Chapter 20: FETAL SYNDROMES

Congenital anomalies are typically organized by organ system. This is an excellent organization in that similar disorders are grouped together. However, the multisystem syndromes do not fit neatly in the organ category organization. Usually the most striking finding or the most unusual finding is the one that leads to the inclusion in one or another group. Yet with the more precise information that one can now acquire it is time to organize syndromes as a separate subject.

In the following pages we will review several syndromes that should be familiar to sonographers and sonologists either because they are fairly characteristic or common, or because their recognition will impact the management of the pregnancy. The selection of the syndromes included is somewhat artificial, but all can be detected prenatally or will affect the pregnancy.

Clearly this review cannot be an exhaustive. The Birth Defects Encyclopedia contains about 2000 syndromes. The OMIM (Online Mendelian Inheritance in Man) was created in December 1995 as of today passed the 18,000-syndrome landmark.¹ Even for physicians dedicated to the subject this is an unmanageable amount of information to grasp. Rather than attempt to read it, it is more important to learn how to investigate unusual cases. That is what we try to show here in this chapter. What are the critical findings? Compare them with some images and try to find the specific diagnosis. If you need more information, go to the Web and search the OMIM.¹

Another aspect of the prenatal diagnosis of a syndrome that must be kept in mind is the fabulous progress of molecular genetics. Since the recognition of the disorders of the fibroblast growth factor receptor (FGFR), the classification of the skeletal dysplasia (see Achondroplasia below) has been completely reorganized. These sources should be consulted because it is likely that a genetic or biochemical test can be made for these disorders that will establish the diagnosis with certainty.

Finally, an important aspect of the prenatal diagnosis is assisting the parents in making management decisions. This is best done by providing them with contacts for support groups, and here again the Internet has revolutionized the communication between parents formerly isolated in small pockets all around the world. A good resource is NORD (National Organization for Rare Disorders), a Web site dedicated to helping people with rare diseases. In this Web site, there are more than 2000 patient organizations and other sources of help.²

Over the last 10 years the function of the sonologist has changed significantly from simply identifying some findings to being much more proactive in the making of the differential diagnosis and the establishment of management plans. Often the sonologist will be the first one to identify the disorder, and will be the one to establish contacts with the genetics department, dysmorphology specialists, and the various cardiologists and surgeons. The ability to provide clear directions to the parents is important, and in such a time of turmoil for the family, being the reference point to which they can come back is important. We routinely provide searches and references to our patients and attempt to identify support groups so they can get other parents' information, which is often more realistic that the information provided within the health care system.

Synonyms: Type IA is the Houston-Harris type; type IB is the Parenti-Fraccaro type; type II is the Langer-Saldino type and is also called chondrogenesis imperfecta, achondrogenesis-hypochondrogenesis type II, and was the type IB achondrogenesis. There are 2 less common types III and IV. Type II and IV were isolated by Whitley and Gorlin on femoral measurement. The validity of these 2 last types is questioned, with type III probably representing type II, and type IV probably representing hypochondrogenesis. These essentially radiological categories have been modified several times and are being replaced by genetic classification (see below) and thus are mainly of historical interest.^3,4

Definition: This group of lethal neonatal chondrodysplasias with short limb dysplasia contains several entities.⁵

Incidence: Rare with probably fewer than 100 cases reported.

Etiology: Autosomal recessive (IB) and dominant (II).

Diagnosis:

• Type I achondrogenesis is a severe chondrodystrophy characterized radiographically by poor ossification of the spine (Figure 20-1) and pelvis bones, which results in stillbirth or early death. The ultrasound manifestation includes very short limbs and short, thin ribs that may have fractures. The short ribs are responsible for lethal pulmonary hypoplasia and polyhydramnios from esophageal compression. The abnormal mineralization may or may not be manifested sonographically as bones that are either very echopenic, or in which both cortical sides can be imaged (Figure 20-2). Normally only the proximal cortical side is imaged and the distal side is shadowed by the proximal side.^{6, 7, 8, and 9}

• Type II also presents with the same findings but the mineralization deficit is less severe and the long bones less short (Figures 20-3 and 20-4).

Key Points: Extremely shortened limbs, normal to poorly ossified skull, poorly ossified spine and pelvis, and severe pulmonary hypoplasia.

Genetic Anomalies: Type IA: unknown. Type IB: mutation in the gene for diastrophic dysplasia sulfate transporter gene (DTDST) on the long arm (locus 32-33) of chromosome 5.^{10, 11, and 12} In these conditions, sulfate transport across the cell membrane is impaired, which results in insufficient sulfation of cartilage proteoglycans and thus an abnormally low sulfate content of cartilage. The diastrophic dysplasia sulfate transporter gene is recessively transmitted and is an allele of the diastrophic dysplasia gene. This is important because type II is an autosomal dominant mutation (and thus involves a new mutation for each case because the disease is lethal), and therefore has a much lower likelihood of recurrence than the 25% risk of type IB. The diagnosis can be made by chorionic villus sampling (CVS) in at-risk couples. Type II achondrogenesis is the Langer-Saldino type and is caused by a new dominant mutation in the type II collagen gene (COL2A1 gene) on chromosome 12.¹³ It is therefore more related to hypochondroplasia, spondyloepiphyseal dysplasia, and the Kniest-Stickler syndrome.¹⁴ These may be allelic variants with hypochondrogenesis related to achondrogenesis as hypochondroplasia is related to achondroplasia.

Differential Diagnosis: Osteogenesis imperfecta (type II and occasionally IIIc) and hypophosphatasia also present with demineralization, but the limb shortening is not usually as severe.

Prognosis: Lethal disorder due to pulmonary hypoplasia.⁴

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered in cases where continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling.

Synonyms: None.

Definition: Rhizomelic micromelia associated with frontal bossing and low nasal bridge.¹

Incidence: Common: 0.5 to 1.5 per 10,000.

Etiology: Defective cartilaginous molding of the bone precursor. It is an autosomal dominant disorder with complete penetrance. Aproximately 80% of cases are due to new mutations. There is a paternal age effect.^15,16

Diagnosis: Micromelia is the most obvious finding with limbs shorter than the 5th percentile after 20 weeks (Figure 20-5). The frontal bossing (Figure 20-6) and depressed nasal bridge can also be recognized. Occasionally more subtle anomalies such as trident hand (an increased interspace between the third and fourth digits) or lack of widening of the lumbar canal can also be identified (Figure 20-7).^{15, 16, and 17}

Key Points: Frontal bossing, megalencephaly, rhizomelic shortening, trident hand.

Genetic Anomalies: Achondroplasia is an autosomal dominant skeletal dysplasia caused by mutation in the fibroblast growth factor receptor-3 gene, which is located on the short arm of chromosome 4 at the 16.3 locus.^15,18 Bellus has demonstrated that the anomaly was due to a glycine to arginine substitution at codon 380.¹⁹ These papers are landmarks in our knowledge about skeletal dysplasias. Before these papers skeletal dysplasias were almost strictly classified by radiological criteria. These papers marked the beginning of an intense and successful search for gene mapping of skeletal dysplasia, many of which where subsequently recognized to result from alterations of the fibroblast growth factors (I-III).^15,16,18

Differential Diagnosis: The differential diagnosis is with multiple conditions such as the following:

• Thanatophoric dysplasia (narrower chest, platyspondyly, more severe micromelia, no trident hand, more severe polyhydramnios)

• Achondrogenesis (very poor mineralization—with lack of echogenicity of the bones—more severe micromelia, more severe polyhydramnios)

• Osteogenesis imperfecta type II (poor mineralization—often the proximal aspect of the brain is well seen through the "transparent" skull—variable micromelia, sometimes visible bone angulations from fractures, bell-shaped chest)

• Diastrophic dysplasias in which the micromelia is associated with joint contractures and in particular abnormal finger and toe positions

Prognosis: Children with achondroplasia have normal intellectual achievements. The major problems are orthopedic problems (narrow spinal canal and foramen magnum). There is a vibrant support group (The Little People of America) that is very active in resolving the problems of affected individuals.^20,21

Management: Although termination of pregnancy can be offered before viability, a majority of these children adapt well in society and lead productive lives.²¹

Synonyms: Agenesis of corpus callosum with chorioretinal abnormality.

Definition: Neurodegenerative disorder inducing cerebral atrophy, intracerebral calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections.²² It is associated with a developmental arrest, agenesis of the corpus callosum, chorioretinal lacunae, infantile spasm, and physical handicaps.

Incidence: The incidence rates per live births were 1 per 105,000.

Etiology: Autosomal recessive inheritance or X-linked dominant disorder that occurs de novo in females and is lethal in the hemizygous male.²² It is genetically heterogeneous with almost 50% of families mapping to the first known locus at 3p21 (AGS1). Another linkage to a second AGS locus (AGS2) at chromosome 13q14-21²² exists, as well as at least one further locus.²²

Pathogenesis: May result from a perturbation of interferon-α metabolism.²²

Sonographic Findings: Microphthalmia, choroid plexus cysts, choroid plexus papilloma, Dandy-Walker malformation, and dysgenesis of the corpus callosum can be recognized prenatally. Callossal agenesis is complete in 72% and partial in 28% of the cases. Infrequently this syndrome has been associated with cleft lip and palate.

Key Points:

• Cerebral anomalies (such as calcifications, cerebral cyst, and a high-riding third ventricle characteristic of agenesis of the corpus callosum) with ultrasound and/or cerebral magnetic resonance imaging (MRI)

• Female fetus

• Investigate the possibility of parental consanguinity

• Increase of interferon-α level in the fetal blood and cerebrospinal fluid

• Exclude an infectious etiology

• Assess the newborn shortly after birth²³

Differential Diagnosis: Dysgenesis of the corpus callosum.

Prognosis: Poor. The risk of death peaked at age 16. Those that survive are profoundly mentally retarded.^24,25

Recurrence Risk: It is sporadic in nature and affects only females.

Management: Termination of pregnancy can be offered before viability. Confirmation of diagnosis after birth is important for genetic counseling.

Synonyms: Alagille-Watson syndrome (AWS), cholestasis with peripheral pulmonary stenosis, arteriohepatic dysplasia (ADH), hepatic ductular hypoplasia, jagged 1 syndrome.

Definition: This is a disorder characterized by the association of biliary hypoplasia (manifesting as neonatal cholestasis), pulmonary stenosis, vertebral abnormalities, and characteristic facies, ocular, and cardiovascular anomaly.^26,27

Etiology: This is a multisystem autosomal dominant disorder with variable penetrance. The JAG1 gene on chromosome 20p12.1-p11.23 is currently the only gene known to be implicated in Alagille syndrome.²⁷

Sonographic Findings: Fetal sonography can reveal facial alteration as broad forehead, pointed mandible, and bulbous tip of the nose; cardiac and vascular anomalies such as enlarged main pulmonary artery (Figure 20-8), pulmonary valvular stenosis (Figure 20-9), and peripheral arterial stenosis; skeletal abnormalities such as abnormal vertebrae ("butterfly" vertebrae), decrease in interpediculate distance in the lumbar spine and in the fingers, and varying degrees of foreshortening; and progressive severe intrauterine growth retardation.^{26, 27, and 28}

Key Points: Broad forehead, triangular face, posterior embryotoxon and retinal pigmentary changes, peripheral pulmonary artery stenosis, butterfly vertebral arch.

Differential Diagnosis: Cystic kidney disorders associated with cholestatic liver disease and all the familial intrahepatic cholestasis: Zellweger syndrome, cholestasis-lymphedema syndrome, Byler disease, and cholestasis with defective formation of cholic acid. α-1-Antitrypsin deficiency may present as neonatal cholestasis with a paucity of intrahepatic bile ducts.

Associated Anomalies: It is frequently associated with growth failure, attributed to concurrent congenital anomalies, cholestasis, malabsorption and/or malnutrition, renal abnormalities, and also unilateral cystic kidney disease with or without renal dysplasia.³⁰

Prognosis: The vascular anomalies such as basilar artery aneurysms, internal carotid artery anomalies, middle cerebral artery aneurysm, aortic aneurysms and coarctations, internal carotid artery anomaly, and renal artery stenosis are the major cause of morbidity and mortality in the affected children. It accounts for 34% of mortality because of the elevated risk of intracranial bleeding.³¹ Absent deep tendon reflexes and poor school performance are frequent in affected infants, as are elevated transaminases and alkaline phosphatase; posterior embryotoxon in the eye examination; generalized xanthomas,³² including oral xanthomas; and marked hypodontia. The degree of biliary hypoplasia is variable.³³ Some patients may have severe cholestasis, progressing to cirrhosis and requiring liver transplantation. Alagille syndrome is one of the major forms of chronic liver disease in childhood with severe morbidity and a mortality of 10% to 20%.

Management: This disorder should be suspected in all infants with cholestasis. It is important to also evaluate newborns with a renal ultrasound examination.

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.³⁴

Definition: Amniotic band syndrome is a set of congenital malformations ranging from minor constriction rings and lymphedema of the digits to complex, bizarre multiple congenital anomalies that are attributed to amniotic bands that stick, entangle, and disrupt fetal parts.^35,36

Prevalence: The prevalence is 7.7 per 10,000 live births, but it can be as high as 178 per 10,000 for spontaneous abortions. The male-to-female ratio is 1:1.^36,37

Etiology: Not precisely known. Some theories have suggested that teratogenic, multifactorial, and genetic factors cause a rupture of the amnion. Teratogenic effect of drugs such as methadone and lysergic acid diethylamide may play an important role in many cases.

Pathogenesis: 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.³⁸

Diagnosis: The syndrome results in structural anomalies that vary from minor to lethal forms. Distribution of involvement is variable and may include craniofacial, thoracic, abdominal, and extremity structures. The most common findings are constriction rings around the digits, arms, and legs; swelling of the extremities distal to the point of constriction; amputation of digits, arms, and legs; asymmetric face; facial clefts; cephalocele; anencephaly; acrania; multiple joint contractures; pterygium; club feet, club hands, and pseudosyndactyly; microphthalmia, uveal coloboma, corneal metaplasia, and unilateral chorioretinal lacunae (Figures 20-10, 20-11, 20-12, and 20-13). A detailed view of the fetus' face, digits, and body with three-dimensional ultrasound exams may contribute to the diagnosis.³⁹

Key Points: Bizarre multiple congenital anomalies that are attributed to amniotic bands.

Differential Diagnosis: A uterine synechia or septation can simulate an amniotic band. The amniotic folds can be differentiated because they are not "sticking" to the body.

Prognosis: The more severe forms are lethal. Mild manifestations sometimes are found just at birth and do not have an impact on survival.

Recurrence Risk: No recurrence expected, except in rare sporadic familial cases, which have been reported in association with epidermolysis bullosum and Ehlers-Danlos syndrome.

Management: It depends on the extent of the anomalies. Termination of pregnancy can be offered for the severe forms. Recently, endoscopic release has been reported and may prove beneficial in releasing the constriction band in threatened limb amputation. Endoscopic fetal therapy with lysis of the constriction ring in utero is an option, but intervention is probably not always warranted. Spontaneous lysis of an amniotic band attached to a fetal elbow has been shown.^{38, 39, 40, and 41}

Synonyms: Trapezoidocephaly-synostosis syndrome, multisynostotic osteodysgenesis with long bone fractures, osteodysgenesis multisynostotic with fractures.

Definition: The Antley-Bixler syndrome is a rare disorder that includes musculoskeletal, craniofacial, and urogenital anomalies.^{42, 43}

Prevalence: Rare. Fewer than 50 to 60 cases have been reported since it was described by Antley and Bixler in 1975.⁴⁴

Etiology: Autosomal recessive.

Pathogenesis: Several pathogenesis have been suggested⁴²:

• A mutation of the fibroblast growth factor (FGF) and fibroblast growth factor receptors FGFR1-3.

• A few cases have been possibly linked to congenital adrenal hyperplasia associated with pregnancy luteoma.

• Toxicity of the antifungal agent fluconazole during early pregnancy.

Sonographic Findings: The most common skeletal anomalies are radiohumeral synostosis, craniosynostosis (coronal and labdoidal), multiple joint contractures, arachnodactyly, femoral and ulnar bowing, camptodactyly, synostoses of carpal and tarsal bones, club foot, and vertebral body anomalies. The facial anomalies include midface hypoplasia often with choanal stenosis or atresia, proptosis, a "pear-shaped nose," and dysplasic ears (Figures 20-14 and 20-15).

Key Points: Midfacial hypoplasia, craniosynostosis, and the radiohumeral synostosis.

Differential Diagnosis: Congenital adrenal hyperplasia, Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Apert syndrome, osteogenesis imperfecta, thanatophoric dysplasia.

Associated Anomalies: Urogenital anomalies include hypoplastic uterus, ectopic kidneys, duplication of the kidneys, renal hypoplasia, horseshoe kidney, hydronephrosis, and ureteral obstruction. Congenital heart defects include transposition of the great vessels, ventricular septal defect, patent foramen ovale, atrial septal defect, and hypoplastic right atrium. Gastrointestinal malformations are rare.⁴³

Prognosis: Early death is common, often due to respiratory complications. One-third of affected children are alive, and some have had quite satisfactory development. Cognitive functioning ranges from moderate mental retardation to normal intelligence. Elbow ankylosis, resulting most commonly from radiohumeral synostosis, causes fixation of the elbow in a flexed position.^42,44,45

Management: Early survival depends in the release of the upper airway obstruction. Longer-term survival depends on the severity of associated malformations. Cranial vault remodeling to relieve craniosynostosis is important for the prevention of mental impairment.⁴⁴

Synonyms: Acrocephalosyndactyly type 1, Apert-Crouzon disease.

Definition: Apert syndrome is a rare developmental deformity characterized by craniofacial and limb malformations accompanied by variable degrees of mental retardation in 50% of the cases. In 1894 Wheaton did the first description, and subsequently in 1906 Apert summarized the disorder, presenting 9 cases.⁴⁶

Incidence: The occurrence of Apert syndrome is estimated at 0.0625 to 0.1 per 10,000 live births. The male-to-female ratio is 1:1.^46,47

Etiology: Most cases are sporadic, and it also follows autosomal disorder with dominant inheritance. Association with advanced paternal age has been described.^48,49

Sonographic Findings: It is a congenital disorder characterized primarily by craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet with a tendency to fusion of bony structures. Brachycephaly and acrocephaly, high forehead, flat occiput, flat face, and hypertelorism can be seen. Other ultrasound findings that are present are agenesis of the corpus callosum, mild ventriculomegaly, and fusion of the cervical vertebrae at the level of C5-C6. In the extremities we can find syndactyly "mitten hand" (osseous and cutaneous) usually involving the second, third, and fourth fingers. There is a broad thumb and hallux. Polyhydramnios (caused by decreased fetal swallowing) and variable degrees of mental retardation have also been found, and their occurrence and intensity seem to be correlated to the severity of central nervous system anomalies.^{46,50, 51, and 52}

Diagnosis: The most typical findings in Apert syndrome are craniosynostosis (by synostosis of the coronal sutures), bilateral symmetric syndactyly of the limbs (mitten-like hands and feet; Figures 20-16, and 20-17), and midfacial hypoplasia. Additional features, which appear with variable frequency, include the following:

• Skeletal anomalies: short and broad head, high cranial vault (acrocephaly), prominent forehead (frontal bossing; Figures 20-18, and 20-19), hypertelorism and proptosis, depressed nasal bridge with parrot-beaked nose, hypoplastic maxilla, prognathism

• Cardiac anomalies: pulmonic stenosis, overriding aorta, ventricular septal defects

• Central nervous system anomalies: hydrocephaly, malformation of the corpus callosum and limbic structures, gyral abnormalities, hypoplasia of the white matter, and heterotopic gray matter.⁵³

Key Points: Craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet (Figures 20-20 and 20-21).

Genetic Anomalies: The most common mutations associated with Apert syndrome are substitution S252W and P253R, which occur in the fibroblast growth factor receptor 2 genes. Genetic molecular studies are recommended for the fetus (by chorionic villi sampling or amniocentesis) and for parents when Apert syndrome is suspected, in particular in those families affected for the first time. The development of molecular techniques for the definitive diagnosis of this condition in prenatal cases was made possible by the finding of the FGFR2 gene mutations.^54,55

Differential Diagnosis: Genetic syndromes also characterized by the presence of craniosynostosis such as Crouzon, Pfeiffer, Carpenter, and Saethre-Chotzen may be included in the differential diagnosis. Molecular genetic studies can exclude these disorders.⁵⁶

Recurrence Risk: When resulting from a fresh mutation, the recurrence risk is improbable. If one of the parents carries the disorder, the recurrence risk is 50%.

Management: If diagnosed before viability, termination of pregnancy can be offered. Severe functional and mental disability is frequently present. Decompression cranial surgery is frequently performed.

Synonym: The nickname "banana sign" has been applied to the deformity of the cerebellum.

Definition: The Arnold-Chiari malformation was first identified in 1883 by Cleland. The term "Chiari malformation" is used in recognition of the work of Hans van Chiari, a Viennese pathologist who practiced medicine in Vienna, Prague, and Strasbourg in the late 19th century.⁵⁷ Chiari, in 1891, described a young woman with elongation of the cerebellar tonsils and medulla into the spinal cord. It is characterized by the prolapse of hindbrain structures below the level of the foramen magnum (Figure 20-22). It can be associated with skeletal abnormalities and neurological dysfunction.⁵⁷ There are 4 types of Arnold-Chiari malformation⁵⁸:

• Type I: just a lip of cerebellum is downwardly displaced with the tonsils, but the fourth ventricle remains in the posterior fossa. It is usually not associated with hydrocephalus. This is mainly an incidental computed tomography (CT) discovery.

• Type II: usually involved in prenatal cases and is a congenital deformity characterized by displacement of cerebellar tonsils, cerebellar inferior vermis, and portions of the cerebellar hemispheres through the foramen magnum into the spinal canal. In 95% percent of the cases it is accompanied by hydrocephalus and myelomeningocele (Figures 20-22, 20-23, 20-24, and 20-25).

• Type III: characterized by caudal displacement of the medulla and herniation of part of the cerebellum in an occipital or cervical meningocele. Part of the hindbrain may also be herniated. Hydrocephalus is associated in 50% of cases.

• Type IV: refers to hypoplasia or aplasia of the cerebellar hemispheres and alterations of the pons with marked dilatation of the fourth ventricle, cisterna magna, and basal cisterns.

Incidence: Commonly associated with spina bifida; rare outside of spina bifida. There is a higher preponderance of Arnold-Chiari type I in females versus males (3:2).^57,58

Etiology: Autosomal dominant for some forms.

Pathogenesis: An understanding of the pathogenesis of Chiari malformations must be aimed at examining the pathophysiology at the craniocervical junction. A defect during embryonic development causes underdevelopment of the posterior fossa and blockage of the normal outlets of the fourth ventricle (foramina of Magendie and Luschka), resulting in increased pressure and causing the cerebellar tonsils to descend into the foramen magnum. Accumulated cerebrospinal fluid (CSF) is then forced caudally through the entrance into the central canal of the spinal cord at the caudal-most portion of the fourth ventricle, because of a pressure gradient.

Diagnosis: The displacement of the cerebellum deforms the lateral lobes (which lose their "round shape") and the vermian notch to appear more continuous (thus the banana sign) (Figure 20-26). The diagnosis has been made as early as the first trimester. D'Addario et al have evaluated the angle between the clivus and supra occiput and found it to be a useful parameter to diagnose Chiari II malformation.^59,60

Genetic Anomalies: Unknown.

Key Points: Lemon shape of fetal skull, dilated lateral ventricles, open neural tube defect in lumbar region, "banana" sign.

Differential Diagnosis: Nonobstructive hydrocephalus, such as dysgenesis of the corpus callosum, aqueductal stenosis, borderline ventriculomegaly, Dandy-Walker malformation, porencephaly, schizencephaly.⁶¹

Associated Anomalies: Hydrocephaly from obstruction of the foramen of Magendie, syringomyelia, diastematomyelia.

Prognosis: Poor, due to the central nervous system anomalies.

Management: Termination of pregnancy can be offered before viability. For those affected by spina bifida, an experimental intrauterine repair done between 23 and 30 weeks' gestation has been proposed in a few centers in the United States. Confirmation of diagnosis after birth is important for genetic counseling and to perform the postanal repair of the anomalies, including the myelomeningocele (Figures 20-27 and 20-28).^60,62

Synonyms: Congenital contractures, fetal akinesia sequence, Pena-Shokeir syndrome.

Definition: This heterogeneous set of conditions shares limitation of movements and joint ankylosis as main findings.⁶³

Incidence: 1 to 3 per 10,000.⁶³

Etiology: Isolated cases. The incidence is higher than expected in identical twins.

Pathogenesis: Arthrogryposis results from 4 major causes^{63, 64}

• Abnormality of muscle tissues, like muscular dystrophy, congenital myopathies, and congenital absence of muscles

• Abnormal nerve functions or innervations that include central nervous malformations, a congenital neuropathy

• Abnormality of connective tissue that interferes with the normal development of tendons, cartilage, and joint tissue

• Mechanical limitation to movement in utero

Diagnosis: Although the anomalies are obvious when recognized, in particular when the baby is born, the prenatal diagnosis may be challenging when fluid is decreased, and the abnormal limb position (Figures 20-29, 20-30, and 20-31) appears attributable to the oligohydramnios. Some forms are associated with polyhydramnios and then the abnormal limb position (knocked knee), genu recurvatum, and club feet and hand make the diagnosis easy. Polyhydramnios is often a manifestation of decreased swallowing, which may be part of the same pathogenesis as the arthrogryposis itself (muscular or neuronal deficit). An increase in nuchal lucency can also be seen in the first trimester.⁶⁵ In the second trimester, the main finding is a decreased movement in utero.

Genetic Anomalies: Several anomalies have been linked to the following sites: 5q35, 9p21-q21, and 11p15.5.⁶⁴

Key Points: The severity of the joint contractures, malposition of the limbs, polyhydramnios.

Differential Diagnosis: Trisomy 18, renal agenesis, and myotonic dystrophy may present with some similar findings.

Associated Anomalies: Because of the heterogeneity of the conditions numerous associated anomalies have been described including scoliosis, central nervous system (CNS) anomalies, and even seizures.

Prognosis: The prognosis will depend on associated anomalies (respiratory limitations, scoliosis).

Management: Termination of pregnancy can be offered before viability, especially if the fetus appears to have a strong likelihood of respiratory insufficiency at birth. Standard prenatal care is not altered when continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling.

Synonyms: Jeune syndrome, thoracic–pelvic–phalangeal dystrophy.

Definition: Autosomal recessive chondrodysplasia characterized by a small thorax, varying degrees of rhizomelic brachymelia, polydactyly, pelvic abnormalities, and renal anomalies.^{66, 67, 68, 69, and 70}

Incidence: 0.14 per 10,000.⁷¹

Pathogenesis: Autosomal recessive disorder.

Diagnosis: The most striking ultrasound finding is a very narrow chest (Figure 20-32) with short limbs. The limbs, however, are not as short as those of other lethal conditions such as thanatophoric dysplasia, achondrogenesis, osteogenesis imperfecta (OI) type 2, and the short rib–polydactyly syndromes. The increased iliac wing angle, reported in the radiographic literature, has not been reported yet with ultrasound. Polydactyly is an inconstant feature of Jeune syndrome. The main visceral abnormality is cystic dysplastic renal disease. Proteinuria and direct hyperbilirubinemia can be detected.

Genetic Anomalies: Defect is probably located on 15q13.⁷¹

Key Points: Long, narrow thorax; short limbs (rhizomelic type); renal dysplasia.

Differential Diagnosis: Ellis-van Creveld syndrome (short arm of chromosome 4) that presents mainly with cardiac anomalies instead of renal anomalies.

Prognosis: In spite of the dreadful name, not all newborns are asphyxiated, and with corrective surgery of the chest some patients have had a fairly normal outcome. The death in infancy is due to pulmonary insufficiency. Survivors may develop renal insufficiency and hepatic dysfunction.⁷²

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling.^66,67,72

Synonyms: Ivemark syndrome, heterotaxia, cardiosplenic syndrome.

Definition: This set of syndromes is due to errors of lateralization of the primary field. It results (with simplifications) in either a fetus with predominant right-sidedness and an isomeric left side (asplenia: a fetus whose left side is a mirror image of its right side) or left-sidedness and an isomeric right side (polysplenia: a fetus whose right side is a mirror image of its left side). These fetuses are usually recognized because of the associated cardiac anomalies (Figure 20-33).^73,74

Incidence: The incidence is very low, estimated at 1 in 10,000 to 20,000 live births.¹

Etiology: Autosomal recessive inheritance with male preponderance the most of the cases, but there are reports of autosomal dominant and X-linked inheritance too. Heterotaxy syndromes could also occur in chromosomal translocation or deletion in sporadic cases.

Diagnosis: The diagnosis is usually made by the recognition of the cardiac anomalies, in particular, the presence of atrioventricular septal defect, mesocardia (the axis of the interventricular septum being almost anteroposterior) with an endocardial cushion defect, an intrahepatic segment of the umbilical vein that is also oriented anteroposteriorly, and an odd-looking stomach. The abnormal lobation of the lungs is difficult to recognize, and the only instance when it can be done is when a sliver of pleural fluid is infiltrated between the lobes. Another typical finding is the interruption of the inferior vena cava with azygos continuation. The typical findings include an inferior vena cava (IVC) that is posterior in the upper abdomen (instead of curving anteriorly to enter the right atrium) and the abrupt decrease in size of the inferior vena cava near the diaphragm. An enlarged azygos arch joining the superior vena cava can also be recognized. The presence of a persistent left superior vena cava is rarely recognized, not because it is a challenging finding, but because it is not sought. Color and pulsed Doppler of the splenic artery has been suggested as an aid in the prenatal diagnosis of the syndrome. Other findings include agenesis of the corpus callosum with pachygyria and hydrocephalus.^{75, 76, and 77}

Genetic Anomalies: Although it was thought that the syndrome resulted from a possible mutation in the gene encoding connexin 43 (CX43), this was not supported by further studies.

Key Points: Polysplenia, complex cardiac malformations, malposition and maldevelopment of the abdominal organs.⁷⁷

Differential Diagnosis: The cardiac anomalies (in particular, endocardial cushion defect) without the syndrome and trisomy 18 may be included in the differential diagnosis.

Associated Anomalies:

Prognosis: Asplenia tends to be a more severe disease because of the cyanotic heart lesions and the superimposed infections. Although morbidity and mortality in the neonatal period are determined mainly by the cardinal cardiac defects, the visceral anomalies may strongly affect the long-term outcome of these patients.⁷⁷

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling. The treatment of the infant will be dictated by the cardiac defects.

Synonym: Exomphalos-macroglossia-gigantism syndrome.

Definition: Beckwith-Wiedemann syndrome is a disorder first described by Beckwith in 1963 and Wiedemann in 1964. It is characterized by the classic triad of macrosomia, omphalocele, and macroglossia.^78,79

Incidence: The incidence has been estimated to be 0.72 per 10,000 births, and more than 500 cases are reported in the literature.^78,79

Pathogenesis: Beckwith-Wiedemann syndrome is a part of the generalized visceromegaly probably secondary to fetal hyperinsulinism mediated by elevated human placental lactogen (hPL) levels.

Diagnosis: The detection of macrosomia, omphalocele (Figures 20-34 and 20-35), and macroglossia (Figure 20-36) associated with normal karyotype makes the diagnosis of Beckwith-Wiedemann syndrome. A diagnostic schema was proposed including 2 major criteria (abdominal wall defect, macroglossia, macrosomia) or 1 major plus 2 minor criteria (nephromegaly/dysgenesis, adrenal cytomegaly, aneuploidy/ abnormal loci, polyhydramnios) to establish a guideline.⁸⁰ Other features occurring in variable incidences include nephromegaly, hepatomegaly, small-groove earlobe and creases (Figures 20-37 and 20-38), diaphragmatic hernia, hemihypertrophy, exophthalmos, enlargement of the testis, enlarged kidneys, adrenocortical macrocyst, single umbilical artery, and cardiac defects. Embryonal tumors such as Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma can be also be detected.^{81, 82, and 83}

Genetic Anomalies: Beckwith-Wiedemann syndrome is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial. Structural anomalies of the chromosome including paternal isodisomy of the 11p15.5 region, isodisomy of 11q, and uniparental disomy may be detected by cytogenetic studies. Thus, aside from a conventional cytogenetic analysis, some authors recommend utilizing polymerase chain reaction (PCR) of polymorphic loci on 11p15.5 to detect possible maternal deletions or inversions, paternal duplications, and uniparental disomy. These may account for 25% of cases of Beckwith-Wiedemann syndrome.

Key Points: The most typical findings include macrosomia, macroglossia, polyhydramnios, visceromegaly, and embryonal tumors.⁸⁴

Differential Diagnosis: Down syndrome must be excluded by chromosomal analysis due to the occurrence of macroglossia in both conditions. Diabetic fetopathy is another cause of macrosomia, and is thus a differential diagnosis. Zellweger syndrome can also combine liver and kidney enlargement and may be diagnosed prenatally by measuring fatty acid concentration and activity of marker enzymes. Perlman syndrome, a rare entity characterized by hypotonia, facial dysmorphism, gigantism, and visceromegaly including nephromegaly, is another differential diagnosis.

Complications: Pancreatic cell hyperplasia may affect 30% to 50% of patients, causing hyperinsulinism and neonatal hypoglycemia on the second or third day of life. Untreated neonatal hypoglycemia is an important complication and may result in further cerebral dysfunction, such as seizures, mild to moderate mental retardation, or neonatal death in more severe cases. Macroglossia can cause variable complications ranging from feeding difficulties to airway obstruction and death. Long-term complications include high risk for abdominal tumors, in particular Wilms tumor (3.7% incidence); hepatoblastoma; neuroblastoma; and adrenal cortical carcinoma. The risk of developing malignant tumors increases when hemihypertrophy is present. Beckwith-Wiedemann syndrome is a favorable biological marker for survival in children who have intraabdominal tumors.^{85, 86, 87, and 88}

Prognosis: Neonatal mortality rate is approximately 21%, due mainly to congestive heart failure. Among those who survive, the prognosis is generally favorable, depending on the severity of the associated anomalies and long-term complications. Preterm delivery is a complication due to the polyhydramnios and gestational hypertension.

Management: When diagnosed before viability, termination can be offered. After viability, sonographic evaluation of fetal growth is suggested. When macrosomia is suspected, cesarean section may be offered due to the risk of shoulder dystocia. An early diagnosis of Beckwith-Wiedemann syndrome is important for counseling the parents concerning potential risk for developing embryonic tumors, selection of the mode of delivery due to potential adrenal cysts that might bleed during labor, and prevention of neonatal hypoglycemia. A serum α-fetoprotein screening, usually in combination with abdominal ultrasound, can lead to early detection of hepatoblastoma. Delivery in a tertiary center is recommended for adjustment of airway sufficiency in the presence of macroglossia, early abdominal wall defect repair, and treatment of the hypoglycemia. Sonographic screening for abdominal tumors is recommended during the first 6 years of life. Aggressive follow-up is warranted in cases of association with hemihypertrophy and/or nephromegaly with or without evidence of a Wilms tumor precursor.^78,9,89

Synonyms: Campomelic dysplasia, campomelic syndrome, campomelic dwarfism, congenital bowing of the limbs.

Definition: Campomelic dysplasia is a congenital disorder characterized by development of abnormal curvature of the long bones, particularly in the lower extremities, such as the femur and tibia. Some authors have classified the disease into 2 varieties: "long limbed" and "short limbed," depending on the type of limbs involved in the pathological process.^90,91

Incidence: The disorder affects 0.05 per 10,000 live births. Sex reversal occurs in some genotypic males that lack the H-Y antigen. Phenotypic sex ratio is approximately M1:F2.3, karyotypic sex ratio is approximately M2:F1.^92,93

Recurrence Risk: Depends on the etiology. If transmitted by autosomal recessive pattern it has a 25% recurrence risk. When transmitted by autosomal dominant pattern, it has 50% recurrence risk, but in fact most are new mutations.

Diagnosis: The most characteristic sign of campomelic dysplasia is the marked anterior bowing of the long bones, particularly of femur (Figure 20-39) and tibia. Severe angulation may mimic fractures and typically occurs at the junction of the upper third and lower third of both femora. Other sonographic features that are commonly present include growth restriction; bell-shaped narrow chest; 11 pairs of ribs; hypoplasia of the midthoracic vertebral bodies, fibula, and scapula; scoliosis; shortness of the limbs; talipes equinovarus; tracheobronchomalacia; flat and small face; high forehead with prominent occiput; low nasal bridge; micrognathia; cleft of the soft palate; hypertelorism; low-set and malformed ears; hydrocephalus; and ambiguous genitalia (Figures 20-40, 20-41, and 20-42).^{94, 95, and 96}

Genetic Anomaly: It is an autosomal dominant disorder. A mutation in SOX9, a sex-determining region of Y (SRY) related gene, located at 17q24 seems to be associated with the occurrence of both campomelic dysplasia and sex reversal.

Pathogenesis: Although many theories have been proposed to explain the development of the anomalies present in this syndrome (in particular the bowing of the bones), the precise mechanism is not known.^{95, 96, and 97} Some of the theories are:

1. Mechanical stress due to faulty fetal position within the uterus

2. Primary muscle imbalance and shortening, particularly of the calf muscles causing secondary bending of the tibia

3. Intrauterine fracture with subsequent healing

4. Abnormal vascular and cellular elements of perichondrium

5. Developmental disturbance in the cartilaginous phase of bone formation

Associated Anomalies: Polyhydramnios and anomalies from the central nervous, cardiac, and renal systems have been described prenatally. After birth, hearing loss may occur.

Key Points: Bilateral bowing of the long bones of the legs, talipes equinovarus, hypoplastic pelvis and scapulas, and macrocephaly.⁹⁸

Differential Diagnosis: Osteogenesis imperfecta types I and II, hypophosphatasia, unclassifiable varieties of congenital bowing of the long bones, thanatophoric dysplasia, mesomelic dysplasia (Reinhart variety), Roberts syndrome, and diastrophic dysplasia.

Prognosis: Almost all result in neonatal or infant death, due to respiratory complications.⁹⁹

Management: Before viability, the option of pregnancy termination should be offered. After viability, standard obstetrical management is not altered, and respiratory function in the newborn must be supported.^100,101

Synonyms: Sacral defect with anterior meningocele, caudal dysplasia sequence, sacral agenesis.

Definition: Caudal regression syndrome is a rare congenital defect characterized by the absence of the sacrum, and defects of variable portions of lumbar spine associated with anomalies from different systems.¹

Incidence: 0.1 to 0.25 per 10,000 in normal pregnancies and 200 to 250 times higher in diabetic pregnancies.^102,103

Etiology: Unknown, but associated with maternal diabetes in 16% of the affected.^{104, 105, and 106}

Recurrence Risk: This anomaly is not thought to be hereditary, and the recurrent risk is very small, although higher in diabetics.

Diagnosis: The sonographic findings are variable and depend on the extent and severity of the defect. It ranges from complete absence of the sacrum associated with abnormalities of the lumbar spine and lower extremities (such as club feet and contractions of the knees and hips) to abnormalities of the sacrum without associated defects. The most typical findings are the absence of a few vertebrae, the shield-like appearance of the fused or approximated iliac wings, and the decreased interspace between the femoral heads. Some sections will intersect the fetus at such an angle that no spine is visible, a very striking and probably pathognomonic finding (Figures 20-43, 20-44, 20-45, 20-46, and 20-47). Decreased movement of the legs is frequently observed. First trimester diagnosis may be hard to accomplish because of the incomplete ossification of the sacrum at that time. A short crown-rump length and abnormal appearance of the yolk sac have been proposed as early sonographic signs of caudal regression syndromes.^105,106

Genetic Anomalies: Unknown.¹⁰⁶

Pathogenesis: Disruption of the maturation of the caudal portion of the spinal cord complex prior to 4 weeks' gestation, leading to motricity deficits and neurologic impairment, varying from incontinence of urine and feces to complete neurologic loss.^102,106

Associated Anomalies: Anomalies of the central nervous, musculoskeletal, genitourinary, cardiac, respiratory, and gastrointestinal systems may be found in association with caudal regression syndrome.

Key Points: Absence of the sacrum and few vertebrae, the shield-like appearance of the fused or approximated iliac wings, and the decreased interspace between the femoral heads.

Differential Diagnosis: Sirenomelia, which was thought to be the most severe form of caudal regression syndrome but today is considered a different entity, is the main differential diagnosis. Fusion of the lower extremities is a typical finding of sirenomelia.¹⁰⁶

Prognosis: Depends on the severity of the spinal defect and associated anomalies, but the vast majority of survivals require urologic and orthopedic interventions. Severe forms are commonly associated with cardiac, renal, and respiratory problems, which are responsible for early neonatal death.

Management: If detected early, pregnancy termination can be offered. Standard prenatal care is not altered if continuation of pregnancy is chosen. If born alive, extensive surgery in a tertiary center is usually needed to repair the defects.

Synonym: Brachmann-De Lange syndrome.

Definition: This syndrome associates abnormal facial characteristics such as abnormal capillary findings (synophrys, long eyelashes, low anterior and posterior hairline), upturned nose, prognathism, long philtrum, downturned mouth angles, with prenatal growth retardation (postnatal too), mental retardation, and common upper limb anomalies.^{107, 108}

Incidence: 0.15 to 0.3 per 10,000; male-to-female ratio 1:1.3.^{107, 108}

Etiology: Unknown. Recent articles have suspected anomalous human chordin gene (CHRD); THPO (thrombopoietin); CLCN2 (a voltage-gated chloride-channel gene); and EIF4G1 (a eukaryotic translation-initiation-factor-γ gene), which maps within a gene cluster at 3q27; and SHOT, a homeobox gene. But others have suggested mitochondrial DNA deletions (which would go with a more common transmission of the disorder from mother to children then from father to children).^{107, 108, 109, 110, and 111}

Diagnosis: Cornelia de Lange syndrome is a rare syndrome characterized by the following associations (Figures 20-48 and 20-49):

1. Abnormal facies, featuring

   • Abnormal hairs

   • Synophrysis (hypertrophy and midline fusion of the eyebrows)

   • Long, curved eyelashes

   • Low anterior and posterior hairline

   • Upturned nose and downturned mouth corners

   • Dysgnathia (prognathia or mandibular protrusion; micrognathia)

   • A long philtrum

2. Various upper limb anomalies. Upper extremity anomalies are a classic Cornelia de Lange syndrome sign, most commonly irreducible flexion of the elbows, aplasia or sometimes agenesis of the cubital bones, oligodactyly, and clinodactyly.

3. Intrauterine growth restriction is nearly always associated with Cornelia de Lange syndrome.^{107,108,112, 113, 114, 115, and 116}

Possibly recognizable on three-dimensional examinations: unusual palpebral fissures, low-set ears, anteverted nostrils, prominent philtrum, thin upper lip, broad and/or depressed nasal bridge, downturned angles of mouth.

Postnatal Findings: Low hairline, synophrys, high arched palate, delayed eruption of teeth, brain malformations, malrotation of the gut, duplications, splenic-pancreatic fusion anomalies, renal anomalies, many ocular anomalies. Developmental delay ranging from borderline (10%), through mild (8%), moderate (18%), and severe (20%) to profound (43%) is more common.¹¹⁷

Genetic Anomalies: Several authors have suggested an autosomal dominant inheritance. There are other reports, though, on affected siblings with no parents affected.^{109, 110}

Differential Diagnosis: Partial trisomy 3q.

Associated Anomalies: Growth retardation, microcephaly, brachycephaly, micrognathia, long eyelashes, hypertrichosis/hirsutism, cardiac anomalies including atrial and ventricular septal defects, hypoplastic left ventricle, anomalous systemic venous drainage, overriding aorta, fibroelastosis, polycystic and ectopic kidneys, and limb anomalies.

Prognosis: Prognosis is mostly affected by the intellectual achievement of those children (and related problems of self-mutilation); orthopedic and respiratory complications also occur.

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling.^112,113,117

Synonym: Fetal alcohol effects.

Definition: Alcohol is a teratogen that results in dysmorphia, growth problems, and abnormalities of the central nervous system in multiple ways. Fetal alcohol syndrome (FAS) is characterized by specific facial abnormalities and significant impairments in neurodevelopment and physical growth. Children exposed to alcohol (approximately 45 to 50 g of ethanol per day or equivalent) in utero suffer from growth and mental retardation, physical abnormalities, and immune dysfunction. There is no "threshold" so some fetuses exhibit signs of fetal alcohol effects at lower exposure. Recommendations for clinicians regarding assessment of thresholds published by the National Institute on Alcohol Abuse and Alcoholism recommend that any woman who reports drinking more than 7 drinks per week or more than 3 drinks on any given day be further assessed for risk of developing alcohol-related problems.¹¹⁸

Incidence: The incidence of FAS ranges from 2 to 30 per 10,000 live births. This represents the most common form of mental retardation in the United States. In the United States, the prevalence of FAS has been estimated to fall between 0.5 and 2.0 cases per 1000 births. It has long been recognized that the true extent of teratogenic injury from alcohol exposure exceeds the clinically recognized prevalence of FAS, as behavioral and physical teratogenesis may be present in the absence of full expression of the syndrome.^{118, 119, and 120}

Etiology: Direct toxicity of alcohol and its metabolites that cross the placenta and are not detoxified by the fetal liver.

Diagnosis: The findings include microcephaly; long, round philtrum; small micrognathia; cleft palate; suppression of the Cupid arch; microphthalmia; dysgenesis of the corpus callosum; malformed ears; atrial septal defect; ventricular septal defect; and growth restriction predominantly involving the limbs and occurring early without oligohydramnios. This lack of specificity suggests that the FAS facies may be a common teratogenic expression of exposure to a variety of substances occurring during a defined period of fetal development.^118,119,121

Key Points: Microcephaly; micrognathia; long, round philtrum.

Differential Diagnosis: Other conditions that involve growth restriction and microcephaly such as toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCHS), and chromosomal anomalies.

Prognosis: Mental retardation and delay in growth that persists postnatally. Most children with FAS are mildly to moderately retarded, but intellectual ability varies widely.^{122, 123, and 124} The severity of mental retardation appears related to the severity of growth deficits and dysmorphogenesis, such that the more phenotypically affected individuals have lower IQ scores. Hyperactivity is frequently observed. As adults, mental illness is highly prevalent with FAS, affecting over 70% in one series in which 60% had alcohol or drug dependence, 44% had depression, and 40% had psychosis.

Management: The management of these pregnancies should be aimed at reducing alcohol consumption; few programs have had much efficacy.

Prevention: Because no safe threshold of alcohol use during pregnancy has been established, the Centers for Disease Control and Prevention (CDC) recommends that women who are pregnant, planning a pregnancy, or at risk for pregnancy should not drink alcohol. Women of child-bearing age who are not pregnant should drink no more than 7 drinks per week and no more than 3 drinks on any one occasion.^118,125

Synonym: Congenital cytomegalovirus (CMV) infection.

Definition: Fetal cytomegalovirus infection is a congenital disorder characterized by hydrops, ascites, ventriculomegaly, and other findings caused by transplacental transmission of cytomegalovirus to the fetus. The double-stranded DNA herpes group virus causes a mild infection or a mononucleosis-type illness in young, healthy adults; chronic disease in older adults; and mild to severe congenital infection.^126,127

Etiology: Cytomegalovirus (a double-stranded DNA herpes group virus).

Incidence: Congenital cytomegalovirus infection occurs in 0.2% to 2.2% of deliveries. Intrauterine transmission of CMV takes place in approximately 40% of infections, and approximately 10% of liveborn infants have symptomatic disease at the time of birth and later. Few cases may have isolated findings such as ascites.^126,127

Diagnosis: Cytomegalovirus infection as well as other congenital infections should be suspected whenever no immune hydrops is found. Suggestive findings that may be present are intracranial calcifications and intracranial hemorrhage, abnormal periventricular echogenicities, intraparenchymal foci, ventriculomegaly, microcephaly, ascites, hyperechoic bowel, intrauterine growth restriction, and oligohydramnios (Figure 20-50). In some cases, other findings can be present such as intraventricular adhesions, periventricular pseudocysts, brain atrophy sulcation and gyral abnormal patterns, hypoplastic corpus callosum, cerebellar and cisterna magna abnormalities, signs of striatal artery vasculopathy, splenomegaly, chorioretinitis (an echogenic lining to the vitreous body), occlusion of the foramen ovale, and signs of right-heart overload from the premature closure.^{128, 129, 130, and 131}

Whenever maternal infection is confirmed, culture and polymerase chain reaction (PCR) testing of amniotic fluid¹²⁹ and/or cordocentesis is required for serologic studies (search for fetal-specific IgM antibody), although it does not have 100% reliability. PCR on amniocentesis samples can be made after 21 weeks of pregnancy, after a 7-week interval between diagnosis of maternal infection and antenatal procedure. The diagnosis can also be made by histologic study of typical inclusion bodies in biopsy or autopsy specimens.^{132, 133, and 134}

Focal sonographic periventricular pattern in association with mild ventriculomegaly, without any abnormalities of the cerebral and cerebellar organogenesis or cephalic biometry alteration in the third trimester of pregnancy, should be considered as a marker of encephalitis following CMV infection of the fetal brain. Fetal MRI is a useful adjunct in the evaluation of intrauterine infection with CMV.

Pathogenesis: The exact mode of transplacental passage is uncertain. The virus replicates in fetal tissues, producing inflammation, tissue necrosis, and organ dysfunction. Cytomegalovirus hepatitis in the neonate can present with an intense inflammatory response involving the portal triads. In these cases, lobular disarray, degeneration of hepatocytes, and cholestasis are also seen. The cause of ascites in congenital cytomegalovirus infection is not certain. Contributing factors may include low serum protein levels due to hepatic dysfunction and portal obstruction resulting from periportal inflammation.

Associated Anomalies: Isolated ascites is an uncommon finding in fetuses with cytomegalovirus infection but may occur. Cardiovascular, gastrointestinal, musculoskeletal, and ocular lesions may be found in association with the classic features. Petechiae, neurosensory hearing loss, and poor intellectual development may also occur after birth.

Key Points: Intracranial calcifications, ventriculomegaly, microcephaly, ascites, hyperechoic bowel, intrauterine growth restriction, and oligohydramnios.

Differential Diagnosis: Because ascites is often the first manifestation of hydrops, the differential diagnosis for fetal ascites is essentially the same as with generalized hydrops, which includes mainly all congenital infections. Conditions that present intracranial calcifications (such as tuberous sclerosis), hyperechoic bowel (cystic fibrosis and Down syndrome), and hepatomegaly (primary liver disease or extramedullary hematopoiesis) should be considered.

Prognosis: In general, neonates with symptomatic cytomegalovirus infection do poorly, with a neonatal mortality rate as high as 30% and a high rate of neurologic handicap in survivors. Cytomegalovirus hepatitis is reversible in survivors, but mental retardation, motor handicaps, and hearing loss are expected long-term sequels. Late sequelae such as sensorineural hearing loss and neurodevelopmental disorders occur in 10% to 15% of infants lacking symptoms at birth. Pediatric neurological morbidity is related to the degree of antenatal ventriculomegaly and, when it is greater than 15 mm, it is associated with an increase in abnormal neurological development.¹³⁵

Recurrence Risk: The cytomegalovirus is a ubiquitous virus that belongs to the herpes virus group. Intrauterine transmission may be caused by either primary or recurrent maternal infection. It seems that recurrent infection is more frequent than primary infection, but is considered less dangerous for the fetus.^133,134

Management: Termination of pregnancy can be offered before viability. If continuation of the pregnancy is chosen, monthly follow-up with ultrasound is recommended to monitor growth restriction, hydrops, and the other fetal manifestations. Decompression with paracentesis to remove fetal ascites may prevent pulmonary hypoplasia and improve the circulatory system in those cases that are severely affected. Some authors described the treatment of fetuses infected with cytomegalovirus using maternal oral administration of valaciclovir (8 g/d). The results are still inconclusive.¹³⁶

Prevention: Of all the ways to fight congenital CMV disease, the development of a vaccine is viewed as the most promising, but it is uncertain when a vaccine will become available. The American College of Obstetricians and Gynecologists guidelines recommend that physicians counsel pregnant women about preventing CMV acquisition through careful attention to hygiene.¹³⁷

Synonym: Fetal rubella effects.

Definition: Fetal rubella syndrome is a congenital disorder resulting from primary maternal infection with the rubella virus. It is characterized mainly by deafness, mental retardation, congenital cataract, heart defects, and other structural anomalies that may be found with variable severity and frequency. During acute rubella in pregnancy, the rate of congenital infection is over 90% in the 12 first weeks of pregnancy, approximately 60% in weeks 13 to 17, 25% in weeks 18 to 24, and then increases again during the last month of pregnancy.^138,139

Etiology: It is caused by an RNA togavirus, which is the only member of the genus Rubivirus. The fetus is infected by transplacental transmission.

Recurrence Risk: None.

Incidence: Not precisely known. Administration of rubella vaccine has significantly reduced the incidence of maternal infection, although reinfection after vaccination is possible. The development of fetal infection reaches 50% among those exposed during the first trimester and 20% during the second trimester.^138,139

Diagnosis: The most frequent sonographic findings are cardiac malformations (in particular, septal defects), eye defects (cataracts, microphthalmia, and retinopathy), microcephaly, hepatomegaly, and splenomegaly and growth restriction. Deafness and mental retardation are expected after birth. The confirmation of fetal infection can be made by isolating rubella viral RNA from amniotic fluid samples and applying polymerase chain reaction (PCR).^138,139

Associated Anomalies: Occasionally the following anomalies can be associated with the classic findings of fetal rubella syndrome: renal disorders, hypospadias, cryptorchidism, meningocele, glaucoma, patent ductus arteriosus, and peripheral pulmonic stenosis.

Key Points: Congenital cataract and heart defects (septal defects).

Differential Diagnosis: All the conditions that can be associated with congenital hepatomegaly and/or cataract should be excluded. It includes congenital infections (TORCHS), fetal anemia, fetal liver tumor, chondrodysplasia punctata, Neu-Laxova syndrome, Smith-Lemli-Opitz syndrome, and Walker-Warburg syndrome.^138,139

Prognosis: Intrauterine death may occur. Postnatal impact of the intrauterine infection varies from absence of any defect to all the anomalies mentioned above with variable severity. The agent may remain for years in the tissues, causing chronic infection and complications such as diabetes mellitus due to chronic viropathy of the pancreas.

Management: Termination of pregnancy should be considered if the infection is detected during the first trimester, due to the severity of the condition in this group. After viability, monthly sonographic monitoring for growth and follow-up of the anomalies is recommended.^138,139

Prevention: Women found to be susceptible during pregnancy should be offered vaccination postpartum and before discharge from the hospital. Breast-feeding is not a contraindication to receiving the rubella vaccine.

Synonyms: None.

Definition: Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii. Toxoplasmosis is normally asymptomatic in immunocompetent individuals. Acute infections in pregnant women can be transmitted to the fetus and cause severe illness (mental retardation, blindness, and epilepsy). The risk of maternal fetal transmission increases with gestational age at the time of exposure, whereas the incidence of severe disease decreases.^140,141

Incidence: An estimated 400 to 4000 cases of congenital toxoplasmosis 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 in this country. The incidence of toxoplasmosis acquisition during pregnancy ranges from 1 to 4 per 10,000. Half of the fetuses escape from the infection, one-third has a subclinical infection, and only one-tenth has a severe infection.¹⁴⁰

Etiology: Infectious. Women infected with Toxoplasma before conception, with rare exceptions, do not transmit the infection to their fetuses. Women infected with Toxoplasma after conception can transmit the infection across the placenta to their fetuses. Fetal involvement results from acute infection in the mother; however, those mothers with chronic infection can transmit the disease by reactivation, which is caused by an immunological dysfunction. The rate of fetal transmission during primoinfection is 25%, 54%, and 65%, in the first, second, and third trimesters, respectively.

Pathogenesis: The fetus is infected hematogenously via the placenta during parasitemia in the mother. Ocular toxoplasmosis causes irreversible damage to the retina in utero. The fetus and infant mount inflammatory responses that may contribute to ocular damage.¹⁴²

Diagnosis: The classic triad of signs suggestive of congenital toxoplasmosis includes chorioretinitis, hydrocephalus (Figure 20-51), and intracranial calcifications (Figure 20-52). However, most infants infected in utero are born with no obvious signs of toxoplasmosis on routine examination, but many develop learning and visual disabilities later in life. If untreated, congenital toxoplasmosis can be associated with severe and even fatal disease. Other findings include microcephaly, encephalomyelitis, seizures, mental retardation, ascites, and hepatosplenomegaly. Although the diagnosis used to be made by serologic techniques and cultures, it can now be done with polymerase chain reaction detection of Toxoplasma gondii in fetal tissues.^{140, 141, and 142}

Key Points: Chorioretinitis, intracranial calcifications, and hydrocephalus.

Differential Diagnosis: The other TORCH infections.

Prognosis: Approximately 75% of congenitally infected newborns are asymptomatic.

Recurrence Risk: Typically none.

Management: Depending on gestational age and whether the fetus is known to be infected, pregnant women have been treated with the antibiotic spiramycin or with sulfadiazine alone, or the combination of pyrimethamine and sulfadiazine. Treatment of acute infection during pregnancy has been associated with an approximately 50% reduction in fetal infection.

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 avoiding changing cat litter or, if no one else is available to change the cat litter, using gloves and then washing hands thoroughly.¹⁴⁴

Synonyms: Congenital varicella syndrome, varicella embryopathy, chickenpox, herpes zoster.

Definition: Fetal varicella zoster is a combination of abnormalities of multiple organs, caused by fetal contamination with maternal chickenpox infection.¹⁴⁴

Incidence: The incidence of maternal infection with herpes virus varicella is 7 out of 10,000 pregnancies. The risk of fetal involvement among all pregnant women infected with varicella during their gestation varies from 1% to 20%. First trimester varicella infections have been associated with a high risk of transplacental contamination and an increased risk of spontaneous abortion. Second trimester varicella infections have been associated with a 2% risk of a congenital syndrome characterized by limb hypoplasia, cutaneous scars, cataracts, microcephaly, and cortical atrophy.^144,145

Etiology: Herpes virus.

Recurrence Risk: Less than 1%.

Diagnosis: Sonographic signs of fetal disease include fetal demise, growth restriction, musculoskeletal abnormalities such as club feet and abnormal position of the hands (caused by both necrosis and denervation of the affected tissue; Figure 20-53), limitation of limb extension due to cicatrices formation, cutaneous scars (Figure 20-54), 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.^{146, 147, and 148} The placenta can show a multifocal chronic villitis with multinucleated giant cells. Fetal infection can be demonstrated by detection of varicella-zoster virus (VZV) DNA by polymerase chain reaction (PCR) in fetal blood and amniotic fluid or by detection of the specific IgM antibody, in the same fluids.

Pathogenesis: Direct damage to fetal tissues by neurotropic virus.

Associated Anomalies: Congenital anomalies from multiple organs with variable severity can be associated with varicella embryopathy. Among survivors, development of mental retardation, seizures, and limitation of movements may happen after birth. The virus may cause serious infections, particularly pneumonia, in adult women.

Key Points: Fetal demise, growth restriction, club feet, abnormal position of the hands, limitation of limb extension due to cicatrices formation, and cutaneous scars.

Differential Diagnosis: Other viral infections, vascular accidents, amniotic band syndrome.

Prognosis: The severity of fetal involvement varies from dermatologic lesions to lethal disseminated disease. Limited scarring tends to have an excellent 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. Mortality rate varies from 39% to 61%. Early maternal infection (first and early second trimester) has a higher association with fetal anomalies, and third trimester infections have a higher risk for varicella-zoster development at the neonatal period. A life-threatening illness may occur when a newborn is delivered within 5 days of the onset of maternal illness.¹⁴⁹

Management: Termination of pregnancy can be offered before viability. If continuation of the pregnancy is chosen, periodic sonographic evaluation is recommended to search for fetal anomalies, limb contractures, and other signs of fetal compromise. If maternal seroconversion is suspected for the varicella-zoster virus, combining prenatal ultrasound and magnetic resonance imaging may document the extent of tissue damage and assist in the counseling. After a therapeutic abortion, fetal infection can be confirmed by detection of VZV DNA in several fetal tissues and placenta, and by histopathological findings like miliary calcified necroses in fetal organs.¹⁴⁹

Prevention: Serological testing and vaccination should be offered to women of child-bearing age, and they should be questioned about immunity to varicella preconceptually. Susceptible pregnancy 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. Also, susceptible neonates should receive VZIG. Acyclovir is active against the varicella-zoster virus, and treatment is indicated in seriously ill adults and neonates.

Synonym: Cryptophthalmos-syndactyly syndrome.

Definition: Fraser syndrome is a rare genetic syndrome with abnormalities of the head, lungs, kidneys, and limbs. It combines acrofacial and urogenital malformations with or without cryptophthalmos.^{150, 151, and 152}

Incidence: 0.043 per 10,000 liveborn infants and 1.1 per 10,000 stillbirths.^151,152

Etiology: Probably autosomal recessive because an unusual proportion of infants are born to consanguineous parents.

Recurrence Risk: Fraser syndrome has a recurrence risk of 25% among siblings, and therefore prenatal diagnosis and counseling the affected families is important.

Diagnosis: The diagnosis has been suggested prenatally by the combination of the major and minor characteristics. Cases are diagnosed on the basis of at least 2 major criteria and 1 minor criterion or at least 4 minor criteria.

The major characteristics are as follows:

• Cryptophthalmos

• Urogenital anomalies (Figures 20-55 and 20-56)

• Syndactyly (Figure 20-57)

• Sibling with Fraser syndrome

The minor characteristics are as follows:

• Alterations of the nose

• Alterations of the ears

• Alterations of the larynx

• Oral clefts (cleft lip and/or palate)

• Umbilical hernia

• Renal agenesis (unilateral or bilateral)

• Skeletal anomalies

The prenatal diagnosis of Fraser syndrome can be suspected, but because of the great variety of malformations the diagnosis will remain doubtful unless a previous child is affected.^{151, 152, 153, 154, and 155}

Pathogenesis: A defect of apoptosis has been suggested because several of the anomalies result from failure of programmed cell death (fusion of eyelids, digits, larynx, and vagina).

Genetic Anomalies: The Fraser syndrome gene is located to 4q21.

Associated Anomalies: Cryptophthalmos, absent or malformed lacrimal ducts, middle and outer ear malformations, high palate, cleavage along the midplane of nares and tongue, hypertelorism, laryngeal stenosis, syndactyly, wide separation of symphysis pubis, displacement of umbilicus and nipples, primitive mesentery of small bowel, maldeveloped kidneys, fusion of labia and enlargement of clitoris, and bicornuate uterus and malformed fallopian tubes.^152,153,155

Key Points: Cryptophthalmos, syndactyly, and urogenital defects.

Differential Diagnosis: The differential diagnosis of the echogenic lungs includes congenital diaphragmatic hernia, cystic adenomatoid malformation (type III), sequestrated lung, and tracheal or bronchial atresia. The differential diagnosis of the cryptophthalmos includes alobar holoprosencephaly, which should be easy to recognize from the simple hydrocephalus of Fraser fetuses.^152,154

Prognosis: Twenty-five percent of affected babies are stillborn. An additional 20% die before age 1 secondary to renal or laryngeal defects. If cryptophthalmos is the main sign, even surgical repair will yield very poor vision (20/200 and 20/360) in the rare correctable cases.¹⁵²

Management: Depends on the predominant associated anomalies. Termination of the pregnancy can be recommended when renal agenesis or laryngeal atresia is present.

Synonyms: None.

Definition: Fryns syndrome is a rare congenital disorder characterized by dysmorphic facial features (coarse face with microphthalmia, hypertelorism, facial hair growth, cloudy corneas, broad and flat nasal bridge, cleft lip and/or palate, microretrognathia, and low-set ears), diaphragmatic hernia, distal limb hypoplasia, and pulmonary hypoplasia. The first description was given by Fryns in 1979.^156,157

Incidence: Unknown. Ayme and coworkers reported a prevalence of 0.7 per 10,000 births in France.

Etiology: Autosomal recessive inheritance.

Recurrence Risk: 25%.

Diagnosis: The phenotypic variability makes the sonographic diagnosis of Fryns syndrome a challenge. The detection of typical facial dysmorphism associated with diaphragmatic hernia (which is a leading sonographic criterion), hypoplastic thorax with widely spaced nipples, hypoplasia or absence of the lobulation of the lungs, distal limb deficiencies with hypoplasia of the terminal phalanges and nails, and postaxial oligodactyly should suggest Fryns syndrome.¹⁵⁸ Development of polyhydramnios late in the second trimester and normal growth or overgrowth of the fetus is also expected. The use of three-dimensional ultrasound may be helpful to precisely define the facial anomalies. Although the frequency of cystic hygroma is not as high as the features mentioned above, this defect has been proposed as a sonographic first trimester marker for recurrent cases. Other findings that can be detected are persistent truncus arteriosus, and interrupted aortic arch, left isomerism, complex central nervous system midline malformations, and multiple pterygias. Maternal and amniotic fluid α-fetoprotein levels may be elevated, in particular in fetuses that carry open defects.^{156, 157, and 158}

Genetic Anomalies: No specific DNA defect has been identified.

Key Points: Dysmorphic facial features, diaphragmatic hernia, distal limb hypoplasia, and pulmonary hypoplasia.

Differential Diagnosis: The differential diagnosis includes trisomy 18 (which can be excluded by karyotype), Killian/Teschler-Nicole syndrome (mosaic tetrasomy 12p), Zellweger syndrome (deficiency of peroxisomal enzyme), and Brachman-DeLange syndrome (usually associated with severe growth restriction).

Associated Anomalies: Anomalies from skeletal, cardiac, central nervous, gastrointestinal, and genitourinary systems.

Prognosis: The majorities are stillborn or die in the early neonatal period. A few reported survivals have severe mental and developmental retardation.

Management: When the syndrome is detected before viability, termination of pregnancy can be offered. After viability, standard prenatal care is not altered.

Synonyms: Oculoauriculovertebral spectrum (OAVS), oculoauriculovertebral dysplasia, facioauriculovertebral sequence.

Definition: It is a predominantly unilateral malformation involving first and second brachial arch derivatives. The characteristic findings include hemifacial microsomia, epibulbar dermoids, preauricular appendages, ear hypoplasia, transverse facial clefts, asymmetry of skull, and spinal anomalies (vertebral segmentation errors).¹⁵⁹

Incidence: This syndrome has an estimated frequency of 1 per 3000 to 1 per 5000 newborns, with a minor male-to-female (3:2) predominance.

Etiology: Probably sporadic, with rare cases suggesting an autosomal recessive or autosomal dominant inheritance.

Diagnosis: The diagnosis is usually made by observing the facial asymmetry (likely to become more common with three-dimensional ultrasound) or a maxillary cleft in association with unilateral microphthalmia. Other findings include anophthalmos, congenital heart defects (atrioventricular septal defects) or urinary anomalies (hydroureteronephrosis, kidney agenesis), and lipoma of the corpus callosum (Figures 20-58 and 20-59).^{159, 160, 161, and 162}

Pathogenesis: Possible fetal hemorrhage in the region of the first and second branchial arches at the time when the blood supply of these arches switches from the stapedial artery to the external carotid artery.

Genetic Anomalies: Most cases are sporadic, but there are rare familial cases that exhibit autosomal dominant inheritance.¹⁶³

Associated Anomalies: Tracheoesophageal fistula, syringohydromyelia, neurodevelopment delay, occipital meningoencephalocele, tetralogy of Fallot, ventricular septal defects, asplenia syndrome, ventricular inversion associated with double-outlet right ventricle, pulmonary atresia with ventricular septal defect, double-outlet right ventricle, infradiaphragmatic total anomalous pulmonary venous connection, ectopic and/or fused kidneys, renal agenesis, vesicoureteral reflux, ureteropelvic junction obstruction, ureteral duplication, multicystic kidney, and single umbilical artery¹⁶³

Key Points: Hemifacial microsomia, unilateral deformity of the external ear and small ipsilateral half of the face with epibulbar dermoid and vertebral anomalies.

Differential Diagnosis: Kaufman syndrome (oculocerebrofacial syndrome), acrofacial dysostosis, and CHARGE (coloboma, heart defects, atresia choanal, retarded growth, genital hypoplasia, and ear deformities) association.

Prognosis: Aside from the mental handicap these patients may have, there are many complications due to upper airways problems as well as vertebral complications.

Recurrence Risk: Probably none unless in an autosomal dominant recessive inheritance.

Management: When the diagnosis is recognized in the early stages of gestation, termination of pregnancy may be offered. In the postnatal period, the management will attempt cosmetic improvements.

Synonyms: Nonne-Milroy lymphedema; lymphedema, early onset; primary congenital lymphedema; Milroy disease.

Definition: Hereditary lymphedema is a rare disease characterized by a firm edema of the lower extremities that can be generalized to the whole leg or limited to feet or toes. It was first described by Milroy in 1828. In general, it is considered as a benign disorder with mainly cosmetic importance. True congenital lymphedema or hereditary lymphedema type I usually presents either at, or soon after, birth and may be associated with other congenital malformations. Onset of clinical symptoms in hereditary lymphedema type II (OMIM 153200) usually occurs during or near either puberty or menopause.¹⁶⁴

Incidence: It is estimated to occur with an incidence of approximately 1 in 6000 newborns. The male-to-female ratio is 1:2.3.^{164, 165, and 166}

Etiology: The disease has autosomal dominant inheritance with incomplete penetrance (80% to 84%), variable expressivity, and variable age of onset. These features tend to appear at birth or in infancy.^167,168

Pathogenesis: All the anomalies found are due to dysgenesis of lymphatic microvessels. This dysgenesis ranges from mild to severe and even to aplasia of both the lymphatic capillaries and collectors. This condition results from impaired lymph drainage in the presence of normal capillary filtration. It may be either primary in type, which implies an intrinsic abnormality of the lymph-conducting pathways, or secondary in type, which implies that external factors such as radiotherapy, severe infection, or surgical excision have damaged lymph drainage routes. Most forms of primary lymphedema are thought to be caused by a congenital abnormality of the lymphatic system.¹⁶⁵

Diagnosis: This condition is suggested by the finding of an isolated edema of the dorsum of the feet in the fetus, a normal karyotype, and absence of other significant malformations (Figures 20-60, 20-61, and 20-62). The disease has variable expressivity and must be suspected in those fetuses with distal subcutaneous edema of the extremities, most frequently of the lower limbs, but the hands can also be involved. Findings can be present in one extremity or in all of them. Occasionally, persistent or transient pleural effusion and ascites can be found.^{164, 165, and 166}

Genetic Anomalies: The exact location of the genetic alteration causing the hereditary lymphedema has not been described. However, it has recently been demonstrated that the gene is located to the region 5q34-q35. There is also evidence that the disorder might be associated with mutations in the FLT4 that encodes the vascular endothelial growth factor receptor-3 (VEGFR-3).¹⁶⁷

Key Points: Lymphedema, predominantly in the lower limbs.

Differential Diagnosis: The following dysmorphic syndromes must be considered: Turner syndrome, Noonan syndrome, lymphedema-distichiasis syndrome (double row of eyelashes), lymphedema and ptosis syndrome, Meige lymphedema (hereditary lymphedema type II), congenital recessive type lymphedema.

Associated Anomalies: There are reports of associations with distichiasis, hydroceles, atrial septal defect, and characteristic facial changes.

Prognosis: Edema, particularly severe below the waist, sometimes complicated with papillomatosis and nail changes. Present in one or both legs, the lymphedema persists throughout life but does not seem to affect longevity. As the patient grows up, the overlying skin displays a slightly rosy hue, while the size of the edematous parts remains proportional to the remainder of the body. The morbidity is due to infections. There are few significant complications associated with this disorder. There are reports of intestinal lymphangiectasia, recurrent septic arthritis, angiosarcoma, and lymphangiosarcoma.¹⁶⁵

Management: If other fetal anomalies are ruled out and fetal karyotype is normal, parental counseling concerning etiology, management, and possible complications is advisable. Some individuals wear compression stockings, which are effective in containing the edema, whereas those who are more severely affected attend the hospital for compression pumping to reduce limb size.

Synonyms: Heart–hand syndrome (this syndrome appears genetically distinct from the heart-hand syndrome types II and III), atriodigital dysplasia.

Definition: The Holt-Oram syndrome consists of an upper-limb malformation involving the carpal bone and, variably, the radial and/or thenar bones (phocomelia [4.5%], radial ray aplasia, triphalangeal thumb, clinodactyly) in association with a congenital heart disease. A congenital heart malformation is present in 75% of individuals.¹

Incidence: It is estimated at 0.1 per 10,000 births. Females are more commonly affected.^168,169

Etiology: It is an autosomal dominant defect with 100% penetrance and no evidence of reduced fitness. Increasing severity occurs in succeeding generations consistent with anticipation.¹⁷⁰

Diagnosis: The radial ray aplasia varies from a difficult to diagnose triphalangeal thumb to more obvious club hand. The absence of the thumb can also be recognized (Figures 20-63 and 20-64). The cardiac lesions include atrioventricular septal defects (Figure 20-65), patent ductus arteriosus, endocardial cushion defect, and hypoplasia of the left ventricle and conduction disturbances. A congenital heart malformation is present in 75% of individuals, and approximately 17% of fetuses have complex cardiac anomalies.^170,171

Pathogenesis: Probable cardiomelic developmental field.¹⁶⁸

Genetic Anomaly: Mutations in 2 of the T-box genes (TBX5 and TBX3) on chromosome 12q24168 have been shown to be responsible for the congenital abnormalities associated with Holt-Oram syndrome. TBX5 is only involved in anterior limb development.¹⁷¹

Associated Anomalies: A few inconstant anomalies such as renal anomalies have been reported.

Key Points: Congenital heart disease and anomalies of the upper limb (Figures 20-63 and 20-67).

Differential Diagnosis: The differential is usually that of the radial ray aplasia and could include the thrombocytopenia with radii aplasia (TAR) syndrome, Fanconi anemia, VACTERL (vertebral, anorectal, tracheoesophageal, renal, and limb anomalies) association, and radial ray–choanal atresia. The Holt-Oram syndrome can look like some chromosomic aberrations like trisomy 18, trisomy 13, and partial trisomy 22.^168,171

Prognosis: Mainly related to the severity of the cardiac and orthopedic handicap.

Recurrence Risk: Offspring of a proband are at 50% risk of being affected.

Management: Usually no alteration of the prenatal care is needed. The management of individuals with Holt-Oram syndrome involves a multidisciplinary team approach, with specialists in medical genetics, cardiology, and orthopedics, including a specialist in hand surgery. Great orthopedic progresses at pollicization of the index finger to provide opposition have decreased the handicap of some of these children.

Synonym: Salonen-Herva-Norio syndrome.

Definition: This syndrome is characterized by multiple developmental defects of the fetus such as polydactyly (postaxial in the hands and preaxial in the feet), central nervous system malformation such as hydrocephalus and absent midline structures of the brain, micrognathia, limb anomalies, and several other abnormalities.^172,173

Incidence: Parents often have some ancestry in an eastern region of Finland where the syndrome was described, for the first time, in 1981. There is an increased frequency in Finland (prevalence of 1 in 20,000). Outside of this subgroup, the incidence is very rare.

Etiology: Autosomal recessive lethal syndrome.

Diagnosis: The findings of massive hydrocephalus, encephalocele, micrognathia, polydactyly (in particular, a duplicated big toe), syndactyly, cardiac malformation, club feet, and polyhydramnios are very suggestive of the diagnosis. Other findings include cleft lip/palate, lung hypoplasia, and endocardial cushion defects. Particularly in families where there has been a previously affected fetus, ultrasound diagnosis can be made in the 11th week of gestation.^172,173

Genetic Anomalies: It is caused by a missense mutation in a novel gene HYLS1.^{174, 175, and 176}

Key Points: Polydactyly, central nervous system malformation (hydrocephalus), and absent midline structures of the brain.

Differential Diagnosis: Other midline malformation syndromes including Pallister-Hall, Smith-Lemli-Opitz, pseudo-trisomy 13, oral facial-digital syndrome, some skeletal dysplasias such as the short rib–polydactyly syndromes and campomelic dysplasia. Meckel syndrome is characterized by polydactyly and central nervous system anomalies as well (cephalocele instead of hydrocephaly), but in addition cystic kidneys; acrocallosal syndrome, which shows severe mental retardation; agenesis or hypoplasia of the corpus callosum; polydactyly of fingers and toes; and anencephaly besides other midline defects.

Prognosis: Neonatal death is the rule. Seventy percent of cases are stillborn and liveborn infants die within a few hours of birth.

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen.

Definition: Hypoplastic left heart syndrome (HLHS) is a congenital cardiac anomaly characterized by the association of a small left ventricle with aortic atresia and/or mitral hypoplasia or atresia.¹⁷⁷

Synonyms: Aortic atresia.

Incidence: Hypoplastic left heart syndrome comprises 5% of prenatally detected congenital heart diseases, and affects 1.6 per 10,000 live births.¹⁷⁷

Etiology: The etiology of hypoplastic left heart is not precisely known. Autosomal recessive, autosomal dominant, and polygenic inheritance have been suggested. Multifactorial is the more likely form of transmition.¹⁷⁸

Diagnosis: The typical findings seen on 4-chamber view include the following¹⁷⁸:

• Diminutive left ventricular chamber

• Hypertrophy of the left ventricle wall

• Hypokinesia of the left ventricle wall

• The right ventricle forms the apex of the heart

• Dysplastic mitral valve

In hypoplastic left hearts the ascending aorta and aortic arch are very tiny. The identification of a small amount of flow (usually only feasible with color Doppler) is important. If the flow is retrograde the septum is usually intact and the prognosis is poor. The presence of anterograde flow signals the presence of a ventricular septal defect. The valve of the foramen ovale flap bulges into the right atrium (Figures 20-68, 20-69, 20-70, and 20-71).

Pathogenesis: Unknown.

Genetic Anomaly: A defect at 11q23.3 has been suggested.

Associated Anomalies: Extracardiac defects are frequently seen and the most common are 2-vessel cord, craniofacial, gastrointestinal, genitourinary, and central nervous system abnormalities.

Key Points: The 3 common appearances in the midtrimester fetus are absent left ventricle, small left ventricle, and dilated left ventricle with poor contractility.

Differential Diagnosis: The single ventricles, hypoplastic right ventricles, and severe forms of endocardial cushion defect may all appear similar in the 4-chamber view. A careful observation of the position of the atria, atrioventricular (AV) valves, and great vessels often allows the correct diagnosis.

Prognosis: Hypoplastic left heart syndrome belongs to the category of heart defects that may progress in utero. There are several possible evolutions^178,179

• If the critical aortic stenosis is tight early in pregnancy the left ventricle becomes dysfunctional and does not grow. At term the size of the left ventricle is small.

• When the obstruction occurs later, the left ventricle has already developed to a fair degree and the obstruction results in mitral regurgitation with subsequent enlargement of the left ventricle.

Hypoplastic left heart syndrome is responsible for 25% of cardiac deaths in the first week of life. Almost all of the affected infants die within 6 weeks if they are not treated. Several palliative procedures, including atrial septectomy, banding of the pulmonary artery, and creation of aortopulmonary shunt, have been used. Patients undergoing these procedures either died at some time after the operation or have been followed for a very limited period. Thus far, Norwood reconstruction and cardiac transplantation are the most successful techniques, but the success rate is still very limited.

Recurrence Risk: The recurrence risk depends on the etiology and varies from 0.5% to 25%, being quoted around 2% in most of the cases. According to Norwood, the recurrence risk is 4% for those families with 1 affected child and 25% for those with 2 or more affected children.¹⁸⁰

Management: When the diagnosis is made before viability, the option of pregnancy termination should be offered. After viability, delivery in a tertiary center should be recommended where a cardiovascular team is prepared to undertake surgical care of the infant.

Synonym: Cervical cerebral fusion.

Definition: Klippel-Feil syndrome first was described by Klippel and Feil in 1975. It is a congenital anomaly characterized by a classic triad including short neck, low posterior hairline, and limited range of motion of the neck due to fusion of cervical vertebrae. It now is known that fewer than 50% of patients with congenital defects of the cervical spine have all 3 signs of this classic triad. Patients with Klippel-Feil syndrome were assigned to 1 of 3 types¹⁸¹:

• Type I comprises fusion of many cervical and upper thoracic vertebrae into bony blocks.

• Type II has fusion at only 1 or 2 vertebrae and may associate hemivertebrae and fusion of the occipito-atlantoic joint.

• Type III has both cervical fusion and lower thoracic or lumbar fusion.

Incidence: It has been estimated that it occurs in approximately 1 in 40,000 to 42,000 births, which may be an underestimate because some mild forms may be underreported. A slight female predominance of approximately 3:2 has been reported.^181,182

Etiopathology: Anomalies of segmentation of the somites in the fourth to eighth week.

Diagnosis: The short neck may be associated with opisthotonos (retroflexion of the head), and the disorganization of the cervical vertebrae is potentially recognizable (Figures 20-72, 20-73, and 20-74). It is sometimes associated with ocular malformations, cleft lip and/or palate and occasional oligodontia in both primary and permanent dentition, craniofacial asymmetry, maxillary constriction and velopharyngeal insufficiency, persistent trigeminal artery, congenital heart defects, and renal (renal agenesis) and genital anomalies. An interesting case has also been reported of an intramedullary mass associated to this syndrome due, perhaps, to a maldevelopment of the cervical spine. Deafness is a well-known feature and may be of sensorineural, conductive, or mixed type.^{183, 184, and 185}

Genetic Anomalies: Dominant inheritance with reduced penetrance and variable expression of a defective gene on the long arm of chromosome 8 at locus 22.2. The possible role of PAX1 in the pathogenesis of Klippel-Feil syndrome is the object of studies.^183,184

Key Points: The clinical triad consists of short neck, low posterior hairline, and limited neck movement.

Differential Diagnosis: Iniencephaly presents with similar opisthotonos but appears more severe (cervical spina bifida); dyssegmental dysplasia presents with similar vertebral findings but adds short limbs and cephaloceles. It is unclear whether Klippel-Feil syndrome is a discrete entity, or if it is part of other syndromes, including segmentation syndrome 1 (Kippel-Feil syndrome with laryngeal malformation) and Murcs association (Müllerian duct aplasia, unilateral renal agenesis, and cervicothoracic somite anomalies).

Prognosis: The complications result from the vertebral fusion and include cord compression syndrome, cervical instability, and motility impairment.

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling.

Synonyms: Klippel-Trenaunay syndrome, angio-osteohypertrophy syndrome, Parkes-Weber syndrome.

Definition: In 1990, Klippel and Trenaunay originally described the entity of limb overgrowth, multiple cutaneous angiomata, and varicose veins, which was confirmed by Parkes-Weber in 1918 and extended by the infrequent finding of arteriovenous fistulae. This syndrome is a rare congenital soft tissue anomaly, with sporadic occurrence, characterized by a triad of multiple hemangiomas, arteriovenous fistulas, and unilateral limb hypertrophy due to bony and soft tissue overgrowth.^186,187

Incidence: Rare.

Etiology: Happle suggested a predominant inheritance that most satisfactorily explains the findings. Heterozygous individuals for a single gene defect are phenotypically normal. The trait is expressed only when a somatic mutation occurs in the normal allele at an early stage of embryogenesis. The embryo is then a mosaic of homozygous or heterozygous cell lines for the mutation. This explains the patchy distribution of the defect.^{186, 187, and 188}

Pathogenesis: The exact mechanism causing Klippel-Trenaunay-Weber syndrome is not known. A mesodermal defect affecting angiogenesis and associated with persistence of the embryonic vascular network might explain the vascular anomalies. Others have suggested that a disturbance in the regulation of tissue growth factors is the underlying mechanism.

Diagnosis: Diagnosis has been made as early as 14 weeks' gestation and is based upon the association of cutaneous or subcutaneous cystic or multicystic lesions and marked enlargement of the soft tissues of a limb or other part of the fetal body (Figures 20-75 and 20-76). Other findings include hydrops fetalis (from high-output cardiac failure), ascites, abnormal abdominal hemangiomatous masses, and hepatomegaly.¹⁸⁹

Genetic Anomaly: This may be due to a single gene defect on either chromosome 5q or p11.

Associated Anomalies: Kasabach-Merritt syndrome of thrombocytopenia due to platelet consumption within the hemangioma, malformation of hands and feet (syndactyly, polydactyly, and macrodactyly), face (asymmetric facial hypertrophy, hemangiomata), brain (calcifications, macrocephaly), and eyes (cataracts).

Key Points: Multiple cutaneous hemangiomata of complex texture and having both anechoic and echogenic areas that may involve any part of the body, but mainly a single lower extremity, buttocks, abdomen, or torso, and vary from simple varicosities to cavernous hemangiomata.¹⁸⁶

Differential Diagnosis: Lymphangioma, Proteus syndrome, and fetal thoracic mass (even if color flow Doppler studies of the mass are negative), Beckwith-Wiedemann syndrome.

Prognosis: When detected prenatally, the disorder is usually more severe and the prognosis is poor when associated with cardiac insufficiency. The ultimate prognosis depends on the location and size of the hemangiomata, which may bleed, leading to life-threatening hemorrhages.^189,190

Recurrence Risk: Probably none, although some cases have raised the possibility of autosomal dominance.

Management: Termination of pregnancy can be offered in the severe forms; otherwise, no alteration of management is expected. Given the rarity of the disease, there isn't enough information available to counsel patients regarding obstetric outcome.

Synonyms: None.

Definition: In 1950, Larsen originally described 6 cases of children who presented with essentially a flat face, a prominent forehead, hypertelorism, and multiple joint luxations. Another 200 cases have been described since. It consists of skeletal dysplasia with multiple joint dislocations, short stature, and abnormal facial features. There are 2 forms of the syndrome: a lethal and a nonlethal form. The lethal form is usually fatal due to pulmonary hypoplasia.^191,192

Incidence: It is a rare anomaly with an estimated incidence of 1 in 100,000 births.

Etiology: Both autosomal dominant and autosomal recessive patterns of inheritance have been reported.

Pathogenesis: Generalized mesenchymal disorder involving connective tissues due to a decreased α-1/α-2 chain ratio in type I collagen.^191,192

Diagnosis: The abnormal joint with dislocations (hip dislocation, genu recurvatum, club hands from accessory carpal bones, club feet) can be associated with rhizomelic shortening of the upper extremities and with hypoplastic fibula (Figures 20-77, 20-78, and 20-79). A coronal cleft in the vertebral body can also be recognized. At the level of the face, a low nasal bridge, frontal bossing, micrognathia, and hypertelorism can be observed. The neurological defects associated with Larsen syndrome include agenesis of the corpus callosum, hydrocephaly, and hearing defects.^{191, 192, 193, and 194}

Associated Anomalies: Some associated anomalies have also been reported including cleft palate, cervical spine instability, cardiac defects, and pulmonary hypoplasia.

Genetic Anomalies: The gene locus is at 3p21.1-p14.1.¹⁹²

Key Points: Skeletal dysplasia occasionally characterized by short stature, multiple joint luxations, and characteristic facies (wide-spaced eyes, flattened nasal bridge, and prominent forehead).

Differential Diagnosis: It has to be differentiated from congenital genu recurvatum (CGR), arthrogryposis multiplex congenital, Pena-Shokeir phenotype, and cerebro-oculo-facio-skeletal syndrome. In the absence of familial history, these patients are usually identified as having arthrogryposis.^191,192

Prognosis: When recognized, the tracheomalacia, pulmonary insufficiency, and vertebral instability (cervical kyphosis from marked hypoplasia of 1 or 2 vertebral bodies—usually the fourth or fifth cervical vertebra) can be managed to improve the prognosis but only for the nonlethal form.

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling.^191,192

Synonyms: None.

Definition: Massive and early hydrops with cystic hygroma and joint contractions. Pterygium is used to describe webbing of the skin across the joint. The term means "wing-like." Limb pterygia at birth indicates an abnormal developmental process probably occurring in the first trimester and involving reduced mobility of the webbed limb. The severity of the web appears to correlate directly with the degree of hypomobility of the affected joint and with the time in development at which the movement reduction began. This syndrome consists of a constellation of multiple anomalies associated with fetal akinesia sequence and fixation and hypomobility of the joints.¹⁹⁵

Incidence: Unknown, but not rare in the first trimester.

Etiology: Autosomal recessive syndrome, with a few cases suggesting an X-linked transmission or a glycogen storage disease type IV.¹⁹⁵

Pathogenesis: The data suggest that the syndrome combines the manifestations of a jugular lymphatic obstruction sequence with those of an early severe fetal akinesia sequence with 2 possible mechanisms: an abnormally fragile collagen constitution or an early fetal muscular "dystrophy."

Diagnosis: In the first trimester, the appearance of a thickened nuchal lucency extending around the whole body and, to a lesser extent, the limbs is characteristic (Figures 20-80 and 20-81).¹⁹⁶ These fetuses have hydrops and bob along in the fluid when shaken. Occasionally the diagnosis is not made until later in the pregnancy, at a time when the hypokinesia, the joint contractions, and the multiple pterygia are more visible. Other findings can be polyhydramnios, craniofacial/ocular findings, short forearms of the fetus, pulmonary hypoplasia, diaphragmatic hernia, scoliosis, and fractures.¹⁹⁷

Genetic Anomalies: Unknown.

Key Points: Cystic higroma, hydrops, hipokinesia.

Differential Diagnosis: Some of the severe aneuploidies may also present with hydrops before 20 weeks. The arthrogryposes (fetal akinesia sequence), the cerebro-oculo-facio-skeletal syndrome and the Pena-Shokeir syndrome show joint contractions as well, so they should be considered in the differential diagnosis. But the most obvious ultrasound finding in lethal multiple pterygium syndrome is not the contractions but the hydrops. Limited pterygia of the popliteal regions can also be seen in fetuses with caudal regression syndrome. Noonan syndrome also presents with cystic hygroma.¹⁹⁷

Associated Anomalies: Some vertebral and other bony anomalies can be present.

Prognosis: Lethal.

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen. Confirmation of diagnosis after birth is important for genetic counseling.

Synonyms: Dysencephalia splanchnocystica, Meckel-Gruber syndrome, Gruber syndrome.

Definition: Meckel-Gruber syndrome was first described by Meckel in 1898 and later by Gruber as a lethal syndrome characterized by occipital cephalocele (80%), postaxial polydactyly (75%), and dysplastic cystic kidneys (95%).¹⁹⁸

Incidence: The incidence of Meckel syndrome is 0.2 per 10,000 live births. Salonen stated that the incidence of Meckel syndrome at birth varies from 0.07 to 0.7 per 10,000 births. In Finland, the disorder is unusually frequent and reaches 1.1 per 10,000 births. It is also estimated that this syndrome corresponds to 5% of all neural tube defects.^198,199

Etiology: Autosomal recessive inheritance.

Genetic Anomalies: The locus for Meckel syndrome is on chromosome 17, long arm, region 2, bands 1 to 4. Phenotype variability and cases that did not have confirmed linkage to 17q suggest that there is some degree of locus heterogeneity.¹⁹⁹

Diagnosis: Finding at least 2 of the 3 features of the classic triad: occipital cephalocele (Figure 20-82), dysplastic cystic kidneys (Figure 20-83), and postaxial polydactyly (Figure 20-84). The kidneys, initially, have microscopic cysts that develop, destroying the parenchyma and enlarging the organ up to 10 or 20 times. The syndrome can be confidently detected and diagnosed by sonography at the 11th to 14th gestational week.²⁰⁰ Unfortunately, the first sonographic finding is often oligohydramnios, which makes it more difficult to establish the diagnosis. It is caused by renal dysfunction, and it develops early in the second trimester when the kidneys replace extracellular diffusion as the main source of amniotic fluid. However, some cases of Meckel syndrome have normal amniotic fluid, and thus the presence of normal fluid does not exclude the diagnosis. Sometimes, absence of the bladder can also be recognized. An early sonogram with normal kidneys, in a family at risk for recurrence, does not exclude Meckel syndrome, and a follow-up at 20 weeks of gestation is recommended.²⁰¹ Occipital cephalocele is present in 60% to 80% of cases. Maternal serum or amniotic fluid–fetoprotein level may be normal, as a membrane may cover the cephalocele. Postaxial polydactyly is present in 55% to 75% of cases.

Key Points: Finding at least 2 of the 3 features of the classic triad (occipital cephalocele, postaxial polydactyly, and dysplastic cystic kidneys) in the presence of normal karyotype makes the diagnosis (Figure 20-85).²⁰²

Differential Diagnosis: Because of several sonographic similarities between these conditions, trisomy 13 must be excluded by karyotype. Another possible differential diagnosis is autosomal dominant polycystic kidney disease.

Associated Anomalies: The constellation of possible anomalies associated with this syndrome is extensive and includes microcephaly, micrognathia, cleft palate, atrioventricular septal defects, single umbilical artery, ambiguous genitalia, hypoplastic bladder, bowed long bones, and others.²⁰²

Prognosis: Meckel syndrome is a lethal disorder. Most infants are stillborn or die hours or days after birth. A few sometimes survive a few months with poor quality of life.

Recurrence Risk: A 25% recurrence risk is involved.¹⁹⁹

Management: A karyotype study should be obtained when Meckel syndrome is suspected in order to exclude chromosomal disorders. If the diagnosis is made before viability, termination can be offered. When the family decides to continue the pregnancy, or if the diagnosis is made after viability, the standard obstetrical management is not altered.

Synonyms: Monosomy X, Ullrich-Turner syndrome.

Definition: Chromosomal disorder of female patients, described by Turner in 1938, characterized by the absence of one X sex chromosome (45, XO).^{203, 204}

Incidence: 2.5 to 5.5 per 10,000 live birth females in white population. 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.^203,204

Etiology: Absence of one sex chromosome, in general the paternal chromosome, which occurs sporadically in most cases. Eight to sixteen percent of all cases are mosaic. Advanced maternal age is not associated with this aneuploidy.

Pathogenesis: In general, the cystic hygroma is consistent with a large septated cystic mass posterior to the neck, due to a dilatation of the jugular lymphatic sacs. It is caused by a developmental delay in the connection with the venous system, or a primary abnormal dilatation or proliferation of the lymphatic channels interfering with a normal flow between the lymphatic and venous systems (Figures 20-86 and 20-87).^{203, 204, and 205}

Diagnosis: Cystic hygroma is the most characteristic prenatal feature in this syndrome. Spontaneous remission of the cyst may occur, in many cases resulting in webbing of the neck. Other common findings include lymphedema, in particular of the dorsum of the hands and feet, or in the more severe cases anasarca, hydrops, short cervical spine, intrauterine growth retardation, short neck, prominent auricles, horseshoe kidney, heart defects (coarctation and bicuspid aortic valve), fetal tachycardia, bone dysplasia, short stature, and umbilical cyst. Dysgenesis of the ovaries occurs in 90% of cases, causing absent menses and infertility in adult life. Variable degrees of mental and developmental retardation are also frequently seen. Elevated maternal serum β human chorionic gonadotropin (hCG) has been reported in association with Turner syndrome.^{203, 204, 205, and 206}

Key Points: Cystic hygroma, lymphedema, anasarca, and hydrops.

Differential Diagnosis: Head and neck cystic mass, such as cephalocele and meningocele, must be excluded. Often, the angle of junction of the cystic mass with skin can be used in the differential diagnosis. Cystic hygromas that lift the subcutaneous tissues tend to have a smooth junction angle, whereas cephaloceles that herniate through the skin tend to have an acute angle of junction. Cystic hygromas may occasionally be present in Roberts syndrome, and other autosomal recessive disorders. Chromosomal analysis can exclude these conditions.

Genetic Anomalies: Absence of or structural abnormalities of one X chromosome, such as deletion of the sex-determining region (XY Yp deletion) or mosaicism (45, X1 46, XX, or 45XI 46XY), can also be responsible for this condition.²⁰³

Associated Anomalies: Other manifestations include intrauterine growth restriction and cardiovascular anomalies such as aortic valve malformations (bicuspide aortic valve) and coarctations.

Prognosis: Intrauterine demise occurs in many cases, generally caused by hydrops, which is the major intrauterine complication. Among survivors, the prognosis will depend basically on the severity of the associated anomalies. Cases of mosaicism tend to have a better prognosis, and in some cases with discrete manifestations the syndrome remains undiagnosed for years.²⁰⁴

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.

Management: A karyotype is recommended when Turner syndrome is suspected. Termination of pregnancy can be offered before viability. After viability, standard prenatal care is not altered. The major considerations regarding the long-term follow-up include treatment of short stature and cardiovascular abnormalities.

Synonyms: Turner syndrome with normal karyotype, female pseudo-Turner syndrome, male Turner syndrome.

Definition: Noonan syndrome is an autosomal dominant dysmorphic syndrome characterized by hypertelorism, a downward eyeslant, and low-set posteriorly rotated ears.¹

Incidence: Its prevalence is 4 to 10 per 10,000 births. Females and males are equally likely to be affected.²⁰⁷

Etiology: Autosomal dominant with sporadic new mutations.²⁰⁷

Diagnosis: The initial anomaly most likely to be observed is a posterior nuchal cystic hygroma, which may regress later in the gestation into a nuchal fold redundancy and/or pterygium colli (Figure 20-88). Other fetuses have been suspected because of special facial features (low-set ears, depressed nasal bridge, and large head), congenital heart disease, pleural effusions, renal abnormalities, polyhydramnios, short stature, hydrops, and familial history. Congenital heart disease may appear in up to 60% of Noonan syndrome patients including left ventricular hypertrophy (25%; Figure 20-89), pulmonary stenosis (19%), atrial septal defect (10%), or dysplastic pulmonary valve (7%). In fact, cardiac abnormality associated with cervical lymphatic abnormalities may provide the only clues to diagnoses of Noonan syndrome.^{207, 208, 209, and 210}

Although the phenotype is distinctive and the syndrome may manifest at birth, the mean age when Noonan syndrome is diagnosed is 9 years, as the dysmorphic features can be subtle.

Genetic Anomalies: X-linked dominant inheritance of either a single mutant gene or a submicroscopic deletion was originally suspected, but now it is recognized that one of the genes for Noonan syndrome is located on chromosome 12 in the 12q24.2–q24.31 region.

Key Points: Cervical lymphatic abnormalities in association with cardiac abnormality.⁴

Differential Diagnosis: Turner syndrome (excluded in boys or otherwise by karyotype) is also unlikely to be familial, whereas Noonan syndrome has a strong familial predilection; trisomy 21; Escobar syndrome.

Associated Anomalies: Other anomalies include lymphedema; pterygium colli; deformity of the sternum with precocious closure of sutures, resulting in a pectus carinatum superiorly and a pectus excavatum inferiorly; coarctation of the aorta; cryptorchidism; and thrombocytopenia.

Prognosis: Fairly normal life expectancy for those without major complications of heart disease.

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation of the pregnancy is chosen.

Synonyms: Mosaic tetrasomy 12 p, Teschler-Nicola/ Killian syndrome, isochromosome 12p syndrome.

Definition: It is a sporadic chromosomal anomaly, caused by a tissue-specific mosaic distribution of an additional isochromosome 12p.²¹¹ About only 60 cases of prenatal diagnosis of Pallister-Killian syndrome have been reported.²¹¹

Incidence: Human autosomal tetrasomies are rare. Among them, tetrasomy 12p is undoubtedly the least unusual. It is more common in women of advanced age.

Etiology: Tissue-specific mosaic distribution of an additional isochromosome 12p. The chromosomal abnormality is observed in either a mosaic or a nonmosaic state on selected tissues, such as bone marrow and skin fibroblast. It generally occurs as a mosaic and the pattern intensity varies from one tissue to another. The reference tissue for isochromosome 12p is the skin fibroblast where the abnormality is most common and clear.²¹¹

Pathogenesis: Tetrasomy 12p is not always diagnosed because the tissues are differently affected. Although it is present in a high percentage of fibroblasts, it is practically absent from the blood. Individuals with Pallister-Killian syndrome are often mosaic of isochromosome 12p, but in some case, the degree of mosaicism in the chorion villus sample is much lower than that in the fetal tissues subsequently examined. Confined placental mosaicism is a well-recognized phenomenon in a number of chromosomal abnormalities and is said to contribute to their intrauterine survival.

Diagnosis: Sonographic findings include facial anomalies such as eye defects (hypertelorism), prefrontal edema, flat profile with a small nose and thin lips, but never micrognathia or clefting; fetal hydrops in the first trimester or a thick nuchal fold; pulmonary abnormalities; heart defect; diaphragmatic defects; rhizomelic limb shortening; acral hypoplasia; square hands; syndactyly, polydactyly; urogenital abnormalities; and rare acral hypoplasia. In such cases the detection of the typical profile may contribute to establishing a diagnosis.^{211, 212, 213, and 214}

Key Points: Abnormal facial profile (flat profile with a small nose and thin lips), hypertelorism, and prefrontal edema (Figures 20-90, 20-91, and 20-92).