Single Suture Craniosynostosis

Sagittal synostosis. This most common single suture synostosis can begin anywhere along the interparietal junction, and once initiated, fusion extends anteriorly and posteriorly. As in all craniosynostoses, timing of sagittal suture fusion is variable. It can occur anytime from the late first trimester to the early postnatal period. Thus, a normal prenatal ultrasonic examination does not rule out the possibility of neonatal synostosis.

The characteristic cranial deformity of sagittal synostosis can be seen prenatally as decreased vertical and transverse dimensions in the parietal region with compensatory increase in frontal and occipital projection (scaphocephaly or bathmocephaly). Biparietal diameter is an established ultrasonographic marker of gestational age and fetal development.⁵ Occipitofrontal diameter and head circumference are also standardized measures that are useful in determining scaphocephaly in utero.^6-8 Sagittal synostosis is more common in males than females; it is rarely associated with hydrocephalus. Sagittal synostosis has been reported at 34 weeks of gestation with coincident polyhydramnios.⁹ The fetus was dolichocephalic with a minor cloverleaf configuration, biparietal diameter was in the 10th percentile, head circumference was in the 60th percentile, and the diagnosis was confirmed at birth.

Sagittal synostosis is believed to be pathogenically heterogeneous. Proposed causes include intrauterine constraint of the head and somatic or germline mutation, as yet undetermined. Lajeunie and coworkers reported 373 probands from 366 families with sagittal synostosis; inherited cases were found in only 6 percent.¹⁰ As yet, there are no genetic screening methods for isolated sagittal synostosis.

Unilateral coronal synostosis. Unilateral fusion of the frontoparietal and frontosphenoid (coronal) suture results in characteristic ipsilateral elevation, lateralization, and posterior displacement of the orbit, deviation of the nasal root, anteriorly displaced mala and ear canal, and compensatory bossing of the contralateral forehead.¹¹ A molecular cause is not found for most patients with synostotic frontal plagiocephaly. However, it can occur in association with Saethre-Chotzen syndrome,¹² FGFR3 Pro250Arg mutation,^13,14 and craniofrontonasal syndrome.¹⁵ If there is a family history of craniofacial dysmorphism or suspicion by ultrasonography, molecular diagnosis is possible for two of these disorders. Until the gene is found, craniofrontonasal syndrome can only be diagnosed by linkage analysis if there is an affected parent.

Prenatal diagnosis of unilateral coronal synostosis has not been reported. The expected sonographic findings would be cranial, orbital, and auricular asymmetry in the axial plane. Biparietal width and orbital size can be compared with established values for fetal craniofacial morphometry. The sonographer must perform multiple transverse views to demonstrate asymmetric landmarks because they are not located in a single plane. Furthermore, a suspiciously fused suture can be specifically targeted with three-dimensional ultrasonography to demonstrate patency or stenosis.¹⁶ This may be of limited value because of variable timing of sutural fusion.

Metopic synostosis. Abnormal interfrontal fusion causes a triangular shape of the anterior cranium and bifrontal narrowing that is best demonstrated by ultrasonic examination in the axial plane. Characteristic hypotelorism can be confirmed by comparison to ocular norms for interorbital distance.¹⁷ Usually, metopic synostosis is isolated (i.e., not associated with recognizable syndromes). Infrequently, it occurs with chromosomal deletions (3q, 7p, 9p, 11q, 13q), Opitz C syndrome, holoprosencephaly, and trisomy 13 with bilateral cleft lip and palate.¹⁸

Craniosynostotic Syndromes

Brachycephaly or turribrachycephaly is the ultrasonic indicator of a fetus with bilateral coronal synostosis. However, unless there is a family history of a known disorder, it is difficult to make a phenotypic diagnosis of a particular craniosynostotic syndrome. Diagnosis is possible if there are pathognomic anomalies of the limbs, such as in Apert or Carpenter syndrome. Otherwise, an eponymous designation can only be assigned after birth. There are always some infants who do not easily fit into conventional subgroups of craniosynostotic syndromes; they are usually labeled bilateral coronal synostosis or unknown brachycephaly. For this reason, it is best for the ultrasonographer not to attempt a precise clinical diagnosis. Molecular diagnosis is increasingly used prenatally and postnatally.¹⁹

Crouzon Syndrome

In addition to bilateral fusion of the coronal sutural ring, Crouzon patients can also have synostosis of the sagittal, lambdoid, and metopic sutures.²⁰ Characteristic findings are increased bitemporal width, decreased anteroposterior cranial dimension, decreased orbital volume, and minor orbital hypertelorism (Fig. 1). There are general guidelines for prenatal ultrasonographic diagnosis of Crouzon syndrome by use of established normal values for cranial and orbital dimension.²¹ Exorbitism, the result of the shortened cranial base and sloped anterior cranial fossa, has been documented in a 35-week Crouzon fetus.²² Leo et al. made a second trimester diagnosis on the basis of increased binocular and interorbital diameters in association with a positive family history.²³ Binocular and interorbital measurements were at the 50th percentile at 16 weeks but increased to the 90th percentile at 24 weeks, whereas biparietal diameter remained at the 50th percentile. David et al. described monozygotic twins with Crouzon syndrome detected antenatally; both fetuses demonstrated cloverleaf cranial anomaly.²⁴ Gollin et al. also made a prenatal diagnosis of Crouzon syndrome on the basis of cranial dysmorphology.²⁵

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Fig. 1. (Left) Second trimester sonogram of a Crouzon fetus. Transverse view shows posterior cranial flattening and parietal angulation (brachycephaly) caused by bilateral coronal synostosis. Electronic calipers (crosses) document biparietal diameter. (Right) Third trimester coronal view of a Crouzon fetus. Note acrocephaly (increased cranial height and bitemporal width).

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Prenatal molecular diagnosis is possible for ultrasonically suspected Crouzon syndrome; there are more than 30 reported FGFR2 mutations on chromosome 10q.²⁶ However, molecular analysis has shown phenotypic overlapping of craniosynostotic syndromes. For example, identical FGFR2 mutations occur in Crouzon and Pfeiffer syndromes.²⁷ Crouzonoid with acanthosis nigricans is a specific, rare entity caused by a FGFR3 mutation on chromosome 4p.¹⁹ Schwartz and coworkers reported first trimester diagnosis of inherited Crouzon syndrome by chorionic villus sampling.²⁸ Biopsy at 11 weeks of gestation showed the common FGFR2 Cys342Tyr mutation. The pregnancy was terminated and analysis of fetal tissue confirmed the diagnosis.

Associated Anomalies of Crouzon Syndrome

Pattern recognition of the syndromic coronal craniosynostosis is aided by finding associated intracranial and extracranial defects. The ultrasonographer is obligated to target the examination looking for these anomalies.

Hydrocephalus occurs in approximately 12 percent of patients with syndromic craniosynostosis; the incidence increases to 40 percent with multiple sutural synosostosis.^29,30 Hydrocephalus can be detected as early as 16 weeks of gestation. Assessment involves measurement of the ventricular width at the atrium (Fig. 2).³¹ Benacerraf and Birnholz diagnosed hydrocephalus on the basis of asymmetric appearance of the choroid plexus and size and configuration of the anterior horns of the lateral ventricles.³² Measurement of the ventricular atrium is reliable and is constant (7 ± 3 mm) throughout the second and third trimesters.³³

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Fig. 2. Third trimester transverse image showing hydrocephalus. Electronic calipers (crosses) measure lateral ventricle, compared with normative size for gestational age.

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Chiari I malformation can be imaged sonographically; it occurs in approximately 70 percent of patients with Crouzon syndrome.³⁴ The posterior fossa is examined at 30 degrees to the axial plane to demonstrate protrusion of the cerebellar tonsils and medulla into the cervical canal. Accompanying syringomyelia (hydromyelia) is also commonly seen in Crouzon infants with Chiari I. Toma et al. reported a 25-week Crouzon fetus in whom signs included fifth percentile head circumference, Chiari II malformation, and myelomeningocele.³⁵ Sonographic examination of the fetal spine demonstrated a thoracic hypoechoic zone corresponding to hydrosyringomyelia. High-resolution sonography at birth confirmed the intrauterine findings. These authors discussed options for early termination of pregnancy or elective caesarian section to prevent birth trauma to the cord.

Thirty-eight percent of patients with Crouzon syndrome have intervertebral cervical fusion, most commonly in the upper vertebrae, as opposed to C5-6 involvement in Apert syndrome.³⁶ Vertebral fusion is unreliably detected by prenatal ultrasonography. It is more accurate for obvious spinal deformities such as scoliosis and spina bifida.

Apert Syndrome

The cranial changes in Apert syndrome comprise the variable expressions of turribrachycephaly, with the additional pathognomonic features of symmetric syndactyly of the hands and feet (simple or complex) (Fig. 3). Unlike Crouzon syndrome, the anterior fontanelle and metopic suture are widely patent in Apert syndrome; the hand anomalies further establish the sonographic diagnosis. Phalangeal ossification begins at 17 to 18 weeks of gestation and, thus, bony syndactyly and symphalangism can be imaged during the early second trimester. Transvaginal ultrasonography is useful to display hand abnormalities.³⁷ Bony fusion of the second, third, and fourth digits with a common nail can be seen. Soft-tissue syndactyly is a diagnosis of exclusion in a fetus at a time when separate fingers cannot be seen, although there are individual bony phalanges.

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Fig. 3. (Left) Coronal view of an Apert fetus showing acrocephaly and hypertelorism (calipers on lateral and medial orbits). (Right) Second trimester sonogram of an Apert fetus showing "mitten" syndactyly.

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In utero diagnosis of Apert syndrome has been reported by several authors.^38-45 Range of detection was 16 to 31 gestational weeks. Brachycephaly has not been reliably detected. Filkins et al. were first to report a first trimester ultrasonic diagnosis of Apert syndrome in a fetus with a "mitten-like" hand; they were aided by a positive family history.⁴⁶

Other associated findings in Apert syndrome that can be seen by ultrasonography include hydrocephalus and Chiari I malformation, although they are less common than in Crouzon syndrome.³⁰ Also lower cervical spinal fusion occurs in 71 percent of patients who have Apert syndrome.³⁶

All patients with Apert syndrome studied to date have one of two adjacent amino acid substitutions in FGFR2 (Ser252Trp, Pro253Arg), thus facilitating molecular diagnosis by chorionic villus sampling or amniocentesis.⁴⁷

Pfeiffer Syndrome

Synostosis is variable in Pfeiffer syndrome, manifesting a spectrum from minor brachycephaly, turribrachycephaly, to cloverleaf cranial deformity (Cohen types 1, 2, and 3) (Fig. 4).^48,49 Midfacial hypoplasia, exorbitism, and broad, medially rotated thumbs and great toes can occur, but they are not obligatory for the diagnosis.

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Fig. 4. (Left) Third trimester sagittal view of a Pfeiffer fetus. Note frontal prominence and depressed nasal bridge. (Right) Cloverleaf (trilobular) cranium in a Pfeiffer fetus; third trimester coronal image. Arrows on prominent temporal bulges.

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Ultrasonographic diagnosis of Pfeiffer syndrome has been reported. Detection is more likely with cloverleaf (type 2) cranial deformity.^50,51 Bernstein and coworkers made the diagnosis of type 2 Pfeiffer syndrome in the second trimester; the sonographic findings included, in addition to cloverleaf skull, hypertelorism and varus deformity of the great toes.⁵²

Pfeiffer syndrome exhibits genetic (locus) heterogeneity. The known mutations are on FGFR1 (8p) and FGFR2 (10q).⁵³ Some patients, described as "Pfeiffer-like" or "pfeifferoid," have the FGFR3 Pro250Arg mutation (4p).^14,15

Saethre-Chotzen Syndrome

Although prenatal diagnosis of Saethre-Chotzen syndrome has not been reported, surely it is possible, particularly if there is a family history. The fetus would exhibit signs of either bilateral or unilateral coronal synostosis. Often there is minor or no midfacial retrusion. The hand and auricular findings are usually too subtle to be seen. Broad great toes can occur, but this is also difficult to detect. Multiple mutations and deletions that cause Saethre-Chotzen occur in the TWIST gene.^54,55

Carpenter Syndrome

This autosomal recessive syndrome is comprised of craniosynostosis, polydactyly, brachydactyly, variable soft-tissue syndactyly, and cardiac defects. There is a case report of prenatal diagnosis with a negative family history.⁵⁶ The 17-week ultrasonographic study revealed twins (presumably dizygotic) with one fetus having club-like hands and abnormal skull shape. The 20-week examination showed a "diamond-shaped head" in the axial plane and preaxial polydactyly of the great toe. The fingers were not separate. The diagnosis of Carpenter syndrome was confirmed at the 38-week delivery.

Cloverleaf Cranial Deformity (Kleeblattschädel)

Cloverleaf cranial deformity is a physical finding, not a diagnosis. Variable synostosis of the coronal and lambdoid sutures presents with bitemporal bulging, bifrontal bossing, and hydrocephalus. Trilobar skull is most commonly associated with type 2 thanatophoric dysplasia (FGFR3, Lys650Glu) and type 2 Pfeiffer syndrome (FGFR2).⁴⁸ It can also occur in Apert syndrome (FGFR2), Crouzon syndrome (FGFR2), and in the very rare Boston-type craniosynostosis (MSX2),^57-59 Beare-Stevenson cutis gyrata, and several other syndromes.¹⁸

Stamm and colleagues reported four cases of prenatally diagnosed cloverleaf cranial deformity and reviewed five cases from the literature.⁶⁰ Gestational age at detection ranged from 18 to 37 weeks, hydrocephalus was present in eight of nine cases, and thanatophoric dwarfism was diagnosed in eight of nine fetuses. Notably, the cloverleaf deformity was misdiagnosed as a encephalocele in five of nine cases. The authors underscored that encephalocele and lethal macrocystic cranionuchal lymphatic anomaly can present similar ultrasonic images, but encephaloceles are primarily posterior midline defects, as compared with Kleeblattschädel, which demonstrates bilateral temporal bulging. They stressed that location and bilaterality are distinguishing features in the differential diagnosis. David et al. described twins with cloverleaf skull and Crouzon syndrome diagnosed by prenatal ultrasonography.²⁴ Saal et al. also documented an infant with prenatal craniosynostosis, marfanoid appearance, and cloverleaf cranium.⁶¹

Disorders with Hypertelorism

Both orbital and interorbital hypertelorism can be determined by standardized measurements (Fig. 5, above, left).¹⁸ Characteristic fetal facial features permit categorization as frontonasal malformation, craniofrontonasal syndrome, paramedian facial clefts, encephalocele, and other miscellaneous features.⁶²

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Fig. 5. (Above, left) Second trimester coronal view of fetus with hypertelorism. Interorbital distance shown by arrows. (Above, right) More anterior coronal section of the same fetus reveals frontonasal malformation and right unilateral complete cleft lip and palate. (Below, left) Sagittal view shows severe nasal hypoplasia. (Below, right) Three-dimensional sonogram more clearly demonstrates the anomalies.

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Prenatal diagnosis of frontonasal malformation has been reported (Fig. 5, above, right).⁶³ Craniofrontonasal syndrome has been detected at 23 weeks of gestation in a fetus with an affected older sibling.⁶⁴ Ultrasonic findings were described as dysmorphic; the diagnosis was confirmed at termination of pregnancy.

Frontoethmoidal encephalocele can be diagnosed in the first trimester (Fig. 6). Although the spherical sac is easily seen, the bony defect can be difficult to visualize. Alpha-fetoprotein is not always elevated, particularly if the scalp is intact. Differential diagnosis includes hemangioma, lymphatic malformation, nasal teratoma, cloverleaf cranium, and dacryocystocele. Pearce et al. reviewed 3000 at-risk fetuses for structural defects and found 21 with encephalocele and 25 with cystic lymphatic malformation.⁶⁵ Distinguishing features of encephalocele were bony defect, midline septum (if present), tissue presence in the fluid sac, and midline position. Associated microcephaly was common and oligohydramnios was rare. Nasal teratoma does not extend intracranially and is more solid in nature.⁶⁶ Cloverleaf cranium manifests bilateral temporal bulging and bony continuity. Dacryocystocele is a cystic structure located medial to the globe. Hemangioma exhibits solid vascular parenchyma with fast-flow; a central cystic space rarely is seen with intrauterine hemangioma.

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Fig. 6. Sagittal view of fetus with anterior encephalocele. Note abnormal lobular frontal protrusion (arrow).

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Given the long list of conditions associated with hypertelorism, it is difficult to provide guidelines for amniocentesis. This decision is usually based on whether there are abnormalities of the brain, limbs, and skeleton.⁴ Molecular confirmation is not yet possible for any of the four major diagnostic categories. If one parent and other family members are affected, prenatal linkage analysis could confirm craniofrontonasal syndrome, which maps to Xp22.⁶⁷ The causative genes are known for several inheritable disorders that exhibit minor hypertelorism, such as Aarskog, Greig cephalopolysyndactyly, Opitz G, and Robinow syndromes. Minor hypertelorism is also seen with syndromic bilateral coronal synostosis. Several chromosomal duplications and deletion syndromes can cause hypertelorism.¹⁸

Pharyngeal and Oromandibular Deformities

Hemifacial Microsomia

Hemifacial microsomia is the second most common craniofacial anomaly after cleft lip and palate. The incidence is estimated at one in 5000 to 10,000 live births, with up to 30 percent of cases being bilateral.⁶⁸ Hemifacial microsomia manifests characteristic orbital, auricular, and mandibular deformities, all of which can be seen sonographically. Search should also be done for possible intracranial and extracranial, skeletal, cardiac, pulmonary, genitourinary, and gastrointestinal anomalies. This is called the hemifacial microsomia-expanded spectrum.⁶⁹ Antenatal diagnosis of hemifacial microsomia relies on asymmetric craniofacial hypoplasia and is supported by finding these nonrandom extracranial anomalies.

Features of the fetal face and midline intracranial structures can be identified sonographically by 10 to 11 weeks of gestation.⁷⁰ By 13 to 14 weeks, the features are distinct, and the fetal profile can be seen in sagittal view, outlining the orbits, nose, maxilla, and mandible. A modified coronal view is used to screen for cleft lip and palate, which occurs in 15 to 18 percent of patients with hemifacial microsomia. Coronal views also scan the maxilla and orbits. The longitudinal view assesses soft and hard tissues of the nose and mandible. The transverse view demonstrates the orbits and is used to measure intraorbital and interorbital distance.

Tamas and coworkers reported ultrasonic diagnosis of hemifacial microsomia at 30 weeks of gestation; the findings included anophthalmia, malformed ipsilateral ear, and facial asymmetry.⁷¹ Antenatal findings were confirmed postpartum, including computed tomographic scan documentation of left maxillary and mandibular hypoplasia. Benacerraf and Frigoletto described a 29-week fetus with hemifacial microsomia exhibiting an abnormal facial profile, micrognathia, and right hydronephrosis and hydroureter.⁷² Findings suggestive of ventriculoseptal defect and right pulmonary agenesis were also noted.

Orbito-ocular anomalies, namely, microphthalmia, anophthalmia, and orbital dystopia, occur in 10 to 12 percent of patients with hemifacial microsomia.⁷³ Feldman and colleagues diagnosed bilateral microphthalmia at 12 weeks of gestation in a fetus with Fraser syndrome.⁷⁴ Interocular distance was within normal range; however, binocular distance was at the fifth percentile, and ocular diameter was below the fifth percentile. Porges and associates described a family with hereditary microphthalmia and colobomatous cysts. Two of five affected children had prenatal diagnosis at 9 and 20 weeks of gestation, and echogenic vitreous bodies were shown in the latter fetus.⁷⁵ Postpartum computed tomographic scan and ultrasonography confirmed the prenatal diagnosis.

Microtia occurs in 75 percent of patients with hemifacial microsomia (Fig. 7, left).⁷³ Shimizu et al. established auricular nomograms between 18 and 42 weeks of gestation.⁷⁶ Birnholz studied the external ear in 90 fetuses from 16 weeks of gestation to term and found at least one ear was visible in 50 fetuses.⁷⁷ The ear cannot be seen whenever the head is supine or prone, if the head is engaged, or if there is marked maternal obesity. Also, hydrocephalus and oligohydramnios decrease the likelihood of detection. In summary, sonographic imaging for auricular asymmetry and position is possible, but visualization of abnormal auricular shape is difficult. Three-dimensional sonography can be helpful in displaying ears.

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Fig. 7. (Left) Sagittal view of fetus with hemifacial microsomia reveals microtia-low-set lobule and absent helix (arrow). (Right) Sagittal view of fetus with hemifacial microsomia. Note mandibular retrognathia.

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Mandibular hypoplasia, a characteristic feature of patients, can be documented in utero.⁷⁸ The transverse view (through the rami) is best to evaluate mandibular asymmetry, whereas midline sagittal or lateral views reveal anteroposterior hypoplasia (Fig. 7, right). Escobar and coworkers examined 53 normal pregnancies at 16 weeks of gestation to establish fetal mandibular morphometrics.⁷⁹ Mandibular depth was defined as gonion-to-menton in the sagittal plane. The mean value was 16.30 mm with 0.33 mm variation and 97.8 percent reproducibility. The incidence of micrognathia may be overreported because mandibular development lags behind maxillary development and can be self-correcting.⁸⁰

Central Nervous System Anomalies in Hemifacial Microsomia

Anomalies of the central nervous system occur in 5 to 15 percent of patients with hemifacial microsomia.⁶⁹ These include hydrocephaly and Chiari I malformation. Ultrasonic diagnosis of the intracranial defects is discussed earlier. Microcephaly associated with hemifacial microsomia is documented as cranial circumference less than 3 SD for gestational age.⁸¹ Agenesis of the corpus callosum also occurs in association with hemifacial microsomia and can be seen by ultrasonography (Fig. 8, above).⁸² The corpus callosum begins to develop at 12 weeks´ gestation, progressing from rostrum to splenium and is complete at 20 weeks of gestation when ultrasonography should be done as a routine examination. In callosal agenesis, myelinated nerve tracts do not cross the interhemispheric fissure and instead are turned back on themselves, forming Probst bundles. Detection of Probst bundles and absence of the coeval cavum septi pellucidi (normally positioned one-third from sinciput and two-thirds from the occiput) confirms the diagnosis.

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Fig. 8. (Above) Agenesis of corpus callosum can occur in hemifacial microsomia. Note "tear drop" configuration of dilated lateral ventricles. (Below) Transverse cranial view showing Dandy-Walker cyst in posterior fossa with severe hydrocephalus.

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Dandy-Walker malformation can be associated with hemifacial microsomia (Fig. 8, below). It is caused by vermal agenesis with abnormal development of the hindbrain wherein the fourth ventricle expands the posterior fossa, forming a cyst and causing the pathognomonic separation of the cerebellar hemispheres. Diagnosis is deferred until the 18th gestational week to allow for vermal development. Prenatal ultrasonic diagnosis has been reported.^83-85 Hatjis and associates counseled that Dandy-Walker malformation cannot be unequivocally distinguished from posterior arachnoidal cyst by prenatal ultrasonography.⁸⁵ Newman et al. detected a posterior fossa cyst by lateral view at 24 weeks of gestation.⁸⁶ This pregnancy was terminated at 26 weeks, and findings were confirmed by autopsy.

Extracranial Anomalies in Hemifacial Microsomia

Skeletal anomalies are the most common extracranial findings in hemifacial microsomia (40 to 60 percent).⁶⁹ The most frequent are scoliosis, vertebral anomalies, rib anomalies, and preaxial hypoplasia. Hemivertebrae can cause scoliosis, and these anomalies can be seen ultrasonographically (Fig. 9).⁸⁷ The vertebrae develop from three ossification centers: the centrum and one on each side of the posterior neural arch. This pattern of ossification of the posterior neural arch provides the clues to neural tube defects. Because ossification initiates at the base of the transverse process and proceeds centrally, an open neural tube defect results if the ossification centers fail to coalesce. Problems are likely when ultrasonography shows displaced or open ossification centers of the spine.⁸⁸ Diagnosis can also be suspected by assay of elevated maternal alpha fetoprotein, an earlier indicator of neural tube defects.

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Fig. 9. Skeletal anomalies frequently observed in hemifacial microsomia. Second trimester coronal view shows T9 hemivertebra (arrow).

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Cardiac anomalies occur in 14 to 55 percent of children with hemifacial microsomia. The most common presentation is heart murmur or ventricular septal defect.^69,89 The fetal heart can be sonographically imaged transvaginally as early as 10 weeks of gestation; however, cardiac examination usually is done between 18 and 20 weeks´ gestation by transabdominal ultrasonography (Fig. 10).

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Fig. 10. Cardiac anomalies often associated with hemifacial microsomia. Short axial view shows ventricular septal defect (arrow).

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Pulmonary anomalies occur in 10 percent of patients with hemifacial microsomia, the most common being tracheoesophageal fistula and pulmonary hypoplasia.⁶⁹ Prenatal diagnosis of tracheoesophageal fistula cannot be made by direct visualization. Rather, it is suspected by associated findings such as polyhydramnios and the absence of fluid in the stomach.⁹⁰ Ultrasonic findings are variable depending on whether there is a distal communication to the stomach. The lungs can be studied ultrasonographically from the end of the first trimester. Pulmonary development can be monitored by chest circumference.⁹¹ Benacerraf and Frigoletto described a 29-week fetus with micrognathia, moderate hydramnios, right hydronephrosis, hydroureter, and an enlarged echogenic left lung thought to represent an "adenomatoid cystic malformation."⁷² The right lung was not visualized. On delivery, the infant had respiratory distress and underwent thoracotomy for suspected adenomatoid cyst. The left lung was found to be hyperinflated, and the right lung was hypoplastic. The authors stressed that if the correct diagnosis of hemifacial microsomia had been made, pulmonary hypoplasia would have been predicted, thus obviating operative intervention.

Renal anomalies comprise 5 to 10 percent of extracranial involvement in hemifacial microsomia.⁶⁹ Discrepancy in size and renal agenesis are the most common findings. The fetal kidney can be seen at 12 weeks´ gestation, but more reliably at 14 to 15 weeks. Standard measurements for renal size are established.⁹² Because the outer renal border can be hard to visualize, small kidneys are more difficult to diagnose than abnormally large kidneys. Romero and coworkers summarized fetal ultrasonic diagnosis of renal anomalies.⁹³ Signs of agenesis are the obvious absence of kidneys, oligohydramnios, and missing bladder (Fig. 11). Diagnosis can be difficult; they described a mistaken diagnosis in an addendum to the article, and related three more instances of false-positive diagnosis of a renal anomaly.

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Fig. 11. Renal anomalies occur in hemifacial microsomia. Second trimester transverse image through renal fossa shows hydronephrosis (arrow).

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Gastrointestinal anomalies constitute 10 percent of associated extracranial involvement with hemifacial microsomia.⁶⁹ The most common are bilateral inguinal hernia, gastroesophageal reflux, displaced rectum, imperforate anus, and intestinal malrotation. Imperforate anus is perhaps the only intestinal anomaly that can be diagnosed by prenatal ultrasonography. Guzman et al. described monoamniotic fetuses at 25 and 28 gestational weeks, neither with sonographic signs of a normal anus.⁹⁴ A circular rim of echogenicity with a central linear echogenic stripe in the perineal region is normally seen. This was absent in the twins. Diagnosis of anal atresia was made and confirmed at birth. Imperforate anus has also been diagnosed on the basis of a distended colon and intraluminal calcifications.⁹⁵

Differential Diagnosis of Hemifacial Microsomia

Hemifacial microsomia is probably pathogenically heterogeneous. There is no evidence of an inheritable tendency in the majority of patients. However, there are reports of familial hemifacial microsomia, usually in an autosomal dominant pattern.^18,68,96 There are at least three inheritable syndromes that are very similar to hemifacial microsomia and should be considered in the antenatal differential diagnosis.

Townes-Brocks syndrome has some similarities to hemifacial microsomia-expanded spectrum. It is characterized by a triad of anal, ear, and thumb anomalies. Imperforate, stenotic, and anteriorly displaced anus are the most common malformations. Renal and cardiac malformations occur, but are uncommon; mandibular asymmetry is rare. This is an autosomal dominant disorder caused by mutations in the SALL1 putative transcription factor (11q).⁹⁷

Branchio-oto-renal syndrome is an autosomal dominant disorder that can easily be mistaken for hemifacial microsomia. It is characterized by facial or mandibular asymmetry, cervical fistulas, microtia, variable hearing loss, and renal anomalies. Greenberg and coworkers report the only case of prenatal diagnosis of branchio-oto-renal syndrome.⁹⁸ Family history was positive for an affected father and nonviable sibling. Examinations at 16 and 18 weeks´ gestation demonstrated marked oligohydramnios and absence of kidneys and bladder. The pregnancy was terminated at 19 gestational weeks. Autopsy showed minor micrognathia, cervical cysts, pulmonary hypoplasia, right renal agenesis, and left renal hypoplasia. There is speculation that branchio-oto-renal syndrome may represent variable expression of an autosomal dominant gene, variable mutations within the same gene, or a continuous gene deletion syndrome. By positioning cloning, a candidate gene has been identified on 8q.⁹⁹ The putative gene is a human homolog of the Drosophila "eyes absent" gene and is symbolized EYA1.

Branchio-oculo-facial syndrome is another autosomal dominant syndrome of high penetrance and variable expressivity involving the first and second pharyngeal arches. Characteristic findings include cervical cutaneous defects; microphthalmia; nasolacrimal duct obstruction; low-set, rotated, and cupped ears; hearing loss; and cleft lip and palate.¹⁰⁰ Ocular, auricular, and labial anomalies can be detected by fetal ultrasonic examination. Severity and the presence of multiple anomalies also aid detection. Positive family history greatly influences suspicion for branchio-oculo-facial syndrome because of the 50-percent recurrence risk. Prenatal diagnosis of branchio-oculo-facial syndrome by ultrasonography has not been reported, and the causative gene is not known.

Treacher Collins Syndrome (Mandibulofacial Dysostosis)

Treacher Collins syndrome is an autosomal dominant disorder manifesting nearly symmetric deformities of structures derived from the first and second pharyngeal arches. This second most common arch anomaly is sonographically detectable by finding micrognathia, symmetric bilateral microtia, and down-turned palpebral fissures. Other associated malformations include hemivertebrae and cardiac anomalies.

Sonographic diagnosis of Treacher Collins syndrome in a 15-week fetus was reported by Behrents and coworkers in 1977.¹⁰¹ Nicolaides et al. described two fetuses with a positive family history diagnosed at 17 and 18 weeks of gestation by the characteristic canted palpebrae, mandibular hypoplasia, and cleft palate in one fetus.¹⁰² Crane and Beaver reported a fetus diagnosed by bilateral microtia and micrognathia at 24 weeks.¹⁰³ Cohen and coworkers made a 31-week gestational diagnosis of Treacher Collins syndrome with a negative family history on the basis of polyhydramnios, slanting forehead, microphthalmia, micrognathia, and overall symmetrical growth restriction.¹⁰⁴ Ultrasonographic findings were confirmed at birth and additional abnormalities included exotropia, lower-lid coloboma, and cleft palate. Hansen et al. described an extreme expression of this disorder with arhinia, anotia, and absent zygomatic bones that was diagnosed at 16 weeks of gestation and confirmed by prenatal linkage analysis (Fig 12).¹⁰⁵

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Fig. 12. (Left) Coronal view of a fetus with Treacher Collins syndrome; diagnosis confirmed by molecular testing. Arrows indicate proptosis, down-slanting lateral palpebral fissures, and hypertelorism. (Right) Sagittal view shows mandibular retrognathia (solid arrow) and nasomaxillary hypoplasia (open arrow).

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Mutations for Treacher Collins syndrome are in the gene TREACLE (5p),¹⁰⁶ so prenatal diagnosis is possible if there is a positive family history or if sonographic features suggest the disorder.

Acrofacial Anomalies

Nager syndrome denotes Treacher Collins-like phenotype with preaxial limb defects.¹⁰⁷ Most cases are sporadic, but there are affected families to suggest variable autosomal dominant and autosomal recessive transmission. Limb anomalies include proximal radioulnar synostosis, limitation of elbow movement, short forearms, and hypoplasia or aplasia of the thumb. Benson et al. described a 30-week fetus with marked oligohydramnios and a negative family history who was found to have malformed ears, mandibular hypoplasia, truncated upper arms, and poorly identified digits.¹⁰⁸ Delivery occurred at 35 weeks of gestation and the diagnosis of Nager syndrome was made. The authors stated that prenatal ultrasonographic findings were not sufficient to make a prenatal diagnosis.

Miller syndrome is another acrofacial anomaly that is characterized by Treacher Collins-like facies and postaxial limb deformities.¹⁰⁹ Transmission is autosomal recessive; the molecular abnormality is unknown. Limb malformations include shortened forearms, absence of fifth digits, and syndactyly. Antenatal detection of Miller syndrome has not been reported. Positive family history would increase suspicion in combination with ultrasonographic findings of abnormal facies and limb anomalies. Postaxial verses preaxial subtleties are difficult to detect prenatally, depending on severity.

Mandibular Micrognathia: Syndromic and Nonsyndromic

Mandibular hypoplasia, present before 9 weeks of gestation, is thought to initiate the Robin sequence (Fig. 13).¹¹⁰ Diminished oral space displaces the tongue upward, impeding elevation and fusion of the palatal shelves. Robin sequence is causally heterogeneous; it can be categorized as nonsyndromic or syndromic. The latter includes over 40 diagnoses.¹¹¹ Although Robin sequence is a postnatal diagnosis (cleft palate, glossoptosis secondary to micrognathia, respiratory distress, and feeding issues), prenatal detection of micrognathia could alter delivery strategy and airway management. Affected fetuses can be otherwise normal or have cardiac anomalies, trisomy 18, or Stickler syndrome. Although there are fetal cephalometric data for mandibular length, there are no established objective criteria for quantifying micrognathia.

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Fig. 13. Micrognathia: Mandibular length measured in sagittal plane during second trimester. Cleft palate cannot be reliably imaged. Robin sequence manifested in nursery in this case. The diagnosis by physical examination was Stickler syndrome.

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Stickler syndrome (hereditary arthro-ophthalmopathy) should be considered in any fetus with mandibular micrognathia. It is the most common syndromic cause of Robin sequence (30 to 40 percent).¹¹² There are no extracranial prenatal sonographic findings. It is transmitted by autosomal dominant inheritance. Because only after the birth of a child with Robin sequence or cleft palate do many families become aware that they may suffer from Stickler syndrome, careful examination of parents and other relatives is essential before accurate counseling can be given. Stickler syndrome can be caused by mutations in genes encoding collagen 2A1, 11A1, and 11A2.^113-115 Therefore, prenatal diagnosis is possible for families in whom disease-causing mutations have been identified in one of these genes.¹¹⁶ Other clinical features of Stickler syndrome in the family can help prioritize these genes for mutational analysis. For example, because type 2 collagen is the most abundant collagen in the vitreous, Stickler syndrome that is associated with severe myopia is more likely caused by type 2 collagen mutations. In contrast, families with Stickler syndrome who have severe hearing impairment are more likely to have collagen 11 gene mutations.

Prenatal sonographic prediction of Robin sequence was made by Pilu and coworkers in a third trimester fetus with a positive family history.⁸⁰ Of note, ultrasonography at 23 weeks showed a normal-sized mandible for age. However, when sonography was repeated at 35 weeks, they found polyhydramnios and micrognathia. Delivery of the fetus at 38 weeks confirmed micrognathia and a cleft of the secondary palate. This case report underscores the importance of distinguishing syndromic and nonsyndromic (deformational) Robin sequence. This infant likely had a syndrome, probably Stickler, given the history of an earlier affected child. Because the cleft palate must have developed between 8 and 12 weeks, it was probably caused by a disorder that was unrelated to the small jaw, which was not observed until later. The presence of polyhydramnios is further evidence for syndromic Robin sequence as the basis for micrognathia. Oligohydramnios would be more likely in a nonsyndromic Robin scenario.

Velocardiofacial syndrome is the second most common syndromic cause of Robin sequence (approximately 17 percent). Ten percent of patients with velocardiofacial syndrome have DiGeorge sequence. Craniofacial phenotype is the same in both velocardiofacial syndrome and DiGeorge sequence and includes minor microcephaly, malar deficiency, prominent nose, maxillary vertical excess, overt or submucous cleft palate, and micrognathia. Whereas these craniofacial anomalies are probably too subtle to be seen by sonography, the cardiac and renal defects can be detected. Cardiac defects include tetralogy of Fallot, truncus arteriosus, right-sided aortic arch and interrupted arch, conotruncal ventricular septal defect, and aberrant left subclavian artery. Renal anomalies, such as polycystic kidney and absent kidney, are seen in about 30 percent of patients with velocardiofacial syndrome.

If there is a family history (autosomal dominance) or suggestive ultrasonic signs, prenatal diagnosis can be made by chorionic villus sampling or amniocentesis. Patients with either velocardiofacial syndrome or DiGeorge sequence often have a deletion of chromosome 22q11 that is detectable by fluorescence in situ hybridization. DNA analysis and fluorescence in situ hybridization have ascertained deletions in 88 percent of patients with DiGeorge sequence and 76 percent of patients with velocardiofacial syndrome.¹¹⁷ Davidson and colleagues made a prenatal diagnosis of 22q11 deletion in a fetus with a negative family history.¹¹⁸ Ultrasonography at 27 weeks of gestation revealed polyhydramnios and interrupted aortic arch. Because DiGeorge sequence was suspected, amniocentesis was performed and fluorescence in situ hybridization analysis of fetal cells confirmed the 22q11 deletion.