A genetic variant in the MAST1 gene is associated with mega-corpus-callosum syndrome with hypoplastic cerebellar vermis, in a fetus.

BACKGROUND: Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations is a rare neurological disorder that is associated with typical clinical and imaging features. The syndrome is caused by pathogenic variants in the MAST1 gene, which encodes a microtubule-associated protein that is predominantly expressed in postmitotic neurons in the developing nervous system. METHODS: Fetal DNA from umbilical cord blood samples and genomic DNA from peripheral blood lymphocytes were subjected to whole-exome sequencing. The potential causative variants were verified by Sanger sequencing. RESULTS: A 26-year-old primigravid woman was referred to our prenatal center at 25 weeks of gestation due to abnormal ultrasound findings in the brain of the fetus. The brain abnormalities included wide cavum septum pellucidum, shallow and incomplete bilateral lateral fissure cistern, bilateral dilated lateral ventricles, hyperplastic corpus callosum, lissencephaly, and cortical dysplasia. No obvious abnormalities were observed in the brainstem or cerebellum hemispheres, but the cerebellum vermis was small. Whole-exome sequencing identified a de novo, heterozygous missense variant, c.695T>C(p.Leu232Pro), in the MAST1 gene and a genetic diagnosis of mega-corpus-callosum syndrome was considered. CONCLUSION: This study is the first prenatal case of MAST1-related disorder reported in the Chinese population and has expanded the mutation spectrum of the MAST1 gene.

First occurrence of Arnold Chiari type II malformation and associated abnormalities in a Gir calf produced in vitro from Brazil - case report / [Primeira ocorrência de malformação de Arnold Chiari tipo II e anormalidades associadas em uma bezerra Gir de produção in vitro no Brasil - relato de caso]

This study characterized the clinical, radiological, ultrasound, and necroscopic findings of a case of Arnold-Chiari type II malformation in a Gir breed calf from Brazil. The animal was hospitalized at sixty days of age, in permanent sternal recumbency, cutaneous appendix at the 4th lumbar vertebra and kyphoscoliosis of the caudal and lumbosacral thoracic spine. Radiographic examination of the spine and skull revealed spina bifida and suspected occipital hypoplasia. Upon examination of myelography with an injection of lumbar and atlantooccipital contrast, it was possible to visualize the meningocele at the 4th lumbar vertebra region and findings at the rhombencephalon level of increased regional pressure with failure to fill the contrast in the posterior fossa, in the presence of clear demarcation of the circumvolutions of the cerebral cortex and the subarachnoid space of the cervical spinal cord. Ultrasonographic examination of the cerebellum showed an insinuation of the cerebellar worm through the foramen magnum. The animal did not show changes in complete blood count, biochemical series, and cerebrospinal fluid and was negative for Pestivirus. There was a worsening of the clinical conditions and the animal died. This malformation of unknown etiology must be studied as a differential diagnosis of the nervous system disorders.(AU)

Este estudo caracterizou os achados clínicos, radiológicos, ultrassonográficos e necroscópicos de um caso de malformação de Arnold-Chiari tipo II em uma bezerra Gir no Brasil. O animal foi hospilatizado aos 60 dias de idade, apresentando decúbito esternal permanente, apêndice cutâneo na altura da quarta vértebra lombar e cifoescoliose da coluna vertebral torácica caudal e lombossacra. Ao exame radiográfico da coluna e do crânio, foram observadas espinha bífida e suspeita de hipoplasia occipital. Ao exame de mielografia com injeção de contraste lombar e atlanto-occipital, foi possivel visualizar a meningocele na altura da quarta vértebra lombar e achados em nível rombencefálico de aumento da pressão regional com falha de preenchimento do contraste na fossa posterior, na presença de nítida demarcação das circunvoluções do córtex cerebral e do espaço subaracnoide da medula espinhal cervical. Ao exame ultrassonográfico do cerebelo, foi observada insinuação do verme cerebelar através do forame magno. O animal não apresentou alterações em hemograma completo, série bioquímica e fluido cérebro-espinhal e foi negativo para Pestivirus. Houve uma piora do quadro clínico e o animal morreu. Essa malformação de etiologia desconhecida deve ser estudada como um diagnóstico diferencial.(AU)

Isolated Upward Rotation of the Fetal Cerebellar Vermis (Blake's Pouch Cyst) Is a Normal Variant: An Analysis of 111 Cases.

INTRODUCTION: The objective of the study was to provide more detailed data about fetal isolated upward rotation of the cerebellar vermis rotation (Blake's pouch cyst) in particular regarding pregnancy outcome. METHODS: This is a retrospective study of all cases of fetal isolated upward rotation of the cerebellar vermis (URCV) diagnosed in 3 referral centers in Italy from January 2009 to November 2019. Whenever possible, prenatal magnetic resonance imaging (MRI) was performed and a fetal karyotype was obtained. A detailed follow-up was obtained by consultation of medical records, interview with the parents, and the pediatricians. RESULTS: Our study population included 111 patients with a prenatal diagnosis of isolated URCV made at a median gestational age of 21 weeks +3 days (interquartile range (IQR) 21 + 0-22 + 2). The median brain stem-vermis (BV) angle was 27° (IQR 24-29°). In 37.9% of the cases, a regression of the finding with restoration of normal anatomy was noted at a follow-up scan or at postnatal checks. A BV angle of 25° or less predicted regression with a probability in excess of 90%. MRI was performed in utero or at birth in 101 patients and always confirmed sonographic diagnosis. Fetal CGH array and/or karyotype was available in 97 cases and was always normal, but in 1 case. A postnatal follow-up was available in 102 infants (mean 7 months, range 0-10 years of age) and documented a normal neurologic development in all the cases. CONCLUSIONS: Isolated URCV is most likely a normal variant of fetal anatomy without clinical consequences, at least at an early follow-up. A BV angle of 25° or less predicts intrauterine regression of the finding, but the outcome is good in all the cases. When a confident sonographic diagnosis is made, MRI is not mandatory. The risk of a chromosomal anomaly in these cases is probably low.

Prenatal diagnosis of rhombencephalosynapsis: neuroimaging features and severity of vermian anomaly.

OBJECTIVES: To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. METHODS: In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES. RESULTS: Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD) < 3rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption. CONCLUSIONS: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

A rare mutant of OFD1 gene responsible for Joubert syndrome with significant phenotype variation.

Joubert syndrome (JBTS), a rare genetic disorder resulted from primary cilium defects or basal-body dysfunction, is characterized by agenesis of cerebellar vermis and abnormal brain stem. Both genotypes and phenotypes of JBTS are highly heterogeneous. The identification of pathogenic gene variation is essential for making a definite diagnosis on JBTS. Here, we found that hypoplasia of cerebellar vermis occurred in three male members in a Chinese family. Then, we performed whole exome sequencing to identify a novel missense mutation c.599T > C (p. L200P) in the OFD1 gene which is the candidate gene of X-linked JBTS (JBST10). The following analysis showed that the variant was absent in the 1000 Genomes, ExAC and the 200 female controls; the position 200 Leucine residue was highly conserved across species; the missense variant was predicted to be deleterious using PolyPhen-2, PROVEAN, SIFT and Mutation Taster. The OFD1 expression was heavily lower in the proband and an induced male fetus compared with a healthy male with a wild-type OFD1 gene. The in vitro expression analysis of transiently transfecting c.599T or c.599C plasmids into HEK-293T cells confirmed that the missense mutation caused OFD1 reduction at the protein level. And further the mutated OFD1 decreased the level of Gli1 protein, a read-out of Sonic hedgehog (SHH) signaling essential for development of central neural system. A known pathogenic variant c.515T > C (p. L172P) showed the similar results. All of these observations suggested that the missense mutation causes the loss function of OFD1, resulting in SHH signaling impairs and brain development abnormality. In addition, the three patients have Dandy-Walker malformation, macrogyria and tetralogy of Fallot, respectively, the latter two of which are firstly found in JBTS10 patients. In conclusion, our findings expand the context of genotype and phenotype in the JBTS10 patients.

Tremor Caused by Dandy-Walker Syndrome Concomitant with Syringomyelia: Case Report and Review of the Literature Review.

BACKGROUND: Dandy-Walker Syndrome (DWS) is a rare congenital brain malformation characterized by underdevelopment of cerebellar vermis and cystic enlargement of the fourth ventricle and enlargement of the posterior fossa. The cooccurrence of DWS and syringomyelia in adults is very rare. CASE DESCRIPTION: We report a man aged 19 years who presented with a 2-year history of tremor. Magnetic resonance imaging showed cystic dilation of the fourth ventricle, hypoplasia of the cerebellar vermis, and syringomyelia. Posterior fossa decompression and spinal cord ostomy were performed. Tremor was markedly improved and the fourth ventricular and the syringomyelia were reduced in size postoperatively. CONCLUSIONS: Tremor can be a clinical manifestation in patients of DWS concomitant with syringomyelia in adults. Spinal cord ostomy combined with posterior fossa decompression may be an effective approach for alleviation of symptoms and syringomyelia.

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

The "vermian-crest angle": does it allow accurate categorisation of fetal upward rotation of cerebellar vermis on intrauterine MRI? A pilot study.

AIM: To test a new parameter to assess the position of the fetal cerebellar vermis in the posterior fossa (PF) using intrauterine magnetic resonance imaging (MRI). MATERIALS AND METHODS: The angle between the cerebellar vermis and the internal occipital crest (vermian-crest angle, VCA) was assessed retrospectively using MRI in fetuses with and without PF anomalies. Spearman's rank test was used to investigate correlation of the VCA with gestational age (GA). Groups were compared using Student's t-test and the one-way analysis of variance (ANOVA) with the Bonferroni adjustment. Box-and-whisker plots were also used. RESULTS: One hundred and two normal cases were identified. Mean±SD GA at MRI was 26.5±2.8 weeks (range: 22-32 weeks). The VCA was 64.49±11.5° independently of GA (r=0.19; p=0.12). In addition, 30 fetuses at 19-28 weeks were identified with Blake's pouch cyst (BPC; n=5), Dandy-Walker malformation (DWM; n=12), mega cisterna magna (MCM; n=10), and vermian hypoplasia (VH; n=3). The VCA was significantly different in the DWM (p<0.001) and BPC (p<0.001) subgroups, but was not significantly different in cases of VH (p=0.84) and MCM (p=0.95) in comparison with controls. CONCLUSIONS: A new method to assess vermian position within the PF using intrauterine MRI was assessed. In combination with the other existing parameters, it may be helpful for addressing the categorisation of upward rotation of the fetal cerebellar vermis; however, further studies are necessary to strengthen the present findings.

Hindbrain morphometry and choroid plexus position in differential diagnosis of posterior fossa cystic malformations.

OBJECTIVE: To assess the differential diagnostic significance of a series of quantitative and qualitative variables of the cerebellar vermis in fetuses with posterior fossa cystic malformation, including Dandy-Walker malformation (DWM), vermian hypoplasia (VH) and Blake's pouch cyst (BPC). METHODS: This was a retrospective study of confirmed cases of DWM, VH and BPC, diagnosed at the Fetal Medicine and Surgery Unit of the Federico II University between January 2005 and June 2013 or the Fetal Medicine and Surgery Unit of G. Gaslini Hospital between July 2013 and September 2017. All included cases had good-quality three-dimensional (3D) volume datasets of the posterior fossa, acquired by transvaginal ultrasound through the posterior fontanelle. The midsagittal view of the posterior fossa was the reference view for the study. We assessed brainstem-tentorium angle and brainstem-vermis angle (BVA), as well as craniocaudal (CCVD) and anteroposterior (APVD) vermian diameters and vermian area (VA), which were normalized by biparietal diameter (BPD) to take into account gestational age (CCVD/BPD × 100, APVD/BPD × 100 and VA/BPD × 100, respectively). Finally, the position of the fourth ventricular choroid plexus (4VCP) was defined as normal ('up') or abnormal ('down'), relative to the roof/cyst inlet of the fourth ventricle. RESULTS: We analyzed 67 fetuses with posterior fossa malformations (24 cases of DWM, 13 of VH and 30 of BPC). The mean gestational age at diagnosis was 23.6 weeks. Regardless of gestational age, the BVA differed significantly between the three groups, and the VA/BPD was able to differentiate between VH and BPC. In differentiating between VH and BPC, the greatest areas under the receiver-operating characteristics curve were those for VA/BPD ratio. The 4VCP position was down in all cases of DWM and VH, while it was up in all cases of BPC. CONCLUSIONS: Our data support the concept that VA/BPD ratio and 4VCP position may be used to differentiate between DWM, VH and BPC in the fetus. In our series, the position of the 4VCP had the highest accuracy, but a larger number of VH cases should be evaluated to confirm that an up position of the 4VCP indicates BPC while a down position indicates DWM or VH. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

The Tonsillouvular Fissure Approach: Access to Dorsal and Lateral Aspects of the Fourth Ventricle.

OBJECTIVE: Although approaches to the fourth ventricle (FV) have been studied well, approaches to the lesions located in the dorsal and lateral aspects of the FV have not been shown in anatomic or clinical studies. The aim of this study is to show for the first time in the literature the tonsillouvular fissure approach (TUFA) in anatomic dissections and its use in surgical series. METHODS: For anatomic studies, 4 formalin-fixed human cadaveric heads infused with colored silicone and 10 cerebellar specimens were dissected in a stepwise manner. Records of 12 patients operated on via TUFA were also retrospectively reviewed. RESULTS: Neurosurgical anatomy and critical steps of TUFA were described in detail. Among 12 patients with lesions around the FV (4 cavernous malformation, 2 pilocytic astrocytoma, 2 hemangioblastoma, 1 B-cell lymphoma, 1 metastatic papillary carcinoma, 1 dermoid cyst, and 1 arteriovenous malformation), 11 gross total and 1 subtotal resection were achieved via TUFA without any mortality or morbidity. Comparative analyses of 4 surgical approaches to FV (TUFA, telovelar/cerebellomedullary fissure, supratonsillar/tonsillobiventral lobule fissure, and transvermian approaches) were also presented. CONCLUSIONS: TUFA provides a direct route and excellent surgical view to lesions around the FV, particularly on dorsal and lateral aspects, inferior vermis, and medial part of the dentate nucleus and cerebellar peduncles. It minimizes traversing the normal cerebellar tissue compared with a transvermian approach.

Cerebellar Vermian Epidermoid Tumor: A Report of 2 Cases.

BACKGROUND: Epidermoid tumors are rare, benign slow-growing congenital tumors, most frequently located in the cerebellopontine angle of the intracranial cavity. They usually grow to a large size before patients become symptomatic. Although these tumors are amenable to surgery, their adherence to neurovascular structures poses a surgical challenge that results in subtotal resection, thus increasing the risk of recurrence. CASE DESCRIPTION: We report 2 adult patients whose imaging studies revealed epidermoid tumors located in the cerebellar vermis, an uncommon site for such tumors. The patients presented with variable symptomatology. We highlight the imaging features and challenges of surgery. Both patients had good outcomes, with resolution of symptoms and neurologic deficits. CONCLUSIONS: A safe complete excision of epidermoid tumor and its capsule is possible with a good understanding of their clinical and radiologic features and a high index of suspicion. To the best of our knowledge, this is the first report of cerebellar vermian epidermoid tumors from sub-Saharan Africa.

Prenatal assessment of cerebellar vermian lobulation: fetal MRI with 3-Tesla postmortem validation.

OBJECTIVES: To optimize the imaging assessment of fetal hindbrain malformations, this observational magnetic resonance imaging (MRI) study aimed to assess whether fetal vermian lobulation can be quantified accurately and whether the relative growth of vermian lobules is uniform. METHODS: This retrospective study included singleton fetuses which underwent T2-weighted MRI in vivo with a 1.5-Tesla (T) scanner or within 24 h postmortem with a 3-T scanner between January 2007 and November 2016 at the Medical University of Vienna. We included only those showing normal structural brain development on ultrasound and MRI and which had image quality appropriate for quantitative analysis, i.e. good image quality and a precise midsagittal slice. Fetal brains were segmented and, for all discernible vermian lobules, we determined the mean relative area contribution (MRAC, the proportion of the lobule relative to the total vermian area, in terms of number of voxels). Inter- and intrarater measurement variability of a representative selection (21 cases) was determined by intraclass correlation coefficient (ICC) for voxel-based differences. A linear regression model was used to assess the correlation between the relative size of each vermian lobule (i.e. MRAC) and gestational age. RESULTS: A total of 78 fetuses scanned in vivo aged 18-32 gestational weeks and seven fetuses scanned postmortem aged 16-30 weeks had a precise midsagittal slice and image quality sufficient for quantitative analysis. After 22 weeks of gestation, seven of the nine known vermian lobules could be discriminated reliably. The MRAC showed a mean ± SD difference of only 2.89 ± 3.01% between in-vivo and postmortem measurements. The ICC of voxel-based interrater differences was mean ± SD, 0.91 ± 0.05 and the intrarater ICC was 0.95 ± 0.03. Growth of cerebellar lobules was non-uniform: the MRAC of culmen and DFT (declive + folium + tuber) increased with gestational age, whereas that of lingula, centralis, pyramis and nodulus decreased. The growth of the uvula showed no significant correlation with gestational age. CONCLUSIONS: Fetal vermian lobulation can be assessed accurately and reliably after 22 weeks on precise midsagittal sequences with 1.5-T T2-weighted MRI. Fetal vermian lobules show non-uniform growth, with expansion of DFT and culmen at the expense of the other vermian lobules. Evaluation and elucidation of vermian lobulation in normal fetuses should enable better characterization of fetuses with hindbrain malformations. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Application of fluorescein sodium in the resection of vermis pilocytic astrocytomas.

BACKGROUND: Pilocytic astrocytomas (PAs) are slow growing neoplasms and usually located at the cerebellum. There has been certainty regarding the truthful benefit of surgical resection for patients with PA. Gross total resection (GTR) of PAs, especially those being situated in deep regions, remains a surgical challenge. Generally, they are considered as benign and usually develop in young patients. PAs, belonging to WHO I can be cured by radical resection. The patients with PA have excellent prognosis if complete resection can be conducted. The use of fluorescein in vermis PA surgery has not been yet reported. Our data presents fluorescein facilitates surgical resection of vermis PA. METHODS: Five milligrams per kilogram of fluorescein sodium was intravenously injected directly before general anesthesia for the three patients with PA. The yellow 560 filter was employed for microsurgical tumor resection. Surgical outcomes were assessed concerning the extent of resection. RESULTS: Most portion of PA in the three cases was found to be highly fluorescent after intravenous fluorescein sodium injection, which markedly enhanced tumor visibility. Gross total resection in all of the patients was achieved without further neurological deficits. No adverse effects and complications resulting from fluorescein sodium were observed over the postoperative course. CONCLUSIONS: Intraoperative guidance by fluorescein sodium as a new, simple, safe, and practical procedure can enhance the fidelity of tumor tissue and increase the possibility of completely resecting PAs.

Prone position craniotomy in pregnancy without fetal heart rate monitoring.

A pregnant patient in second trimester scheduled for posterior fossa craniotomy in prone position is a challenge for the anesthesiologist. Things to consider are physiological changes during pregnancy, non-obstetric surgery in pregnant patients, neuroanesthetic principles, effects of prone positioning, and need for fetal heart rate (FHR) monitoring. We have described the anesthetic management of this case and discussed intra-operative FHR monitoring including controversies about its role, indications, and various options available as per fetal gestational age. In our case we attempted intermittent intra-operative FHR monitoring to optimize maternal positioning and fetal oxygenation even though the fetus was pre-viable. However the attempt was abandoned due to practical difficulties with prone positioning. Patient made good neurological recovery following the procedure and delivered a healthy term baby 4 months later. Decisions regarding fetal monitoring should be individualized based on viability of the fetus and feasibility of emergency cesarean delivery. Good communication between a multidisciplinary team involving neurosurgeon, anesthesiologist, obstetrician, and neonatologist is important for a successful outcome for mother and fetus. We conclude that prone position neurosurgery can safely be carried out in a pregnant patient with pre-viable fetus without FHR monitoring.