11 May 2023: Articles
Isolated Agnathia-Otocephaly Complex Diagnosed Prenatally for Ex-Utero Intrapartum Treatment: A Case Report
Challenging differential diagnosis, Unusual or unexpected effect of treatment, Diagnostic / therapeutic accidents, Unexpected drug reaction , Congenital defects / diseases, Educational Purpose (only if useful for a systematic review or synthesis)Tokumasa Suemitsu1ABDEF*, Ami Takesawa1ABDEF, Mayu Hosokawa1ABD, Takahiro Mitani1ABD, Mizuho Kadooka1ABDEF, Yoshiaki Furusawa1ABDF, Motoyoshi Kawataki2ABDEF, Satoshi Dohi 3ABDEF
Am J Case Rep 2023; 24:e939016
BACKGROUND: Agnathia-otocephaly complex (AOC) is a rare congenital malformation due to a first-branch arch disorder and has been considered lethal. However, milder variants of the isolated type of AOC have been reported as nonlethal. The ex-utero intrapartum treatment (EXIT) procedure is basically indicated for a fetus with a high risk of airway obstruction immediately after birth; it is not indicated for all AOC cases but is chosen to treat cases until the airway can be evaluated to achieve a better prognosis.
CASE REPORT: A 37-year-old woman was referred with reported fetal facial deformity and polyhydramnios at 27 weeks of gestation. Our fetal ultrasound scans showed agnathia, microstomia, and synotia, but not holoprosencephaly. Isolated AOC was diagnosed prenatally. Magnetic resonance imaging and microbubble tests revealed delayed fetal lung maturation, although it was not completely unmatured. With patient agreement, an emergency cesarean section with EXIT was performed because of clinical chorioamnionitis at 35 weeks of gestation. Tracheostomy was attempted for 16 min during EXIT and was completed 4 min after delivery. Despite this, the neonate died 12 h after delivery from severe respiratory failure and a tension pneumothorax caused by a hypoplastic lung.
CONCLUSIONS: There is controversy surrounding the non-lethality of all isolated AOC cases and the non-contraindication of EXIT procedures. Our case was estimated as the milder variant, and the EXIT procedure was indicated; however, the neonate died of the hypoplastic lung. The evaluation methods of lung maturation are inconsistent, and the indication of the invasive EXIT procedure must be carefully considered.
Keywords: Agnathia-Microstomia-Synotia, case reports, Ex Utero Intrapartum Treatment Procedures, otocephaly, Prenatal Diagnosis
Agnathia-otocephaly complex (AOC) is a rare congenital malformation resulting from a first-branch arch disorder. This anomaly is characterized by the absence of the mandible, hypoplastic mandible, and abnormalities of the ear and oropharyngeal systems. This has been regarded as a lethal condition, especially if it is complicated by anomalies of the central nervous system. However, milder variants of AOC, such as the isolated type without central nervous system involvement, have fewer neurological complications, thus having a better prognosis and subsequently requiring an approach for airway management. There have been reports of non-lethal isolated AOC cases treated with tracheostomies for airway obstruction management. Otherwise, certain AOC cases could complicate hypoplastic lungs, necessitating an evaluation of lung maturity to attain a more favorable prognosis .
Ex-utero intrapartum treatment (EXIT) is a well-known acute airway management modality for fetuses with abnormalities such as mechanical airway obstruction of either the upper or lower airway [2,3]. Commonly, EXIT is indicated for large oropharyngeal masses, intrinsic airway obstruction, or severe micrognathia . Although controversial for use in AOC, several cases have reported that EXIT is indicated for AOC [3,5].
Herein, we report a case of isolated AOC diagnosed using prenatal ultrasonography and lung maturity evaluated with magnetic resonance imaging (MRI) to manage the fetal airway using EXIT.
A 37-year-old woman (gravida 3, para 0) was referred for fetal facial abnormalities based on fetal ultrasonography at 27 weeks of gestation. The patient’s past medical history was unremarkable, including no fetal abnormalities. Gestational diabetes mellitus was diagnosed incidentally at 34 weeks of gestation and was well controlled with insulin.
At the patient’s first visit to our hospital, fetal ultrasonography detected the normal estimated body weight and well-being of the fetus; however, the lower part of the face was undetectable with polyhydramnios. Subsequently, a detailed ultrasonography was performed, which revealed no mandible, a stick-like nose, and an ear situated lower than expected; however, all other structures were normal (Figure 1).
MRI revealed a hypoplastic mandible and extremely low-positioned bilateral auricles at 31 weeks of gestation, with only the tract from the inferior of the larynx to the trachea and no evidence of holoprosencephaly (Figure 2). A 3-dimensional (3D) computed tomography (CT) scan revealed no mandible, without any other bone deformities, at 32 weeks of gestation (Figure 3).
Prenatally, an isolated AOC type was diagnosed.
After diagnosis, the fetus’ growth and well-being were maintained, but the polyhydramnios worsened; thus, we performed amnioreduction twice per week from 33 weeks to 35 weeks of gestation (6 times in total). The amniotic fluid testing revealed the karyotype of 46, XY with G-band testing. Furthermore, a course of antenatal corticosteroids was given at 33 weeks, which was 6 days after admission.
MRI findings showed that the fetal lung maturation was at the lower end of the normal range of the lung-to-liver signal intensity ratio (LLSIR). Furthermore, the microbubble test of the amniotic fluid showed weak results (quantity of stable micro-bubbles <10/mm2), which implied inadequate lung maturation for the gestational age. Therefore, we considered that complete fetal lung maturity was not achieved at gestation; however, the neonate may have been resuscitated to survive with appropriate airway management for the isolated AOC type.
Emergent tracheostomy was required owing to the fetal severe upper airway dysplasia; thus, we repeatedly informed the patient of the fetal prognosis and discussed the airway management, including the EXIT procedure. However, the patient could not decide whether to receive the procedure, knowing the prognosis of this disease and the maternal risk of surgery.
Unfortunately, clinical chorioamnionitis was complicated, probably due to the frequent amnioreduction; therefore, we conveyed the requirements of terminating the pregnancy and informed the patient of the EXIT procedure. The patient decided to receive medical attention, and an emergency cesarean section with the EXIT procedure was performed for airway management at 35 weeks and 6 days of gestation.
The cesarean section with general anesthesia was performed without complications, and the EXIT procedure was almost successful but was interrupted because of fetal bradycardia that continued for 4 min, with the pressed umbilical cord. Tracheostomy was completed in 16 min during the EXIT procedure and was accomplished in 4 min after delivery (Figure 4).
After birth, the neonatal heart rate recovered to normal with the tracheostomy; however, oxygenation did not improve, despite a high flow of oxygen, owing to the non-expanding lungs. Resuscitation was performed in the operating room. The neonate was male, with a body weight of 2144 g, an Apgar score of 1 (1 min)/2 (5 min), and an umbilical artery pH of 7.207 (Figure 5).
Following admission to the Neonatal Intensive Care Unit, the intratracheal administration of the surfactant was ineffective enough, and the respirator ventilation system failed to improve oxygen deficiency, resulting in the neonate’s severe respiratory failure, with tension pneumothorax. Consequently, we suspected the severe hypoplastic lung more than we initially anticipated during prenatal evaluation. In this situation, a favorable prognosis for the neonate can reasonably not be expected, even with extracorporeal membrane oxygenation. Furthermore, the neonate is not expected to withdraw from the application. Therefore, after consultation with the mother, we decided not to indicate it. In the end, the neonate died 12 h after birth with severe respiratory failure, with tension pneumothorax due to the hypoplastic lung.
The autopsy revealed abnormal structural findings as we estimated with the fetal diagnosis (Figure 5). Pathology showed no tracheobronchial complications, such as bronchial stenosis and bronchomalacia. Pathological findings and lung weight were used to diagnose severe hypoplastic lungs. Pathological findings showed the alveolar ducts, not the alveoli, in the observation range. The lung development was in the canalicular stage . In terms of the tissue weight of his lungs, the lung-to-body weight ratio was calculated as 0.0079% (17 g lungs and 2144 g neonate), which was much lower than the ratio of 2.27 for a 28- to 36-week-old neonate  (Figure 6). The presence of hypoplastic lungs lacking proper alveolar structure is the underlying cause of the ineffectiveness of intratracheal surfactant administration. The neonate was diagnosed with isolated AOC, and the cause of death was concluded as respiratory failure with hypoplastic lung.
PRENATAL DIAGNOSIS OF ISOLATED AOC:
Prenatal diagnosis of AOC has been reported through ultrasonography, detecting hypoplastic and absence of the mandible and low-presence ears . Recently, this malformation has also been detected during early pregnancy . Other diagnostic methods, such as CT and MRI, have also been employed to provide further details of the malformation. The differential diagnosis of the syndrome encompasses Treacher-Collins syndrome, Goldenhar syndrome, Nager syndrome, and Pierre Robin syndrome .
In this case, we struggled to give a prenatal diagnosis of isolated AOC with detailed ultrasonography owing to polyhydramnios. To gain further information for an accurate fetal diagnosis, we performed MRI and 3D CT. The following characteristics were revealed in this case: no mandible in the 3D CT bone window setting and extremely low-presence ears in the MRI. No fetal growth restriction or other abnormalities, including those of the central nervous system, were detected with those imaging studies. Furthermore, we consulted other facilities specializing in such extremely rare fetal congenital abnormalities in Japan. Finally, we diagnosed the fetus with isolated AOC, excluding the differential diagnosis.
EVALUATION OF FETAL LUNG MATURATION:
Fetal lung maturity is critical for determining the perinatal prognosis and planning the delivery management . In AOC cases, the development of the lungs is uncertain owing to the insufficiency of the fetus to swallow amniotic fluid because of the absence of the mandible. Therefore, besides the microbubble testing, we conducted imaging evaluations of lung maturation.
It is challenging to evaluate intrapartum fetal lung maturation. Several studies have discussed the evaluation of lung maturity with MRI by measuring the fetal lung volume (FLV) or LLSIR [10,11].
FLV to assess fetal lung hypoplasia was calculated using a freehand region-of-interest tracing tool with an MRI, and a volumetric measurement was generated. The mean FLV of 31 weeks of gestation was 66.2 mL, following the reference, although we did not measure the FLV accurately in this case, as previously described .
LLSIR is calculated by utilizing the lung and liver signal intensities in the same slice of the MRI scan . In the present case, the average LLSIR (2.12) suggested that the maturity of the fetal lungs was within the normal limits expected at its gestational age, following the reference. However, pathological findings revealed hypoplastic lungs.
Previous studies have reported that neonates with AOC had hypoplastic lungs, based on autopsy pathology [12,13]. Several genes related to the molecular interactions during craniofacial development relevant to AOC resulted in hypoplastic lungs in genetically engineered mouse models . These data suggest that AOC would be involved in the pathogenesis of hypoplastic lungs, which is lethal in several cases.
Furthermore, a previous study showed that the LLSIR exceeded the upper prediction intervals in cases of congenital pulmonary airway malformations or tumors ; thus, the LLSIR would not have been adequate to detect abnormal lungs. In such cases, the FLV measurement could be an alternative evaluation to LLSIR to assess fetal lung maturity, with careful consideration of proper lung maturation in the fetus.
REQUIREMENT OF THE EXIT PROCEDURE IN THIS CASE:
AOC is lethal; however, some recent reports have shown that isolated agnathia could have a better prognosis with acute airway management. Alexander et al showed that 9 patients with isolated agnathia survived from 10 months to 27 years.
In almost all cases, a tracheostomy was required to manage the acute airway obstruction . Furthermore, Golinko et al reported 4 cases detailing various reconstructive strategies beyond infancy, as well as longitudinal follow-up into adulthood. They suggest that AOC could be considered a nonfatal or untreatable condition and that a good quality of life can be achieved . Another report discussed 3 cases of micrognathia in which the fetal airway was stabilized before surgery with the EXIT procedure, using the uteroplacental circulation .
In our case of isolated AOC, the tract from the larynx to the trachea was visualized and unobstructed, although the pharynx was not detected on the MRI scans; thus, we considered tracheostomy to resuscitate the fetus. As the emergent tracheostomy was challenging to accomplish right after delivery, we decided to perform the EXIT procedure to avoid hypoxic encephalopathy. We reasoned that, with lung maturity certainly progressing, an EXIT procedure may help achieve a better prognosis.
Although acute airway management was successful, immature lungs led to early neonatal death. Therefore, we should recognize that the majority of the AOC cases would be lethal; thus, EXIT is not indicated. More studies are required to discuss the indications for the EXIT procedure.
PATIENT’S ACCEPTANCE OF THE FETUS AND THE MANAGEMENT PLAN:
On her first visit to our hospital, the patient found it difficult to accept that the investigations revealed severe facial abnormalities. After we repeatedly informed her about the baby’s condition, she understood. Furthermore, her emotional attitude changed positively, and the patient consented to the EXIT procedure to try to resuscitate the neonate just before her delivery.
In our case, the EXIT procedure was recommended for the estimated milder variant of AOC after careful evaluation of lung maturity. However, the neonate’s death occurred 12 h after the EXIT procedure, which was much worse than expected prenatally due to the hypoplastic lung, a known cause of mortality in isolated AOC cases such as ours. On the other hand, several cases have reported extended survival with airway management, particularly in isolated types.
The EXIT procedure, which is not always contraindicated in all AOC cases, basically is indicated for a fetus with a high risk of airway obstruction immediately after birth.
There have been concerns that the evaluation method of lung maturation has not been entirely consistent, and that the EXIT procedure might be invasive to the patient. Therefore, the application of EXIT should be approached with caution and with an evaluation of fetal lung maturity. Further cases are required to verify the appropriateness of this procedure.
FiguresFigure 1.. Fetal detail ultrasonography at 30 weeks of gestation. (1) Lower presence of ears. (2) No mandible. (3) Stick-like nose. Figure 2.. Fetal magnetic resonance imaging at 31 weeks of gestation. (A) Sagittal plane and (B) coronal plane showed fetal facial abnormalities. (1) Pathway only inferior from the larynx to the trachea. (2) Hypoplastic mandible. (3) Extreme lower position of bilateral auricles. Figure 3.. Fetal 3-dimensional computed tomography scan at 32 weeks of gestation. (1) Extremely hypoplastic mandible. Figure 4.. (A) The tracheostomy was completed in 16 min with the EXIT procedure before delivery. (B) Tracheostomy was completed 4 min after delivery. Figure 5.. Neonate died 12 h after the EXIT procedure due to respiratory failure. (1) Malformed nose. (2) Malformed mouth. (3) Bilateral auricles. Figure 6.. Hematoxylin and eosin stain. The lung development was in the canalicular stage. The alveolar ducts, which are empty spaces, indicate the air trapped in the lungs. No alveoli.
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