Fetal acrania diagnosed at 17 weeks of gestation by 2D/3D ultrasound: a case report and literature review

Abstract

Acrania is a fetal malformation characterized by complete or partial absence of the calvaria above the orbits and supraciliary ridge. No exact mechanism is demonstrated for this anomaly but disturbances in mesenchymal migration during the fourth week of development are the most documented. The key sonographic features of acrania are absent calvaria and dorsally bulging brain (Mickey Mouse head). Due to the normal process of ossification of cranial bones, the diagnosis can be established only after 11 weeks of gestation. Early detection is extremely important. The prognosis is extremely poor so elective termination of pregnancy is the treatment of choice. In this paper, we discuss the things we know about pathogeny and ultrasonographic features of fetal cranial malformations based on a case diagnosed late during gestation.

Introduction

Fetal acrania is a congenital malformation in which the skull bones are completely or partially absent.

The incidence of this anomaly is estimated to be between 3.68 and 5.4 cases per 10 000 live births [1]. Other reports show an even smaller incidence of about one case per 20 000 deliveries [2].

Since there is no specific cause of this malformation, multiple mechanisms have been proposed. Obviously, anomalies in mesenchymal migration during the fourth week of embryological development are the most discussed mechanism but, what triggers that is still to be determined [3].

As in other neural tube defects (NTDs), fetal acrania could be the result of improper mixture of abnormal developmental genes and environmental factors. Regarding the genetic factor, anomalies of the genes involved in folate metabolism are proved to be very much associated with NTDs. Mutations in genes like methylenetetrahydrofolate reductase (MTHFR) as well as Van Gogh-like planar cell polarity protein 1 (VANGL1, a membrane-associated signaling complex protein) have been associated with an increased risk of sporadic or familial NTDs [4]. Moreover, fetal chromosomal abnormalities have also been associated with this malformation. In a series of 14 cases published by Gorgal et al., three out of eight fetal karyotypes were abnormal [5].

Hyperthermia, antiepileptic drugs, uncontrolled diabetes, maternal obesity, and folate deficiency are the most documented environmental factors associated with NTDs [6].

In a series of 14 cases of acrania published by Gorgal et al., one mother known to have epilepsy was taking anticonvulsants and another one had uncontrolled diabetes mellitus [5]. In a recent meta-analysis published by Vena et al., maternal obesity proved to be a risk factor to NTDs in general with an odds ratio (OR) of 1.62 [7].

Other drugs taken prior or during first weeks of pregnancy have also been reported as risk factors for fetal acrania. In a recent report published by Daham et al., fetal acrania was associated with maternal exposure to Adalimumab, a fully human, recombinant, immunoglobulin G1 (IgG1) monoclonal antibody that targets tumor necrosis factor-alpha (TNF-α), used for the treatment of psoriasis [8].

Moreover, several reports from the literature suggest the association between amniotic band syndrome (ABS) and fetal acrania [9]. The exact mechanism is not well understood but it seems that early disruptions of the amniotic membranes and attachment of these bands to the cranial pole of the embryo will consequently lead to improper development of the calvarial bones. This hypothesis was first promoted by Torpin in 1968 and sustained by several authors later on [10, 11].

Although numerous reports from the literature emphasize the relationship between NTDs and genetics, as well as environmental factors during early stages of embryonic development, only a few are addressing acrania alone.

Fetal acrania is mainly diagnosed by ultrasound (US) in the late first trimester or early second trimester of gestation [12]. Too early diagnosis must be formulated with great caution as the calvarial bones will not be fully calcified until 11 weeks of gestation [13]. The key sonographic feature of acrania is absent calvaria. Moreover, two-dimensional (2D) as well as three-dimensional (3D) obstetric US shows prominent inter-hemispheric cerebral fissure and dorsally bulging brain (Mickey Mouse head) [14, 15, 16].

Due to its extremely poor prognosis, the management of fetal acrania is by elective termination of pregnancy. In almost all cases, the prognosis is lethal, with 65% dying in utero and 35% dying during delivery. Short-term survival (minutes to days) has also been reported as well as a 2–5% recurrence risk in future pregnancies [17].

Aim

The aim of this report was to emphasize the importance of first trimester malformation screening in all pregnant women. We present a rare case of fetal acrania diagnosed in second trimester of pregnancy and emphasize the major diagnostic challenges and the need for careful first trimester morphological screening for all pregnant women.

Case presentation

We present the case of a 25-year-old pregnant women (gravida 2, para 1), 17 weeks of gestation, who was admitted in the Department of Obstetrics and Gynecology, St. Apostle Andrew Emergency County Hospital, Galaţi, Romania, with suspicion of fetal cranial malformation. She had one previous vaginal delivery resulting in a healthy baby weighing 3600 g, Apgar score 9 at one minute and 10 at five minutes.

The patient did not have significant medical or surgical history and she did not take any vitamin supplements or folic acid during preconception or early gestation period. There was also no history of teratogenic drug intake during pregnancy.

The pregnancy was regularly monitored, and no pregnancy associated pathology has been noticed so far. Moreover, no familial history of genetic or congenital abnormalities was recorded.

First trimester screening for chromosomal anomalies performed at 11 weeks and three days of gestation showed a low risk pregnancy and no structural defects whatsoever.

Routine investigations on admission, like complete blood count, renal and liver tests, were all within normal limits.

US evaluation on admission revealed a live fetus with biometry appropriate for 17 weeks and two days of gestation with absent calvaria and dorsally bulging brain (Mickey Mouse head) (Figure 1A). The brain tissue, although present, was totally unorganized, with no specific differentiation of structures (Figure 1B, 1C). The skull base and the facial structures appeared normal. No evidence of myelo-meningocele or other types of spinal dysraphism was noticed. Also, internal organs as well as extremities appeared normal.

Figure 1.

(A) Coronal section of the fetal head showing the absence of bone structures above the orbits and supraciliary ridge (Mickey Mouse head); (B) Coronal section of the fetal head showing the displacement of the abnormal brain; (C) Sagittal section of the fetal head showing the absence of calvaria and dorsally bulging brain

Figure 2.

(A–C) Three-dimensional (3D) reconstruction of the fetal head showing absent calvaria and dorsally bulging brain.

The patient was informed about the very poor prognosis of fetal cranial malformation. After obtaining the informed written consent, the pregnancy was electively terminated using Mifepristone and prostaglandins. The patient delivered a dead fetus weighing 210 g, with absent cranial bones. The brain tissue was very much destroyed during labor and delivery process so that only the meningeal membranes could be identified.

No facial anomalies were noted; the orbits, nasal bone and lips appeared normal. The thoracic and lumbar spine appeared normal. Upper and lower limbs, as well as internal organs, were normal on autopsy report.

Placenta was in anterior position, appropriate in size and thickness with gestational age.

The macroscopic appearance of the delivered fetus was very much consistent with the US findings (Figure 3A, 3B).

Figure 3.

(A and B) Macroscopic appearance of the fetus showing the absence of cranial bones. No other macroscopic anomalies were noticed at the moment of delivery

Discussions

Acrania is the most common anomaly in the acrania–exencephaly–anencephaly spectrum (AEAS). This syndrome actually refers to a continuum spectrum of lesions starting from the absence of the cranial vault (acrania), exposure of the virtually normal developed brain into amniotic cavity (exencephaly) and finally anencephaly as a consequence of progressive brain destruction.

In fetal acrania, there is a partial or complete absence of flat bones in the cranial vault. Even if the cerebral tissue develops, it is mostly abnormal [18]. The cerebral tissues fail to form the two hemispheres, but brainstem, cerebellum, and cranial nerves are usually normal in fetuses with acrania. Additional criteria for diagnosis include normally developed facial bones, normal vertebral column, and brain tissue volume at least one-third of that appropriate to gestational age.

Although there are reports in the literature that easily suggest the possibility of diagnosis during the first trimester prenatal screening, in the large majority of acrania reports the diagnosis is established in late first or early second trimester of gestation.

In a recent study published by Miguelez et al., the diagnosis of anencephaly/exencephaly was established as early as eight weeks and two days of gestation. The report included only three cases and the diagnosis was formulated based on the abnormal shape of the head in sagittal and coronal sections. Thus, according to the authors, the elongated, short, irregular, broad on coronal section, lobulated or bilobed embryonic head are very much suggestive for fetal acrania [19].

In a large retrospective study of 3600 pregnant women who have received first trimester screening at 10 to 13 weeks of gestation, acrania was easily diagnosed in seven cases [20]. In contrast, Gorgal et al. reported, in their series of 14 cases, a median gestational age of 13 weeks of gestation, with limits of 12 to 15 weeks, at the moment of diagnosis [5].

Specifically, the diagnosis of fetal acrania cannot be clearly formulated before 11 weeks of gestation and that is explained by the normal process of ossification of calvarial bones. In this respect, between 11 and 14 weeks of gestation, the majority of cranial ossification is located in the lateral aspects of the frontal bones and lower part of the parietal bones [21]. Thus, on a perfect midsagittal section used for the measurement of nuchal translucency, no vault ossification could be seen at this moment. In this circumstance, the fetal head may appear relatively normal, and misdiagnosis may occur. In addition, in cases with severe osteogenesis imperfecta and congenital hypophosphatasia, conditions associated with inadequate bone mineralization, the poorly defined calvaria is very tricky and difficult to be differentiated of fetal acrania [22, 23]. It is thus very important to obtain not only the midsagittal plane but also the axial and coronal planes that clearly illustrate frontal bone ossification [24, 25].

In order to overcome these difficulties that could potentially lead to misdiagnosis, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) has issued guidelines emphasizing the need to recognize the fetal head, cranial bones, choroid plexus, and cerebral ventricles for all first trimester pregnancy scans [26].

According to Bianca et al., the US features of fetal acrania are [18]:

▪ Development of brain tissue with no evidence of a calvarium (in partial acrania, portions of the skull may be observed);

▪ Brain tissue may appear to be unorganized with irregular echogenicity;

▪ Prominent sulcal markings.

In a recent study published by Szkodziak et al., in 2020, the “beret” sign was assigned as a promising tool in the diagnosis of acrania. In five cases of acrania out of 4060 US scans analyzed, the “beret” sign was described as an inertial rippled thin membrane that encompasses the brain structures. Between these two structures, a thin layer of anechoic space corresponding to cerebrospinal fluid can be described [27].

With the recent improvements in US technology, 3D US has become an important tool in assessment of fetal anatomy [28]. Many reports from the literature have already demonstrated the usefulness of 3D US in early diagnosis of different central nervous system malformations, such as spina bifida or holoprosencephaly [29]. In this respect, 3D US could also be very useful in early and accurate detection of fetal acrania, as in our case, not only by providing a very suggestive visual depiction after reconstruction [30] but also by providing specific diagnostic clues, such as absence of the skull, prominent inter-hemispheric cerebral fissure, deformed brain tissue or dorsally bulging brain (Mickey Mouse head) [14, 15, 16].

As the pregnancy continues, the contact between the fetal brain and amniotic fluid, placenta or other fetal parts will lead to progressive brain destruction. These changes are consistent with the acrania–anencephaly spectrum. In advanced stages of evolution, fetal brain tissue will be reduced to echogenic floating particles, which will increase the amniotic fluid US texture.

Conclusions

In all cases, early in utero diagnosis helps manage maternal expectations and directs appropriate counselling. In order to achieve an early and accurate diagnosis, we recommend the examination not only the standard midsagittal plane used for assessment of nasal bone and nuchal translucency at 11 to 13 weeks of gestation but also the axial and coronal planes for a better identification of frontal bone ossification. Based on our experience, we recommend the screening for fetal anomalies in the first trimester of pregnancy to be realized starting from 12 weeks of gestation. Once the diagnosis is established, termination of pregnancy, after careful counselling of the parents, is the treatment of choice. Taking into consideration the strong association between the folate metabolism and NTDs, we strongly suggest the supplementation of diet in periconceptional period with 400 μg of folic acid daily or even better with its active form 5-methyltetrahydrofolate (5-MTHF) especially in countries not applying a fortification program.

Conflict of interests

The authors declare that they have no conflict of interests.