Heterogeneity in defining fetal corpus callosal pathology: systematic review.

OBJECTIVE: Fetal anomalies of the corpus callosum (CC) have been reported in the prenatal imaging literature since 1985, and, especially when isolated, pose challenges for both the patient and fetal medicine specialist. The purpose of this study was to review systematically the literature on prenatally diagnosed abnormalities of the CC, focusing on the terminology used to describe abnormalities other than complete agenesis of the CC, and to assess the heterogeneity of the nomenclature and definitions used. METHODS: This study was conducted in accordance with the PRISMA statement for reporting systematic reviews. A literature search was performed to identify prospective or retrospective case series or cohort studies, published in English, French, Italian, German or Spanish, reporting fetal imaging findings and describing anomalies of the CC. Quality and risk of bias of the studies were evaluated using the Newcastle-Ottawa scale and a modification of the scale developed by Conde-Agudelo et al. for other fetal imaging studies. The data extracted included the number of patients, the number of different anomalies identified, the descriptive names of the anomalies, and, where applicable, the definitions of the anomalies, the number of cases of each type of anomaly and the biometric charts used. Secondary tests used to confirm the diagnosis, as well as the postnatal or post-termination tests used to ascertain the diagnosis, were also recorded. RESULTS: The search identified 998 records, and, after review of titles and abstracts and full review of 45 papers, 27 studies were included initially in the review, of which 24 were included in the final analysis. These 24 studies had a broad range of quality and risk of bias and represented 1135 cases of CC anomalies, of which 49% were complete agenesis and the remainder were described using the term partial agenesis or nine other terms, of which five had more than one definition. CONCLUSIONS: In comparison to the postnatal literature, in the prenatal literature there is much greater heterogeneity in the nomenclature and definition of CC anomalies other than complete agenesis. This heterogeneity and lack of standard definitions in the prenatal literature make it difficult to develop large multicenter pooled cohorts of patients who can be followed in order to develop a better understanding of the genetic associations and neurodevelopmental and psychological outcomes of patients with CC anomalies. As this information is important to improve counseling of these patients, a good first step towards this goal would be to develop a simpler categorization of prenatal CC anomalies that matches better the postnatal literature. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

PlexinA1 is crucial for the midline crossing of callosal axons during corpus callosum development in BALB/cAJ mice.

The corpus callosum (CC) is the biggest commissure that links cerebral hemispheres. Guidepost structures develop in the cortical midline during CC development and express axon guidance molecules that instruct neurons regarding the proper direction of axonal elongation toward and across the cortical midline. Neuropilin-1 (Npn1), a high affinity receptor for class 3 semaphorins (Sema3s) localized on cingulate pioneering axons, plays a crucial role in axon guidance to the midline through interactions with Sema3s. However, it remains unclear which type of Plexin is a component of Sema3 holoreceptors with Npn1 during the guidance of cingulate pioneering axons. To address the role of PlexinA1 in CC development, we examined with immunohistochemistry the localization of PlexinA1, Npn1, and Sema3s using embryonic brains from wild-type (WT) and PlexinA1-deficient (PlexinA1 knock-out (KO)) mice with a BALB/cAJ background. The immunohistochemistry confirmed the expression of PlexinA1 in callosal axons derived from the cingulate and neocortex of the WT mice on embryonic day 17.5 (E17.5) but not in the PlexinA1 KO mice. To examine the role of PlexinA1 in the navigation of callosal axons, the extension of callosal axons toward and across the midline was traced in brains of WT and PlexinA1 KO mice at E17.5. As a result, callosal axons in the PlexinA1 KO brains had a significantly lower incidence of midline crossing at E17.5 compared with the WT brains. To further examine the role of PlexinA1 in CC development, the CC phenotype was examined in PlexinA1 KO mice at postnatal day 0.5 (P0.5). Most of the PlexinA1 KO mice at P0.5 showed agenesis of the CC. These results indicate the crucial involvement of PlexinA1 in the midline crossing of callosal axons during CC development in BALB/cAJ mice.

Cilia in hereditary cerebral anomalies.

Ciliopathies are complex genetic multi-system disorders causally related to abnormal assembly or function of motile or non-motile cilia. While most human cells possess a non-motile sensory/primary cilium (PC) during development and/or in adult tissues, motile cilia are restricted to specialised cells. As a result, PC-associated ciliopathies are characterised by high phenotypic variability with extensive clinical and genetic overlaps. In the present review, we have focused on cerebral developmental anomalies, which are commonly found in PC-associated ciliopathies and which have mostly been linked to Hedgehog signalling defects. In addition, we have reviewed emerging evidence that PC dysfunctions could be directly or indirectly involved in the mechanisms underlying malformations of cerebral cortical development including primary microcephaly.

Clinical outcomes following prenatal diagnosis of asymmetric ventriculomegaly, interhemispheric cyst, and callosal dysgenesis (AVID).

OBJECTIVES: When identified prenatally, the imaging triad of asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum (AVID) can indicate a more serious congenital brain anomaly. In this follow-up series of 15 fetuses, we present the neurodevelopmental outcomes of a single institution cohort of children diagnosed prenatally with AVID. METHODS: Our fetal ultrasound database was queried for cases of AVID between 2000 and 2016. All available fetal MR imaging studies were reviewed for the presence of (a) interhemispheric cysts or ventricular diverticula and (b) dysgenesis or agenesis of the corpus callosum. Clinical records were reviewed for perinatal management, postnatal surgical management, and neurodevelopmental outcomes. RESULTS: Fifteen prenatal cases of AVID were identified. Twelve were live-born and three pregnancies were terminated. Of the 12 patients, 11 underwent neurosurgical intervention. Of the eight patients surviving past infancy, seven of eight have moderate to severe neurodevelopmental delays or disabilities, encompassing both motor and language skills, and all have variable visual abnormalities. CONCLUSION: In our cohort of 15 prenatally diagnosed fetuses with AVID, eight survived past infancy and all have neurodevelopmental disabilities, including motor and language deficits, a wide range of visual defects, craniofacial abnormalities, and medical comorbidities.

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.

Variability of T1-weighted signal intensity of pericallosal lipomas in the fetus.

BACKGROUND: Pericallosal lipomas are often associated with corpus callosum dysgenesis. The diagnosis of lipoma, suggested on ultrasonography, relies on the classic T1 hyperintensity on magnetic resonance imaging (MRI). However, this feature may be absent prenatally. OBJECTIVE: Our objective was to study the changes of T1 intensity in fetal lipomas with comparison to postnatal/postmortem data and to assess the factors influencing the signal variations of pericallosal lipomas on prenatal MRI. MATERIALS AND METHODS: Patients with callosum dysgenesis and interhemispheric hyperechogenicity suggestive of a pericallosal lipoma with available postnatal or postmortem data were included. Gestational age, lipoma size and pattern, corpus callosum size and changes in fetal fat T1 intensity were recorded. Comparison with postmortem neuropathology was available for one fetus. RESULTS: Eleven patients with callosum dysgenesis and pericallosal lipomas (seven curvilinear and four tubulonodular) were included. All MRI scans were performed in the third trimester. Curvilinear lipomas were thinner and six cases were associated with prenatal T1 iso-intensity. Typical T1 hyperintensity appeared on postnatal MRI only. All tubulonodular lipomas were much larger and showed prenatal T1 hyperintensity. In two patients, the lipoma increased in size on postnatal MRI. CONCLUSION: The type and size of a lipoma influence T1 prenatal intensity. Absence of T1 intensity was observed in curvilinear lipomas only. Curvilinear lipomas are much thinner. Changes in T1 intensity may also be related to fat maturation within the lipoma and, subsequently, to gestational age. In the case of callosum dysgenesis, absence of prenatal T1 pericallosal hyperintensity should not exclude the diagnosis of pericallosal lipoma.

Four Steps in Diagnosing Complete Agenesis of the Corpus Callosum in Prenatal Life.

PURPOSE: Among congenital brain anomalies, complete agenesis of the corpus callosum (cACC) including cases of callosal hypoplasia has a prevalence of 1.8 per 10 000 in the general population. It is also one of the most challenging brain anomalies to detect during the mid-trimester ultrasound scan. Standard axial planes do not provide enough information to make the definitive diagnosis of cACC. MATERIALS AND METHODS: From our library of images and ultrasound reports, we reviewed our most recent cases of complete agenesis of the corpus callosum in the fetus at the mid-trimester scan. In our analysis we included only cases that were confirmed postnatally or by autopsy. Exams were performed between January 2010 and June 2012. All of the patients were scanned transabdominally by means of 2 D and static 3 D. From the 2 D and 3 D images we identified 4 anatomical views that consistently gave us enough information to identify cACC: axial biparietal transthalamic view (AX1); axial biparietal falx view (AX2); coronal transthalamic view (COR); mid-sagittal view (SAG). RESULTS: From our library 30 cases were selected with confirmed cACC postnatally or in autopsy findings. The mean gestational age at the time of referral to our center was 20.7 weeks (range 19 - 23 weeks). In all analyzed cases sufficient 2 D images were found and in 93.3 % of them informative 3 D volumes were also available for off-line review. We identified the following patterns of cACC at the mid-trimester scan: A- normal size of 3 rd ventricle + normal size of the lateral ventricles or mild ventriculomegaly; B1- dilated 3 rd ventricle + normal size of the lateral ventricles; B2- dilated 3 rd ventricle + mild or moderate ventriculomegaly; C- dilated 3 rd ventricle + severe ventriculomegaly; D- gross dilatation of 3 rd ventricle with the appearance of interhemispheric cyst. The AX1 view revealed: absence of the cavum septum pellucidi in all cases; dilatation of the third ventricle in 86.6 % of cases; separation of frontal horns in 83.3 % of cases; ventriculomegaly in 73.3 % of cases, including 13.6 % with severe forms. The AX2 view showed separation of the interhemispheric fissure (IHF) in 90 % of cases and upward displacement of the 3 rd ventricle in 80 % of cases. The COR view confirmed separation of the interhemispheric fissure in 90 % of cases including gross separation in 7.4 % of cases; absence of CC fibers at this level and descent of the falx towards the roof of the 3 rd ventricle in all cases, and upward displacement of the 3 rd ventricle in 80 % of cases. The SAG view revealed the absence of the CSP-CC complex in all cases and dilatation of the 3 rd ventricle in 86.6 % of cases. CONCLUSION: 1. We suggest a stepwise ultrasound diagnostic approach for cACC and variations of this condition. 2. We suggest a classification of characteristic patterns found in fetuses with proven cACC based on findings presented in axial views.

Detection of Fetal Corpus Callosum Abnormalities by Means of 3D Ultrasound.

PURPOSE: The objective of this study was to prenatally detect corpus callosum pathologies such as agenesis, partial agenesis, hypo- and hyperplasia and enhanced echogenicity. MATERIALS AND METHODS: Between 2009 and 2013 detailed 3D ultrasound examinations of the fetal corpus callosum were carried out as part of a level III examination for fetal anomalies. All scans were performed using Voluson E8 equipment (GE, Zipf, Austria) with a 5 - 8 MHz 3D transabdominal and 5 - 9 MHz 3D transvaginal transducer. All cases were evaluated for the following variables: inner, outer and curved length of the corpus callosum, height of the different segments of the corpus callosum and the corpus callosum area. All parameters were compared with normal growth charts. In all cases of suspected corpus callosum anomaly direct and indirect signs for corpus callosum agenesis and associated malformations were observed. RESULTS: 31 fetuses with pathological corpus callosum were diagnosed with 3D ultrasound. Gestational age at the time of diagnosis ranged from 20 to 38 weeks. 12 cases showed agenesis, 11 cases partial agenesis, 5 cases hypoplasia, 2 cases a combination of partial hyper- and hypoplasia and one case a lipoma of the corpus callosum. In corpus callosum underdevelopment, the more affected parts were the body and splenium. Associated anomalies were present in 25 of the 31 cases (80.6%) of corpus callosum pathologies. CONCLUSION: 3D neurosonography serves as an excellent tool to precisely demonstrate the pathological development of the fetal corpus callosum. By correlating the measures with the function of each affected corpus callosum segment, we can try to get a vague prediction of the neurological prognosis.

The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor.

Agenesis of the corpus callosum (AgCC) is a frequent brain disorder found in over 80 human congenital syndromes including ciliopathies. Here, we report a severe AgCC in Ftm/Rpgrip1l knockout mouse, which provides a valuable model for Meckel-Grüber syndrome. Rpgrip1l encodes a protein of the ciliary transition zone, which is essential for ciliogenesis in several cell types in mouse including neuroepithelial cells in the developing forebrain. We show that AgCC in Rpgrip1l(-/-) mouse is associated with a disturbed location of guidepost cells in the dorsomedial telencephalon. This mislocalization results from early patterning defects and abnormal cortico-septal boundary (CSB) formation in the medial telencephalon. We demonstrate that all these defects primarily result from altered GLI3 processing. Indeed, AgCC, together with patterning defects and mispositioning of guidepost cells, is rescued by overexpressing in Rpgrip1l(-/-) embryos, the short repressor form of the GLI3 transcription factor (GLI3R), provided by the Gli3(Δ699) allele. Furthermore, Gli3(Δ699) also rescues AgCC in Rfx3(-/-) embryos deficient for the ciliogenic RFX3 transcription factor that regulates the expression of several ciliary genes. These data demonstrate that GLI3 processing is a major outcome of primary cilia function in dorsal telencephalon morphogenesis. Rescuing CC formation in two independent ciliary mutants by GLI3(Δ699) highlights the crucial role of primary cilia in maintaining the proper level of GLI3R required for morphogenesis of the CC.

Protooncogene Ski cooperates with the chromatin-remodeling factor Satb2 in specifying callosal neurons.

First insights into the molecular programs orchestrating the progression from neural stem cells to cortical projection neurons are emerging. Loss of the transcriptional regulator Ski has been linked to the human 1p36 deletion syndrome, which includes central nervous system defects. Here, we report critical roles for Ski in the maintenance of the neural stem cell pool and the specification of callosal neurons. Ski-deficient callosal neurons lose their identity and ectopically express the transcription factor Ctip2. The misspecified callosal neurons largely fail to form the corpus callosum and instead redirect their axons toward subcortical targets. We identify the chromatin-remodeling factor Satb2 as a partner of Ski, and show that both proteins are required for transcriptional repression of Ctip2 in callosal neurons. We propose a model in which Satb2 recruits Ski to the Ctip2 locus, and Ski attracts histone deacetylases, thereby enabling the formation of a functional nucleosome remodeling and deacetylase repressor complex. Our findings establish a central role for Ski-Satb2 interactions in regulating transcriptional mechanisms of callosal neuron specification.