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OBJECTIVE: Clinical validity of genome sequencing (GS) (>30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies. METHODS: We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines. RESULTS: Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in SON, L1CAM, KMT2D, and ASPM. Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a de novo mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses. CONCLUSION: GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.

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BACKGROUND: Congenital defects of the central nervous system are the second cause of disability in childhood, representing up to 20 % of structural malformations diagnosed prenatally. The accurate prenatal diagnosis of fetal neurological anomalies and the assessment of cortical development are critical for early intervention and improved long-term outcomes. Neurosonography plays a vital role in this process, providing detailed insights into the structural and functional development of the fetal brain. This systematic review aims to synthesize current knowledge on neurosonographic indicators for prenatal diagnosis, with a special focus on cortical development and its impact in cases of fetal growth defects. MATERIAL AND METHODS: We conducted a comprehensive search for primary literature in PubMed database were searched for English and Spanish-language, peer-reviewed literature published in the last 15 years. Additional articles were identified by scrutinizing others search platforms (Cochrane Library, UpToDate). Inclusion criteria were single pregnancy and no known feto-maternal pathologies at the beginning of the study. RESULTS: Of the 361 published abstracts identified, 35 met criteria for inclusion. The review highlighted the importance of detailed neurosonographic assessments, including the evaluation of cerebral fissures such as the Sylvian fissure, parieto-occipital fissure, and calcarine fissure. Targeted ultrasound techniques were found to provide comprehensive insights comparable to fetal magnetic resonance imaging. We underscored the significant impact of intrauterine growth restriction on cortical development, with early intervention being crucial. Genetic and congenital infection screenings were emphasized as essential components of prenatal assessment. CONCLUSION: The assessment of fetal brain maturation patterns according to gestational age allows us to rule out a delay in cortical development. The heterogeneity of methods and evaluable parameters in fetal neurodevelopment makes it necessary to standardize the evaluation of the main structures of interest both for screening and for the diagnosis of cortical development anomalies, even with the aim of trying to improve upgrade prognostic advice.

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Aicardi-Goutières syndrome (AGS) is a rare genetic early-onset progressive encephalopathy with variable clinical manifestations. The IFIH1 mutation has been confirmed to be responsible for type I interferon production and activation of the Janus kinase signaling pathway. We herein stress neurological observations and neuroimaging findings in a severe case report of an infant with AGS type 7 due to an IFIH1 mutation who was diagnosed in the first month of life. We also review neurological characteristics of IFIH1 mutations through recent literature.

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CLINICAL ISSUE: Malformations of the central nervous system belong to the most common developmental disorders in humans. The clinical presentation of brain malformations is nonspecific including developmental delay, hypotonia, and/or epilepsy. The great heterogeneity concerning etiology, mechanisms of development and morphology is challenging for diagnosis and classification of brain malformations. Thereby recognizing specific malformations is essential for optimal patient management and prognostic evaluation. The aim of this article is to give an overview of several clinically relevant brain malformations occurring from different disrupted developmental processes in brain formation. STANDARD RADIOLOGICAL METHODS: Several brain malformations are already diagnosed during routine ultrasound in pregnancy. However pre- and postnatal magnetic resonance imaging remains the gold standard in detecting the partially subtle changes and to classify the malformations. METHODICAL INNOVATIONS: Advances in pre- and postnatal neuroimaging techniques and increasing investigation of genetic mechanisms underlying brain formation and its abnormalities have led to a better understanding of embryologic development and pathogeneses of brain malformations. CONCLUSION: Besides patient's history and clinical phenotype, neuroimaging plays a key role in diagnosis. Not always a specific diagnosis can be made, but neuroimaging patterns often enable a focused genetic testing and therefore are revolutionary for etiologic and prognostic assignment. Basic knowledge of brain development facilitates understanding and classifying of structural brain abnormalities.

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PARS2 encodes an aminoacyl-tRNA synthetase that catalyzes the ligation of proline to mitochondrial prolyl-tRNA molecules. Diseases associated with PARS2 primarily affect the central nervous system, causing early infantile developmental epileptic encephalopathies (EIDEE; DEE75; MIM #618437) with infantile-onset neurodegeneration. Dilated cardiomyopathy has also been reported in the affected individuals. About 10 individuals to date have been described with pathogenic biallelic variants in PARS2. While many of the reported individuals succumbed to the disease in the first two decades of life, autopsy findings have not yet been reported. Here, we describe neuropathological findings in a deceased male with evidence of intracranial calcifications in the basal ganglia, thalamus, cerebellum, and white matter, similar to Aicardi-Goutières syndrome. This report describes detailed autopsy findings in a child with PARS2-related mitochondrial disease and provides plausible evidence that intracranial calcifications may be a previously unrecognized feature of this disorder.

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These guidelines follow the mission of the World Association of Perinatal Medicine, in collaboration with the Perinatal Medicine Foundation, which brings together groups and individuals worldwide, with the aim to improve prenatal detection of central nervous system anomalies and the appropriate referral of pregnancies with suspected fetal anomalies. In addition, this document provides further guidance for healthcare practitioners with the goal of standardizing the description of ultrasonographic abnormal findings.

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Aicardi-Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early-onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in nine genes: TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1. Diagnosis is established by clinical findings (encephalopathy and acquired microcephaly, intellectual and physical impairments, dystonia, hepatosplenomegaly, sterile pyrexia, and/or chilblains), characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), or the identification of pathogenic/likely pathogenic variants in the known genes. One of the genes associated with AGS, SAMHD1, has also been associated with a spectrum of cerebrovascular diseases, including moyamoya disease (MMD). In this report, we describe a 31-year-old male referred to genetics for MMD since childhood who lacked the hallmark features of AGS patients but was found to have compound heterozygous SAMHD1 variants. He later developed mitral valve insufficiency due to recurrent chordal rupture and ultimately underwent a heart transplant at 37 years of age. Thus, these data suggest that SAMHD1 pathogenic variants can cause MMD without typical AGS symptoms and support that SAMHD1 should be assessed in MMD patients even in the absence of AGS features.

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Lissencephaly with cerebellar hypoplasia (LCH) is a rare variant form of lissencephaly, its distinctive neuroradiological phenotype being an important investigation clue regarding the potential involved genes, including variants in RELN gene. We report on a case of LCH whose clinical and neuroradiological features led to the identification of a homozygous pathogenic variant in RELN gene that has not been previously reported in the scientific literature.

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BACKGROUND: To evaluate the role of a standardized first-trimester scan in screening different kinds of central nervous system malformations and to report a 3-year experience from a tertiary center using an unselected cohort. METHODS: This was a retrospective analysis of prospectively collected data from a single center evaluating first-trimester scans with predesigned standardized protocols performed between 1 May 2017 and 1 May 2020, involving 39,526 pregnancies. All pregnant women underwent a series of prenatal ultrasound scans at 11-14, 20-24, 28-34 and 34-38 weeks of gestation. Abnormalities were confirmed by magnetic resonance imaging, postmortem examination or trained ultrasound professionals. Pregnancy outcomes and some postnatal follow-up were obtained from maternity medical records and telephone calls. RESULTS: A total of 38,586 pregnancies included in the study. The detection rates of CNS anomalies by ultrasound in the first, second, third and late third trimester were 32%, 22%, 25%, and 16%, respectively. And there were 5% of CNS anomalies missed by prenatal ultrasound. In the first-trimester scan, we diagnosed all cases of exencephaly, anencephaly, alobar holoprosencephaly and meningoencephalocele, and some cases of posterior cranial fossa anomalies (20%), open spina bifida (67%), semilobar holoprosencephaly (75%) and severe ventriculomegaly (8%). Vein of Galen aneurysmal malformation, closed spina bifida, lobar holoprosencephaly, intracranial infection, arachnoid cyst, agenesis of the corpus callosum, cysts of the septum pellucidum and isolated absence of the septum pellucidum were never detected during the first trimester. The abortion rates of fetal CNS anomalies detected by first-trimester scan, second-trimester scan, and third- trimester scan were 96%, 84% and 14%, respectively. CONCLUSIONS: The study showed that almost 1/3 of central nervous system anomalies were detected by the standard first-trimester scan and these cases were associated with a high rate of abortion. Early screening for fetal abnormalities gives parents more time for medical advice and safer abortion if needed. It is therefore recommended that some major CNS anomalies should be screened in the first trimester. The standardized anatomical protocol, consisting of four fetal brain planes, were recommended for routine first trimester ultrasound screening.

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OBJECTIVE: To evaluate the utility of prenatal exome sequencing (pES) in fetuses with central nervous system (CNS) abnormalities. METHODS: This was a retrospective cohort study of fetuses identified to have CNS abnormality on prenatal ultrasound and/or magnetic resonance imaging. All fetuses were first analyzed by chromosomal microarray analysis (CMA). Fetuses with a confirmed aneuploidy or causal pathogenic copy-number variant (CNV) on CMA did not undergo pES analysis and were excluded, while those with a negative CMA result were offered pES testing. RESULTS: Of the 167 pregnancies included in the study, 42 (25.1%) were identified to have a pathogenic or likely pathogenic (P/LP) variant. The diagnostic rate was significantly higher in fetuses with a non-isolated CNS abnormality than in those with a single CNS abnormality (35.7% (20/56) vs 14.5% (8/55); P = 0.010). Moreover, when a fetus had three or more CNS abnormalities, the positive diagnostic rate increased to 42.9%. A total of 25/42 (59.5%) cases had de-novo mutations, while, in the remaining cases, mutations were inherited and carried a significant risk of recurrence. Families whose fetus carried a P/LP mutation were more likely to choose advanced pregnancy termination than those with a variant of uncertain significance, secondary/incidental finding or negative pES result (83.3% (25/30) vs 41.3% (38/92); P < 0.001). CONCLUSION: pES improved the identification of genetic disorders in fetuses with CNS anomalies without a chromosomal abnormality or CNV identified on CMA, regardless of the number of CNS anomalies and presence of extracranial abnormality. We also demonstrated that pES findings can significantly impact parental decision-making. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

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OBJECTIVES: To evaluate the concordance of conventional autopsy (CA) and postmortem magnetic resonance (MR) after termination of pregnancy (TOP) in fetuses with prenatally detected central nervous system (CNS) anomalies. Second, to determine the most informative postmortem investigation in parental counseling. METHODS: All TOPs between 2006 and 2016 with prenatally detected CNS involvement and having a postmortem MR and CA as postmortem examinations were retrospectively analyzed and concordance levels were established. RESULTS: Of 764 TOPs, 255 cases had a CNS anomaly detected prenatally (33.4%). Fetal genetic anomalies (n = 40) and cases without both postmortem MR and CA were excluded, leaving 68 cases for analysis.Disagreement between postmortem MR and CA was observed in 22 cases (32.4%). In eight cases (11.8%), more information was obtained by CA compared with MR. However, only two cases with major additional findings were found when compared with prenatal diagnosis. In 14 cases (20.6%), MR was superior to CA either because of additional cerebral anomalies undetected by CA (n = 5) and/or because of severe autolysis hindering pathology of the CNS (n = 9). CONCLUSIONS: Our data point out that an adequate postmortem evaluation, valuable in parental counseling, can be provided by a postmortem MR in 97% of the cases.Key PointsAn adequate postmortem evaluation, valuable in parental counseling, can be provided by a postmortem (PM) magnetic resonance (MR) in the majority of cases.PM MR is an excellent postmortem imaging tool for the brain.In cases with brain autolysis, PM MR is often the only informative PM investigation tool.PM MR is an essential adjunct to CA in the PM evaluation of pregnancies terminated for a central nervous system (CNS) anomaly.

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Aicardi-Goutières syndrome (AGS) is an autosomal recessive disease that mimics congenital viral infection and mainly affects the brain, immune system, and skin. The dominant clinical symptom is the subacute onset of severe encephalopathy, which manifests as irritability, loss of ability, slowing of head growth, and poor nutrition. Arteriopathy in AGS is an uncommon manifestation usually associated with mutations in the SAMHD1 gene. We present a rare case of a 3-year-old male due to failure to thrive, global developmental delay, microcephaly, poor vision, upper and lower limbs spasticity, and gastroesophageal reflux disease (GERD), who harbored early stenotic lesions of the large and medium intracranial arteries with ischemic sequelae in the early postnatal life. Performed genetic testing confirmed homozygous gene mutation, SAMHD1 associated with AGS type 5. By reviewing the available literature, we were able to find only one patient whose arterial lesions were diagnosed after 6 months.

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BACKGROUND AND PURPOSE: Medullary tegmental cap dysplasia is a rare brainstem malformation, first described and defined by James Barkovich in his book Pediatric Neuroimaging from 2005 as an anomalous mass protruding from the posterior medullary surface. We describe the neuroimaging, clinical, postmortem, and genetic findings defining this unique malformation. MATERIALS AND METHODS: This is a multicenter, international, retrospective study. We assessed the patients' medical records, prenatal ultrasounds, MR images, genetic findings, and postmortem results. We reviewed the medical literature for all studies depicting medullary malformations and evaluated cases in which a dorsal medullary protuberance was described. RESULTS: We collected 13 patients: 3 fetuses and 10 children. The medullary caps had multiple characteristics. Associated brain findings were a rotated position of the medulla, a small and flat pons, cerebellar anomalies, a molar tooth sign, and agenesis of the corpus callosum. Systemic findings included the following: polydactyly, hallux valgus, large ears, and coarse facies. Postmortem analysis in 3 patients revealed that the cap contained either neurons or white matter tracts. We found 8 publications describing a dorsal medullary protuberance in 27 patients. The syndromic diagnosis was Joubert-Boltshauser syndrome in 11 and fibrodysplasia ossificans progressiva in 14 patients. CONCLUSIONS: This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. Due to the variations in the clinical, imaging, and postmortem findings, we conclude that there are multiple etiologies and pathophysiology. We suggest that in some patients, the pathophysiology might be abnormal axonal guidance.

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OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of fetuses with anomalies of the central nervous system (CNS) and summarize the outcome of the pregnancies and follow-up. METHODS: A total of 636 fetuses from June 2014 to December 2020 who were referred to the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects. Based on the ultrasound findings, the fetuses were divided into ventricular dilatation group (n = 441), choroid plexus cyst group (n = 41), enlarged posterior fossa group (n = 42), holoprosencephaly group (n = 15), corpus callosum hypoplasia group (n = 22), and other anomaly group (n = 75). Meanwhile, they were also divided into isolated (n = 504) and non-isolated (n = 132) groups based on the presence of additional abnormalities. Prenatal samples (amniotic fluid/chorionic villi/umbilical cord blood) or abortus tissue were collected for the extraction of genomic DNA and CMA assay. Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis. RESULTS: In total 636 fetuses with CNS anomalies (including 89 abortus tissues) were included, and 547 cases were followed up. The overall detection rate of CMA was 11.48% (73/636). The detection rates for the holoprosencephaly group, ACC group, choroid plexus cyst group, enlarged posterior fossa group, ventricular dilatation group and other anomaly group were 80% (12/15), 31.82% (7/22), 19.51% (8/41), 14.29% (6/42), 7.48% (33/441) and 9.33% (7/75), respectively. Compared with the isolated CNS anomaly group, the detection rate for the non-isolated CNS anomaly group was significantly higher (6.35% vs. 31.06%) (32/504 vs. 41/132) (χ² = 62.867, P < 0.001). Follow up showed that, for 52 fetuses with abnormal CMA results, 51 couples have opted induced labor, whilst 1 was delivered at full term with normal growth and development. Of the 434 fetuses with normal CMA results, 377 were delivered at full term (6 had developmental delay), and 57 couples had opted induced labor. The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses (26.56% vs. 10.54%) (17/64 vs. 39/370) (χ² = 12.463, P < 0.001). CONCLUSION: Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause. Most fetuses with negative CMA result have a good prognosis, but there is still a possibility for a abnormal neurological phenotype. Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.

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OBJECTIVE: To describe the prenatal ultrasound (US) findings, genetic results, and clinical outcomes of fetuses with suspected agenesis of the septum pellucidum (ASP) in the Chinese population. METHODS: This retrospective, single-center study included a cohort of fetuses with ASP diagnosed by prenatal imaging over a 10-year period. We evaluated US findings, associated anomalies, genetic results, and clinical outcomes. Prenatal and postnatal imaging findings were compared as well as the clinical outcome of delivery. RESULTS: Ninety patients were included, with a median follow-up time of 36 months (1-96 months). Thirty-six fetuses (40%) with isolated ASP were diagnosed by prenatal US or magnetic resonance imaging (MRI); 39 cases (43.3%) had ASP with central nervous system malformations and 15 cases (16.6%) had ASP with non-CNS abnormalities. Additional imaging findings were supplemented with prenatal MRI in 13 cases. Genetic tests were performed on 32 patients, of whom six had abnormalities. Prenatal US results of 40 patients (40/70) diagnosed by referral hospitals did not correspond to our findings. Of the 38 patients with postnatal records, 11 had abnormal neurological development. CONCLUSION(S): The outcome of an isolated ASP is usually favorable; however, neurological developmental delay is commonly observed if it is combined with other malformations.

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Ventriculomegaly (VM) is defined as an enlargement of the lateral ventricles of the developing fetal brain. The diagnosis is easily made by measuring the lateral ventricle width at the level of the atrium, which is normally <10 mm. VM is defined as mild when the atrial width is 10-12 mm, moderate 12-15 mm, severe >15 mm. VM is a non-specific sonographic sign which is common to different pathological entities and genetic conditions. When no associated anomaly can be found VM is defined as isolated. Since the prognosis of fetal VM mainly depends on the presence of associated anomalies, a careful diagnostic approach is necessary to rule out CNS and extra- CNS fetal anomalies. Magnetic Resonance Imaging can be a useful diagnostic tool complementary to ultrasound in order to recognize subtle brain anomalies, particularly cortical disorders. In this review the diagnostic approach to fetal VM will be discussed starting from ultrasound screening, moving to neurosonographic and MRI examination and genetic evaluation, in order to recognize the cause of VM and offer the appropriate counselling to the parents.

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OBJECTIVE: To explore pathogenic/likely pathogenic copy number variations (P/LP CNVs) and regions of homozygosity (ROHs) in fetal central nervous system (CNS) malformations. METHODS: A cohort of 539 fetuses with CNS malformations diagnosed by ultrasound/MRI was retrospectively analyzed between January 2016 and December 2019. All fetuses were analyzed by chromosomal microarray analysis (CMA). Three cases with ROHs detected by CMA were subjected to whole-exome sequencing (WES). The fetuses were divided into two groups according to whether they had other structural abnormalities. The CNS phenotypes of the two groups were further classified as simple (one type) or complicated (≥ 2 types). RESULTS: (1) A total of 35 cases with P/LP CNVs were found. The incidence of P/LP CNVs was higher in the extra-CNS group [18.00% (9/50)] than in the isolated group [5.32% (26/489)] (P < 0.01), while there was no significant difference between the simpletype and complicated-type groups. (2) In the simple-type group, the three most common P/LP CNV phenotypes were holoprosencephaly, Dandy-Walker syndrome, and exencephaly. There were no P/LP CNVs associated with anencephaly, microcephaly, arachnoid cysts, ependymal cysts, or intracranial hemorrhage. (3) Only four cases with ROHs were found, and there were no cases of uniparental disomy or autosomal diseases. CONCLUSION: The P/LP CNV detection rates varied significantly among the different phenotypes of CNS malformations, although simple CNS abnormalities may also be associated with genetic abnormalities.

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OBJECTIVE: To describe neurosonographic findings diagnostic or highly suggestive of the presence of malformations of cortical development involving the cortex that may be identified before 24 weeks of gestation. METHODS: This was a retrospective single-center study of fetuses referred for neurosonography, during 2012-2019, with an abnormal cortical or sulcation pattern diagnosed early in the mid trimester. Stored files were analyzed for demographic data, abnormal brain findings, non-central nervous system abnormalities, final diagnosis and postnatal outcome. RESULTS: The study cohort included 20 fetuses, with a mean gestational age at diagnosis of 18.7 (range, 14.4-23.6) weeks, in 11 of which the diagnosis was made before 20 weeks of gestation. Reasons for referral were: midline anomaly (n = 7), ventriculomegaly (n = 4), infratentorial findings (n = 3), suspected malformation of cortical development (n = 3), 'abnormal brain' (n = 2) and skeletal dysplasia (n = 1). On neurosonography, both the sulcation pattern and the cortical layer were abnormal in four cases, only the sulcation pattern was considered abnormal in seven and only the cortical layer was abnormal in nine. Nineteen fetuses presented with associated central nervous system anomalies and six also had non-central nervous system malformations. One case was recurrent. Eighteen parents opted for termination of pregnancy, including one selective termination in a twin pregnancy, and two fetuses were liveborn. CONCLUSIONS: Familiarity with fetal brain anatomy and its early sonographic landmarks allowed early diagnosis of malformations involving cortical development. These patients are likely to represent the most severe cases and all had associated malformations. The presence of an abnormal cortical layer and/or abnormal overdeveloped sulci appear to be early signs of malformation of cortical development. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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