Prenatal diagnosis of holoprosencephaly with proboscis and cyclopia caused by monosomy 18p resulting from unbalanced whole-arm translocation of 18;21

Introduction

Holoprosencephaly (HPE) is an anomaly of the forebrain resulting from the total or incomplete absence of division of the prosencephalon during embryogenesis. The frequency of HPE is estimated to be 1/250 conceptuses and 1/16,000 live births [1, 2]. Cyclopia is the most severe facial malformation associated with HPE, occurring in 1 in 100,000 births [3]. HPE shows a heterogeneous etiology and several causative factors have been implicated in this congenital disorder [4].

Recent genetic studies have identified genes associated with HPE, including the gene for transforming growth-interacting factor (TGIF), located on the short arm of chromosome 18 at 18p11.3 [5]. According to the literature review, nine cases with prenatal diagnosis of monosomy 18p with HPE have been reported (Table 1) [6, 8–13]. The nine cases were diagnosed only by prenatal ultrasound examinations. However, detailed anatomical analyses in utero using different modalities would be additional information for the parents and medical staffs other than obstetricians to accept the situation more rationally. The present case, for the first time, was morphologically evaluated with 3D-CT and MRI. We present a case of alobar HPE with proboscis and cyclopia with monosomy 18p.

Case report

A 33-year-old woman, gravida 1 para 0, was referred to Kobe University Hospital at 28 weeks of gestation because of fetal growth restriction and polyhydramnios. She had no history of smoking, drinking alcohol, exposure to medical and illicit drugs, or infections during pregnancy. Fetal ultrasonography at 28 weeks and 4 days of gestation revealed cerebral ventricular dilation, cerebellar hypoplasia, and dilation of the posterior cranial fossa (Figure 1). The frontal part of the brain was fused and the septum was undetectable. The fetal nose bone and orbits were not detected. A small protrusion in front of the fetal forehead was suspected to be a proboscis, and subsequently it was confirmed by three-dimensional ultrasound (Figure 1).

Figure 1:

(A) Absent midline and dilated and single ventricle were detected by ultrasound at 28 GW. (B, C) Suspected proboscis detected by two- and three-dimensional ultrasound (arrow). (D) Single orbital cavity confirmed by computed tomography at 29 GW.

Thereafter the amniotic fluid index (AFI) increased to 28 cm. The normal structures of stomach and urinary tract were detected. There were no cardiovascular anomalies. The estimated fetal body weight and biparietal diameter were 834 g (−2.5 SD) and 6.0 cm (−3.6 SD), respectively. Magnetic resonance imaging (MRI) at 28 weeks and 6 days showed a single cerebral ventricle, and fusion of the bilateral cerebral hemispheres and thalami (Figure 2). MRI also demonstrated a single orbit containing two eyes located on the midline of the face. Computer tomography (CT) performed at 29 weeks and 6 days of gestation demonstrated the single orbit. Based on these findings, alobar HPE with proboscis and cyclopia was diagnosed prenatally.

Figure 2:

(A) Absent midline and dilated and single ventricle detected by magnetic resonance imaging. (B) Cytogenetic analysis of amniotic fluid at 28 GW showed a karyotype of 45,XY,der(18;21)(q10;q10). (C) Facial appearance of the neonate at delivery, showing a mid-frontal proboscis and a single orbit containing two eyes.

Amniocentesis performed at 28 weeks and 6 days revealed an abnormal karyotype of 45,XY,der(18;21)(q10;q10) of the fetus (Figure 2). The karyotypes of both parents were found to be normal. The AFI continued to increase and blood transaminase levels of the mother elevated to AST 49 U/L and ALT 42 U/L at 32 weeks and 5 days. Maternal dyspnea developed and the pregnancy ended in a premature delivery of a male neonate weighing 1716 g with Apgar scores of 2 (1′) and 1 (5′) at 34 weeks and 3 days. Macroscopically, there was a mid-frontal proboscis and a single orbit with two eyes without normal nasal structures (Figure 2). He died 1 h after birth. The parents accepted well the natural course of the neonate according to appropriately provided prenatal information. No consent to an autopsy was obtained. The couple had a normal delivery in the next pregnancy.

Discussion

Cytogenetic analysis of amniotic cells in the present case revealed an abnormal karyotype, 45,XY,der(18;21)(q10;q10), resulting from an unbalanced whole-arm translocation between chromosome 18 and chromosome 21. It suggested monosomies of 18p and 21p with deletion of the short arm of one chromosome 18 and one chromosome 21. The couples’ karyotypes were found to be normal, indicating a de novo origin of the abnormal karyotype of the neonate. Two cases of HPE with the same de novo karyotype have been reported so far [6, 13].

It is acknowledged that monosomy 18p is one of the causes of HPE, as described in previous reports [3]. The incidence of monosomy 18p is estimated at about 1 in 50,000 live births. The manifestations of monosomy 18p are heterogeneous, with the main clinical features being short stature, facial dysmorphism, and skeletal and cardiac anomalies, with severe brain malformation in 10–15% of cases [3]. Overhauser et al. [5] confirmed an association between the TGIF gene at 18p11.3 and HPE. TGIF is involved in retinoic acid regulation, and retinoic acid signaling plays a role in patterning the central nervous system and in craniofacial organogenesis [14]. These roles might account for the presence of HPE with proboscis and cyclopia in infants with deletion of 18p. Facial dysmorphism and severe brain malformation were confirmed in the present case. The individual prognosis depends on the severity of the brain malformation in HPE, and most neonates with HPE and severe brain malformation die during the neonatal period [15].

Early prenatal diagnosis of monosomy 18p with HPE is uncommon. In the present case, severe brain malformation was diagnosed by fetal ultrasound at 28 weeks of gestation, and most cases of monosomy 18p with HPE are diagnosed in the second trimester (Table 1). Sepulveda [10] for the first time reported a case of first trimester detection of monosomy 18p with HPE. In this case ultrasound examinations during the first trimester detected increased nuchal fold thickness together with anomalies of brain and face, allowing the early diagnosis of monosomy 18p. Failure to identify a normal butterfly-shaped choroid plexus during the first trimester was also suggestive of HPE [10]. Unfortunately, no such signs were evident during the first trimester in the present case. However, many cases of HPE might be diagnosed only by ultrasound, MRI could evaluate brain structure and malformation more clearly. In the present case, MRI could detect of complete absence of the septum and diagnose it as alobar type.

Considering such a poor prognosis, prenatal explanation of the fetal status should be presented to the parents not only by obstetricians but also neonatologists and other caregivers participating in mental support to them. The information obtained by MRI and 3D-CT might be more useful for the medical stuffs other than obstetricians because they are not habituated to the fetal ultrasound.

Most reported cases of monosomy 18p were of de novo origin (Table 1). The risk of recurrence of HPE in de novo cases is slightly higher than in the general population [7]. In the present case, chromosome karyotypes of the couples were both normal and their subsequent pregnancy was unaffected. It is important to analyze chromosome karyotypes of the couples to inform them about a risk of the recurrence in subsequent pregnancies.