Navigating Prenatal Diagnosis of Fetal Agnathia: A Complex Case and Diagnostic Journey

A 27-year-old Gravida 7 Para 1142 woman received a second opinion referral to our maternal-fetal medicine (MFM) center at 31 1/7 gestational weeks for a palliative induction of labor for fetal agnathia. Maternal history was significant for recurrent first-trimester spontaneous abortions, and no other significant maternal medical, surgical, or family history was reported. Although the pregnancy was initially uneventful, imaging at 29 weeks’ gestation showed possible fetal agnathia. At this time, the amniotic fluid index (AFI) was markedly high at 39.5 cm (>97th percentile, normal AFI >5 to 24 cm, severe polyhydramnios AFI ≥24 cm), indicating severe polyhydramnios, with the largest pocket noted at 14.9 cm (normal depth 2 to 8 cm).1 Ultrasound imaging additionally noted no visible mandible or lower lip, which is concerning for agnathia. Magnetic resonance imaging was recommended and completed at the referring hospital. This was described as challenging to determine with certainty the presence of a mandible. Genetic testing, including chromosomal microarray analysis with reflex testing to an agnathia-otocephaly complex (AOC) panel (Prevention Genetics), was initiated following amniocentesis/amnioreduction. The patient was subsequentially referred to our MFM center for a second opinion and consideration of a palliative induction of labor.The patient received a comprehensive ultrasound examination at 31 1/7 weeks’ gestation with our MFM specialist. At this time, a two-dimensional (2D) grayscale and three-dimensional (3D) reconstruction of the fetal face, including profile and coronal views, were conducted. The 2D ultrasound and 3D reconstructions failed to visualize the fetal mandible (Figures 1 and 2), although the fetal maxilla was present. The ears were low-set on 2D and 3D images (Figures 3 and 4), and the mouth appeared small, indicative of microstomia (Figures 5 and 6). Polyhydramnios was reconfirmed, with the deepest vertical pocket measuring 10.4 cm (Figures 7 and 8). The stomach bubble remained small throughout the examination (Figure 9). The estimated fetal weight was 2176 g, consistent with the 95th percentile. The MFM team detected no other fetal abnormalities.The 2D and 3D reconstruction fetal ultrasound images in this case supported the diagnosis of agnathia. Normally, mandibular formation occurs in the embryo around the third gestational week.2 Goenka et al explain that detection of AOC can occur as early as 11 to 14 weeks of gestation.3 If a normal-appearing mandibular arch is not visualized by the start of the second trimester, repeat imaging should be obtained at 15 to 16 weeks’ gestation to exclude agnathia.3 On the other hand, fetuses severely affected by the AOC may have other abnormalities, including central nervous system, skeletal, renal, or cardiac anomalies, that prompt an earlier diagnostic evaluation.4 Most cases of agnathia are diagnosed in the second or third trimesters.3 Although several different facial ultrasound screening methods have been proposed, no universal facial ultrasound screening exists.5 Later in gestation, ultrasound may fail to clearly detect the fetal stomach because of swallowing difficulties secondary to the agnathia and microstomia. Other syndromes in the differential diagnosis for agnathia include Goldenhar syndrome, Nager syndrome, Pierre Robin syndrome, and Treacher-Collins syndrome.5Polyhydramnios commonly occurs in the third trimester. Importantly, the absence of polyhydramnios in early gestation does not exclude agnathia.5 Different imaging modalities during pregnancy can help characterize the spectrum of involvement in AOC. Initially, 2D and 3D ultrasound are used. As the pregnancy advances, the lower part of the jaw may be difficult to fully visualize.5 At this point, helical computerized tomography or magnetic resonance imaging scans may be used later in pregnancy to better monitor the fetus. Intrauterine management of agnathia may include amnioreduction for severe polyhydramnios.6 Families require interdisciplinary care throughout the pregnancy. Overall, AOC carries a very poor, if not lethal, prognosis.5 The outcome worsens for individuals with agnathia and associated defects, especially abnormalities of the central nervous syndrome.6 Without treatment immediately following delivery, infants with agnathia die from respiratory failure due to airway obstruction.7 Survival beyond the intrapartum period requires perinatal tracheostomy and gastrostomy placement.4 An individualized plan of care for each family must be established during the pregnancy to optimize management during delivery.The AOC represents a spectrum of malformation of the first branchial arch that occurs in early embryogenesis and is usually lethal.1,8 Current genetic testing options for congenital malformations include chromosomal microarray, single-gene testing, panel gene testing, and whole-exome sequencing. Genetic testing may identify a molecular cause in either of the two genes known to be associated with AOC, PRRX1 or OTX2. Despite advances in technology, more than half of individuals with AOC do not have an identifiable genetic etiology. This makes counseling families on recurrence risk extremely challenging. Diagnostic rates may increase as newer technologies such as whole-genome sequencing are increasingly used, but data on this have not been published to date on patients with AOC. Families should still be offered genetic counseling when agnathia is identified prenatally given the complexity of clinical findings and likely poor outcome.From an otolaryngology perspective, intrauterine management of agnathia is expectant. Based on prognosis and the family’s requests, the interdisciplinary team caring for the infant with agnathia can plan intrapartum management. Parents requesting full resuscitation for milder cases of agnathia may be offered the option of ex utero intrapartum treatment (EXIT).5 An EXIT procedure may be planned so that the otolaryngologist can evaluate the severity of airway obstruction and possible treatment options.6 Intrapartum management with an EXIT procedure remains controversial due to the overall poor outcome associated with AOC.6 When parents elect for aggressive treatment and resuscitation, an airway is established, usually via tracheostomy, during delivery while the neonate is still on placental support. Nutrition requires a nasogastric tube or gastrostomy tube. Patients with agnathia surviving past infancy typically require multiple surgeries for craniofacial, and specifically mandibular, reconstruction.9,10In this case, the family declined the EXIT procedure and decided to pursue palliative induction due to the confirmed agnathia on multiple imaging modalities. The male infant was born without a spontaneous cry and was apneic. The infant exhibited pallor and mottling with minimal spontaneous movements. Notable physical examination findings included agnathia, absent lower lip, presence of the upper lip, inability to open the mouth, low-set ears that were posteriorly rotated, and downslanting palpebral fissures (Figure 10). The infant never had an audible cry. The family lovingly held the baby, and he died at 70 minutes after birth.With parental consent, a pediatric otolaryngologist performed bedside endoscopy shortly after death. A photograph of the external mouth showed microstomia and absent lower lip (Figures 11 and 12). The scope was then passed into the mouth opening. A photograph obtained just within the oral cavity revealed an abnormally narrow hard palate with a midline groove superiorly and a triangular bud inferiorly, presumed to be a part of the unformed mandible (Figure 13). The posterior oropharynx beyond this had a mucosal membrane that did not allow the scope to pass into the oropharynx or larynx. The scope was then passed through the naris, which was connected to the nasopharynx, oropharynx, and larynx. A smooth, ovoid structure on the inferior aspect mouth represents a presumed, rudimentary tongue, or microglossia (Figures 14 and 15). The visualized vocal cords and epiglottis appeared unremarkable other than clear secretions (Figures 16 and 17). The scope was also passed through the vocal cords. The trachea was filled with secretions but otherwise appeared to be intact with normal rings and carina.The infant’s clinical features appeared most consistent with PRRX1-related AOC. Chromosome microarray performed on amniotic fluid cells was nondiagnostic and revealed an 18.4-kb deletion at 14q11.2, classified as a variant of uncertain significance (VUS). This VUS is not known to be associated with agnathia. The AOC panel, which included sequencing and deletion/duplication analysis of OTX2 and PRRX1, was negative. Trio exome analysis later identified maternal inheritance of the 14q11.2 deletion without other additional findings.Agnathia is a rare congenital craniofacial defect with a prevalence of less than 1 in 70 000 live births. The condition is primarily characterized by severe underdevelopment or absence of the mandible, resulting in a missing lower jaw, restricted mouth opening, and an underdeveloped chin. Agnathia encompasses a spectrum of severity, ranging from partial mandibular agenesis to complete absence of the mandible. When agnathia occurs concurrently with other craniofacial anomalies involving the first pharyngeal arch, such as auricular fusion (synotia), microstomia with oroglossal hypoplasia, or aglossia, it forms the AOC. The AOC presents complex medical challenges due to upper airway obstruction. Most cases of AOC occur sporadically. Genes associated with AOC in humans include OTX2 and PPRX1 as previously mentioned; however, most affected individuals do not have mutations in OTX2 or PPRX1, suggesting the involvement of other genes or multifactorial or nongenetic factors. Survival with AOC necessitates perinatal tracheostomy and gastrotomy placement.This case underscores the importance of multidisciplinary collaboration in neonatal care to further the understanding of congenital anomalies. A team consisting of MFM physicians, a pediatric otolaryngologist, geneticists, and neonatal specialists partnered to provide comprehensive support to a family with antenatal diagnosis of agnathia. Further investigations and ongoing genetic counseling may provide additional insights into the underlying factors contributing to this rare condition.We would like to give a special thanks to baby F and his loving parents who eagerly awaited the publication of this case report to be able to spread knowledge of this condition to the medical community and families facing similar circumstances. We are forever grateful for your strength, love, and dedication.