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.

Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K-AKT-mTOR signaling pathway.

OBJECTIVES: To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway. METHODS: We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K-AKT-mTOR pathway genes by next-generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid. RESULTS: During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the PI3K-AKT-mTOR pathway were referred for analysis. Of these, 17 fetuses had brain overgrowth, including six with isolated megalencephaly (MEG) and 11 with hemimegalencephaly (HMEG). Of the six with MEG, germline variants were identified in four cases, in either PIK3R2, AKT3 or MTOR, and a postzygotic PIK3R2 variant was found in the other two cases. Of the 11 with HMEG, a postzygotic PIK3CA variant was found in three fetuses with extracerebral features of PIK3CA-related overgrowth spectrum, and in seven fetuses with isolated HMEG. No pathogenic variant was identified in the 11th case with HMEG. Four fetuses with limb overgrowth also had one or more lymphatic malformations (LM) and harbored a postzygotic PIK3CA variant. NGS on cultured amniocytes performed in 10 cases, of which nine had been found positive on analysis of pathological fetal tissue, showed variants in four, in either PIK3CA, PIK3R2 or AKT3. CONCLUSIONS: Isolated MEG or HMEG may lead to identification of genetic variants in the PI3K-AKT-mTOR signaling pathway. Cases of limb overgrowth and LM or isolated HMEG are likely associated with PIK3CA variants. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Two different prenatal imaging cerebral patterns of tubulinopathy.

To illustrate the prenatal cerebral imaging features associated with tubulinopathy, we report on five affected fetuses from unrelated families, with a de-novo heterozygous variant in a tubulin gene (TUBA1A, TUBB2B or TUBB3). We identified two distinct prenatal imaging patterns related to tubulinopathy: a severe form, characterized by enlarged germinal matrices, microlissencephaly and a kinked brainstem; and a mild form which has not been reported previously in the prenatal literature. The latter form is associated with non-specific features, including an asymmetric brainstem, corpus callosal dysgenesis, a lack of Sylvian fissure operculization and distortion of the anterior part of the interhemispheric fissure with subsequent impacted medial borders of the frontal lobes, the combination of which, in the absence of additional extracerebral anomalies, is highly suggestive of tubulinopathy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.

Prenatal diagnosis of pericallosal curvilinear lipoma: specific imaging pattern and diagnostic pitfalls.

We report the first series of cases of pericallosal curvilinear lipoma (CL) diagnosed prenatally and highlight the limitations in identifying a specific prenatal imaging pattern using ultrasound and magnetic resonance imaging (MRI). In all five of our cases, on ultrasound, the main feature leading to referral was a short corpus callosum. This subtle callosal dysgenesis was associated with a band of hyperechogenicity surrounding the corpus callosum, mimicking the pericallosal sulcus, which increased in size during the third trimester in three of the four cases in which sonographic follow-up was performed. On T2-weighted MRI, this band showed typical hypointensity in all cases; in contrast, on T1-weighted imaging, in only one case was there hyperintensity, suggestive of fat, as seen typically in the postnatal period. For appropriate prenatal counseling regarding outcome, it is important to identify or rule out CL when mild corpus callosal dysgenesis is observed. One should be aware of subtle diagnostic findings, such as a thin band of echogenicity surrounding the corpus callosum that is seen as a band of hypointensity on T2-weighted fetal MRI, and which may increase in size during gestation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome.

Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.

Prenatal diagnosis of cobblestone lissencephaly associated with Walker-Warburg syndrome based on a specific sonographic pattern.

We report a specific sonographic cerebral pattern of cobblestone lissencephaly (CL) that has not been described previously. This pattern was encountered in four index cases and allowed prenatal diagnosis of CL associated with Walker-Warburg syndrome. The pattern included both an outer echogenic band with reduced pericerebral space, corresponding to an infra- and supratentorial extracortical layer of neuroglial overmigration on pathological examination, and a 'Z'-shaped appearance of the brainstem. This pattern was found as early as 14 weeks' gestation in one of our cases.

Distortion of the anterior part of the interhemispheric fissure: significance and implications for prenatal diagnosis.

In order to illustrate the significance of a new anatomical finding, distortion of the interhemispheric fissure (DIHF) associated with impacted medial borders of the frontal lobes, we report a retrospective observational study of 13 fetuses in which DIHF was identified on prenatal imaging. In 10 cases there were associated anatomical anomalies, including mainly midline anomalies (syntelencephaly (n=2), lobar holoprosencephaly (n=1), Aicardi syndrome (n=2)), but also schizencephaly (n=1), cortical dysplasia (n=1) and more complex cerebral malformations (n=3), including neural tube defect in two cases. Chromosomal anomaly was identified in two cases, including 6p deletion in a case without associated central nervous system anomalies and a complex mosaicism in one of the cases with syntelencephaly. In two cases, the finding was apparently isolated on both pre- and postnatal imaging, and the children were doing well at follow-up, aged 4 and 5 years. The presence of DIHF on prenatal imaging may help in the diagnosis of cerebral anomalies, especially those involving the midline. If DIHF is apparently isolated on prenatal ultrasound, magnetic resonance imaging is recommended for careful analysis of gyration and midline, especially optic and olfactory structures. Karyotyping is also recommended.

Prenatal abnormal features of the fourth ventricle in Joubert syndrome and related disorders.

Joubert syndrome and related disorders (JSRD) are characterized by absence or underdevelopment of the cerebellar vermis and a malformed brainstem. This family of disorders is a member of an emerging class of diseases called ciliopathies. We describe the abnormal features of the brain, particularly the fourth ventricle, in seven fetuses affected by JSRD. In three cases abnormality of the fourth ventricle was isolated and in four cases there were associated malformations. The molar tooth sign (MTS) was always present and visible on two-dimensional ultrasound and, when performed, on three-dimensional ultrasound and magnetic resonance imaging. The fourth ventricle was always abnormal, in both axial and sagittal views, presenting pathognomonic deformities. It is important to identify JSRD, preferably prenatally or at least postnatally, due to its high risk of recurrence of about 25%. A detailed prenatal assessment of the fourth ventricle in several views may help to achieve this goal.

Prenatal unilateral cerebellar hypoplasia in a series of 26 cases: significance and implications for prenatal diagnosis.

OBJECTIVE: To define imaging patterns of unilateral cerebellar hypoplasia (UCH), discuss possible pathophysiological mechanisms and underline the etiology and prognosis associated with these lesions. METHODS: In this retrospective study we reviewed the charts of 26 fetuses diagnosed between 2003 and 2011 with UCH, defined by asymmetrical cerebellar hemispheres with or without decreased transverse cerebellar diameter. The review included analysis of the anatomy of the cerebellar hemispheres, including foliation, borders and parenchymal echogenicity, and of the severity of the hypoplasia. Data from clinical and biological work-up and follow-up were obtained. RESULTS: Our series could be divided into two groups according to whether imaging features changed progressively or remained constant during follow-up. In Group 1 (n = 8), the progression of imaging features, echogenic cerebellar changes and/or hyposignal in T2*-weighted MR images were highly suggestive of ischemic/hemorrhagic insult. In Group 2 (n = 18), imaging features remained constant during follow-up; UCH was associated with abnormal foliation in three proven cases of clastic lesions, a cystic lesion was noted in three cases of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac abnormalities/aortic coarctation, eye abnormalities) syndrome and, in the remaining cases, UCH remained unchanged, with no imaging pattern typical of hemorrhage. In 24 cases the infant was liveborn and follow-up was continued in 23, for a mean period of 3 years. Among these, neurological complications were identified in seven (in one of seven (at a mean of 46 months) in Group 1 and in six of 16 (at a mean of 35 months) in Group 2). The surface loss of cerebellar hemisphere was > 50% in 19/24 fetuses and the vermis was clearly normal in appearance in 19/24. Predisposing factors for fetal vascular insult were identified in eight cases: these included maternal alcohol addiction, diabetes mellitus, congenital cytomegalovirus infection and pathological placenta with thrombotic vasculopathy and infarctions. CONCLUSION: UCH is defined as a focal lesion of the cerebellum that may be secondary to hemorrhage and/or ischemic insult, suggesting a clastic origin, particularly when imaging follow-up reveals changes over time. UCH may also be a clue for the prenatal diagnosis of PHACE syndrome. The amount of surface loss of cerebellar hemisphere does not correlate with poor prognosis. UCH with normal vermis is often associated with normal outcome.

Severe second-trimester obstructive ventriculomegaly related to disorders of diencephalic, mesencephalic and rhombencephalic differentiation.

By review of a series of cases, we set out to identify sonographic features suggestive of an obstructive mechanism in second-trimester fetuses with ventriculomegaly and describe developmental disorders related to pathological differentiation of the diencephalon, mesencephalon and rhombencephalon that lead to obstruction of cerebrospinal fluid flow. We studied retrospectively 11 fetuses referred for severe second-trimester ventriculomegaly of undetermined origin. Neurosonography was performed with detailed analysis of the third ventricle, thalami, cerebral aqueduct and cerebellum. The cerebral imaging data were compared with neuropathological data in eight patients, with a focus on the level and etiology of the obstruction. Parenchymal thinning and reduction of the pericerebral spaces were highly suggestive of ventriculomegaly due to an obstructive mechanism. The ventriculomegaly was related to diencephalosynapsis (thalamic fusion and third ventricle atresia) in five cases and partial/complete aqueduct stenosis in six; it was associated with cerebellar hypoplasia in six cases, including rhombencephalosynapsis in two cases. In nine patients, disorders of the diencephalon, mesencephalon and rhombencephalon were present. In cases of severe isolated ventriculomegaly in which sonographic features are suggestive of an obstructive mechanism, close examination of the third ventricle, thalami, aqueduct of Sylvius and cerebellum may reveal pathological differentiation of the diencephalon, mesencephalon or rhombencephalon, often in combination.