Prenatal diagnosis of craniorachischisis totalis

Abstract

Craniorachischisis totalis (anencephaly with total open spina bifida) is the most severe form of neural tube defects. The exact aetiology of neural tube defects remains poorly understood. We report a case of a primigravida in her 20s with a fetus in which craniorachischisis totalis was diagnosed during the first-trimester ultrasound at 11 weeks of gestation. The parents opted for pregnancy termination and the diagnosis was confirmed postnatally. Besides the lack of folic acid supplementation during preconception, no other risk factor was found. This case highlights the importance of the first-trimester ultrasound in the diagnosis of severe malformations. The right diagnosis is crucial for future prenatal counselling, yet investigation is still required to better understand the aetiology behind neural tube defects and assess the possibility of underlying genetic features, thus enabling better counselling.

Background

Craniorachischisis totalis is an extreme and rare example of defective closure of the neural tube during early embryogenesis where the entire brain and spinal cord remain open. It is the most severe form of neural tube defects (NTD) and is incompatible with life.^{1 2} Its prevalence is still unknown and there are only a few cases reported.^1–3 Several risk factors related to neural tube defects are known; however, the exact aetiology of this condition remains poorly understood due to its rarity. Growing evidence is accumulating towards the possible role of some specific genes identified by investigation in mouse models. We report a case in which no clear known predisposing factor for the occurrence of such an extreme neural tube defect was identified.

Case presentation

A primigravida in her 20s was referred to our hospital for the first-trimester screening. It was a spontaneous, unplanned conception. Parents were not consanguineous. We investigated the mother’s medical history, which was unremarkable, and she also had no history of medication use, cigarette smoke, drug intake or substance abuse, before or during conception and throughout the pregnancy. There was no relevant family history of disease or congenital malformations. She had a normal body mass index and followed a balanced diet, thus no nutritional deficit was known; folic acid intake was initiated at 8 weeks of gestation right after pregnancy diagnosis. First-trimester ultrasound revealed a fetus at the 11th week with a crown-rump length of 41.9 mm, presenting open spina bifida (from the cervical region to the sacral region of the spine) and a fetal head with an abnormal shape, resulting from the absence of the occipital bone and the frontal portion of the cranial vault, and presence of an amorphous heterogeneous intracranial content, in which no midline falx or choroid-plexus-filled ventricles could be identified—suggesting the diagnosis of craniorachischisis totalis (figures 1 and 2).

Figure 1.

Axial oblique view of the fetal head showing bulging eyes as a result of the absence of the frontal portion of the cranial vault, absence of occipital bone and amorphous heterogeneous intracranial content, being impossible to identify the midline falx and the choroid-plexus-filled ventricles.

Figure 2.

Coronal view of the fetus showing anencephaly contiguous with total open spina bifida, from the cervical region to the sacral region of the spine.

Outcome and follow-up

Parents were informed about the malformations found and their poor prognosis and council was given regarding their reproductive options. They decided to terminate the pregnancy, which was performed a few days later and went uneventfully.

The fetal autopsy revealed anencephaly, low-set and abnormally shaped ears, prominent eyes, flat nose, macroglossia, short neck, open spina bifida from head to sacrum and skeletal malformations with vertebra defects and anterior bulging of the costal grid (figures 3 and 4). There were no limb defects or other organ malformations associated. These findings were consistent with the diagnosis of craniorachischisis totalis. Karyotype of the fetal skin was performed and came out normal. COVID-19 maternal infection was also ruled out and there was no previous administration of any vaccine.

Figure 3.

Macroscopic view of the fetus after delivery showing total absence of normal brain structures and total open spina bifida.

Figure 4.

Macroscopic view of the fetal autopsy showing anencephaly with prominent eyes, low-set ears and short neck.

Before another pregnancy, parents were advised to undergo genetic counselling regarding the risk of recurrence of NTD. The couple was also referred to a preconceptive appointment and counselling was given regarding preventive measures in future pregnancies, namely on folic acid supplementation at a dose of 4 mg/day before conception and throughout the pregnancy to prevent recurrence of NTD.^{1 2}

Discussion

The neural tube is the embryonic precursor of the brain and spinal cord and is formed when the lateral edges of the neural plate (thick layer of ectodermal cells) start to roll and form the neural folds and then fuse to form the neural tube. The process begins in the cervical region and extends bi-directionally, rostrally and caudally. The development and closure of the neural tube are normally completed within 28 days after conception. When the neural tube fails to close during the third and fourth weeks after conception it leads to a group of disorders called NTD. The type and severity of these NTD vary with the level of the body axis affected.^{2 4 5} The prevalence of NTD in Europe is estimated to be 9.1 per 10 000 births and in the USA around 9.40 per 100 000 live births.^{6 7} The risk of recurrence of NTD is approximately 2%–4% when one sibling is affected and higher if two siblings are affected.^{8 9}

The exact aetiology of NTD remains poorly understood and probably results from an additive contribution of several risk factors, which are each individually insufficient to disrupt the neural tube closure. Epidemiological and experimental models suggest various genes implicated and environmental and nutritional factors, as well as the potential for gene–gene and gene–environment interactions.^{2 10} Identified predisposing factors include the use of teratogenic drugs or toxicants, maternal obesity and diabetes, maternal fever in early gestation and folate deficiency (inadequate intake, use of folate antagonists or variants in genes related to its metabolism such as the gene encoding 5,10-methylenetetrahydrofolate reductase).^{2 5 10} For this reason, supplementation of maternal diet with 0.4–0.8 mg/day of folate preconceptionally is universally recommended as a prophylactic measure to reduce the risk of occurrence of NTD, with a higher dose of 4 mg/day being recommended for cases of increased risk of NTD (such as in women with previous history of an NTD-affected pregnancy).^{5 11}

Craniorachischisis totalis, which combines anencephaly and total open spina bifida, is the most severe form of NTD and represents an extreme and rare example of defective closure of the neural tube during early embryogenesis, around 20–22 days of gestation. Since it occurs at a very early gestational age, prenatal ultrasound assumes a crucial role in its prompt diagnosis. It constitutes a lethal congenital malformation with affected fetuses often miscarrying during the pregnancy or dying shortly after birth.¹

The majority of currently known cases of mouse craniorachischisis have been found to result from the disturbance of the molecular signalling cascade planar cell polarity pathway-PCP.² Sequencing of PCP genes in humans has identified putative mutations in CELSR1, VANGL1, VANGL2, FZD6, SCRIB1 and DVL2 in some patients with craniorachischisis, spina bifida, anencephaly or closed forms of spina bifida.¹⁰ Recent studies have suggested that craniorachischisis in humans may involve combined heterozygous mutations of two or more genes affecting PCP signalling: specifically, CELSR1 and SCRIB genes’ mutations have been involved.¹² Other genes identified from mouse models have been implicated, although association studies have failed to provide strong evidence, probably because they need to interact with other genetic variants and environmental factors to modulate the severity of the NTD phenotype.^{10 13}

Polat et al reported for the first time the association of Pentalogy of Cantrell with craniorachischisis by describing three cases of Pentalogy of Cantrell diagnosed prenatally, with two of them being associated with craniorachischisis.¹⁴ Since that time, other authors have described it as well.^{15 16} The association between sirenomelia with craniorachischisis totalis has also been described, but it is extremely rare with only nine cases reported in the literature to date.^17–20

Furthermore, association with other malformations or chromosomal abnormalities has been reported, such as trisomy 18, trisomy 11, Fryns syndrome and conjoined twins.^{1 2} While most cases of craniorachischisis reported in the literature are in association with syndromes, few cases are illustrated without further abnormalities.^{2 5}

In our case, despite other small defects associated (low-set and abnormally shaped ears, prominent eyes, flat nose, macroglossia, short neck, vertebra defects and anterior bulging of the costal grid), we could not identify any specific syndrome or chromosomal abnormality since the karyotype of the fetal skin was normal. Jaganmohan et al described a case with some similar findings, identifying, in addition to the NTD, bulging eyes and a protruded tongue.²¹ A case from India also narrates a fetus with anencephaly and total spina bifida in combination with exomphalos and sternal cleft and no other malformations pointed.⁵

In this case, apart from folate supplementation only starting at the eighth week of gestation, no other evident predisposing factor was identified and there was not any evident genetic susceptibility since there was no family history of repeated miscarriages or NTD, nor other affected siblings. However, and even though the involvement of PCP genes in craniorachischisis is still under investigation, a genetic factor could play a role in the underlying aetiology of this case, and so additional genetic testing could improve our understanding of this pathology. Similar to our report, Coskun et al described a case detected during the first-trimester ultrasound in which no aetiological factor was found and suggested that further investigation is needed to understand the role of PCP genes in the aetiology of human NTD.²

Antenatal diagnosis is possible by ultrasonographic monitoring namely through the first-trimester screening.^{1 2 5} Yet, it is also possible during the second-trimester especially using magnetic resonance for confirmation.²¹ In our case, the diagnosis was suspected in the first-trimester ultrasound and confirmed postnatally, highlighting the importance of the first-trimester screening in the early diagnosis of severe malformations—in this case, a lethal congenital malformation eligible for elective termination of pregnancy.

In the future, further investigation and exome sequencing studies should help understand better the contribution of different genes in the pathogenesis of NTD, allowing the improvement of genetic counselling in families with a previously affected pregnancy.

Learning points.

• Craniorachischisis totalis combines anencephaly and total open spina bifida and is a very rare and extreme form of neural tube defects (NTD).

• Although its exact aetiology remains poorly understood, known predisposing factors for NTD and other malformations or chromosomal abnormalities can be associated and should be ruled out. Understanding a possible genetic cause could improve genetic and prenatal counselling.

• First-trimester ultrasound plays a crucial role in the early diagnosis of this lethal malformation allowing appropriate and timely family counselling.

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