Prenatal diagnosis of microcephaly with simplified gyral pattern: series of eight cases

Microcephaly with simplified gyral pattern (MSG) is an intrinsic genetic central nervous system disorder, characterized by microcephaly (a reduction of brain volume) and a simplified gyral pattern (a reduced number of gyri and shallow sulci associated with normal cortical thickness and neuroanatomical architecture), related to a reduced number of neuronal progenitors in the germinal matrix. We report the first prenatal series of MSG and define the prenatal imaging pattern, which should inform diagnosis and guide prenatal counseling in cases of fetal microcephaly. In this single‐center retrospective study of fetuses with MSG, we assessed features on ultrasound and magnetic resonance imaging (MRI), as well as genetic and neuropathological/postnatal data. We included eight patients who had been referred following observation of microcephaly. Ultrasound examination confirmed microcephaly, with a mean growth delay in head circumference of 3.4 weeks, associated with both a lack of gyration and a lack of opercularization of the Sylvian fissure and without any extracephalic anomaly. Fetal brain MRI confirmed lack of gyration with normal cortical thickness and normal intensity of the white matter in all cases. These MRI features led to exclusion of migration/corticogenesis disorders (lissencephaly/polymicrogyria), instead suggesting MSG. The posterior fossa was normal in seven of the eight cases. The corpus callosum was thin in four cases, hypoplastic in two and dysgenetic in two. In four cases, the pregnancy was terminated. The diagnosis of MSG was confirmed from neuropathological and postnatal MRI data. MSG was associated with a genetic diagnosis of RTTN (n = 1) and ASPM (n = 2) biallelic variants in three of the six cases in which genetic work‐up was performed. Mild or moderate intellectual deficit with speech delay was present in the three surviving children who were at least 5 years of age at their last examination, without seizures. In conclusion, in the presence of isolated fetal microcephaly with lack of gyration on ultrasound, fetal cerebral MRI is key to diagnosing MSG, which, in the majority of cases, affects the supratentorial space exclusively, and to ruling out other cortical malformations that show a similar sonographic pattern. In addition to imaging, genetic assessment may guide prenatal counseling, since the prenatal prognosis of MSG is different from that of both diffuse polymicrogyria and lissencephaly. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Microcephaly with simplified gyral pattern (MSG) is an intrinsic genetic central nervous system disorder, characterized by microcephaly (a reduction of brain volume) and a simplified gyral pattern (a reduced number of gyri and shallow sulci associated with normal cortical thickness and neuroanatomical architecture), related to a reduced number of neuronal progenitors in the germinal matrix.We report the first prenatal series of MSG and define the prenatal imaging pattern, which should inform diagnosis and guide prenatal counseling in cases of fetal microcephaly.In this single-center retrospective study of fetuses with MSG, we assessed features on ultrasound and magnetic resonance imaging (MRI), as well as genetic and neuropathological/postnatal data.We included eight patients who had been referred following observation of microcephaly.Ultrasound examination confirmed microcephaly, with a mean growth delay in head circumference of 3.4 weeks, associated with both a lack of gyration and a lack of opercularization of the Sylvian fissure and without any extracephalic anomaly.Fetal brain MRI confirmed lack of gyration with normal cortical thickness and normal intensity of the white matter in all cases.These MRI features led to exclusion of migration/corticogenesis disorders (lissencephaly/polymicrogyria), instead suggesting MSG.The posterior fossa was normal in seven of the eight cases.The corpus callosum was thin in four cases, hypoplastic in two and dysgenetic in two.In four cases, the pregnancy was terminated.This was a single-center retrospective study of fetuses with MSG, utilizing ultrasound and fetal magnetic resonance imaging (MRI) data, to assess imaging features, as well as genetic and neuropathologic/postnatal data.The study was approved by our local ethics committee, and informed patient consent was obtained for each case.
We included eight patients who had been referred following observation of fetal microcephaly at a mean gestational age of 27.7 (range, 23.0-31.5)gestational weeks, associated with fetal growth restriction in three cases (Table S1).Abnormal gyration (lack of Sylvian fissure opercularization or sulcation) was detected on the initial ultrasound examination in six cases, including a misdiagnosis of polymicrogyria in one case.There was a family history of MSG (a previous affected child of the couple) in two cases.In our center, ultrasound assessment (performed using an Aplio i800 machine (Canon Medical Systems France, Suresnes, France)) confirmed fetal microcephaly, with a mean growth delay in head circumference of 3.4 (SD, 0-4) weeks.Microcephaly was associated with both delayed Sylvian fissure opercularization and a lack of sulcation compared with the expected chronology regarding appearance of the main brain sulci (Figure 1).No extracephalic anomaly was found on imaging.
Fetal brain MRI (performed using a 1.5-Tesla Ingenia scanner (Philips, Amsterdam, The Netherlands)) confirmed delayed sulcation and showed normal cortical thickness, large pericerebral cerebrospinal fluid (CSF) spaces (due to parenchymal volume reduction) and normal white-matter intensity (Figures 2 and 3).These MRI features led to exclusion of migration/corticogenesis disorders (lissencephaly/polymicrogyria), instead suggesting a diagnosis of MSG.The posterior fossa was normal in seven of the eight cases, while in one there was pontocerebellar hypoplasia.The corpus callosum was thin in four cases; hypoplastic in two and dysgenetic in two.
In three cases, the pregnancy was terminated (between 25 and 29.4 weeks' gestation), and in one, the affected twin was selectively terminated at 33 weeks; in all of these cases, the diagnosis of MSG was confirmed on assessment of neuropathologic data (Table S1).In the four live-born infants, postnatal MRI confirmed simplified gyration.In the three children who were at least 5 years of age at their last examination, there was mild or moderate intellectual deficit, with speech delay.They did not have seizures.A genetic diagnosis of RTTN (n = 1) and ASPM (n = 2) biallelic variants was made in three of the six cases in which genetic work-up was performed (Table S1).

DISCUSSION
Congenital microcephaly is suspected on sonographic examination based on a fetal head circumference measurement < 3 rd percentile.It should be borne in mind that a head circumference measurement on ultrasound is an   assessment of fetal skull biometry and is thus an indirect and incomplete assessment of brain volume.Indeed, as in two cases in our series, microcephaly (reduction of brain volume) may be associated with cephalic biometry in the normal range on ultrasound when the pericerebral CSF spaces are large (Table S1).In such circumstances, fetal cerebral MRI is particularly useful, allowing direct measurement of encephalic biometry, which correlates well with brain weight, defining pathologically microcephaly and allowing precise analysis of the brain anatomy, especially by identification of the whole cortical ribbon.
On observation of a smooth cortical surface on ultrasound, fetal brain MRI is crucial to differentiate between polymicrogyria, MSG and lissencephaly, based on analysis of the cortical surface and thickness and the white-matter intensity.These different malformations correspond to different cellular impairment mechanisms, which are driven by different genes at certain stages of brain formation: at the cell-proliferation stage in MSG, at neuroblast migration in lissencephaly Type 1 and at corticogenesis in polymicrogyria.On MRI, MSG is characterized by a reduced number of gyri, shallow sulci, normal cortical ribbon and normal white matter, whereas polymicrogyria is associated with a thick undulating cortex and lissencephaly with persisting, layered white matter related to arrest of the normal waves of neuronal migration.These differences in MRI features correlate well with the pathology, MSG having normal six-layered cortical architecture, in contrast to lissencephaly and polymicrogyria 1,2 .
Since, in MSG, there is characteristic depletion of precursor cells within the germinal matrix, characteristic imaging features of this malformation are encountered in the supratentorial space.However, other features may affect the posterior fossa or midline, either as a result of the reduced number of neurons and decreased supratentorial brain volume, or, less frequently, there may be additional anomalies.As a direct consequence of the depletion of precursor cells at the supratentorial stage, the transverse cerebellar diameter, which has been shown to be proportional to supratentorial biometry, may be slightly decreased and, similarly, the corpus callosum may be thin, related to axonal commissural depletion.In contrast, Vermeulen et al. 3 reported partial or complete agenesis of the corpus callosum in 58% of children with MSG, and we observed hypoplastic or dysgenetic corpus callosum in four cases in our series.There have also been some reports of MSG associated with cerebellar or pontocerebellar hypoplasia (as in one of our cases) and, in one case, with rhombencephalosynapsis [4][5][6] .
MSG occurs due to allelic variants responsible for neural pool reduction (by a lack of cell proliferation due to a disorder of mitosis or by increased apoptosis), with autosomal recessive transmission in most cases 1 .Relevant genes reported in the literature include: ASPM (OMIM# 605481), KIF2A (OMIM#602591), CENPE (OMIM# 117143), WDR62 (OMIM#613583), CPAP (OMIM# 609279), STIL (OMIM#181590), NDE1 (OMIM# 609449), MCPH1 (OMIM#607117) and CDK5RAP2 (OMIM#608201) 1,[7][8][9][10] .A common function of many of these genes includes a role in microtubule and centrosomal organization, which is necessary to achieve the correct balance of symmetrical and asymmetrical mitoses of neural progenitors in the germinative matrices of the developing cortex 11 .More broadly, the list of genes involved in autosomal recessive microcephaly has been expanded to include genes implicated in a wide variety of molecular and cellular mechanisms, such as DNA replication and repair, cytokinesis, centromere and kinetochore function, transmembrane or intracellular transport, Wnt signaling autophagy and the apical polarity complex function 9,12 .The genotype-phenotype correlations are not so clear, since some of these genes have also been reported in other brain malformations.For example, homozygous WDR62 variations have been reported in patients with microcephaly, pachygyria, lissencephaly, schizencephaly, neuronal heterotopia, polymicrogyria, cerebellar hypoplasia and/or corpus callosal dysplasia 13,14 .
Concerning outcome, the children with MSG from our series showed mild or moderate intellectual deficit without seizures.Similarly, Basel-Vanagaite and Dobyns 15 studied 247 patients with MSG from a cohort of 4442 patients with brain malformations and reported that almost all of the patients with MSG showed near-normal development, with only mildly delayed milestones and absence of seizures.Notably, patients with ASPM variants show good social interactions and preserved long-term memory 16 .The importance of a genetic work-up in MSG is also supported by rare postnatal case reports of MSG with a more severe outcome.For example, Kelley et al. 17 reported a lethal metabolic disorder with severe MSG in a family with consanguinity, which corresponded to thiamine metabolism dysfunction syndrome 3 due to biallelic variants of the SLC25A19 (OMIM#606521) gene.One should note that the postnatal outcome is also more severe in the reported cases in which MSG was associated with additional anomalies involving the posterior fossa (especially in the case of pontocerebellar hypoplasia) and the midline [4][5][6] .
To conclude, on observation of isolated fetal microcephaly, the contribution of fetal cerebral MRI and a genetic work-up is crucial to diagnose MSG.Its diagnosis is based on both a specific MRI pattern and identification of specific variants on genetic work-up.These variants differ from those that are encountered in polymicrogyria or lissencephaly, anomalies which may present a sonographic pattern similar to that of MSG.Achieving a diagnosis is also crucial for prenatal counseling, since MSG has, in most of cases, a more favorable outcome than do either polymicrogyria or lissencephaly.

Figure 1
Figure 1 Expected chronology of identification of main cerebral sulci on prenatal imaging, showing expected gestational age at first appearance and location of sulci (arrows) on magnetic resonance images from 31.4-week fetus.

Figure 2
Figure 2 Prenatal brain imaging in four fetuses with microcephaly with simplified gyral pattern and one control fetus: axial ultrasound imaging (a-e), axial magnetic resonance imaging (MRI) (f-j) and coronal MRI (k-o).(a,f,k) Case 1 at 25 weeks' gestation.(b,g,l) Case 2 at 28.4 weeks' gestation.(c,h,m) Case 7 at 26 weeks' gestation.(d,i,n) Case 8 at 32 weeks' gestation.(e,j,o) Control: second fetus of twin pregnancy (Case 8) at 32 weeks' gestation.MRI showed simplified gyration with normal cortical thickness, large pericerebral fluid spaces (due to parenchymal volume reduction) and normal white-matter intensity.

Figure 3
Figure 3 Prenatal (a-l) and postnatal (m-p) brain imaging in four fetuses/newborns with microcephaly with simplified gyral pattern: axial ultrasound imaging (a-d), axial magnetic resonance imaging (MRI) (e-h) and coronal MRI (i-p): Case 3 at 27.5 weeks' gestation (a,e,i) and postnatally (m); Case 4 at 30.5 weeks' gestation (b,f,j) and postnatally (n); Case 5 at 31.5 weeks' gestation (c,g,k) and postnatally (o); Case 6 at 29.6 weeks' gestation (d,h,l) and postnatally (p).MRI showed simplified sulcation with normal cortical thickness, increased pericerebral cerebrospinal fluid spaces (due to parenchymal volume reduction) and normal white-matter signal.Note progression of gyration over time by comparing successive prenatal and postnatal imaging.
The diagnosis of MSG was confirmed of the precise imaging patterns are key to correct diagnosis and should guide counseling in cases of prenatal microcephaly.In this study, we report the first prenatal series of MSG and describe the prenatal imaging pattern.