A de novo pathogenic variant in DHX30 gene in a fetus with isolated dysgenesis of the corpus callosum.

A 36 years old woman in her first pregnancy was referred at 24w3d for a dedicated neurosonographic examination due to a suspected short corpus callosum (CC). The examination depicted a dysgenetic CC with asymmetric thickness at the level of the body in coronal views, very thin in the midline and thicker in both sides, suggesting bilateral formation of Probst bundles. The BPD, HC, and transverse cerebellar diameters were in the normal low range without associated growth restriction. Associated anomalies were not detected in the brain or other organs. Following genetic consultation and a normal CMA, trio exome sequencing was performed and a de novo missense pathogenic mutation c.2353 C > T in the DHX30 gene was detected. This variant has been previously reported in children and adults, mostly with a severe phenotype including neurodevelopmental disorder with variable motor and language impairment, but also mild phenotypes have been reported. MRI describes delayed myelination, ventriculomegaly, and cortical and cerebellar atrophy as imaging features in affected patients. This is the first prenatal report of a DHX30-associated neurodevelopmental disorder in which the fetus presents with isolated callosal dysgenesis, stressing the importance of exome sequencing in fetuses with this condition, as far as it is phenotypic presentation of numerous syndromes with different outcomes.

Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts.

Orofacial clefts (OFCs) represent the most prevalent congenital craniofacial anomalies, significantly impacting patients' appearance, oral function, and psychological well-being. Among these, non-syndromic OFCs (NSOFCs) are the most predominant type, with the etiology attributed to a combination of genetic and environmental factors. Rare variants of key genes involved in craniofacial development-related signaling pathway are crucial in the occurrence of NSOFCs, and our recent studies have identified PTCH1, a receptor-coding gene in the Hedgehog signaling pathway, as a causative gene for NSOFCs. However, the role of PTCH2, the paralog of PTCH1, in pathogenesis of NSOFCs remains unclear. Here, we perform whole-exome sequencing to explore the genetic basis of 144 sporadic NSOFC patients. We identify five heterozygous variants of PTCH2 in four patients: p.L104P, p.A131G, p.R557H, p.I927S, and p.V978D, with the latter two co-occurring in a single patient. These variants, all proven to be rare through multiple genomic databases, with p.I927S and p.V978D being novel variants and previously unreported. Sequence alignment suggests that these affected amino acids are evolutionarily conserved across vertebrates. Utilizing predictive structural modeling tools such as AlphaFold and SWISS-MODEL, we propose that these variants may disrupt the protein's structure and function. In summary, our findings suggest that PTCH2 may be a novel candidate gene predicted to be associated with NSOFCs, thereby broadening the spectrum of causative genes implicated in the craniofacial anomalies.

Divergent growth of the transient brain compartments in fetuses with nonsyndromic isolated clefts involving the primary and secondary palate.

Cleft lip/palate is a common orofacial malformation that often leads to speech/language difficulties as well as developmental delays in affected children, despite surgical repair. Our understanding of brain development in these children is limited. This study aimed to analyze prenatal brain development in fetuses with cleft lip/palate and controls. We examined in utero MRIs of 30 controls and 42 cleft lip/palate fetal cases and measured regional brain volumes. Cleft lip/palate was categorized into groups A (cleft lip or alveolus) and B (any combination of clefts involving the primary and secondary palates). Using a repeated-measures regression model with relative brain hemisphere volumes (%), and after adjusting for multiple comparisons, we did not identify significant differences in regional brain growth between group A and controls. Group B clefts had significantly slower weekly cerebellar growth compared with controls. We also observed divergent brain growth in transient brain structures (cortical plate, subplate, ganglionic eminence) within group B clefts, depending on severity (unilateral or bilateral) and defect location (hemisphere ipsilateral or contralateral to the defect). Further research is needed to explore the association between regional fetal brain growth and cleft lip/palate severity, with the potential to inform early neurodevelopmental biomarkers and personalized diagnostics.

Genotype-phenotype correlation study of structural abnormalities in a fetal brain caused by a novel KDM4B variant.

BACKGROUND: Fetal ventriculomegaly (VM), a common brain structure malformation detected during prenatal ultrasound diagnosis, is associated with an increased risk of neurodevelopmental disorders (NDDs) after birth. KDM4B encodes a lysine-specific demethylase that interacts with histone H3K23me3. Variations in KDM4B are reportedly associated with human NDDs; however, only 11 such patients have been reported. Herein, we report a fetus with VM and agenesis of the corpus callosum (ACC), which suggests that KDM4B plays an important role in fetal brain development. METHODS: Fetal skin tissue and parental peripheral venous blood samples were collected. Whole-exome and Sanger sequencing were performed to analyze fetal germline variants. Human 293T cells transfected with wild-type or mutant KDM4B were used for western blotting (WB) to analyze protein expression levels. RESULTS: An insertion variant of KDM4B, NM_015015.3: c.2889_2890insGAGAGCATCACGGTGAGCTGTGGGGTGGGGCAGGGGGCGGGGGGAGGCTGGGAGCACAGTGACAACCTGTACCCC, was identified in the fetal tissue; however, the parents carried the wild-type gene. The WB results indicated significantly reduced expression of the mutant protein, likely owing to decreased stability. CONCLUSIONS: The structural abnormalities in the brain of the studied fetus may be attributed to an insertion variant of KDM4B. This study highlights the importance of screening for KDM4B variants and considering potential copy number variations when observing VM or ACC in prenatal ultrasound imaging.

Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts.

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb-/- embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.

The role of liver transplantation in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis): A review of the literature.

BACKGROUND: COACH syndrome is a rare autosomal recessive genetic disease characterized by liver fibrosis, which leads to severe complications related to portal hypertension. However, only a few patients with COACH syndrome undergoing liver transplantation (LT) have been reported. MATERIALS AND METHODS: We herein report the outcomes of four children who underwent LT for COACH syndrome at our institute and review three previously reported cases to elucidate the role of LT in COACH syndrome. RESULTS: All four patients in our institute were female, and three received living donors LT. All patients were diagnosed with COACH syndrome by genetic testing. LT was performed in these patients at 3, 7, 9, and 14 years old. The indication for LT was varices related to portal hypertension in all patients. One showed an intrapulmonary shunt. Blood tests revealed renal impairment due to nephronophthisis in three patients, and one developed renal insufficiency after LT. The liver function was maintained in all patients. A literature review revealed detailed information for three more patients. The indication for LT in these three cases was portal hypertension, such as bleeding from esophageal varices. One patient had chronic renal failure on hemodialysis at LT and underwent combined liver and kidney transplantation. Of these three previous patients, one died from hepatic failure due to de novo HCV infection 3 years after LT. CONCLUSIONS: LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension. However, a detailed follow-up of the renal function is necessary.

Menthol and Other Flavor Chemicals in Cigarettes from Vietnam and the Philippines.

INTRODUCTION: Tobacco product flavors can increase product appeal, adolescent initiation and experimentation, and difficulty quitting. Flavored tobacco products are not restricted in Vietnam or the Philippines despite the high smoking prevalence among those 15 years of age and older (24% and 23%, respectively). There are no published reports to our knowledge on the levels of flavor chemicals in the cigarettes sold in these two countries. METHODS: Cigarettes were purchased in Vietnam (32 brand variants) and the Philippines (19 brand variants) during 2020. Chemical analyses gave the mg/filter, mg/rod, and mg/stick (= mg/(filter + rod)) values for 180 individual flavor chemicals. Values were calculated for menthol, clove-related compounds, and "other flavor chemicals" (OFCs). RESULTS: Five flavor groupings were found among the brand variants purchased in Vietnam: menthol + OFCs (n = 15), OFCs only (n = 8), nonflavored (n = 7), menthol + OFCs with a clove flavorant (n = 1) and menthol only (n = 1). Three flavor groupings were found among the brand variants purchased in the Philippines: menthol + OFCs (n = 10), nonflavored (n = 5), and menthol only (n = 4). CONCLUSIONS: A range of flavored cigarette products are being offered by tobacco companies in Vietnam and the Philippines, presumably to maximize cigarette sales. Regulation of flavor chemicals should be considered in these two countries. IMPLICATIONS: Article 9 of the WHO Framework Convention on Tobacco Control (FCTC), ratified by both Vietnam and the Philippines, states that "there is no justification for permitting the use of ingredients, such as flavoring agents, which help make tobacco products attractive." Flavors increase product appeal, adolescent initiation and experimentation, and difficulty quitting. These analyses found that cigarettes purchased in Vietnam and the Philippines contained menthol and other flavor chemicals. Tobacco companies are offering multiple flavor chemical profiles and nominally nonflavored versions in these countries; regulation of flavor chemicals should be considered in these two countries.

Commentary on "Brain Injury During Transition in the Newborn With Congenital Heart Disease: Hazards of the Preoperative Period".

BRAIN INJURY DURING TRANSITION IN THE NEWBORN WITH CONGENITAL HEART DISEASE: HAZARDS OF THE PREOPERATIVE PERIOD: Jennifer M. Lynch, J. William Gaynor, Daniel J. Licht Seminars in Pediatric Neurology Volume 28, December 2018, Pages 60-65 Infants born with critical congenital heart disease are at risk for neurodevelopmental morbidities later in life. In-utero differences in fetal circulation lead to vulnerabilities which lead to an increased incidence of stroke, white matter injury, and brain immaturity. Recent work has shown these infants may be most vulnerable to brain injury during the early neonatal period when they are awaiting their cardiac surgeries. Novel imaging and monitoring modalities are being employed to investigate this crucial time period and elucidate the precise timing and cause of brain injury in this population.

Brain MRI segmentation of Zika-Exposed normocephalic infants shows smaller amygdala volumes.

BACKGROUND: Infants with congenital Zika syndrome (CZS) are known to exhibit characteristic brain abnormalities. However, the brain anatomy of Zika virus (ZIKV)-exposed infants, born to ZIKV-positive pregnant mothers, who have normal-appearing head characteristics at birth, has not been evaluated in detail. The aim of this prospective study is, therefore, to compare the cortical and subcortical brain structural volume measures of ZIKV-exposed normocephalic infants to age-matched healthy controls. METHODS AND FINDINGS: We acquired T2-MRI of the whole brain of 18 ZIKV-exposed infants and 8 normal controls on a 3T MRI scanner. The MR images were auto-segmented into eight tissue types and anatomical regions including the white matter, cortical grey matter, deep nuclear grey matter, corticospinal fluid, amygdala, hippocampus, cerebellum, and brainstem. We determined the volumes of these regions and calculated the total intracranial volume (TICV) and head circumference (HC). We compared these measurements between the two groups, controlling for infant age at scan, by first comparing results for all subjects in each group and secondly performing a subgroup analysis for subjects below 8 weeks of postnatal age at scan. ZIKV-exposed infants demonstrated a significant decrease in amygdala volume compared to the control group in both the group and subgroup comparisons (p<0.05, corrected for multiple comparisons using FDR). No significant volume differences were observed in TICV, HC, or any specific brain tissue structures or regions. Study limitations include small sample size, which was due to abrupt cessation of extramural funding as the ZIKV epidemic waned. CONCLUSION: ZIKV-exposed infants exhibited smaller volumes in the amygdala, a brain region primarily involved in emotional and behavioral processing. This brain MRI finding may lead to poorer behavioral outcomes and warrants long-term monitoring of pediatric cases of infants with gestational exposure to Zika virus as well as other neurotropic viruses.

Increased rate of significant findings on brain MRI during the early stage of the COVID-19 pandemic.

OBJECTIVES: To assess the effect of the COVID-19 pandemic on the proportion of abnormal paediatric neuroimaging findings as a surrogate marker for potential underutilisation. METHODS: Consecutive paediatric brain MRIs performed between March 27th and June 19th 2019 (Tbaseline) and March 23rd and June 1st 2020 (Tpandemic) were reviewed and classified according to presence or absence and type of imaging abnormality, and graded regarding severity on a 5-point Likert scale, where grade 4 was defined as abnormal finding requiring non-urgent intervention and grade 5 was defined as acute illness prompting urgent medical intervention. Non-parametric statistical testing was used to assess for significant differences between Tpandemic vs. Tbaseline. RESULTS: Fewer paediatric MRI brains were performed during Tpandemic compared to Tbaseline (12.2 vs 14.7 examinations/day). No significant difference was found between the two time periods regarding sex and age (Tbaseline: 557 females (44.63%), 7.95 ± 5.49 years, Tpandemic: 385 females (44.61%), 7.64 ± 6.11 years; p = 1 and p = .079, respectively). MRI brain examinations during Tpandemic had a higher likelihood of being abnormal, 41.25% vs. 25.32% (p<.0001). Vascular abnormalities were more frequent during Tpandemic (11.01% vs 8.01%, p = .02), congenital malformations were less common (8.34% vs 12.34%, p = .004). Severity of MRI brain examinations was significantly different when comparing group 4 and group 5 individually and combined between Tbaseline and Tpandemic (p = .0018, p < .0001, and p <.0001, respectively). CONCLUSIONS: The rate of abnormality and severity found on paediatric brain MRI was significantly higher during the early phase of the pandemic, likely due to underutilisation.

Novel homozygous LAMB1 in-frame deletion in a pediatric patient with brain anomalies and cerebrovascular event.

Biallelic pathogenic variants in LAMB1 have been associated with autosomal recessive lissencephaly 5 (OMIM 615191), which is characterized by brain malformations (cobblestone lissencephaly, hydrocephalus), developmental delay, and epilepsy. Pathogenic variants in LAMB1 are rare, with only 11 pathogenic variants and 11 patients reported to date. Here, we report on a 6-year-old patient from a consanguineous family with profound developmental delay, microcephaly, and a history of a perinatal cerebrovascular event. Brain magnetic resonance imaging (MRI) showed cerebellar cystic defects, signal intensity abnormalities, and a hypoplastic corpus callosum. Trio-exome analysis revealed a homozygous in-frame deletion of Exons 23 and 24 of LAMB1 affecting 104 amino acids including the epidermal growth factor (EGF)-like units 11 and 12 in Domain III. To our knowledge, this is the first reported in-frame deletion in LAMB1. Our findings broaden the clinical and molecular spectrum of LAMB1-associated syndromes.

Ganglionic eminence: volumetric assessment of transient brain structure utilizing fetal magnetic resonance imaging.

OBJECTIVE: To provide quantitative magnetic resonance imaging (MRI) super-resolution-based three-dimensional volumetric reference data on the growth dynamics of the ganglionic eminence (GE) relative to cortical and total fetal brain volumes (TBV). METHODS: This was a retrospective study of fetuses without structural central nervous system anomalies or other confounding comorbidities that were referred for fetal MRI. Super-resolution reconstructions of 1.5- and 3-Tesla T2-weighted images were generated. Semiautomatic segmentation of TBV and cortical volume and manual segmentation of the GE were performed. Cortical volume, TBV and GE volume were quantified and three-dimensional reconstructions were generated to visualize the developmental dynamics of the GE. RESULTS: Overall, 120 fetuses that underwent 127 MRI scans at a mean gestational age of 27.23 ± 4.81 weeks (range, 20-37 weeks) were included. In the investigated gestational-age range, GE volume ranged from 74.88 to 808.75 mm3 and was at its maximum at 21 gestational weeks, followed by a linear decrease (R2 = 0.559) throughout the late second and third trimesters. A pronounced reduction in GE volume relative to cortical volume and TBV occurred in the late second trimester, with a decline in this reduction observed in the third trimester (R2 = 0.936 and 0.924, respectively). Three-dimensional rendering allowed visualization of a continuous change in the shape and size of the GE throughout the second and third trimesters. CONCLUSIONS: Even small compartments of the fetal brain, which are not easily accessible by standardized two-dimensional modalities, can be assessed precisely by super-resolution processed fetal MRI. The inverse growth dynamics of GE volume compared with TBV and cortical volume reflects the transitory nature and physiological involution of this (patho-)physiologically important brain structure. The normal development and involution of the GE is mandatory for normal cortical development. Pathological changes of this transient organ precede impairment of cortical structures, and their detection may allow an earlier diagnosis of such anomalies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse.

PURPOSE: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. METHODS: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. RESULTS: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. CONCLUSION: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.

Comprehensive quantitative analyses of fetal magnetic resonance imaging in isolated cerebral ventriculomegaly.

Isolated cerebral ventriculomegaly (IVM) is the most common prenatally diagnosed brain anomaly occurs in 0.2-1 % of pregnancies. However, knowledge of fetal brain development in IVM is limited. There is no prenatal predictor for IVM to estimate individual risk of neurodevelopmental disability occurs in 10 % of children. To characterize brain development in fetuses with IVM and delineate their individual neuroanatomical variances, we performed comprehensive post-acquisition quantitative analysis of fetal magnetic resonance imaging (MRI). In volumetric analysis, brain MRI of fetuses with IVM (n = 20, 27.0 ± 4.6 weeks of gestation, mean ± SD) had revealed significantly increased volume in the whole brain, cortical plate, subcortical parenchyma, and cerebrum compared to the typically developing fetuses (controls, n = 28, 26.3 ± 5.0). In the cerebral sulcal developmental pattern analysis, fetuses with IVM had altered sulcal positional (both hemispheres) development and combined features of sulcal positional, depth, basin area, in both hemispheres compared to the controls. When comparing distribution of similarity index of individual fetuses, IVM group had shifted toward to lower values compared to the control. About 30 % of fetuses with IVM had no overlap with the distribution of control fetuses. This proof-of-concept study shows that quantitative analysis of fetal MRI can detect emerging subtle neuroanatomical abnormalities in fetuses with IVM and their individual variations.

Halo sign in fetal cytomegalovirus infection: cerebral imaging abnormalities and postmortem histopathology in 35 infected fetuses.

OBJECTIVE: To evaluate the correlation of periventricular echogenic halo (halo sign) with histopathological findings and its association with other brain imaging abnormalities in fetuses with cytomegalovirus (CMV) infection. METHODS: This was a retrospective study of fetuses diagnosed with severe CMV infection based on central nervous system (CNS) abnormalities seen on ultrasound, which had termination of pregnancy (TOP) or fetal demise at a single center from 2006 to 2021. All included cases had been evaluated by conventional complete fetal autopsy. A maternal-fetal medicine expert reanalyzed the images from the transabdominal and transvaginal neurosonography scans, blinded to the histological findings. The halo sign was defined as the presence of homogeneous periventricular echogenicity observed in all three fetal brain orthogonal planes (axial, parasagittal and coronal). Cases were classified according to whether the halo sign was the only CNS finding (isolated halo sign) or concomitant CNS anomalies were present (non-isolated halo sign). An expert fetal radiologist reanalyzed magnetic resonance imaging (MRI) examinations when available, blinded to the ultrasound and histological results. Hematoxylin-eosin-stained histologic slides were reviewed independently by two experienced pathologists blinded to the neuroimaging results. Ventriculitis was classified into four grades (Grades 0-3) according to the presence and extent of inflammation. Brain damage was categorized into two stages (Stage I, mild; Stage II, severe) according to the histopathological severity and progression of brain lesions. RESULTS: Thirty-five CMV-infected fetuses were included in the study, of which 25 were diagnosed in the second and 10 in the third trimester. One fetus underwent intrauterine demise and TOP was carried out in 34 cases. The halo sign was detected on ultrasound in 32 (91%) fetuses (23 in the second trimester and nine in the third), and it was an isolated sonographic finding in six of these cases, all in the second trimester. The median gestational age at ultrasound diagnosis of the halo sign was similar between fetuses in which this was an isolated and those in which it was a non-isolated CNS finding (22.6 vs 24.4 weeks; P = 0.10). In fetuses with a non-isolated halo sign, the severity of additional ultrasound findings was not associated with the trimester at diagnosis, except for microencephaly, which was more frequent in the second compared with the third trimester (10/18 (56%) vs 1/8 (13%); P = 0.04). With respect to histopathological findings, ventriculitis was observed in all fetuses with an isolated halo sign, but this was mild (Grade 1) in the majority of cases (4/6 (67%)). Extensive ventriculitis (Grade 2 or 3) was more frequent in fetuses with a non-isolated halo sign (21/26 (81%)) and those without a periventricular echogenic halo (2/3 (67%); P = 0.032). All fetuses with an isolated halo sign were classified as histopathological Stage I with no signs of brain calcifications, white-matter necrosis or cortical injury. On the other hand, 25/26 fetuses with a non-isolated halo sign and all three fetuses without a periventricular echogenic halo showed severe brain lesions and were categorized as histopathological Stage II. Among fetuses with a non-isolated halo, histological brain lesions did not progress with gestational age, although white-matter necrosis was more frequent, albeit non-significantly, in fetuses diagnosed in the second vs the third trimester (10/15 (67%) vs 3/11 (27%); P = 0.06). CONCLUSIONS: In CMV-infected fetuses, an isolated periventricular echogenic halo was observed only in the second trimester and was associated with mild ventriculitis without signs of white-matter calcifications or necrosis. When considering pregnancy continuation, detailed neurosonographic follow-up complemented by MRI examination in the early third trimester is indicated. The prognostic significance of the halo sign as an isolated finding is still to be determined. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Marked intrafamilial variability of clinical and neuroimaging manifestations in NFIB-related developmental disorder.

NFIB belongs to the nuclear factor I (NFI) family of transcription factors that, by activating or repressing gene expression during embryogenesis, has a relevant role in the development of several organs including the brain. Heterozygous pathogenic variants of NFIB have recently been associated with developmental delay and mild-to-moderate intellectual disability, macrocephaly, nonspecific facial dysmorphisms, and corpus callosum dysgenesis. We identified a heterozygous missense variant in the NFIB gene in a 15-year-old boy with neurodevelopmental disorder and brain malformations, who inherited the variant from his substantially healthy mother presenting only minor physical and neuroanatomical defects.

Relevance of Fetal Brain Magnetic Resonance Imaging Compared to Ultrasound for Detecting Cerebral Anomalies in Fetuses with Cleft Lip and/or Palate: A Cohort Study.

INTRODUCTION: Relevance of fetal brain magnetic resonance imaging (MRI) in cases of cleft lip and/or palate (CL/P) is still discussed to date. The aim of our study was to review the contribution of fetal brain MRI for detecting cerebral anomalies in cases of CL/P comparing antenatal data with neonatal outcomes. METHODS: A retrospective multicenter study was conducted from January 2010 to October 2020 in two multidisciplinary prenatal diagnosis centers among women with a fetal ultrasound (US) diagnosis of CL/P. Prenatal imaging and genetic analysis data were collected, as well as postnatal data, including outcomes of children who had an abnormal prenatal MRI. RESULTS: Among the 202 fetuses with a US diagnosis of CL/P, 96 underwent US and fetal brain MRI. 19 brain MRIs were found to be abnormal: 14 (73.7%) involved CL/P associated with other US abnormalities and five (26.3%) involved isolated clefts, of which four were cleft lip and alveolus and secondary palate (CLP). MRI identified severe abnormalities that changed the prognoses of 3 cases of clefts associated with other US abnormalities. In contrast, MRI found only minor abnormalities for the five isolated clefts, with no postnatal disorders found in these children. CONCLUSION: Fetal brain MRI should be proposed in cases of clefts associated with other anomalies or if US examination is limited by local conditions. MRI could also be discussed in cases of isolated CLP but should not be performed in cases of isolated cleft lip.

The fetal brain: migration and gyration anomalies - pre- and postnatal correlations.

The cerebral cortex represents a laminar structure of precisely spatially organized neurons in horizontal layers and vertical columns. Neurogenesis, neuronal migration and neuronal wiring are tightly regulated and coordinated procedures that result in the accurate formation of the human cerebral cortex. Abnormal fetal corticogenesis results in several types of migration and gyration anomalies, known as malformations of cortical development, which have long been a topic of investigation. According to the stage of cortical development that is affected, with diverse genetic and non-genetic etiologies, these malformations can cause abnormal head size, abnormal brain surface and abnormal cortical layering with various degrees of neurodevelopmental delay and epilepsy. The pathogenesis of these malformations is multifactorial and includes genetic mutations or environmental insults, acquired either in utero at varying stages of brain development or during the perinatal period after corticogenesis. In this article, we focus on cortical malformations detected on fetal MRI. We present the main antenatal findings that should raise suspicion for malformations of cortical development, together with findings that might be missed on prenatal imaging and describe the correlations between fetal and postnatal MRI.