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.
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.
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.
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.
