventricular white matter, as well as leukodystrophy-like changes best seen by MRI. White matter changes are commonly seen in the frontotemporal regions. Temporal cyst-like formations (similar to CMV infection) may also be seen.119,120
Diagnosis: Based on the phenotypic features simulating congenital infections described previously after exclusion of CMV, toxoplasmosis, rubella, herpes simplex, HIV infection (TORCH), as well as other known metabolic or neurodegenerative disorders. CSF fluid shows lymphocytosis, increased concentration of interferon-alpha and neopterin. Peripheral blood shows markedly increased expression of interferon-stimulated genes (so called “interferon signature”) which can be assessed by quantitative PCR analysis of RNA/cDNA. Sequential sequence analysis of the coding regions and splice sites of the six known genes associated with the Aicardi-Goutières phenotype can identify pathogenic variants in approximately 90% to 95% of patients with clinical and imaging findings suggestive of the syndrome.120-122
Prenatal Diagnosis: Approximately 80% of infants diagnosed with Aicardi-Goutières syndrome are normal in the neonatal period.120 However, prenatal diagnosis of Aicardi-Goutières syndrome has been reported based on suspicion of congenital infection following brain abnormalities diagnosed by fetal ultrasound and MRI (eg, microcephaly, cerebral calcifications, hyperechogenic periventricular white matter involving mainly the intermediate zone [see Figure 24-19 for the same finding in a fetus with CMV infection], temporal lobe cysts and delayed sulcation), failure to identify an infectious etiological agent, and a high concentration of interferon-alpha level in fetal blood.123-125
Differential Diagnosis: Aicardi-Goutières syndrome should be included in the differential diagnosis of any fetus presenting with ultrasonographic findings suggestive of a congenital TORCH infection not confirmed by serologic testing and/or PCR. Other conditions included in the differential diagnosis, particularly when the disease manifests postnatally are microcephaly-intracranial calcifications syndrome (pseudo-TORCH), band-like calcification with simplified gyration and polymicrogyria, demyelinating conditions that may have overlapping brain MRI findings (eg, Alexander disease, megalencephalic leukoencephalopathy with subcortical cysts [MLC], and leukoencephalopathy with vanishing white matter [VWM]), familial hemophagocytic lymphohistiocytosis, Cockayne syndrome, neonatal lupus erythematosus, Hoyeraal Hreidarsson syndrome, mitochondrial cytopathies, 3-hydroxyisobutyric aciduria, and cerebroretinal microangiopathy with calcifications and cysts.120
Prognosis: Severe intellectual and physical impairment for most affected individuals, with the majority exhibiting severe acquired microcephaly. Although hearing is almost always normal, vision may range from normal to cortical blindness.120
Synonyms: Alagille-Watson syndrome (AWS), cholestasis with peripheral pulmonary stenosis, arteriohepatic dysplasia (AHD), hepatic ductular hypoplasia.126
OMIM Number(s): 118450 (ALGS1), 610205 (ALGS2)124,126
Inheritance: Autosomal dominant (ALGS1 and ALGS2)126
Prevalence: 1 in 40,000 to 1 in 100,000 live births.126
Etiology: ALGS1 is caused by mutations in the JAG1 gene whereas ALGS2 is caused by mutations in the NOTCH2 gene.126
Phenotypic Features: Alagille syndrome is characterized by biliary hypoplasia in association with 5 main clinical abnormalities: cholestasis, congenital heart disease (pulmonic valve stenosis and peripheral arterial stenosis in ~75%), vertebral anomalies (butterfly vertebrae, hemivertebrae, and decreased interpedicular distance in the lumbar spine), ocular anomalies (posterior embryotoxon in ~95% and retinal pigmentary changes), and characteristic facies (broad forehead, pointed mandible, and nose with a bulbous tip). All affected individuals have hepatic, cardiac, and facial anomalies. Ocular anomalies are seen in approximately 80% of the patients and vertebral defects in approximately 60%. Renovascular anomalies, middle aortic syndrome, as well as cerebral vascular anomalies (moyamoya, basilar, carotid, and middle cerebral artery) have also been reported.127
Diagnosis: Based on clinical findings and confirmed by sequence analysis of JAG1 (which may detect pathogenic variants in over 89% of affected individuals), deletion/duplication analysis to detect exon and whole-gene deletions of 20p12 (7%), and sequence analysis of NOTCH 2 (1%-2% of affected individuals).128
Prenatal Diagnosis: There are only a handful of case reports documenting prenatal diagnosis of Alagille syndrome, since in the majority of cases the condition is mild and diagnosed in the first years of life.129 In families at risk, ultrasound would be more likely to identify the characteristic features, including facial (broad forehead, pointed mandible, and bulbous tip of the nose), cardiac (pulmonic stenosis [Figures 24-28 and 24-29]), skeletal (butterfly vertebrae, hemivertebrae, decrease in interpediculate distance in the lumbar spine, varying degrees of finger foreshortening), and FGR.130-134 In addition, in families with a known mutation of a first-degree relative, prenatal diagnosis using DNA obtained by chorionic villus sampling would be possible.131
Differential Diagnosis: Consider Alagille syndrome in the differential diagnosis of any fetus presenting with a combination of the featured cardiac (pulmonic stenosis) and skeletal anomalies (hemivertebrae, butterfly vertebrae), particularly if the gallbladder cannot be visualized.132
Prognosis: Liver disease may lead to cirrhosis and liver failure requiring transplantation in approximately 15% of affected individuals.135 Cerebral vascular accidents accounted for 34% of mortality in one large study.136 Posterior embryotoxon (a defect of the anterior eye chamber seen in 78%-89% of individuals with Alagille syndrome) does not affect visual acuity. Other causes of morbidity include morphological and functional renal abnormalities, pancreatic insufficiency, growth failure, mild delay of gross motor skills (~16%), craniosynostosis, delayed puberty, and a high-pitched voice.128
Synonyms: ADAM complex (amniotic deformities, adhesion, mutilation), amniotic band sequence, amniotic disruption complex, annular grooves, congenital amputation, congenital constricting bands, stricter bands, transverse terminal defects of limb, aberrant tissue bands, amniochorionic mesoblastic fibrous strings, amniotic bands.137
OMIM Number(s): 217100138
Inheritance: Sporadic.138
Prevalence: 7.7 per 10,000 live births, but it can be as high as 178 per 10,000 for spontaneous abortions. Male-to-female ratio is 1:1.139
Etiology: Not precisely known. Some theories suggest that teratogenic, multifactorial, and genetic factors cause a rupture of the amnion. Teratogenic effect of drugs such as methadone and lysergic acid diethylamide (LSD) are thought to play a role in some cases.139 Rupture of the amnion in early pregnancy leads to entrapment of fetal structures by “sticky” mesodermic bands that originate from the chorionic side of the amnion, followed by disruption. It has been suggested that the bands lead to a decreased blood flow in the constricted limb and subsequent natural amputation.140
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