Partial Rhombencephalosynapsis Research Articles

Associations and outcomes of prenatally detected rhombencephalosynapsis.

To describe the association between prenatal imaging and neurodevelopmental outcomes of fetuses with rhombencephalosynapsis (RES). Thirty-four pregnancies complicated by RES were identified from our institutional databases based on US and/or MRI findings. Genetic testing results were gathered. In cases of termination of pregnancy, we studied the association between prenatal imaging and neuropathologic findings. For those who opted for expectant management, comprehensive developmental assessments and postnatal MRI imaging were evaluated. Over one third of fetuses in our cohort had complete RES. Common intracranial anomalies identified were mesencephalosynapsis, aqueduct stenosis and diencephalosynapsis. The degree of RES was not associated with the frequency of additional central nervous system anomalies. MRI had a good correlation with neuropathologic findings with regard to the degree of RES, aqueduct stenosis and mesencephalosynapsis. Postmortem autopsy showed that one third of our cases had VACTERL-H and almost all of those had complete RES. All liveborn neonates(n=6) had aqueduct stenosis requiring ventriculoperitoneal shunting within days of delivery (median 5days). While a large proportion of prenatally suspected complete RES were found to have partial RES on postnatal imaging, prenatal diagnosis of aqueduct stenosis remained unchanged. All children that were at least 2years old (n=3) had global developmental delay. Prenatal assessment of the RES severity is challenging and may be unreliable. Nevertheless, postnatal prognosis is poor for both complete and partial RES. Associated aqueductal stenosis, can be reliably assessed prenatally and this may contribute to worse postnatal prognosis than the degree of RES.

EP262: De novo heterozygous variant in the RAB11B gene presenting with combined cardiac defect and neurodevelopmental disorder: A case report

The RAB11B gene (OMIM: 604198) encodes for a GTP-binding protein within the Rab11 GTPase subfamily which is associated with the regulation of exocytic and endocytic pathways. It also plays an essential role in ciliogenesis and vesicular trafficking. Pathogenic variants in RAB11B were first described in five patients in 2017. Subsequently, an additional patient was diagnosed through the Korean Undiagnosed Diseases Program (KUDP) in 2019. Clinical features shared by these patients were predominantly a neurological phenotype, including global developmental delay, epilepsy, hypotonia and gait disturbances. Ophthalmological, musculoskeletal, dermatological, and urological findings were also reported in some patients. MRI brain abnormalities were present in many of these patients and include decrease in white matter volume, patchy white matter signals, cerebellar hypoplasia, ventriculomegaly, thin corpus callosum and atypical partial rhombencephalosynapsis. Here we describe a 6-year-old male with previously unreported clinical findings of congenital heart defect in this disorder. A 5-year-old term male presented with prenatal complications of fetal congenital heart disease, maternal hypertension and maternal gestational diabetes. Fetal echocardiogram identified a tetralogy of Fallot (TOF) and post-natal echocardiogram confirmed the TOF with pulmonary valve atresia and 2 aorto-pulmonary collateral vessels from the descending aorta. Clinical examination at birth revealed bilateral congenital vertical talus but no other dysmorphic features. Fluorescent in-situ hybridization test for 22q11.2 deletion was negative. Chromosomal microarray analysis revealed a 133kb deletion of uncertain significance on chromosome 5q14.3. A head and renal ultrasound was normal at birth. He was diagnosed with congenital nystagmus and microcoria at 6 months of age with low amplitude on visual evoked potential testing. MRI brain revealed an extremely hypoplastic corpus callosum and brainstem, bilateral optic nerve hypoplasia, marked depletion of white matter and delayed myelination. He requires a G-tube for feeding. He has significant global developmental delays and is non-verbal. A clinical trio exome sequencing revealed a de novo, heterozygous, missense variant of unknown significance in the RAB11B gene (c.64 G>A; p.al22Met). This variant has since been re-classified as a pathogenic variant based on the published case series of 6 other individuals with similar phenotype. Given the fact that RAB11B is highly expressed in brain, cardiac and testicular tissue with various roles in ciliogenesis and vesicular trafficking, this patient’s cardiac defect is likely secondary to the pathogenic variant the RAB11B gene. We present this case of a de novo, heterozygous RAB11B variant presenting with a congenital heart defect in addition to a neurodevelopmental phenotype, thus expanding the phenotypic spectrum of this rare disorder.

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

To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. 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. 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. 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 Novel Pathogenic Variant in the MN1 Gene in a Patient Presenting with Rhombencephalosynapsis and Craniofacial Anomalies, Expanding MN1 C-terminal Truncation Syndrome.

Meningioma-1 is a transcription activator that regulates mammalian palate development and is required for appropriate osteoblast proliferation, motility, differentiation, and function. Microdeletions involving the MN1 gene have been linked to syndromes including craniofacial anomalies, such as Toriello-Carey syndrome. Recently, truncating variants in the C-terminal portion of the MN1 transcriptional factor have been linked to a characteristic and distinct phenotype presenting with craniofacial anomalies and partial rhombencephalosynapsis, a rare brain malformation characterized by midline fusion of the cerebellar hemispheres with partial or complete loss of the cerebellar vermis. It has been called MN1 C-terminal truncation (MCTT) syndrome or CEBALID (Craniofacial defects, dysmorphic Ears, Brain Abnormalities, Language delay, and Intellectual Disability) and suggested to be caused by dominantly acting truncated protein MN1 instead of haploinsufficiency. As a proto-oncogene, MN1 is also involved in familial meningioma. In this study, we present a novel case of MCTT syndrome in a female patient presenting with craniofacial anomalies and rhombencephalosynapsis, harboring a de novo pathogenic variant in the MN1 gene: c.3686_3698del, p.(Met1229Argfs*87).

Septopreoptic holoprosencephaly in intracranial abnormalities: an under-diagnosed midline finding.

Septopreoptic holoprosencephaly is a mild form of holoprosencephaly in which the midline non-separation is restricted to the septal or preoptic regions. This entity has only been described in a small case series in which associated intracranial abnormalities were limited to the midline structures. To describe the radiologic findings of septopreoptic holoprosencephaly and highlight that it can be associated with a variety of intracranial abnormalities, not merely with abnormalities restricted to midline structures as previously reported. We retrospectively identified 22 children whose MRIs were confirmed to have non-separation restricted to the septal and preoptic region, fulfilling the criteria for septopreoptic holoprosencephaly. We then categorized MRIs as having, in addition, either intracranial abnormalities limited to the midline structures or major abnormalities not limited to the midline structures. Five children had intracranial abnormalities limited to the midline structures. Seventeen children had major intracranial abnormalities not limited to the midline structures. The major abnormalities included: patterning defects of the midbrain-hindbrain (elongated midbrain, shortened pons, shortened/elongated medulla, partial rhombencephalosynapsis), bilateral perisylvian polymicrogyria, microcephaly, megalencephaly and a spheno-ethmoidal encephalocele. Recognized syndromes/chromosomal abnormalities were also observed in this patient group. Our results suggest that septopreoptic holoprosencephaly has been under-recognized and under-reported to date. We propose that searching for this anomaly should be part of the complete assessment of the midline in all children undergoing brain MRI for intracranial malformations.

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.

Mutated zinc finger protein of the cerebellum 1 leads to microcephaly, cortical malformation, callosal agenesis, cerebellar dysplasia, tethered cord and scoliosis

Heterozygous gain of function mutations in the ZIC1 gene have been described with syndromic craniosynostosis, variable cerebral or cerebellar abnormalities and mild to moderate developmental delay. Deletion of chromosome 3q25.1 including both adjacent ZIC1 and ZIC4 genes have been described as a cause of variable cerebellar abnormalities including Dandy-Walker malformation.We report two siblings presenting with neonatal microcephaly, agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, cerebellar and pons hypoplasia, scoliosis and tethered cord (closed neural tube defect). One of the siblings had apparent partial rhombencephalosynapsis. Trio analysis of exome sequencing data revealed a novel heterozygous frameshift mutation in ZIC1 at the end of exon 3 in one sibling and was confirmed by Sanger sequencing in both children. The mutation was not detected in DNA of both parents, which suggests parental gonadal mosaicism. We show that expression of the mutant allele leads to synthesis of a stable abnormal transcript in patient cells, without evidence for nonsense-mediated decay. Craniosynostosis was not present at birth, which explains why ZIC1 mutations were not initially considered. This severe brain malformation indicates that premature closure of sutures can be independent of the abnormal brain development in subjects with pathogenic variants in ZIC1.

Microcephaly with Simplified Gyral Pattern Associated with Partial Rhombencephalosynapsis: A Case Report

AbstractCongenital microcephaly with simplified gyral pattern has been well documented in the literature. It is characterized by a head circumference of less than two standard deviations for age associated with abnormal sulcation. In its mild presentation, this entity is usually described as an isolated anomaly. It presumably results from a brain insult associated with hypoxic–ischemic damage, intracranial infection, or metabolic disease. Rhombencephalosynapsis is a rare condition usually consisting of vermian agenesis or severe hypogenesis, fusion of the cerebellar hemispheres, and apposition or fusion of the dentate nuclei. There are several recent studies focusing on each one of those entities individually, but they do not show any correlation/association between the two of them. This is a case report of an 8-year-old child with neurodevelopmental delay who had episodes of seizures up to 3 years of age. An MRI scan showed marked craniofacial disproportion with dominance of the face over the skull, simplified gyral pattern associated with hypogenesis of the cerebellar vermis, and communication of the folia in the posterior segments of the cerebellar hemispheres. In this case report, we will briefly discuss cerebellar embryology and the process of cortical differentiation, as well as possible associations between rhombencephalosynapsis and other brain abnormalities.

Rhombencephalosynapsis and Chiari II Malformation with Spinal Deformities

Rhombencephalosynapsis is a rare congenital intracranial malformation. Partial rhombencephalosynapsis is a variation of this anomaly with few reported cases. We report a unique case of a patient with partial rhombencephalosynapsis associated with Chiari II, and various spinal malformations, which is very rare, and only few such cases have been reported in literature. These findings suggest that rhombencephalosynapsis can be associated with spinal malformations and, furthermore, that cases with the common features of rhombencephalosynapsis and Chiari II malformation can exist. Such an association likely represents a new anomaly of the hind brain with spine.

An Atypical Case of Chiari II Malformation Mimicking Partial Rhombencephalosynapsis

Partial rhombencephalosynapsis in the presence of Chiari II malformation has been proposed as a "new abnormality of the hindbrain and spine". We describe a case of Chiari II malformation with imaging features mimicking partial rhombencephalosynapsis. Our case demonstrates how the imaging findings of Chiari II malformation can be confused with the above entity and highlights the differentiating features to help radiologists make an accurate diagnosis.

ZIC2 mutations are seen in holoprosencephaly and not partial rhombencephalosynapsis

<i>ZIC2</i> mutations are seen in holoprosencephaly and not partial rhombencephalosynapsis

Partial Rhombencephalosynapsis and Chiari Type II Malformation in a Child: a True Association Supported by DTI Tractography

Partial rhombencephalosynapsis (PRECS) has been recently reported in association with Chiari II (CII). However, its existence as a true malformation is challenged due to the anatomical changes potentially induced by CII. The aim of this report was to investigate the contribution of midbrain/hindbrain tractography in this setting. A 13-year-old boy with a known CII malformation and operated myelomeningocele was referred for brain imaging after a first complex partial seizure. In addition to the classical features of CII, MRI showed partially fused cerebellar hemispheres and multiple supratentorial abnormalities. Diffusion tensor imaging (DTI) color map and tractography showed absent transverse fibers on the midsection of the cerebellum, scarce fibers of the middle cerebellar peduncle (MCP), absence of the middle pontine crossing tract, and fibers running vertically in the medial part of the cerebellum. Vertical mediocerebellar fibers are a feature of classical RECS and the paucity or absence of MCP fibers is mainly described in CII. In our patient, DTI and FT therefore demonstrated structural characteristics of both RECS and CII confirming their potential coexistence and suggesting possible shared embryological pathway.

Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2

Rhombencephalosynapsis (RES) is a rare congenital brain malformation typically identified by magnetic resonance imaging and characterized by fusion of the cerebellar hemispheres and dentate nuclei and vermian agenesis or hypogenesis. Although RES is frequently found in conjunction with other brain malformations and/or congenital anomalies, no specific molecular etiology has been discovered to date and no animal models exist. We identified two half sisters with alobar or semi-lobar holoprosencephaly (HPE) and partial RES, suggesting that genes linked to HPE may also contribute to RES. A deletion of seven base pairs in exon one of the ZIC2 gene (c.392_98del7) was identified in each of the two half sisters with HPE and partial RES. To identify genetic causes of RES and to assess whether genes identified in HPE have a role in RES, we tested 11 additional individuals with RES by high-resolution chromosome analysis, chromosomal microarray analysis, and sequencing of four HPE genes. No mutations in ZIC2 or in other genes that cause HPE were identified, suggesting that mutation of ZIC2 is a rare cause of, or contributor to, RES associated with HPE. In addition, an individual with a complex rearrangement of chromosome 22q13.3 and RES was identified, suggesting the presence of a dosage-sensitive gene that may contribute to RES in this region.

Chiari II Malformation Mimicking Partial Rhombencephalosynapsis? A Case Report

Rhombencephalosynapsis is a rare congenital intracranial malformation with very few cases reported in literature. Partial rhombencephalosynapsis is a variation of this anomaly with fewer reported cases. We present the case of a patient with Chiari II malformation mimicking partial rhombencephalosynapsis.

Partial Rhombencephalosynapsis of the Superior Cerebellum Associated with GM1 Gangliosidosis

Partial Rhombencephalosynapsis of the Superior Cerebellum Associated with GM1 Gangliosidosis