Further insights into unusual acrania-exencephaly-anencephaly sequence caused by amniotic band – first trimester fetoscopic correlation with two- and three-dimensional ultrasound

Introduction

Fetal anencephaly constitutes a rare lethal condition with an estimated frequency of 5.4 per 10.000 pregnancies [1]. Morphologically, this lesion results from segmental changes initiated by an absence of the flat bones of the cranial vault originating from various primary causes that may share similar pathogenic features. Thus, cranial vault defects refer to a spectrum of anomalies, which include acalvaria, hypocalvaria, acrania with exencephaly, and anencephaly. It has been thought that these lesions might occur after fatal early events that impact the multisite process of neurulation. Acrania has been considered as a precursor of exencephaly that eventually progresses to anencephaly owing to the breakdown of the brain as a result of the exposure of the denuded brain. Another proposed etiopathogenic mechanism of acrania-exencephaly-anencephaly (AEA) sequence are disruptive events following an amniotic rupture early in gestation. An amniotic rupture sequence has been estimated to occur in 1:1,200 to 1:15,000 live births. The craniofacial region might be involved in up to one third of the cases, inevitably having severe asymmetric dysmorphic sequelae to the developing embryo. First-trimester diagnosis of acrania is feasible as early as 9 gestational weeks and may be suspected even earlier (seven completed weeks) using two- and three-dimensional (2D/3D) transvaginal ultrasound (US). It reportedly relies on reduced crown-rump length (CRL) and crown-chin length, and is predicated on an abnormal early shape of the brain resembling a Mickey mouse appearance of both distorted hemispheres [2], [3], [4], [5]. An echogenic amniotic fluid has also been considered to be an early hint of AEA sequence [4].

In the present report we highlight the superior value of a more extensive morphological examination using 2D/3D US and discuss the additional information gained by first-trimester fetoscopy in an unusual case of AEA sequence caused by an amniotic rupture. We briefly review previously described first trimester characteristics in terms of etiologic and prognostic considerations.

Case presentation

A 29-year-old primigravida was referred to our US unit for targeted first-trimester examination due to an abnormally shaped cranial pole of the fetus at 11+5 weeks of gestation. Both parents were healthy and phenotypically normal. The family history was otherwise unremarkable, and the mother had no regular medication. The early anatomic survey revealed a normally proportioned fetus with a crown-rump-length of 62 mm whose cranial part was somewhat entrapped by the clearly visible amnion. Detailed transvaginal US assessment showed a firm constriction ring surrounding the external base of the developing skull separating a distorted balloon-like part of the brain within the extraembryonic coelom (Figure 1; Supplemental Material, Video Clips 1 and 2). The calvarian bones were absent. Additionally, the fetus had an abnormally arranged maxilla-mandibula complex with median clefting of the upper lip and jaw (confirmed in coronal and sagittal views) corroborating the diagnosis of an amniotic band sequence. The residual anatomy including the nuchal translucency thickness was normal. The pregnancy was terminated on parental request. The mother agreed a transcervical fetoscopy in advance of the voluntary dilatation and evacuation. As demonstrated during 2D/3D US the fetus’ cranial part was wrapped by an amniotic strand traversing the face above the eyes, thereby expulsing the cystic remnant of the brain towards the chorionic cavity (Figures 2 and 3; Supplemental Material, Video Clips 2–4).

Figure 1:

2D sagittal and frontal US views of the severely deformed skull lacking calvarian bones (panels A and B).

There is a midfacial hypoplasia and general craniofacial distortion suggestive of asymmetrical clefting (abnormal retronasal triangle view). Panel (C) shows a thin amniotic membrane traversing the face at the level of the eyes (arrows).

Figure 2:

Surface-rendered 3D reconstruction of the fetus, clearly depicting the amniotic entrapment of the skull leaving the cystic degenerated brain in the extraamniotic cavity (panels A and B).

Figure 3:

Fetoscopic images providing a direct view on the amniotic constriction ring that releases the fetal cranial pole into the extraamniotic cavity.

The disorganized brain tissue is covered by a thin translucent membrane (panels A and B). Partial (panel C) and complete blunt liberation of the fetus’ head from the amniotic entrapment. The median cleft of the upper lip is clearly demonstrated (panel D).

Discussion

There is compelling evidence that one of the morphological consequences of disrupted neural tube closure during primary neurulation (4th gestational week) is a failed mesenchymal migration that inevitably results in the inability to form the bony vault of the developing skull (acrania). The programmed final path of this lethal condition is a process of complete degeneration of the unprotected early brain (exencephaly) that precedes a subsequent replacement of the neural tissue by the area cerebrovasculosa (anencephaly) with ongoing pregnancy.

In contrast (albeit not fully understood) a faulty separation of the neural and surface ectoderm after the closure of the rostral neuropore during the 4th week of gestation enables herniation of the closed neural tube through a skull defect and is considered to be the neuroembryological basis of cranial encephaloceles (postneurulation origin). However, these pathophysiological mechanisms do not apply for the AEA sequence of the case described herein. The fetus’ head was entrapped by an amniotic constriction ring above the level of the orbits forcing the fetus to rest in a relatively fixed position.

According to Torpin’s theory, the amnion constitutes an integral part of the fetus, that has a tendency to produce mesodermic fibrous strings after incidental rupture. With gradual enlargement of the uterine cavity the amniotic fluid emerges into the extraembryonic coelom (chorionic cavity) and the amniotic sac ceases to grow appropriately, while parts of the fetus are exposed to the coarse chorion and may rub against the firm wall subsequently resulting in superficial lesions. The denuded chorion, in turn, also generates mesodermic fibrous strings that potentially entangle fetal organs leading to constriction and even amputation. Swallowing of these filaments (also referred to as Simonart’s bands) that are commonly less than 1 µm in diameter may lead to bizarre orofacial clefts by interfering the programmed fusion of the facial processes. Two prior publications provided fetoscopic evidence for the cobweb-like appearance of amniotic bands in early pregnancy that interlocked between themselves resulting in malformation and disruption of the developing craniofacial structures (or constriction of other fetal parts) [7, 8]. In three recent studies that aimed at defining subtypes of AEA sequence with respect to their phenotypic appearance during first-trimester US (e.g. bilobular, cystic, elongated, irregular, foreshortened, or overhanging) the authors stated that these changes at least partly relate to the gestational age at diagnosis supporting already established facts that the early occurrence of the underlying cause significantly dictates the extent and severeness of the resulting distortions [3, 9, 10]. The unique US features of our present case were confirmed during fetoscopy that clearly showed the firm amniotic entrapment of the skull leaving the cystic degenerated brain in the chorionic cavity only covered by meninges. Despite its much smaller thickness, amnion is shown to be stiffer, stronger and tougher than chorionic layer [6]. The orofacial cleft seen in both sagittal (maxillary gap) and coronal sonographic planes (abnormal retronasal triangle view) could also be validated. The calvarian bones were absent as demonstrated during transvaginal US. The case shows striking similarities to those recently described by Sepulveda and colleagues, who postulated that with advancing early pregnancy and progressive growth of the fetal head, the constriction ring compresses the base of the skull, leading to impaired circulation to the vulnerable developing brain as well as abnormal circulation of the cerebrospinal fluid (turkish turban sign) [2]. This hypothesis is further supported by Wertaschnigg et al., who also attributed the cystic subtype of AEA sequence to vascular disruption early in gestation [10]. This subtype was present in 1 out of 10 cases in their retrospective cohort of early AEA sequence. Interestingly, none of the cases from the latter study were linked to disruptive amniotic bands. This might be explained by the retrospective nature of the study and the unawareness of this causative presentation. In fact, acrania in the context of amniotic bands diagnosed in the first trimester has been described in 10 fetuses (including the present case), out of whom seven were assigned to early AEA sequence. However, most of these reports are lacking a detailed antenatal description of the craniofacial characteristics.

Recently a new sonographic marker, the ‘beret sign’ has been proposed, potentially enabling an improved differentiation of acrania from exencephaly and anencephaly in early gestation [3]. It describes an anechoic space above the expelled brain tissue covered by a thin echoic membrane visible in both sagittal and coronal planes. It shares cystic, prolonged and irregular phenotypic features of AEA sequence as described previously. In the exceedingly rare case of exencephaly and grossly preserved brain structure it has been suggested that vascular disruption does not play a primary role in the pathogenesis of the anomaly. It seems most likely that this lesion might rather result from faulty control of gene function involved in the formation of a normal brain. Accordingly, it might be speculated that complex cases lacking severe craniocerebral distortions occur later in pregnancy representing a distinct phenotype supporting a rather intrinsic mechanism for amniotic band sequence.

In conclusion, the case delineated herein further supports the theory of a disruptive event during early gestation. Given the progressive nature of AEA sequence on one hand and the capabilities of meticulous sonographic work up on the other hand it illustrates the particular importance to elaborate the early appearance of AEA sequence facilitating a more detailed and timely diagnosis. An additional fetoscopic approach might further contribute to the final diagnosis as exemplified in the present case. It has been proposed that categorization into different subtypes might aid an earlier detection and optimized antenatal management and future antenatal counseling. It seems plausible that risk factors might differ between these lesions as acrania caused by amniotic bands represents a sporadic postneurulation event that is probably not dependent on the folate pathway comprising a very low recurrence risk, whereas the presence of anencephaly following defective neural tube closure increases the risk of occurrence of another neurulation defect in any subsequent pregnancy.