Prenatal diagnosis is a rapidly evolving speciality. Screening for aneuploidy begins with non-sonographic features of background risk of maternal age and past and family history. It is possible to diagnose major structural defects in the foetus using second trimester scans. Serum biochemistry markers in the early second trimester were added to increase the detection rate of aneuploidy. However, as some of these abnormalities were amenable to detection earlier in the first trimester, newer modalities were introduced. Nuchal translucency (NT) measurement was one of the main advances with regard to first trimester screening. Additional markers such as the presence of nasal bone, tricuspid regurgitation, ductus venosus and megacystis; together with first trimester serum biochemistry, further enhanced the detection rate of chromosomal abnormalities.
Advances in research and technology have resulted in the availability of non-invasive prenatal testing from 10 weeks of gestation. This has facilitated the detection of the three major chromosomal aneuploidies at very early gestation. However, there are a wide range of genetic syndromes that are not confined to the main trisomies. There are specific markers on ultrasound that can be linked to specific syndromes. Hence, a structured and stepwise approach is needed to identify and reach a possible diagnosis. As anomalies are classified into malformations, deformations and disruptions, it is important to note that not all markers detected are due to genetic syndromes and not all genetic syndromes can be detected on ultrasound scan. In this chapter, we outline common structural markers and their association with main genetic syndromes.
Highlights
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Prenatal diagnosis is a rapidly evolving speciality.
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Nuchal translucency measurement was one of the main advances with regard to first trimester screening.
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There is now widespread availability of non-invasive prenatal testing.
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There are specific markers on ultrasound that can be linked to certain genetic syndromes.
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A structured and stepwise approach is needed to identify and reach a possible diagnosis.
Introduction
Ultrasound assessment of foetal abnormalities can be performed as early as the first trimester. A NT measurement of ≥3.5 mm should warrant an anatomical survey and appropriate genetic testing, depending on the risk profile . The second trimester anomaly scan is routinely performed to elucidate congenital malformations, which may suggest an aneuploidy or genetic disorder. There are some abnormalities that become apparent in late gestation such as cardiac anomalies, skeletal dysplasias and neuromigrational disorders of the brain as these lesions are progressive in nature. It is pertinent to take a structured approach to the various organ systems to not miss out relevant findings. We have approached this topic in an individual organ-based manner, dealing with important aspects of each system, followed by a brief outlook on ultrasound appearances of various genetic syndromes.
Ultrasound markers
Ultrasound markers are described according to various body systems, progressing craniocaudally. This is a deliberate approach to enable an organ- and problem-based strategy to reach a diagnosis.
Central nervous system markers
Central nervous system (CNS) markers represent the second most common serious congenital anomaly after the heart . Ultrasound is an effective modality to detect the anomaly but would typically need further imaging such as magnetic resonance imaging (MRI) to confirm the diagnosis to aid in management.
Ventriculomegaly
Normal size of the ventricles provides reassurance of normal brain development. Mild ventriculomegaly can sometimes be an early sign of abnormal or delayed brain maturation. It is the most common noted congenital CNS anomaly, with incidence of 0.3–1.5 per 1000 live births. Ventriculomegaly can be isolated or associated with other abnormalities ( Figure 1 ). The mechanism is due to the obstruction of the cerebrospinal fluid (CSF) pathway, CNS malformations, brain destruction or overproduction of CSF. Unilateral ventriculomegaly is typically physiological but in rare instances occurs in brain destruction caused by congenital infection or vascular or mechanical insult, while bilateral ventriculomegaly occurs in CNS malformations . Chromosomal abnormalities are found in 11% of the cases, mostly trisomy 21. The most common associated syndromes are Aicardi, Fraser, Meckel–Gruber, Joubert, X-linked hydrocephalus, Miller–Dieker, Neu–Laxova and Walker–Warburg syndromes .
Agenesis of corpus callosum
The incidence of agenesis of corpus callosum (ACC) is approximately 1.4 per 10,000 live births and may be described as either complete or partial. It is important to distinguish primary ACC ( Figure 2 ) from secondary destruction of initially normal appearance of the corpus callosum due to trauma, infection, haemorrhage or metabolic disease. The overall rate of chromosomal abnormality is 17.8%. The genetic syndromes associated are trisomies 8, 13, and 18, holoprosencephaly sequence, and Aicardi and Andermann syndromes. Recurrence risk is 1% if sporadic or chromosomal, 25% if autosomal recessive and 50% in boys if X-linked recessive .
Holoprosencephaly
This is a heterogeneous entity due to impaired midline cleavage of the forebrain. It is graded according to alobar, semilobar and lobar presentations. Associated facial malformations are cyclopia, cebocephaly and ethmocephaly. The incidence is 0.6 –1.9 per 1000 births. More than half are associated with trisomy 13. Familial holoprosencephaly can be inherited as autosomal dominant or recessive .
Lissencephaly
This is a rare cortical developmental disorder with reduced or absent brain gyri caused by abnormal neuronal migration. It has a female predilection, associated with deletion on chromosome 17p13, including LIS1, which is inherited in an X-linked dominant form. If it occurs de novo, the recurrence risk is low. However, if inherited from one parent with balanced translocation, recurrence is observed in 25% of the cases. Associated syndromes include Miller–Dieker, Walker–Warburg and Neu–Laxova .
Mega cisterna magna
Mega cisterna magna is characterised by a cystic malformation of the posterior fossa with intact vermis, enlarged cisterna magna and normal size of the fourth ventricle. Incidence is approximately 1% and occurs mainly in trisomy 18 when non-isolated. In the absence of other ultrasound findings, mega cisterna magna is unlikely to be clinically significant .
Dandy–Walker continuum
This continuum is characterised by cystic enlargement of the fourth ventricle with upward displacement of the tentorium, with partial or complete agenesis of the vermis ( Figure 3 ). Its incidence is 1 in 25,000–35,000 births. The risk of chromosomal anomalies is high, with up to 35% of the cases having trisomies 18 and 13. Common associated syndromes are Aicardi, Meckel–Gruber, Joubert, Walker–Warburg and Neu–laxova syndromes .
Cephalocele
Cephalocele is the protrusion of intracranial structures through a cranial bone defect. The herniated structures may consist of meninges only or meninges and cerebral tissue. The cephalocele can occur at the frontal, parietal, occipital and frontoethmoidal regions. Occipital is the most common site of occurrence in Europe, while frontal is the most common in Southeast Asia . There is a high incidence of chromosomal anomalies (14%–18%), especially trisomies 13 and 18. Other syndromes are Meckel–Gruber, frontonasal dysplasia and Walker–Warburg syndromes. Approximately 70%–80% of the cases will have associated CNS abnormalities that are detectable on scan, e.g. ACC, ventriculomegaly, holoprosencephaly, spina bifida and microcephaly .
Spina bifida
Most open spinal tube defects are amenable to detection by scan. The skin and muscles overlying the defect are absent, but the neural canal may be exposed or covered by a thin meningeal membrane. The defect consists of meninges (meningocele) or neural tissue and meninges (meningomyelocele). Seventy-five per cent of these defects occur in the lumbar region ( Figure 4 a and b). Chromosomal abnormalities occur in approximately 8%–16% of the cases; frequently associated abnormalities are trisomies 13 and 18; triploidy; and Meckel–Gruber, Walker–Warburg, Marfan and Ehlers-Danlos syndromes . Associated abnormalities are ventriculomegaly and hypoplasia of the posterior fossa structures, especially Arnold Chiari II malformation. Club foot may also occur.
Skull shape markers
Skull shape deformities are amenable to detection in early second trimester ultrasound study. The most common is the lemon-shaped skull that is associated with spina bifida ( Figure 5 ). This is postulated to be due to reduced intraspinal pressure resulting in reduced intracranial pressure and eventual downwards shift of the brain. The frontal bones respond by flattening or scalloping forward. Dolichocephaly is the second most common skull deformity and seen in malpresentations such as breech birth and in oligo- or anhydramnios. This is likely due to the compression effect of the uterine fundus and diminished amniotic fluid environment on to the foetal cranium. Aneuploidies such as trisomy 21 are associated with brachycephaly, while trisomy 18 is associated with strawberry-shaped head ( Figure 6 ). Other deformities occur as a result of premature closure of the foetal cranial sutures or craniosynostosis. Closure of the sagittal sutures causes scaphocephaly or dolicocephaly, coronal sutures brachycephaly and metopic sutures trigonocephaly . Apert, Crouzon and Pfeiffer syndromes present with brachycephaly. Thanatophoric dysplasia has cloverleaf-shaped skull ( Figure 7 ).
Facial markers
Cleft lip and palate
Cleft lip with or without cleft palate is relatively common, with an incidence of 1 in 700–1000 live births. Eighty per cent of cleft lip cases have an associated cleft palate. If the cleft is an isolated finding, then there is a very low risk of karyotypic abnormality. However, if it is a midline cleft, there is very frequently an associated karyotypic abnormality . The risk of chromosomal abnormality increases to approximately 28%–32% in the presence of other structural abnormalities . Frequently associated aneuploidies are trisomies 13 and 18.
Micrognathia
The mandible represents a common site for effects associated with genetic conditions. Agnathia is the most severe form of maldevelopment, with complete agenesis or hypoplasia of the mandible. Micrognathia and retrognathia involve arrested development of the mandible, with the former resulting in a small chin and the latter in a posteriorly positioned chin in relation to the maxilla ( Figure 8 ). As micrognathia is almost always an ominous sign, it is important to look for associated abnormalities . Chromosomal abnormalities such as trisomy 18; triploidy; and Cri-du-Chat, Cat Eye and Pallister–Killian syndromes are among those associated, as are various neuromuscular disorders. If there is concurrent cleft palate, Pierre Robin sequence maybe considered as a diagnosis .
Lung lesions and thoracic wall deformity
Congenital diaphragmatic hernia
This is a defect in the diaphragm resulting in herniation of the abdominal contents into the chest cavity ( Figure 9 ). Eighty per cent of the time it occurs on the left side, with 50%–60% being an isolated finding . The majority of congenital diaphragmatic hernias (80%) have no genetic association . Associated chromosomal anomalies are trisomies 18 and 13 and Fryns, Cornelia de Lange, Pallister–Killian and Marfan syndromes.
Congenital pulmonary airway malformation and bronchopulmonary sequestration
Congenital pulmonary airway malformation (CPAM) and bronchopulmonary sequestration (BPS) are collectively termed echogenic lung lesions and are the most common hyperechogenic lung lesions in the foetus ( Figure 10 ), with an incidence of 1 in 3000 live births. Although it is known that the main differentiating factor between the two entities is that BPS derives an anomalous systemic vascular supply, the presence of some hybrid lesions suggests that there might be an overlap and similar embryological origin for CPAM and BPS . It is usually not related to chromosomal aberration, especially if isolated. However, in the presence of a large lung lesion, cardiac defects (mainly conotruncal), congenital diaphragmatic hernia or tracheoesophageal fistula, genetic analysis is recommended .
Rib abnormalities
Increased number of ribs is rarely seen as a normal variant. It is usually associated with trisomy 21 and VACTERL (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal or radial anomalies, and limb defects) syndrome. Although reduced number of ribs can be a normal variant, it can be seen in one-third of Down syndrome cases and in cleidocranial dysplasia and camptomelic dysplasia . Short ribs do not extend beyond the anterior axillary line, resulting in a narrow chest ( Figure 11 a, b and c). Many syndromes and skeletal dysplasias are associated with rib abnormalities, and it is important to identify lethal skeletal dysplasia. The differential diagnoses are thanatophoric dysplasia, Jeune asphyxiating thoracic dysplasia, achondrogenesis, Ellis–van Creveld syndrome and short-rib polydactyly syndrome.
Cardiac defects
The incidence of congenital heart disease (CHD) is 2–6.5 per 1000 births. For foetal heart ultrasound screening, the abdominal situs views, 4-chamber view, outflow tracts views, 3-vessel view and 3-vessel trachea view are basic requirements. Some genetic syndromes are strongly associated with cardiac defects.
In total, 40%–50% of trisomy 21 foetuses have CHD, mainly atrioventricular septal defects (AVSD), ventricular septal defects (VSD) or atrial septal defects (ASD). A total of 90%–100% of trisomy 18 cases have one of the following: AVSD, VSD, patent ductus arteriosus (PDA), tetralogy of Fallot (TOF), double-outlet right ventricle (DORV) and transposition of great arteries (TGA). As for trisomy 13, 80% would be affected by ASD, VSD, PDA, hypoplastic left heart syndrome (HLHS), laterality defects or atrial isomerism. Interrupted aortic arch type B or truncus arteriosus occur in 75% of 22q11 deletion syndrome. Monosomy X foetuses would have coarctation of aorta (CoA), valvar aortic stenosis (AS), HLHS or bicuspid aortic valve in 25%–35% of the cases .
Cardiac tumours such as rhabdomyoma occur in almost all cases of tuberous sclerosis, while fibroma can be detected in Beckwith–Wiedemann syndrome or Gorlin syndrome.
Cardiomyopathies occur in single gene disorders such as Noonan syndrome, familial cardiomyopathy and metabolic abnormalities .
Abdominal wall defects
The most common abdominal wall defects are omphalocele, gastroschisis, bladder exstrophy and ectopia cordis. Omphalocele or exomphalos is due to the failure of physiologically herniated bowel to return to the abdominal cavity by 12 weeks of gestation. The latter three defects are due to abnormal closure of the body wall folds at the midline. Exomphalos may involve bowel loops or liver ( Figure 12 ). Spontaneous resolution of the hernia detected in the first trimester is seen in approximately 95% of euploid foetus but has not been observed in cases of herniated liver . Spontaneous rupture of the sac in utero mimicking gastroschisis can be differentiated by the umbilical cord insertion in a normal segment of the abdominal wall in gastroschisis. Approximately 60% of exomphalos cases have underlying chromosomal abnormality, the most frequent being trisomy 18. Other associated abnormalities include trisomy 13, Beckwith–Wiedemann syndrome, X-linked disorder (gene locus between Xq25-p26.1) and Pentalogy of Cantrell . Gastroschisis ( Figure 13 ) associated with chromosomal abnormalities is rare.
Renal abnormalities
Renal agenesis
The congenital absence of kidneys can be unilateral or bilateral. Bilateral renal agenesis occurs in 0.1–0.3 per 1000 births and is a lethal condition. The lumbar fossa appears empty and the adrenals elongated (lying down adrenal sign); moreover, lack of recognisable renal arteries on colour Doppler and oligo- or anhydramnios can clinch the diagnosis. Risk of genetic syndromes can be as high as 30%, including Fraser, Smith–Lemli–Opitz and Gorlin syndromes .
Multicystic dysplastic kidneys
The kidneys appear large and bright, with multiple thin-walled cysts occupying the renal parenchyma ( Figure 14 ). Bilateral involvement results in lung hypoplasia due to oligohydramnios and is lethal. The presence of other anomalies suggests genetic or syndromic link . Mosaic trisomies 7 and 8; triploidy; and VACTERL, Meckel–Gruber and Fraser syndromes are some of the associated syndromes.
Polycystic kidney disease
Polycystic kidney disease can be classified as infantile and adult types. Infantile (IPKD) is autosomal recessive and carries a 25% risk of recurrence. It is a single gene disorder caused by mutations in the PKHD1 gene on the short arm of chromosome 6. The age of onset varies and is divided into perinatal, neonatal, infantile and juvenile. Ultrasound features are enlarged echogenic kidneys with small cysts of 1–2 mm and normal renal pelvis with or without oligohydramnios. These findings may not be present till late in the second trimester. Adult polycystic kidneys is autosomal dominant and the most common type. The recurrence rate is 50%, and the genes involved are on 6p and 4q . The scan findings can be normal or similar to infantile type, except the bladder and amniotic fluid appear normal. Therefore, it is pertinent that the family history, renal ultrasound of the parents, karyotype and genetic referral be considered.
Bilateral renal pelvis dilatation
Renal pelvic dilatation (RPD) is caused by transient obstruction at the level of the pelvi-ureteric junction or vesico-ureteric junction, which mostly improves over time ( Figure 15 ). Mild RPD (7–10 mm), if associated with other anomalies or maternal risk factors, is a risk for trisomy 21 . In isolated RPD, or where prior aneuploidy screening has been undertaken, the risk for aneuploidy is low.
Megacystis
It is defined by the longitudinal diameter of the bladder measuring >7 mm in the first trimester ( Figure 16 ). In foetuses with megacystis, there is 25% risk of aneuploidy, mainly trisomies 13 and 18, and other associated malformations .
Limb abnormalities
The prevalence of limb abnormalities is 6 in 10,000 live births. They are more common in the upper limb and are mostly unilateral and right sided . Limb abnormalities are generally sporadic but may be due to single gene disorders or chromosomal abnormalities.
Clubfoot
Congenital talipes equinovarus (CTEV) or clubfoot is due to the subluxation of the talocalcaneonavicular joint, which usually occurs secondary to a neurological deficit, resulting in underdevelopment and weakness of the muscles on the lateral side of the calf, or from intrauterine crowding ( Figure 17 ). One-third of the cases have an isolated deformity. Nevertheless, it is important to look for CNS abnormalities and, if present, to rule out chromosomal abnormality .
Clinodactyly
This is commonly seen in the fifth finger. It is due to the fixed deviation of the digit due to hypoplasia of the mid phalanx. Eighteen per cent of the normal population have clinodactyly. However, it can be seen in 60% of Down syndrome cases .
Clenched hands
In clenched hands, the second and the fifth fingers overlap the third and fourth fingers with an adducted thumb. If this is constant throughout the scan, it can be associated with trisomy 18 or foetal akinesia sequence, and both have poor prognosis .
Clubhand
This abnormality can be either due to radial or ulnar deficiency, although ulnar is more common. It is often associated with other abnormalities and is mostly inherited. Examples are thrombocytopenia absent radius syndrome ( Figure 18 ), skeletal dysplasia and arthrogryposis.
Polydactyly
The presence of extra digits in the upper or lower extremities is polydactyly. The incidence of polydactyly is 1 in 700 pregnancies. If it occurs on the radial side, it is preaxial and on the ulnar side, it is postaxial. Postaxial polydactyly occurs more frequently and can be isolated or autosomal dominant in inheritance . Preaxial polydactyly ( Figure 19 ) can be isolated and related to mutation in the genes affecting the Sonic hedgehog (SHH) pathway.
