Advances in prenatal diagnosis of fetal otocephaly by 3D imaging

Background

Defects in the development of the first branchial arch are thought to lead to the rare and lethal malformation complex of otocephaly. It affects less than 1 in 70 000 newborns.1 About one-third of all genetically tested cases carry a mutation or deletion in the OTX2 or PRRX1 genes.2 In individual cases, the use of beclomethasone, theophylline and salicylates during pregnancy has been associated with otocephaly.3 4

Isolated forms of otocephaly are characterised by microstomia, agnathia and synotia. Otocephaly is often associated with midline defects such as holoprosencephaly, proboscis, hypotelorism or cyclopia. Further possible malformations include cephalocele, cardiac defects, situs inversus, adrenal hypoplasia and neural tube defects.5 6 All of these additional anomalies can help to diagnose otocephaly in the first trimester, whereas isolated forms are often not recognised until the third trimester. Due to fetal microstomia and agnathia with associated dysphagia, severe polyhydramnios is a common finding after the second trimester.

In most cases, a detailed evaluation by a specialist leads to the correct diagnosis of otocephaly. Synotia is the leading anomaly that distinguishes it from other syndromes with facial dysplasia.7–9

Case presentation

A gravida II, para I in her 30s presented to our tertiary hospital at 27 weeks of gestation because of an unclear polyhydramnios. Except for a preterm caesarean section due to amniotic infection syndrome, her medical history was unremarkable. The patient denied any medication use, was unaware of any recent infection and was not exposed to any teratogen during pregnancy.

We confirmed polyhydramnios and performed detailed obstetric ultrasound with genetic amniocentesis and amniodrainage of 900 mL. We were able to visualise numerous signs of craniofacial dysplasia. Agnathia was diagnosed as the mandible was not visible in the midsagittal view of the fetal profile. In the coronal view of the anterior face, we saw the typical appearance of microstomia with a small, round mouth throughout the examination. In the axial views and especially in three-dimensional (3D) imaging we could see fetal synotia with an abnormal position of the fetal ears. These appeared to be fused in the anterior neck region. Otherwise, we did not detect other fetal anomalies. Genetic analysis revealed a normal karyotype, a normal microarray and normal whole genome sequencing. In particular, there were no mutations in the PRRX1 or OTX2 genes, which have been described in relation to otocephaly.

The illustration of fetal malformations by 3D imaging was very important for the expectant parents to understand the extent of the disease. Three weeks after our initial consultation and before the scheduled palliative care team meeting, the patient presented at 30+3 weeks of gestation with premature rupture of membranes and onset of labour. We discussed the poor prognosis of suspected fetal otocephaly with the couple again. Together we agreed to refrain from induction of lung maturity and tocolysis.

After a short and uncomplicated birth, the newborn presented all the suspected signs of otocephaly. Since respiratory treatment was impossible, the parents approved palliative care. As the newborn did not show any signs of pain, we provided comfort care without the need for drug therapy.

At the age of 48 min, the newborn boy passed away peacefully in the arms of his parents. The parents refused autopsy, but agreed to photographic documentation and postmortal CT that confirmed mandibular agenesis.

After uncomplicated third and fourth stage of labour, the patient left our hospital 1 day after delivery. Due to the psychological stress situation, we registered the patient for psychological support at her request. In the psychological consultation, 10 days later, the couple showed good coping behaviour and did not want to arrange a follow-up appointment.

Investigations

Due to the referral with unclear polyhydramnios, we performed a detailed sonography. During the examination, we noticed numerous abnormalities of the fetal face. These suggested the suspicion of fetal otocephaly.

We confirmed all our findings by 3D imaging (figures 1 and 2) and performed genetic amniocentesis and amniodrainage.

Genetic analysis of karyotyping, microarray and whole genome sequencing were normal.

The parents refused autopsy, but agreed to photographic documentation and postmortal computed tomography (figures 3 and 4).

Differential diagnosis

After ultrasound examination, we primarily considered Treacher Collins syndrome as differential diagnosis. It is characterised by midface hypoplasia, micrognathia and external ear as well as lower eyelid abnormalities. The causes of Treacher Collins syndrome are heterozygous pathogenic variants in TCOF1, POLR1D, POLR1B genes or biallelic pathogenic variants in POLR1C or POLR1D genes.7 As whole genome sequencing was normal in our case, we were able to exclude Treacher Collins syndrome. Another possible differential diagnosis was the embryologically related Nager syndrome. This is a mostly sporadically occurring disease with maldevelopment of the first branchial arch.8 Typical signs of Nager syndrome are craniofacial, limb and musculoskeletal anomalies.9

Since no cases of synotia have been described in connection with Nager syndrome, we have excluded it as well.

We also considered Goldenhar syndrome as a possible differential diagnosis. It is also known as oculo-auriculo-vertebral dysplasia with hemifacial macrosomia. Due to the symmetrical nature of the findings in our patient, Goldenhar syndrome was unlikely.

Outcome and follow-up

As in our case, otocephaly usually occurs sporadically. We excluded mutations in PRRX1 and OTX2 genes by whole genome sequencing. This is why recurrence risk in following pregnancies will be low, although germ cell mutations can contribute to some increase in risk.

We discussed all findings with the patient and her partner. We offered and recommended further counselling before any future pregnancy.