A Case of Recurrent Schizencephaly with Prenatal and Postnatal Ultrasound and Magnetic Resonance Imaging Details

Abstract

Schizencephaly is a rare congenital disorder of cerebral cortical development classified under cell migration defects. Here we report a case of recurrent schizencephaly diagnosed prenatally and confirmed postnatally in two consecutive pregnancies of a nonconsanguineous couple. Prenatal ultrasound is a valuable tool for the early detection, evaluation, and management of schizencephaly. Magnetic resonance imaging complements the diagnosis of schizencephaly by confirming the diagnosis and providing information on additional abnormalities such as polymicrogyria, heterotopias, and closed lip schizencephaly. Whole exome sequencing revealed a heterozygous missense variant in exon 1 of the PEX13 gene, associated with peroxisome biogenesis disorder type 11A (Zellweger syndrome). Our case highlights the potential genetic etiology of schizencephaly.

 

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Keywords

schizencephaly - prenatal diagnosis - PEX13 gene - zellweger syndrome - nonconsanguineous marriage

Introduction

Schizencephaly is a cleft in the brain that connects the ependyma of the lateral ventricle with the pial surface on the convexity of the brain. It is rare, with an estimated incidence of 1.48:100,000 live births.[1] Familial cases of schizencephaly are exceptionally rare and highlight the potential hereditary nature of the condition. Here we report a rare case of schizencephaly in two consecutive pregnancies in a nonconsanguineous marriage.

 

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Case Report

A 23-year-old second gravida woman, who had a nonconsanguineous marriage, was referred to our fetal medicine center at 31 weeks of gestation due to a suspected brain anomaly. Her baseline investigations and antenatal examinations were normal. A mid-trimester morphology scan performed elsewhere had shown normal findings. She had a history of a previous elective termination of pregnancy at 22 weeks due to left open lip schizencephaly, septal agenesis, and Blake's pouch cyst. Chromosomal microarray and karyotype results were normal.

Upon referral, an ultrasound examination of the fetal brain was performed, revealing several key findings: a bilateral cleft of the cerebral parenchyma extending from the lateral aspects of the fetal brain and communicating inward with the lateral ventricles, a fusion of the bodies of the lateral ventricles in the midline, and normal thalami and well differentiated posterior fossa structures ([Fig. 1]). The corpus callosum and vermis appeared to be normal. Three-dimensional ultrasound images supported our diagnosis of schizencephaly with absence of cavum septum pellucidum (CSP), both frontal horns communicating with each other, and cleft extending from lateral ventricle to subarachnoid space ([Fig. 2]).

Fig. 1 The prenatal ultrasound image of schizencephaly. 2D gray scale ultrasound coronal section of fetal brain showing cerebral cleft extending from ventricles to subarachnoid space. 2D, two-dimensional.

Fig. 2 3D fetal CNS evaluation with tomographic ultrasound imaging. This figure showing absence of cavum septum pellucidum with both frontal horns communicating with each other. 3D, three-dimensional; CNS, central nervous system.

The diagnosis of bilateral open-lip schizencephaly was made, and given the recurrence in the family, genetic evaluation and a fetal magnetic resonance imaging (MRI) were recommended.

MRI revealed a large gray matter lined open parenchymal defect in the right cerebral hemisphere involving the frontoparietal lobe, extending into the lateral ventricle, and two large gray matter lined open parenchymal defects in the left cerebral hemisphere, affecting the frontal and parietal regions, extending into the lateral ventricles ([Fig. 3A]). The additional findings were polymicrogyria and absence of CSP. The optic nerves and optic chiasm appeared normal ([Fig. 3B]).

Fig. 3 The prenatal and postnatal MRI images. This figure showing the prenatal and postnatal MRI. (A) Coronal T2-weighted fetal MR image showing bilateral open lip schizencephaly. (B) Axial T2-weighted fetal MR image showing optic chiasma. (C) Coronal T2-weighted postnatal MR image demonstrating bilateral open lip schizencephaly. (D) Sagittal T2-weighted postnatal MR image demonstrating polymicrogyria along clefts. MRI, magnetic resonance imaging.

The couple was informed that the prognosis could be poor due to the involvement of both cerebral hemispheres and the open type of schizencephaly. After considering the potentially poor prognosis, the couple opted for a termination of pregnancy. However, the medical board did not permit the termination of the pregnancy as the gestational age had exceeded 24 weeks. The patient delivered an alive female infant at 36 weeks of gestation, weighing 1.9 kg. The baby was followed up until 5 months of age, during which microcephaly and generalized spasticity were noted. No episodes of seizures were reported, and developmental milestones appropriate for age were achieved. Postnatal MRI findings were consistent with bilateral open-lip schizencephaly ([Fig. 3C]) and polymicrogyria along the cleft ([Fig. 3D]). Whole exome sequencing revealed a heterozygous missense variant in exon 1 of the PEX13 gene, associated with peroxisome biogenesis disorder type 11A (Zellweger syndrome). The variant is classified as a variant of uncertain significance and follows an autosomal-recessive inheritance pattern.

 

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Discussion

Schizencephaly is a rare congenital disorder characterized by developmental malformation of the cerebral cortex, characterized by dysmorphic gray matter–lined clefts in the cerebral cortex extending medially from the subarachnoid space into and continuous with the ipsilateral lateral ventricle.[2] It was first described in 1946 by Yakovlev and Wadsworth who coined the name “schizencephaly” as congenital clefts in the cerebral mantle, in their work on cadavers.[3]

Schizencephaly has two types: type I (closed-lip) schizencephaly is characterized by gray matter lined lips that are in contact with each other and type II (open lip) schizencephaly has separated lips and a cleft of cerebrospinal fluid (CSF), extending to the underlying ventricle.[4]

Griffith updated the classification of schizencephaly as follows [5]:

Schizencephaly type 1: characterized by a trans-mantle column of abnormal gray matter, but no evidence of a CSF containing cleft on MRI.

Schizencephaly type 2: involves a CSF containing cleft, with the cleft abutting the lining lips of abnormal gray matter.

Schizencephaly type 3: features a CSF containing a cleft, with nonabutting lining lips of abnormal gray matter.

The pathogenesis of schizencephaly is not well understood, with conflicting theories, but different etiologic factors are likely involved. The most accepted theory is that a vascular insult at the early phase of neuro-embryogenesis results in an ischemic area in the germinal matrix, preventing neuronal migration, and leading to the formation of cerebral cleft.[6] The risk factors of schizencephaly are younger maternal age, maternal stress, exposure to organic solvents, cytomegalovirus infection, death of a co-twin, alloimmune thrombocytopenia, psychoactive drugs, and warfarin use.[6]

Ultrasound is an inexpensive first line imaging modality for diagnosing schizencephaly prenatally, but it is limited in detecting the closed-lip type. Some cases of schizencephaly may present with ventriculomegaly and agenesis of the CSP. MRI enables the identification of the pial ependymal cleft and the visualization of cortical dysplasia and heterotopic gray matter. MRI delineates the features of schizencephaly and identifies associated anomalies, but it is less accessible.

Its recurrence in siblings strongly implicates a genetic basis. In this report, we describe two siblings diagnosed with schizencephaly, further identified to have Zellweger spectrum disorder (ZSD), a peroxisomal biogenesis disorder caused by mutations in *PEX* genes. Familial schizencephaly was reported by Robinson, Hosley et al, and Hilburger et al.[7] [8] [9] A review of literature of familial cases of schizencephaly is illustrated in [Table 1]. Several genes have been implicated in familial schizencephaly, including *EMX2*, a homeobox gene essential for cortical development and patterning.[10] Mutations in *EMX2* are associated with defects in neuronal migration and cortical organization, contributing to schizencephaly.[11] Among the genes implicated in schizencephaly, COL4A1 is noteworthy. This gene encodes the α-1 chain of type IV collagen, a critical component of basement membranes in blood vessels.[12] Mutations in COL4A1 are associated with small-vessel disease, which can result in perinatal ischemic events that disrupt cortical development, potentially leading to schizencephaly.[13] Unlike primary neuronal migration defects, COL4A1-related schizencephaly is thought to result from vascular fragility and secondary disruption of neurogenesis.[14] The SIX3 gene, a transcription factor crucial for forebrain development, has been associated with abnormal midline structures, leading to defects like cortical clefts.[15] Similarly, SHH signaling, essential for early neural patterning and the development of the cerebral cortex, is disrupted in some cases of schizencephaly, resulting in malformations in the forebrain.[16] In our case, pathogenic variants in *PEX* genes were identified, which disrupt peroxisome biogenesis and critical metabolic processes like plasmalogen synthesis and very long-chain fatty acid metabolism. These disruptions likely impair neuronal migration and cortical organization, contributing to schizencephaly's pathogenesis in ZSD.[17]

Table 1 Review of literature on familial schizencephaly

Study	Relation	Type	Associated malformation	Outcome	Genetics
Robinson[7]	Siblings	Op, B/L	Pmg, Htp	Seizure, ID, CP	Not done
		Op, B/L	Pmg, Htp	Seizure, ID, CP
Hosley et al[8]	Half sibling	Cl, U/L	Htp, ASP	Seizure, HP	Not done
		Op, B/L	ASP	Seizure, CP
Haver kamp et al[18]	Sibling	Op, Cl, B/L	ASP, Htp	Seizure, ID, CP	KT-N
		Op, B/L	ASP, Htp	Seizure
Ian titjen et al[19]	Siblings	Cl, U/L	Pmg	Seizure	Ch - 8q24.22–24.3 (AR), CR5q21.3–23.2(AD) Microsatellite markers
		Op, B/L	Pmg	Seizure, ID
		Op, B/L	Pmg	Seizure
Granata et al[10]	Siblings	Op, B/L	ACC	ID	EMX2- mutation
		Op, B/L	PACC	ID
This study	Siblings	Op, U/L	ASP, BPC	Terminated at 21 weeks	Kt-N CMA-N
		Op, U/L	ASP, Pmg	Follow-up done till 5 months, milestone normal	Heterozygous missense variant in exon 1 of the PEX13 gene

Abbreviations: OP, open schizencephaly; Cl, closed schizencephaly; B/L, bilateral; U/L, unilateral; Pmg, polymicrogyria; Htp, heterotopia; ASP, absent septum pellucidum; ACC, agenesis of corpus callosum; PACC, partial agenesis of corpus callosum; BPC, Blake pouch cyst; ID, intellectual disability; CP, cerebral palsy; HP, hemiparesis; KT, karyotype; N, normal.

 

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Conclusion

This case report highlights a rare instance of familial schizencephaly diagnosed prenatally through ultrasound and confirmed by MRI. Subsequent genetic analysis identified a variant in the PEX13 gene associated with Zellweger syndrome. The findings emphasize the importance of integrating advanced imaging modalities with genetic testing for precise prenatal diagnosis of complex central nervous system malformations. Familial recurrence underlines the necessity for genetic counselling to guide reproductive decisions and early intervention strategies. This case adds to the growing evidence linking PEX13 variants to brain malformations.

 

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Conflict of Interest

None declared.

Ethical Approval

This study was approved by the Institutional Review Board of ARMC AEGIS hospital. The research conforms to the principles outlined in the Declaration of Helsinki.

Authors' Contributions

S.E.: data analysis, manuscript writing, literature review on schizencephaly, prepared the figures legends for the imaging aspect of manuscript.

S.K.V.: conceptualization of the case report, performed and interpreted the advanced neurosonography, provided expert guidance on prenatal counseling and prognosis for the parents, conducted the genetic study to assess chromosomal and genetic abnormalities, manuscript review.

S.K.P.: interpreted the MRI images, contributed to the imaging and neuroanatomical analysis, manuscript review, assisted in the preparation of imaging figures and legends.

P.D.C.: drafted the background and discussion sections of the manuscript.

P.R.U.: data collection, edited the manuscript for language clarity and clinical accuracy.

R.C.: data collection, edited the clinical details and management aspects in the manuscript.

S.M.: data collection, edited the manuscript for language clarity and clinical accuracy.

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Publication History

Article published online:
05 August 2025