Definition

Fetal cytomegalovirus (CMV) infection is a congenital disorder characterized by hydrops, ascites, and ventriculomegaly caused by transplacental transmission of CMV 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. Congenital infection is mostly caused by maternal primary infection.

Synonym

Fetal cytomegalovirus infection is also known as congenital cytomegalovirus infection.

Etiology

Cytomegalovirus (a double-stranded DNA herpes group virus) is the cause of the infection.

Incidence

Congenital CMV infection occurs in approximately 1% of all deliveries and is the most common congenital infection. 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.

Diagnosis

CMV infection, as well as other congenital infections, should be suspected whenever nonimmune hydrops is found. Other suggestive findings include intracranial calcifications and intracranial hemorrhage, microcephaly, brain atrophy, abnormal periventricular echogenicities, intraparenchymal foci, ventriculomegaly, intraventricular adhesions, periventricular pseudocysts, sulcation and gyral abnormal patterns, hypoplastic corpus callosum, cerebellar and cisterna magna abnormalities, signs of striatal artery vasculopathy, splenomegaly, chorioretinitis, occlusion of the foramen ovale, signs of right-sided heart overload from the premature closure, ascites, hyperechoic bowel, fetal growth restriction, and oligohydramnios. Most features can be found by sonography beginning at approximately 20 weeks’ gestation. Whenever maternal infection is confirmed, polymerase chain reaction (PCR) testing of amniotic fluid should be performed. PCR testing of amniocentesis samples should be performed after a 6-week interval following the diagnosis of maternal infection and is most sensitive after 21 weeks’ gestation. The diagnosis can also be made by histologic study of typical inclusion bodies in biopsy or autopsy specimens. Focal sonographic periventricular increased echogenicity associated 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 a marker of encephalitis following CMV infection. 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. CMV 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 CMV 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 CMV infection but may occur. Cardiovascular, gastrointestinal (GI), musculoskeletal, and ocular lesions may be found in association with the classic features. Petechiae, sensorineural hearing loss, and poor intellectual development may also occur after birth.

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 many congenital infections. Conditions that present with 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 CMV infection do poorly, with a neonatal mortality rate of 5%, and 50% to 60% of survivors suffer severe long-term neurologic morbidity. CMV hepatitis is reversible in survivors, but intellectual disability, motor deficits, and hearing loss are expected long-term sequelae. Late sequelae, such as sensorineural hearing loss and neurodevelopmental disorders, occur in 10% to 15% of infants lacking symptoms at birth. Pediatric neurologic morbidity is related to the degree of antenatal ventriculomegaly and, when greater than 15 mm, is associated with an increase in abnormal neurologic development. A normal ultrasound examination does not exclude the possibility of symptoms in the newborn or long-term complications.

Recurrence Risk

Given that viral infection confers immunity in most patients, there is only a small theoretical risk of reinfection in another pregnancy.

Management

Termination of pregnancy can be offered before viability. If continuation of the pregnancy is chosen, follow-up with ultrasound examinations every 2 to 4 weeks is recommended to monitor for growth restriction, hydrops, and other fetal manifestations. Antiviral medications have not been shown to decrease the rate of perinatal trans­mission. Trials are under way for treatment of pregnant women with CMV infection early in pregnancy with hyperimmunoglobulin therapy.

Sonogram of a second trimester fetus with proven cytomegalovirus infection. Hepatic calcifications ( arrows ) are seen as well as fetal ascites ( asterisk ).

Definition

Infection with parvovirus B19 causes erythema infectiosum and is a common childhood illness characterized by a “slapped cheek” facial appearance and a lacy erythematous rash on the trunk and extremities. Patients may have systemic symptoms prior to the appearance of the rash, including arthropathy.

Synonym

Fetal parvovirus B19 infection is also known as fifth disease.

Etiology

Acute maternal parvovirus B19 viremia leads to transplacental passage of the B19 virus and subsequent fetal infection.

Incidence

Acute parvovirus B19 infection occurs in 3% to 4% of pregnant women, with the highest infection rates in school teachers and day care workers. Approximately 35% to 53% of pregnant women have immunity from a prior infection.

Pathogenesis

The interval between maternal infection and fetal hydrops is about 3 weeks, and 93% of cases of fetal hydrops occur within 8 weeks of maternal diagnosis. Acute infection can lead to fetal loss or hydrops fetalis. Hydrops occurs because parvovirus B19 preferentially infects rapidly dividing cells and is cytotoxic to fetal red blood cell precursors, leading in some cases to severe fetal anemia and subsequent hydrops. Parvovirus B19 can also infect myocardial cells and cause myocarditis; this infection may also initiate apoptosis in cells. The risk of hydrops is greater if infection occurs in the first half of pregnancy. Hydrops can either lead to rapid fetal death or resolve spontaneously (although the rate of spontaneous resolution is uncertain).

Associated Anomalies

In case reports, other congenital abnormalities have been noted, including ocular abnormalities, hydrocephalus, cleft lip/palate, joint webbing, musculoskeletal anomalies, hepatocellular damage, myocarditis, congenital cardiomyopathy, and myositis.

Diagnosis

Acute maternal parvovirus infection can be diagnosed by positive IgM serologic findings; IgM can be detected 10 days after infection and may persist for 3 months or longer. IgM can be falsely negative, however, and failure to detect IgM antibodies therefore does not rule out B19 infection. Parvovirus B19 IgG develops several days after IgM and indicates past infection. Maternal B19 viremia can also be confirmed by PCR with improved sensitivity. Fetal parvovirus infections can be confirmed by PCR for B19 DNA in amniotic fluid.

Differential Diagnosis

Differential diagnosis includes other conditions leading to nonimmune hydrops in the fetus.

Prognosis

Risk of fetal death is largely limited to parvovirus B19 infections diagnosed in the first half of pregnancy (13% in first trimester, 9% from weeks 13 to 20, and <1% after 20 weeks). Intrauterine transfusion of hydropic fetuses improves prognosis. In addition to fetal anemia, severe fetal thrombocytopenia can occur and lead to exsanguination at the time of intrauterine red blood cell transfusion. Children who survive fetal hydrops generally do well; an increased risk of developmental delay has been reported, but this has not been demonstrated in all studies.

Recurrence Risk

There is virtually no recurrence risk because pathogenesis occurs with primary maternal parvovirus B19 infection.

Management

Pregnant women exposed to parvovirus should have serologic testing for B19 IgM and IgG; positive IgG indicates maternal immunity, and the fetus should be protected. A positive IgM antibody indicates acute infection. Fetal intervention prior to 18 to 20 weeks is often not feasible, and transfusions this early in gestation are associated with an increased risk for fetal loss. Women diagnosed after 20 weeks should receive weekly ultrasound examinations to assess for fetal anemia and hydrops for at least 8 weeks after infection. If severe anemia is detected, intrauterine fetal blood transfusion is indicated.

Parvovirus infection. Ascites ( A ) and pericardial effusions ( B ) in a fetus with anemia due to parvovirus infection. Fetal ascites is often the initial sonographic finding in parvovirus infection.

Definition

Fetal rubella syndrome is a congenital disorder resulting from primary maternal infection with the rubella virus. It is characterized by deafness, mental retardation, congenital cataract, heart defects, and other structural anomalies found with variable severity and frequency. The rate of congenital infection with acute rubella during pregnancy is higher than 90% in the first 12 weeks of pregnancy, approximately 60% in weeks 13 to 17, 25% in weeks 18 to 24, and increases again during the last month of pregnancy.

Synonyms

Synonyms for fetal rubella syndrome are fetal rubella effects, congenital rubella syndrome, and German measles.

Etiology

Fetal rubella is caused by an RNA togavirus, which is the only member of the genus Rubivirus . The fetus is infected by transplacental transmission followed by hematogenous spread.

Recurrence Risk

There is no recurrence risk of fetal rubella syndrome.

Incidence

Cases of fetal rubella syndrome are rare in the United States since 2004 following comprehensive vaccination; however, reinfection after vaccination is possible. There were 13 cases reported in the United States between 2001 and 2004. It remains a clinical issue in other parts of the world.

Diagnosis

The most frequent sonographic findings are cardiac malformations (in particular, septal defects), eye defects (cataracts, microphthalmia, and retinopathy), microcephaly, hepatomegaly, splenomegaly, and growth restriction. The risk of congenital defects is limited to maternal infection during the first 16 weeks of pregnancy. Sensorineural hearing loss and developmental delay are also associated with congenital rubella sydrome. The confirmation of fetal infection can be made by isolating rubella viral RNA from amniotic fluid samples and testing using PCR.

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 pulmonary stenosis.

Differential Diagnosis

Other conditions associated with congenital hepatomegaly and cataracts should be considered. This includes other congenital infections (TORCH [ t oxoplasmosis, o ther infections, r ubella, c ytomegalovirus, h erpes simplex]), fetal anemia, fetal liver tumors, chondrodysplasia punctata, Neu-Laxova syndrome (NLS), Smith-Lemli-Opitz (SLO) syndrome, and Walker-Warburg syndrome.

Prognosis

Spontaneous abortion and intrauterine death may occur. The postnatal impact of intrauterine infection varies from absence of any defect to all the anomalies mentioned earlier with variable severity. The virus may remain for years in body tissues, causing complications of chronic infection (such as diabetes mellitus from chronic viropathy of the pancreas).

Management

Termination of pregnancy should be discussed when fetal infection is detected during the first trimester, owing to the severity of the condition in this group. After viability, monthly ultrasound examinations for growth and follow-up of the anomalies are recommended.

Prevention

Women found to be rubella nonimmune during pregnancy should be offered vaccination postpartum prior to discharge from the hospital. Breastfeeding is not a contraindication to vaccination.

Definition

Fetal syphilis is caused by fetal infection with the spirochete Treponema pallidum, which readily crosses the placenta leading to fetal infection.

Synonym

A synonym for fetal syphilis is congenital syphilis.

Etiology

Maternal infection with T. pallidum leads to transplacental transmission of the virus and resultant fetal infection.

Incidence

Incidence in 2008 was 10.1 cases per 100,000 liveborn infants with many cases found in women without prenatal care. The risk of transmission is higher for primary and secondary syphilis (50%) than for early latent (40%) and late (10%) syphilis. Transmission can occur at any gestational age. The frequency of vertical transmission increases as gestation advances but severity decreases with infection later in pregnancy.

Diagnosis

In women with positive syphilis testing, clinical findings concerning for congenital syphilis include growth restriction, as well as liver and placental findings. Signs of liver dysfunction include hepatomegaly and ascites, which can lead to nonimmune hydrops. The placenta is typically large and edematous. Silver-staining of the placenta following delivery is positive for spirochetes. Fetal serologic tests are positive for antitreponemal IgM.

Associated Anomalies

Clinical findings in neonates may include the following:

• •
  

  Early congenital syphilis: hepatomegaly, syphilitic rhinitis (“snuffles”), maculopapular rash, generalized lymphadenopathy, and skeletal abnormalities.

  
  
• •
  

  Late congenital syphilis (generally a result of gumma formation in various tissues): facial features (frontal bossing, saddle nose, short maxilla), eye findings (interstitial keratitis, glaucoma, corneal scarring, optic atrophy), sensorineural hearing loss, Hutchinson teeth, mulberry molars, perforation of hard palate, rhagades, gummas, anterior bowing of shins (“saber shins”), and paroxysmal cold hemoglobinuria.

Differential Diagnosis

Findings in neonates can resemble other congenital infections.

Prognosis

The severity of fetal effects depends on the duration of infection as well as the stage of development at the time of infection.

Recurrence Risk

Recurrence is likely only if maternal syphilis infection remains untreated.

Management

All women presenting for prenatal care should be evaluated for syphilis infection. If positive, penicillin treatment should be given; regimens vary according to the chronicity of the disease. If the duration of the disease is unknown, three doses of benzathine penicillin given at weekly intervals is recommended. If maternal syphilis is treated at least 30 days prior to delivery, only 1% to 2% of infants will be infected. This rate is greater than 70% if maternal syphilis remains untreated. If maternal syphilis is diagnosed after 20 weeks’ gestation, an ultrasound examination should be obtained to assess for congenital syphilis.

Syphilis. Darkfield micrograph of Treponema pallidum , the organism that causes congenital syphilis.

(From Centers for Disease Control and Prevention: Sexually Transmitted Diseases, 2016. Available at http://www.cdc.gov/std/syphilis/images.htm .)

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.

Synonym

Fetal toxoplasmosis syndrome is also known as congenital toxoplasmosis.

Incidence

An estimated 400 to 4000 cases of congenital toxoplasmosis occur annually 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 the United States. The incidence of toxoplasmosis acquisition during pregnancy ranges from 1 to 4 per 10,000. Half of fetuses escape the infection, one third have subclinical infection, and about 10% have severe infection.

Etiology

Fetal toxoplasmosis is caused by transplacental transmission of parasites following maternal primary infection. Transmission from mothers with chronic infection via reactivation is rare but can be caused by immunologic dysfunction. The rate of fetal transmission increases greatly as the gestational age at time of seroconversion increases, with transmission rates of 25%, 54%, and 65%, in the first, second, and third trimesters, respectively.

Pathogenesis

The fetus is infected hematogenously through 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.

Diagnosis

The classic triad suggestive of congenital toxoplasmosis includes chorioretinitis, intracranial calcifications, and hydrocephalus. Less common findings include ascites, pericardial and pleural effusions, and intrahepatic densities. 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 left untreated, congenital toxoplasmosis can be associated with severe and even fatal disease. Other findings include microcephaly, encephalomyelitis, seizures, intellectual disability, ascites, and hepatosplenomegaly. The diagnosis can be made by using PCR to detect of Toxoplasma gondii in amniotic fluid, with increased sensitivity later in pregnancy.

Differential Diagnosis

Other TORCH infections should be considered.

Prognosis

Approximately 75% of congenitally infected newborns are asymp­tomatic.

Recurrence Risk

There is typically no recurrence risk.

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 should avoid changing cat litter or, if no one else is available to change the cat litter, use gloves, then wash their hands thoroughly.

Severe dilatation of posterior horns of the lateral ventricles in a fetus with toxoplasmosis infection.

(Courtesy of Julio Cesar Coub, 2006.)

Toxoplasmosis. Intracranial calcifications ( arrows ) in a fetus with toxoplasmosis infection.

(Courtesy of Julio Cesar Coub, 2006.)

Definition

Fetal varicella zoster is characterized by abnormalities of multiple organs caused by fetal infection with varicella following maternal chickenpox infection.

Synonyms

Fetal varicella zoster is also known as congenital varicella syndrome, varicella embryopathy, and chickenpox.

Incidence

The incidence of maternal varicella infection was 1 to 5 in 10,000 pregnancies in the United States in the 1980s but has decreased since vaccination began in 1995. The risk of fetal involvement among all pregnant women infected with varicella varies from 1% to 20%. First trimester varicella infections have been associated with an increased risk of spontaneous abortion. Second trimester varicella infections have been associated with 2% risk of a congenital syndrome characterized by limb hypoplasia, cutaneous scars, cataracts, microcephaly, and cortical atrophy.

Etiology

Herpesvirus is the etiologic agent.

Recurrence Risk

Recurrence risk is less than 1%.

Diagnosis

Maternal infection at any time in pregnancy exposes the fetus to a high risk of transplacental contamination and warrants follow-up. The risk of fetal anomalies, however, is the greatest from 8 to 20 weeks’ gestation. Sonographic signs of fetal disease include fetal demise, growth restriction, musculoskeletal abnormalities (such as clubfeet and abnormal position of the hands, caused by both necrosis and denervation of the affected tissue), limitation of limb extension due to cicatrices formation, cutaneous scars, 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. The placenta can show a multifocal chronic villitis with multinucleated giant cells. Fetal infection can be demonstrated by detection of varicella zoster virus DNA by PCR in fetal blood and amniotic fluid.

Pathogenesis

Maternal viremia leads to placental infection with subsequent fetal transmission. Direct damage occurs to fetal tissues by the neurotropic varicella virus.

Associated Anomalies

Congenital anomalies in multiple organs with variable severity can be seen in varicella embryopathy. Among survivors, intellectual disability, seizures, and limitation of movements may develop after birth. The virus may cause serious infections, particularly pneumonia, in adult women.

Differential Diagnosis

Other viral infections, vascular accidents, and amniotic band syndrome should be considered.

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 encephalitis, are indicators of an extremely high risk for fetal demise. The rate of fetal demise varies from 39% to 61%. Maternal infection in the first and early second trimester has a higher association with fetal anomalies, whereas third trimester infections have a higher risk for varicella zoster development at the neonatal period. A life-threatening illness may occur in the newborn when delivery occurs within 5 days of the onset of maternal illness.

Management

Termination of pregnancy can be offered before viability. If continuation of the pregnancy is chosen, ultrasound follow-up is recommended to assess for fetal anomalies, limb contractures, and other signs of fetal compromise. If maternal seroconversion is suspected for varicella zoster, prenatal sonography and MRI may document the extent of tissue damage and assist in counseling. After a therapeutic abortion, fetal infection can be confirmed by detection of varicella zoster viral DNA in fetal tissues and the placenta, as well as by histopathologic findings such as miliary calcified necroses in fetal organs.

Prevention

Serologic testing and vaccination should be offered to women of childbearing age, and women should be questioned prior to conception about varicella immunity. Susceptible pregnant patients should be counseled to avoid contact with individuals who have chickenpox. If exposure occurs, varicella zoster immunoglobulin should be administered within 96 hours in an attempt to prevent maternal infection. Susceptible neonates should also receive varicella zoster immunoglobulin. Acyclovir is active against the varicella zoster virus, and treatment is indicated in seriously ill adults and neonates.

Varicella zoster infection. The fetal face at autopsy (26 weeks). Note the collapsed cranium, intact skin (very little maceration), disproportionate necrosis of the ocular globes, and flattened midface.

(Courtesy of R.R. Lebel, 1992.)

Synonyms

FAS is one of the fetal alcohol spectrum disorders.

Incidence

The incidence of FAS ranges from 2 to 30 per 10,000 live births. FAS is the most common cause of intellectual disability in the United States and is thought to occur in 0.5 to 2.0 in 1000 births. The true extent of teratogenic injury from alcohol exposure exceeds the clinically recognized prevalence of FAS, because behavioral and physical teratogenesis may be present in the absence of full expression of the syndrome.

Etiology/Pathogenesis

FAS is caused by direct toxicity of alcohol and its metabolites that cross the placenta and are not detoxified by the fetal liver. Alcohol is a teratogen and inflicts irreversible damage on the CNS. The rate of alcohol elimination from the fetal compartment is only 3% to 4% that of the maternal rate. Alcohol has fetal effects in all trimesters of pregnancy.

Diagnosis

The findings include microcephaly, long round philtrum, small micrognathia, cleft palate, suppression of the cupid arch, microphthalmia, microcephaly, dysgenesis of the corpus callosum, malformed ears, atrial septal defect (ASD), ventricular septal defect (VSD), 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.

Differential Diagnosis

Other conditions that involve growth restriction and microcephaly, such as congenital infections and chromosomal anomalies, should be considered.

Prognosis

Intellectual disability and delayed growth persist postnatally. Most children with FAS have mild to moderate intellectual disability, but this can vary widely. The severity of intellectual disability 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, psychiatric disorders are highly prevalent in individuals with FAS, affecting more than 70% in one series, in which 60% had alcohol or drug dependence, 44% depression, and 40% psychosis.

Recurrence Risk

Recurrence risk is high (up to 70%) in subsequent pregnancies if mothers continue to drink alcohol.

Management

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

Characteristic facial features in a child with fetal alcohol spectrum disorders. Findings may include a smooth philtrum, thin upper lip, upturned nose, flat nasal bridge and midface, epicanthal folds, small palpebral fissures, and small head circumference.

(Courtesy Darryl Leja, NHGRI, National Institutes of Health.)

Characteristic features of an ear of a child with fetal alcohol spectrum disorders. Note the underdeveloped upper part of the ear parallel to the ear crease below (“railroad track” appearance).

(Courtesy Darryl Leja, NHGRI, National Institutes of Health.)

Characteristic features of a hand of a child with fetal alcohol spectrum disorders. Note the curved fifth finger (clinodactyly) ( small arrow ) and the upper palmar crease ( large arrow ) that widens and ends between the second and third fingers (“hockey stick” crease).

(Courtesy Darryl Leja, NHGRI, National Institutes of Health.)

Definition

Fetal valproic acid exposure syndrome results from maternal valproate (an anticonvulsant) use during pregnancy and is characterized by CNS dysfunction, spina bifida, developmental delay, fetal growth restriction, and cardiac anomalies.

Synonym

Depakote exposure is a synonym for fetal valproic acid syndrome.

Incidence

Fetal valproic acid syndrome is rare, and the incidence is unknown. Any epileptic pregnant mother has two to three times increased risk for congenital anomalies compared with the general population. If the exposure to valproic acid takes place between the 17th and 30th days after fertilization, the incidence of neural tube defects approaches 1% to 2%. In general, the teratogenic risks are higher with increasing doses of valproic acid, with a significantly higher rate of malformations in doses up to 1000 mg/day.

Etiology

Exposure to valproic acid is the cause of this syndrome.

Pathogenesis

The pathogenesis of fetal valproic acid syndrome is unknown.

Diagnosis

The findings include cardiovascular abnormalities, hypotonia, spina bifida, hypospadias, and limb reduction. The facial appearance can be characterized by an oral cleft, small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micrognathia/retrognathia. Fetal growth restriction, microcephaly, generalized hypertrichosis sparing palms and soles, coarse face, gum hypertrophy, clubfeet and clubhands, musculoskeletal abnormalities, genital abnormalities, and urogenital defects may also be present. Heart defects have also been reported. In 26% of patients with fetal valproic acid exposure syndrome, cardiovascular abnormalities, most frequently VSDs, aortic or pulmonary stenosis, and persistent ductus arteriosus also occur. Pulmonary hypoplasia is also reported. Epilepsy and intellectual disability may develop after birth.

Associated Anomalies

Associated anomalies include omphalocele, inguinal hernia, duodenal atresia, and scoliosis. Hyperbilirubinemia, hepatotoxicity, transient hyperglycinemia, afibrinogenemia, and fetal or neonatal distress may be found.

Differential Diagnosis

Neural tube defects of alternative origin should be considered. However, the clinical history in the presence of spina bifida and cardiac anomaly should suggest the diagnosis.

Prognosis

Fetuses with major anomalies have a poor prognosis. Metabolic disturbances may also complicate the neonatal period. Affected children can die in infancy, and the surviving patients can have intellectual disability.

Recurrence Risk

If the mother is exposed to valproic acid in a second pregnancy, the teratogenic effect is likely to be similar.

Fetal valproate syndrome. Note low-set ears, slanting forehead, broad nasal bridge, hypertelorism, epicanthal folds, depressed nasal bridge, long philtrum, upturned nose, thin upper llip, and small mouth .

(From Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN: Fetal valproate syndrome. Indian J Pediatr 73(10):937-939, 2006.)

Definition

Fetal warfarin syndrome is characterized by specific bone and cartilage abnormalities in the fetus, including nasal hypoplasia, limb hypoplasia, and stippled epiphyses. It is caused by fetal exposure to warfarin between weeks 6 and 12 of gestation.

Synonyms

Fetal warfarin syndrome has also been described as warfarin embryopathy and coumadin exposure.

Incidence

A wide range has been reported, but the best estimate is that less than 10% of exposed fetuses will have embryopathy. The teratogenic effect is dose-dependent, with greater safety if the dose is less than 5 mg/day.

Etiology

Warfarin freely crosses the placenta and is a known teratogen, with the highest risk between weeks 6 and 12 of gestation.

Pathogenesis

The pathogenesis is unknown. Some hypotheses suggest that the drug interferes with post-translational modification of calcium-binding proteins essential for the development of bony structures.

Diagnosis

Common sonographic findings include developmental abnormalities of bone and cartilage, specifically nasal and limb hypoplasia and stippled epiphyses.

Associated Anomalies

CNS abnormalities have been more rarely reported and include microcephaly, optic atrophy, intellectual disability, hypotonia, and spasticity.

Differential Diagnosis

Differential diagnosis includes other disorders affecting the bone and cartilage, specifically chondrodysplasia punctata.

Prognosis

Because warfarin freely crosses the placenta, it can cause fetal bleeding at any gestational age. The most serious fetal complications are related to cerebral hemorrhage. Data on long-term survivors are lacking.

Recurrence Risk

The recurrence risk is unknown. Fetal warfarin syndrome is related to warfarin exposure in subsequent pregnancy.

Management

When detected prior to viability, termination of the pregnancy can be offered. If the pregnancy continues, no alteration in management is needed. If warfarin is continued throughout the pregnancy, it should be discontinued at 34 to 36 weeks’ gestation and an alternative agent should be used for anticoagulation to minimize the risk of fetal bleeding at the time of delivery.

Profile of a fetus with nasal hypoplasia, as is seen with fetal warfarin syndrome.

Definition

Caudal regression syndrome is a rare congenital defect, characterized by the absence of the sacrum, variable defects of portions of lumbar spine, and anomalies in other systems.

Synonyms

Caudal dysplasia sequence and sacral agenesis are other terms that have been used to describe caudal regression syndrome.

Incidence

The incidence of caudal regression syndrome is 0.25 to 1 per 10,000 normal pregnancies. This risk is 200 to 250 times higher in diabetic pregnancies.

Etiology

The cause is unknown, but caudal regression syndrome is associated with maternal diabetes in 16% of the affected fetuses.

Recurrence Risk

This anomaly is not thought to be hereditary, and the recurrence risk is very small, although it is 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 clubfeet 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 decreased interspace between the femoral heads. Some sonographic planes of section will intersect the fetus at such an angle that no spine is visible, a very striking and probably pathognomonic finding. Decreased movement of the legs is frequently observed. First trimester diagnosis may be difficult because of 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 syndrome.

Genetics

The genetics of caudal regression syndrome is unknown.

Pathogenesis

This syndrome is thought to be due to disrupted maturation of the caudal portion of the spinal cord complex before 4 weeks’ gestation, leading to motricity deficits and neurologic impairment, varying from incontinence of urine and feces to complete neurologic loss.

Associated Anomalies

Anomalies of the central nervous, musculoskeletal, genitourinary, cardiac, respiratory, and GI systems may be found in association.

Differential Diagnosis

Sirenomelia is the main alternative diagnosis and was thought to be the most severe form of caudal regression syndrome previously; it is now considered a separate entity. Fusion of the lower extremities is generally seen in sirenomelia.

Prognosis

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

Caudal regression syndrome associated with poorly controlled maternal diabetes. A, Absent distal sacral spine ( arrow ); B, fixed extension of the lower extremity.

Caudal regression syndrome associated with poorly controlled maternal diabetes. Postnatal radiographs demonstrate vertebral segmentation abnormality ( A ) ( arrow ) and absent sacrum ( B ) ( arrow ).

Caudal regression syndrome. The lack of sacrum allows the iliac wings to be approximated, giving them a shield-like appearance ( arrow ).

Definition

Aicardi syndrome is a neurodegenerative disorder first described in 1965, characterized by cerebral atrophy, intracerebral calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serologic investigations for common prenatal infections. It was classically characterized by agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms.

Incidence

More than 100 cases have been reported. It is seen only in females and 47,XXY males.

Etiology

The disorder is thought to be caused by an X-linked dominant de novo gene mutation with lethality in 46,XY males. The causative gene has not been identified.

Genetics

The genetics of Aicardi syndrome are unknown.

Diagnosis

The diagnosis is based on clinical features, including chorioretinal lacunae, brain MRI findings (corpus callosum dysgenesis, cerebral asymmetry, periventricular and intracortical gray matter heterotopia, choroid plexus cysts, choroid plexus papillomas, ventriculomegaly), and skeletal findings (abnormal vertebrae and missing ribs). Increased levels of interferon-α can been found in fetal blood and cerebrospinal fluid.

Associated Anomalies

Other features include characteristic facial features, GI difficulties, small hands, vascular malformations, skin pigmentary lesions, and increased incidence of tumors. Infrequently, there is associated cleft lip and palate.

Differential Diagnosis

Consider other causes of dysgenesis of the corpus callosum, including infectious causes.

Prognosis

Survival is highly variable, with mean age of death at about 8 years old. Patients have profound intellectual disability and severe global developmental delay. Medically refractory epilepsy with a variety of seizure types develops over time. Multiple antiepileptic drugs are generally required for seizure control. Costovertebral defects can lead to scoliosis. Constipation and other GI problems are frequent.

Recurrence Risk

The recurrence risk is less than 1%.

Aicardi syndrome. A, Ventriculomegaly; dilated lateral ventricle ( arrow ) is demonstrated in an axial image; B, Dandy-Walker malformation with agenesis of the cerebellar vermis ( arrow ); C, coronal magnetic resonance image of the fetal brain demonstrating agenesis of the corpus callosum and an interhemispheric cyst.

Definition

Meckel syndrome (MKS) is a lethal ciliopathy characterized by occipital encephalocele, postaxial polydactyly of the hands and feet, and renal cystic dysplasia. It is commonly associated with ductal plate malformations of the liver.

Synonyms

Dysencephalia splanchnocystica and Meckel-Gruber syndrome are synonyms for MKS.

Incidence

The prevalence of MKS in Finland is estimated to be 1 in 9000. In U.S. and European populations estimates are 1 in 13,250 to 1 in 140,000. MKS is the most common syndromic form of neural tube defects and polydactyly. MKS includes approximately 5% of all neural tube defects.

Etiology

MKS is a ciliopathy, and the proteins encoded by the genes implicated in the disorder encode for proteins involved in primary ciliary function.

Genetics

The disorder is genetically heterogeneous. The earliest implicated genes include MKS1 and MKS3 . Polydactyly is commonly found with MKS1 mutations and is rare with MKS3 mutations. Milder CNS phenotypes are seen with MKS3 mutations. The list of involved genes now includes at least 13 genes, MKS1 through 10 , TMEM231 , TMEM237 , and C5orf42 . Inheritance is autosomal recessive with significant phenotypic variability. Many of the same genes are also involved in Joubert syndrome.

Recurrence Risk

There is a 25% recurrence risk for MKS.

Diagnosis

The disorder can be detected prenatally as early as 11 to 14 weeks. Cystic dysplastic kidneys are seen in almost all cases of MKS (95-100%). The kidneys initially develop microscopic cysts that destroy the parenchyma and enlarge the organ up to 10 or 20 times. Occipital cephalocele is present in 60% to 80%. Maternal serum or amniotic fluid alpha-fetoprotein (AFP) level may be normal, as a membrane may cover the cephalocele. Other CNS findings include Dandy-Walker malformation and hydrocephalus. Postaxial polydactyly is present in 55% to 75% of fetuses. Other limb anomalies, such as bowing and shortening, may also be present. Liver histologic examination commonly demonstrates ductal plate malformations. Unfortunately, the first sonographic finding is often oligohydramnios, which makes the diagnosis more difficult to establish. Oligohydramnios is caused by renal dysfunction and develops early in the second trimester when the kidneys replace extracellular diffusion as the main source of amniotic fluid. Some cases of MKS have normal amniotic fluid; thus, the presence of normal fluid does not exclude the diagnosis.

Differential Diagnosis

Conditions that can present with similar findings include trisomy 13 and 18, Joubert syndrome, Bardet-Biedl syndrome, and Smith-Lemli-Opitz syndrome. Karyotype and molecular genetic testing can assist in clarifying the diagnosis.

Prognosis

MKS is a lethal disorder. Most infants are stillborn or die hours or days after birth. A few have survived to a few months of age.

Meckel syndrome: occipital encephalocele ( arrow ).

(Courtesy of Marcos V. Sanchez, 2005. Available at thefetus.net .)

Meckel syndrome: cystic dysplastic kidneys.

(Courtesy of Marcos V. Sanchez, 2005. Available at thefetus.net .)

Meckel syndrome: polydactyly ( arrow ).

(Courtesy of Marcos V. Sanchez, 2005. Available at thefetus.net .)

A fetus with Meckel syndrome. Note the small posterior encephalocele, the large abdominal distention due to the bilateral cystic kidneys, and the postaxial polydactyly.

Definition

Lissencephaly is a cerebral developmental disorder, with agyria of the brain, which may be accompanied by pachygyria, minimal or no hydrocephalus, a wide cortical mantle, and characteristic dysmorphic features. The reduced or absent brain gyri are caused by disturbed neuronal migration in the neocortex. Miller in 1963 and Dieker in 1969 provided the first descriptions.

Synonyms

See later discussion of specific syndromes.

Incidence

Incidence is uncertain, but estimates range from 11.7 to 40 cases per 1 million births.

Etiology

Many of the causative genes for lissencephaly have now been identified (see later).

Pathogenesis

Lissencephaly is due to abnormal cortical development in which migration of neurons from the ventricular zone (a region close to the lateral ventricles) have slow or arrested migration to the cortical plate, leading to reduced folding or stranded neurons. Lissencephaly is now classified into types including the following.

Recurrence Risk

Recurrence risk is dependent on the particular lissencephaly syndrome.

Diagnosis

Sonographic diagnosis is difficult prior to the late second trimester, when the characteristic cerebral anomalies can be noted. The progressive microcephaly and failure of development of both sulci and gyri (which normally become well defined by 26 to 28 weeks) are suggestive of lissencephaly. Specific lissencephaly-related syndromes are difficult to differentiate prenatally. First-line genetic investigations involve chromosomal microarray, followed by next-generation sequencing multigene panels or exome sequencing.

Prognosis

Prognosis varies depending on the particular disorder.

Abnormal sylvian fissure/insula at 26 weeks. A, Axial ultrasound image at 26 weeks in a fetus with lissencephaly associated with Miller-Dieker syndrome shows a shallow, flat sylvian fissure/insula ( arrow ) with absence of angularity at the insular margins. Inset shows the expected appearance of the sylvian fissure/insula in a 26-week normal fetus. Infolding of the operculum should be seen with acute angles ( black arrows in inset) at the margins of the insula ( white arrowhead in inset) at 24.5 weeks’ gestation. Axial ( B ) and coronal ( C ) T2-weighted magnetic resonance images at 28 weeks in the same fetus with Miller-Dieker syndrome showing a shallow sylvian fissure ( arrow ). The brain has an hourglass or figure-of-eight appearance on the axial image. Also note the agyria, large subarachnoid space, and mildly dilated occipital horns.

(From Fong KW, Ghai S, Toi A, et al: Prenatal ultrasound findings of lissencephaly associated with Miller-Dieker syndrome and comparison with pre- and postnatal magnetic resonance imaging. Ultrasound Obstet Gynecol 24:716, 2004, used with permission.)

Definition

Septo-optic dysplasia is a syndrome characterized by anomalies of cerebral midline structures, such as absence of the septum pellucidum, congenital optic nerve dysplasia, and panhypopituitarism, leading to multiple endocrine defects (diabetes insipidus, hypogonadotropic hypogonadism, hypothyroidism, adrenal insufficiency, abnormal thyrotropin-releasing hormone test, gonadotropin-releasing hormone test, and gonadotropin hormone–releasing hormone test). Septo-optic dysplasia may represent a mild form of holoprosencephaly.

Synonym

Septo-optic dysplasia is also known as de Morsier syndrome.

Incidence

The incidence is estimated at 1 in 10,000 newborns.

Etiopathology

Environmental factors such as viral infections, medications, and vascular disruption have been postulated to play a role. The implicated genes (see later) are involved in embryonic development and are essential for formation of the eyes, the pituitary gland, and forebrain structures such as the optic nerves.

Genetics

Mutations in HESX1, OTX2, and SOX2 are thought to be causative in a small subset of patients.

Recurrence Risk

The recurrence risk is unknown, depending on the cause.

Clinical Findings

• •
  

  CNS: seizures, mental retardation, atrophy of the optic nerve, dilatation of the suprasellar cistern, empty sella, cortical atrophy and dystrophic corpus callosum, and anterior cephalocele.

  
  
• •
  

  Face: hypotelorism, microphthalmia, visual impairment with nystagmus, unilateral or bilateral optic disk hypoplasia with double rim appearance (choroidal pigment in the outer margin and pale nerve tissue in the inner), variable visual loss, coloboma, strabismus, astigmatism, bilateral cleft lip and palate, high arched palate, and flat nasal bridge.

  
  
• •
  

  Endocrine system: low growth rate and short stature. The most common problem is growth hormone deficiency (93%), followed by adrenocorticotropic hormone (ACTH) deficiency (57%), hypothyroidism (53%), diabetes, and gonadotropin deficiency. Hypothalamic dysfunction is the basic origin of these endocrine abnormalities. Septo-optic dysplasia is responsible for approximately 4% of all growth hormone deficiencies in children.

Diagnosis

Absence of the cavum septum pellucidum (CSP) is the most common finding. Sometimes, the standard sonographic views of the brain, obtained along the axial planes at midgestation, will fail to identify this absence. Absence of the CSP may not be detected because of the close proximity of the walls of the lateral ventricles, which are typically normal in size and may generate an artifact resembling a normal CSP. MRI is helpful for demonstration of hypoplastic optic tracts, allowing more definitive diagnosis. Hypotelorism, enlarged cerebral ventricles, communicating lateral ventricles, and bilateral cleft lip and palate have also been recognized prenatally.

Differential Diagnosis

Several variants with associated schizencephaly, dysgenesis of the corpus callosum, or microphthalmos, as well as incomplete forms, have been described. Lobar holoprosencephaly may also resemble septo-optic dysplasia.

Prognosis

The variable degree of intellectual disability (from minimal to severe), as well as the presence of multiple endocrine dysfunctions, affects the prognosis for each infant. Hyperthermia (in case of fever), dehydration (fever and diabetes insipidus), and other endocrine dysfunctions should be investigated and corrected.

Second trimester sonogram of the fetal head in a patient with septo-optic dysplasia. Absence of the septum pellucidum and communication of the frontal horns of the lateral ventricles ( arrows ) is seen.

Definition

Tuberous sclerosis is characterized by abnormalities of the skin (facial angiofibromas, hypochromic patches), brain (cortical tubers, subependymal nodules and giant cell astrocytomas, seizures, intellectual disability), kidneys (cysts, renal cell carcinomas, angiomyolipomas), heart (rhabdomyomas, arrhythmias), and lungs (lymphangioleiomyomatosis).

Synonyms

Tuberous sclerosis is also called Bourneville sclerosis and Bourneville disease.

Incidence

The incidence of tuberous sclerosis is up to 1 in 5800 births. Onset occurs in the first decade of life.

Etiology

Tuberous sclerosis is transmitted through autosomal-dominant inheritance. Two thirds of affected individuals have a de novo mutation. The expression is highly variable.

Pathogenesis

Tubers are the expression of an early disorder of embryogenesis. The greater the number of tubers, the greater the number of neurologic impairments. They can be found throughout the cerebral hemispheres, including in the subependymal region located in the walls of lateral ventricles and on the surface of the basal ganglia. They may extend into the ventricles including in the foramen of Monro area and can cause obstruction and hydrocephalus. They may also appear in the cortical gyri and sulcus terminalis. Tuberous sclerosis induces a reduction of the number of neurons, which are substituted by “monster” multinucleated giant neurons. The overgrowth of the fibrillary astrocytes can result in malignant astrocytomas. The sclerosis induces a demyelination, as well as calcium deposition in the glia and the blood vessels, which go through hyaline degeneration.

Clinical Findings

Tuberous sclerosis can present with a wide variety of signs that involve many organs as a consequence of the multifactorial origin of this genetic disorder ( Table 16-1 ).

Diagnosis

The diagnosis is usually suggested by the discovery of cardiac tumors, which resemble small uterine myomas (round, usually well-delineated homogeneous masses). Between 51% and 86% of cardiac rhabdomyomas are seen in patients with tuberous sclerosis. Occasionally, the finding of a rhabdomyoma during routine second trimester ultrasound examination may lead to the recognition that the mother is affected. Cardiac rhabdomyomas increase prenatally, may regress in early infancy, remain unchanged during childhood, and regress in adolescence. The rhabdomyomas may cause rhythm disruptions (Wolff-Parkinson-White syndrome, supraventricular tachycardia, paroxysmal arrhythmias), as well as obstructions or regurgitation. Renal angiofibromas have not been recognized prenatally, although this may simply be a matter of time. Some recent unpublished reports have demonstrated that the periventricular subependymal nodules may also be detected prenatally. 2D Doppler echocardiography is a useful, noninvasive method to diagnose fetal cardiac rhabdomyomas and to monitor their influence on fetal cardiac function. However, it does not help to determine which fetuses affected by rhabdomyomas have tuberous sclerosis. Some studies report that 39% of prenatal suspected cardiac rhabdomyomas will be diagnosed at birth as a tuberous sclerosis syndrome. Family history remains the strongest predictor of the syndrome in prenatal counseling, whereas size of the cardiac tumor cannot reliably be used. The presence of more than one rhabdomyoma is more likely to be associated with tuberous sclerosis than a single identified lesion. MRI can be performed to assess for the associated malformations.

Genetics

Tuberous sclerosis is caused by defects or mutations in one of two genes, TSC1 and TSC2 . TSC1 produces a protein called hamartin. TSC2 produces a protein called tuberin. These proteins act as tumor suppressors, which are agents that regulate cell proliferation and differentiation. At least 1% of patients with tuberous sclerosis have somatic mosaicism for TSC1 or TSC2 .

Differential Diagnosis

The predominant prenatal finding is rhabdomyomas. Other cardiac tumors, such as a fibroma, should also be considered.

Recurrence Risk

Recurrence risk is generally low in cases of new mutations, but up to 1% to 2% due to gonadal mosaicism, 50% if a parent is affected.

Prognosis

As long as hydrops is not present from the presence of the rhabdomyomas, the prognosis depends on other complications of the disorder. CNS tumors are the leading cause of morbidity and fatality. Renal disease is the second leading cause of early death. Because of the wide variability of expression, an accurate prediction of a child’s phenotype is difficult to infer from the status of the parent. Genetic evidence indicates that the degree of intelletual disability depends on the particular genetic alteration present.

Tuberous sclerosis. Cardiac rhabdomyoma is demonstrated as a large, solid echogenic mass ( arrow ) in the left cardiac ventricle of this fetus with tuberous sclerosis.

The typical café-au-lait spot of tuberous sclerosis.

(Courtesy of Philippe Jeanty, 1999. Available at thefetus.net .)

Axial view (T2-weighted) in a fetus of 26 weeks’ gestation showing a typical subependymal nodule ( arrow ).

(Courtesy of Heron Werner, 2005. Available at thefetus.net .)

Definition

L1 syndrome includes a spectrum of phenotypes (see following synonyms) and is generally characterized by severe hydrocephalus, adducted thumbs, spasticity, and severe intellectual disability.

Synonyms

Synonyms for L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA (mental retardation, aphasia, spastic paraplegia, adducted thumbs) syndrome, SPG1 (X-linked complicated hereditary spastic paraplegia type 1), and X-linked corpus callosum agenesis.

Incidence

The incidence is 1 in 30,000 births, accounting for 5% to 10% of males with congenital hydrocephalus not associated with another syndrome.

Pathogenesis

Mutations in the L1CAM gene are thought to lead to the clinical phenotype. L1CAM is an adhesion surface protein involved in transmembrane signaling and is essential for the development and function of neurons.

Diagnosis

Clinical findings include hydrocephalus with or without stenosis of the aqueduct of Sylvius, as well as corpus callosum agenesis or dysgensis, cerebellar hypoplasia, small brainstem, and bilateral absence of the pyramids. Bilateral absence of the pyramids on MRI or at autopsy is pathognomonic. Prenatally, hydrocephalus can be seen, but is often not seen prior to 20 to 24 weeks’ gestation, and sometimes is not seen even in the third trimester of pregnancy.

Genetics

L1 syndrome is caused by mutations in L1CAM gene. Inheritance is X-linked recessive.

Recurrence Risk

Recurrence risk is 50% for women who are carriers of an L1CAM mutation.

Associated Anomalies

Hirschsprung disease has been seen in some individuals with L1 syndrome.

Differential Diagnosis

Other syndromic and nonsyndromic causes of hydrocephalus should be excluded.

Prognosis

The phenotype can range from mild to severe even within the same family.

Management

A multidisciplinary team is required for optimal management. Head imaging should be performed. Surgical treatment is often required to relieve hydrocephalus. Regular neurologic, developmental evaluation and follow-up are needed. Surgery for adducted thumbs is generally not indicated.

Antley-Bixler Syndrome

Apert Syndrome

Recurrence Risk.

Most mutations are de novo and the recurrence risk is low. If one of the parents carries the disorder, the recurrence risk is 50%.

Apert syndrome. Ultrasound images demonstrating frontal bossing and midface hypoplasia on two-dimensional (2D) ( A ) and 3D ( B ) images, as well as by magnetic resonance imaging ( C ). Ultrasound image also demonstrated syndactyly of the foot ( D ), which is characteristic of Apert syndrome.

Apert syndrome. Syndactyly of the hand demonstrated with two-dimensional (2D) ( A ) and 3D ( B ) ultrasound images. Syndactyly of the foot is also present ( C ).

Newborn with Apert syndrome. Note appearance of the head, with frontal bossing ( A and B ), and syndactyly of the hand ( C ) and foot ( D ).

Carpenter Syndrome

Crouzon Syndrome

Pfeiffer Syndrome

Saethre-Chotzen Syndrome

Branchiooculofacial Syndrome

Frontonasal Dysplasia

Goldenhar Syndrome

Gorlin Syndrome

Hallerman-Streiff Syndrome

Nager Syndrome

Oral-Facial-Digital Syndrome, Type I

Pierre Robin Sequence

Associated Syndromes.

See Table 16-3 for a complete list of associated syndromes.

TABLE 16-3

Selected Syndromes and Chromosomal Anomalies Associated With Pierre Robin Sequence

Condition	OMIM	Causative Gene	Inheritance Pattern	Additional Features
Primary Skeletal Dysplasias
Campomelic dysplasia	114290	SOX9	Autosomal dominant	Short stature, campomelia, hearing loss, scoliosis
Stickler syndrome	108300, 604841, 184840	COL2A1, COL11A1, COL11A2	Autosomal dominant	Myopia, retinal detachment, hearing loss, mild short stature
Spondyloepiphyseal dysplasia congenita	183900	COL2A1	Autosomal dominant	Short spine, pectus carinatum, myopia, normal hands and feet
Kniest dysplasia	156550	COL2A1	Autosomal dominant	Short trunk, kyphosis, lumbar lordosis, short limbs, reduced joint mobility
Marshall syndrome	154780	COL11A1	Autosomal dominant	Hypoplastic nasal bones, congenital cataracts, myopia, sensorineural hearing loss
Otospondylomegaepiphyseal dysplasia	277610, 215150	COL11A2	Autosomal dominant	Sensorineural hearing loss, enlarged painful joints, short stature, short limbs
Diastrophic dysplasia	222600	SLC26A2	Autosomal recessive	Short stature, short limbs, joint contractures, talipes equinovarus, kyphoscoliosis
Osteopathia striata with cranial sclerosis	300373	WTX	X-linked dominant	Macrocephaly, frontal bossing, hearing loss, skull base sclerosis, linear metaphyseal bands
Otopalatodigital syndrome type II	304120	FLNA	X-linked semidominant	Frontal bossing, short thumbs and halluces, bowed long bones, conductive hearing loss
Multiple Congenital Anomaly Syndromes
Catel-Manzke syndrome	302380	Unknown	Probably autosomal recessive	Clinodactyly of index finger due to accessory ossicle between metacarpal and proximal phalanx, congenital cardiac defects
Toriello-Carey syndrome	217980	Unknown	Possibly autosomal recessive	Agenesis corpus callosum, telecanthus, developmental delay
Treacher Collins syndrome	154500	TCOF1	Autosomal dominant	Downslanting palpebral fissures, lower eyelid colobomas, zygomatic hypoplasia
Nager preaxial acrofacial dysostosis	154400	SF3B4	Autosomal dominant	Downslating palpebral fissures, absence of medial third lower lid lashes, conductive hearing loss, radial ray defects
Miller postaxial acrofacial dysostosis	263750	DHODH	Autosomal recessive	Lower lid ectropion, cupped ears, hearing loss, bilateral absence of fifth fingers, supernumerary nipples
Mandibulofacial dysostosis Guion-Almeida type	610536	EFTUD2	Autosomal dominant	Microcephaly, developmental delay, dysplastic ears, preauricular tags, choanal atresia
Auriculocondylar syndrome	602483, 614669	GNAI3, PLCB4	Autosomal dominant	“Question mark” ears, small mouth, prominent cheeks, anomalies of the temporomandibular joint and condyle
Cerebrocostomandibular syndrome	117650	Unknown	Autosomal dominant and recessive reported	Narrow thorax, rib anomalies, conductive hearing loss, growth restriction
Cerebrocostomandibular-like syndrome	606973	COG1	Autosomal recessive	Costovertebral defects, microcephaly, growth restriction, developmental delay, brain anomalies, cryptorchidism
Talipes, ASD, PRS, and persistence of left superior vena cava (TARP)	311900	RBM10	X-linked recessive	Talipes, congenital cardiac defects, persistence of left superior vena cava
Distal arthrogryposis-PRS (Illum syndrome)	208155	Unknown	Autosomal recessive	Joint contractures, autonomic instability, “whistling face,” nervous system classification
PRS, cleft mandible, limb anomalies (Richieri-Costa-Pereira syndrome)	268305	Unknown	Autosomal recessive	Short stature, hypoplastic thumbs, talipes, laryngeal malformations
Andersen-Tawil syndrome	170390	KCNJ2	Autosomal dominant	Cardiac arrhythmias, periodic paralysis, low-set ears, short stature, digital anomalies
PRS + oligodactyly	172880	Unknown	Probably autosomal dominant	Oligodactyly
Fetal alcohol syndrome	—	N/A	Teratogenic	Microcephaly, growth and developmental delay, short palpebral fissures
Neuromuscular Conditions
Congenital myotonic dystrophy	160900	DMPK	Autosomal dominant	Severe hypotonia, respiratory insufficiency
Carey-Fineman-Ziter syndrome	254940	Unknown	Probably autosomal recessive	Hypotonia, Moebius anomaly, growth delay, feeding difficulties, scoliosis
Chromosomal Abnormalities
Trisomy 18	—	Unknown	Sporadic chromosomal	Microcephaly, severe growth and cognitive impairment, prominent occiput, cardiac defects, low-set ears, short sternum, overlapping flexed fingers, prominent calcaneus
22q11 microdeletion	188400/192430	TBX1	Autosomal dominant chromosomal	Upslanting palpebral fissures, prominent tubular nose, conotruncal heart defects, renal and endocrine abnormalities, neuropsychiatric problems
17q24 translocations and microdeletions	261800	SOX9	Autosomal dominant chromosomal	Isolated PRS
17q21.31q24.3 inversion and deletion	—	SOX9	Autosomal dominant chromosomal	PRS with hypoploastic scapula and bilateral clubfeet
2q33 microdeletion	608148	SATB2	Autosomal dominant chromosomal	Growth restriction, feeding difficulties, downslating palpebral fissures, prominent nose, dental anomalies, behavioral problems, developmental delay
4q terminal deletion	—	Unknown	Autosomal dominant chromosomal	Cardiac defects, mild developmental delay, but can be normal, stiff hypoplastic fifth fingers with hooked or volar nails
1q duplication	—	Unknown	Autosomal dominant chromosomal	Bilateral fixed flexion deformities of fingers, cardiac and brain anomalies
Partial trisomy 11q	—	Unknown	Autosomal dominant chromosomal	Developmental delay, congenital heart defects
t(1;2)(p34;q33)	613857	FAF1	Chromosomal	PRS in father and son with translocation disrupting FAF1 at 1p34
20p12.3 microdeletion	112261	BMP2	Autosomal dominant chromosomal	Long philtrum, digital anomalies, hypotonia
22q12 microdeletion	—	MN1	Autosomal dominant chromosomal	Developmental delay, features of NF2 and Toriello-Carey due to contiguous gene deletion

 

ASD, atrial septal defect; PRS, Pierre Robin sequence; OMIM, Online Mendelian Inheritance in Man.

From Tan TY, Kilpatrick N, Farlie P: Developmental and genetic perspectives on Pierre Robin sequence. Am J Med Genet C Semin Med Genet 163C:295-305, 2013, Table 1.

Stickler Syndrome.

Stickler syndrome is characterized by ocular findings (myopia, cataract, retinal detachment) and hearing loss (conductive and sensorineural) in addition to Pierre Robin sequence. Joint issues are also common (hypermobility, spondyloepiphyseal dysplasia, precocious osteoarthritis). Mutations in one of five genes are often present: COL2A1 , COL11A1 , and COL11A2 (autosomal dominant inheritance; COL2A1 most common, at 80-90%), as well as COL9A1 and COL9A2 (autosomal recessive; rare). Penetrance is complete but significant phenotypic variability occurs even within families. From 20% to 30% of patients with Pierre Robin sequence may have Stickler syndrome.

Cerebrocostomandibular Syndrome.

Cerebrocostomandibular syndrome (CCMS) is characterized by costovertebral anomalies (dorsal rib defects) in addition to Pierre Robin sequence. Rib defects often lead to a bell-shaped thorax and can result in flail chest. Other anomalies include growth retardation, scoliosis, dental anomalies, feeding issues, and conductive hearing loss. Severity is highly variable, although prognosis is often poor. This disorder is very rare, with slightly over 80 cases reported. Genetics are unknown, although possible defects in sonic hedgehog signaling have been implicated.

Micrognathia. Profile of a fetus shows mild micrognathia.

Severe micrognathia in a fetus with Nager syndrome. This can result in severe airway compromise at birth.

Micrognathia in a fetus with Pierre Robin sequence.

Treacher Collins Syndrome

Van der Woude Syndrome

Prognosis.

Multiple surgeries are often needed to treat lip pitting and can lead to scarring and decreased ability to open the mouth. Psychomotor development is generally normal.

Coronal ultrasound image showing unilateral cleft lip ( arrow ) in a fetus with van der Woude syndrome.

X-linked Opitz G/BBB Syndrome

Thanatophoric Dysplasia

Management.

The option of pregnancy termination should be offered before viability. Sonographic evaluation of hydrocephalus is recommended because it can lead to malpresentation and difficult delivery. If massive hydrocephalus has developed, cephalocentesis or elective cesarean delivery should be considered to avoid maternal trauma.

Typical cloverleaf skull such as that seen in thanatophoric dysplasia in sagittal ( A ), coronal ( B ), and axial ( C ) planes.

Thanatophoric dysplasia. A, Markedly short femur with telephone receiver morphologic appearance; B, axial images demonstrating small thorax with short ribs; C, frontal bossing.

Osteogenesis Imperfecta

Management.

Owing to the uniformly fatal outcome, termination of pregnancy should be offered when type II is diagnosed early in pregnancy and palliative care provided if delivery is undertaken. If continuation of the pregnancy is chosen, cesarean delivery is often recommended for nonlethal OI for prevention of fetal and maternal trauma.

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