Rhombencephalosynapsis Research Articles

Neuropsychiatric Symptoms in Rhombencephalosynapsis: A Clinical Report.

Rhombencephalosynapsis (RES) is a hindbrain malformation characterized by a missing cerebellar vermis with apposition or fusion of the cerebellar hemispheres. The present clinical case report provides a comprehensive, longitudinal overview of cognitive and affective manifestations in a 22-year-old patient with RES. The patient shows clinical signs of emotional reactivity and dysregulation, impulsivity, and impairments in executive functioning since early childhood. These features fit the constellation of neuropsychiatric symptoms observed in patients with congenital and acquired abnormalities of the posterior vermis. It is proposed that patients with RES may show affective and cognitive difficulties which increase their vulnerability to psychological stress and risk of developing mental health issues.

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.

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.

Rhombencephalosynapsis, The Famous Unknown: Own Experience and Literature Review of Prenatal Diagnosis with Sonography and Magnetic Resonance Imaging

Rhombencephalosynapsis (RES) is a rare cerebellar malformation characterized by congenital fusion of the hemispheres and absence of the vermis. This condition is associated with developmental delay, seizures and involuntary head movements. Although the clinical and imaging aspect of this condition have been thoroughly investigated in the adult, prenatal diagnosis remains still a challenge in the modern Fetal-Maternal Medicine. Here we report our experience with 3 cases and review the current literature as well, focusing specifically on the obstetric imaging as well as on the prenatal diagnosis and management of this rare condition. RES should be considered in the differential diagnosis when absence of the vermis in the Posterior Fossa (PF) is suspected at prenatal Ultrasound Sonography (US), especially when ventriculomegaly or other Central Nervous System (CNS) anomalies are detected. A complete anatomical workup is necessary in these cases. Magnetic Resonance Imaging (MRI) remains to be the imaging modality of choice in confirming the diagnosis.

Clinical and molecular evaluation of 13 Brazilian patients with Gomez-López-Hernández syndrome.

We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology.

Normal intellectual skills in patients with Rhombencephalosynapsis.

Rhombencephalosynapsis (RES) is a very rare cerebellar malformation. Neurodevelopmental outcome of apparently isolated RES remains poorly documented and standardized cognitive assessment, reported in only nine published cases so far, is lacking. Prenatal counselling is challenging considering the uncertain prognosis of isolated RES. The aim of this study was to focus on cognitive and motor outcome of isolated RES with a clinical description of six new cases and a detailed review of the literature. A single-centre retrospective study of all RES patients over a 15-year period. Ataxia and fine motor skills were scored using a five-grade scale, according to the degree of disturbance of daily living. Intelligence Quotient (IQ) was established according to age-related Weschler Intelligence Scales. A systematic literature review included published cases with relevant outcome data. Six new cases of apparently isolated RES were reported, including three diagnosed in prenatal settings. The onset age for walking was delayed in four patients. Three patients had head shaking and three had a strabismus. One patient had a mild motor disability, one had subtle ataxia that did not impair daily life and four patients had a normal neurological examination at the last visit. Intellectual abilities were normal in all patients (full IQ score from 90 to 142), although three had ADHD. All received standard schooling. Based on these six new cases, as well as cases from 12 publications in the literature, a total of 28 patients with non-syndromic RES were analysed. Concerning motor outcome, 72% had no complaint or minimal impairment, 16% moderate and 12% severe impairment. Concerning cognitive outcome, 68% had normal cognitive skills, 18% borderline intellectual functioning and 14% moderate to severe disability.

Rhombencephalosynapsis: Fused cerebellum, confused geneticists.

Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other brain malformations such as midbrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic malformations (heart, kidney, spine, and limb defects). Similar to known genetic brain malformations, the RES cerebellar malformation is highly stereotyped, yet no genetic causes have been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating brain malformation.

Prenatal aqueduct stenosis: Association with rhombencephalosynapsis and neonatal outcome.

To examine prenatal MRI and postnatal imaging in fetuses with congenital aqueductal stenosis (CAS) to determine the frequency of association of rhombencephalosynapsis (RES) and how it may affect neonatal intensive care unit (NICU) course. A single center IRB-approved retrospective study of children with CAS was performed. Prenatal MRI, postnatal images, and clinical data were reviewed. Statistical analysis was performed with SAS statistical software package version 9.3. Aqueduct obstruction was confirmed for all 30 participants. Hydrocephalus required shunting in all but one (97%). Fifteen neonates had CAS with rhomboencephalosynapsis (RES) (50%). Although neonatal course between the two groups was comparable, 53% of CAS with RES neonates required feeding assistance versus 20% in CAS only (P=0.128). Shunting in the CAS with RES group occurred at average of 6days of life versus CAS group at 55days (P=0.196). Biometry measurements showed a statistically significant decrease in pons antero-posterior diameter in both groups (CAS only P=0.0049 and CAS with RES P=0.0003) when compared with norms for gestational age. CAS has a high association with RES. Feeding assistance in the NICU and earlier neurosurgical intervention may be required in patients with CAS who also have RES.

Cerebellotrigeminal Dermal Dysplasia (Gómez-López-Hernández Syndrome)

Cerebellotrigeminal dermal (CTD) dysplasia is a rare neurocutaneous disorder characterized by a triad of symptoms: bilateral parieto-occipital alopecia, facial anesthesia in the trigeminal area, and rhombencephalosynapsis (RES), confirmed by cranial magnetic resonance imaging. CTD dysplasia is also known as Gómez-López-Hernández syndrome. So far, only 35 cases have been described with varying symptomatology. The etiology remains unknown. Either spontaneous dominant mutations or de novo chromosomal rearrangements have been proposed as possible explanations. In addition to its clinical triad of RES, parietal alopecia, and trigeminal anesthesia, CTD dysplasia is associated with a wide range of phenotypic and neurodevelopmental abnormalities.Treatment is symptomatic and includes physical rehabilitation, special education, dental care, and ocular protection against self-induced corneal trauma that causes ulcers and, later, corneal opacification. The prognosis is correlated to the mental development, motor handicap, corneal–facial anesthesia, and visual problems. Follow-up on a large number of patients with CTD dysplasia has never been reported and experience is limited to few cases to date. High degree of suspicion in a child presenting with characteristic alopecia and RES has a great importance in diagnosis of this syndrome.

Gómez‐López‐hernández syndrome versus rhombencephalosynapsis spectrum: A rare co‐occurrence with bipartite parietal bone

Rhombencephalosynapsis (RES) is a rare hindbrain malformation that could occur in isolation or as a part of a syndrome for example, Gómez-López-Hernández syndrome (GLH) or VACTERL-H. We identified male patient with severe RES. Ventriculomegaly, agenesis of septum pellucidum, very thin corpus callosum with interhemispheric cyst were additional neuroimaging findings. He had brachyturricephaly, midface retrusion, low-set posteriorly rotated ears and bilateral parietal well circumscribed areas of alopecia. No corneal anesthesia was observed; thus, demonstrating many of the diagnostic criteria of GLH. Interestingly, he additionally had bilateral bipartite parietal bone (BPB) that is an extremely rare anomaly of the parietal sutures. This is the first co-occurrence of this rare anomaly with GLH. We believe the presence of this unique finding could represent an important clue for understanding the pathogenesis of this malformation.

Persistent figure‐eight and side‐to‐side head shaking is a marker for rhombencephalosynapsis

Head-shaking stereotypies have been described in patients with neurological impairment. We noted an unusual preponderance of head shaking in patients with rhombencephalosynapsis (RES). We sought to delineate the movements further and determine whether oculomotor and vestibular testing could reveal their cause. Information was collected from direct observation, video review and parental questionnaire from 59 patients with RES. Oculomotor and vestibular testing was performed in 4 children. Of 59 patients, 50 had persistent head shaking that was often observed years before RES was recognized. Three affected children demonstrated abnormal central vestibular processing. Head-shaking is common in RES. These characteristic movements may provide input to a defective vestibular system or may represent a motor pattern that is usually suppressed by vestibular feedback. Persistent head shaking should alert clinicians to the possible presence of a congenital hindbrain abnormality that affects the vestibulocerebellum, particularly RES.

Beyond Gómez-López-Hernández syndrome: recurring phenotypic themes in rhombencephalosynapsis.

Rhombencephalosynapsis (RES) is an uncommon cerebellar malformation characterized by fusion of the hemispheres without an intervening vermis. Frequently described in association with Gómez-López-Hernández syndrome, RES also occurs in conjunction with VACTERL features and with holoprosencephaly (HPE). We sought to determine the full phenotypic spectrum of RES in a large cohort of patients. Information was obtained through database review, patient questionnaire, radiographic, and morphologic assessment, and statistical analysis. We assessed 53 patients. Thirty-three had alopecia, 3 had trigeminal anesthesia, 14 had VACTERL features, and 2 had HPE with aventriculy. Specific craniofacial features were seen throughout the cohort, but were more common in patients with alopecia. We noted substantial overlap between groups. We conclude that although some distinct subgroups can be delineated, the overlapping features seen in our cohort suggest an underlying spectrum of RES-associated malformations rather than a collection of discrete syndromes.

Rhombencephalosynapsis Spectrum of Severity

Investigators at University of Washington, Seattle, University of Southern California, and Children’s Hospital Los Angeles evaluated neuroimaging findings in 42 patients (17 female, 25 male; age range, 2 days to 44 years) with rhombencephalosynapsis (RES).

Rhombencephalosynapsis - isolated anomaly or complex malformation?

Rhombencephalosynapsis (RES) is a rare malformation of the posterior cranial fossa, characterized by fusion of the cerebellar hemispheres, medial cerebellar peduncles and dentate nuclei. Over the period of 7 years 8 cases of this anomaly have been diagnosed in two pediatric centers in Warsaw including one on the prenatal magnetic resonance imaging (MRI). Material consists of involves one fetus examined at the gestational age of 27 and 33 weeks and 7 children (5 girls and 2 boys) aged 8 months - 16 years. All of them underwent brain MRI with the use of 1.5T scanners. In 1 case RES was an isolated anomaly, in 1 case it was accompanied by hydrocephalus only, in the remaining 6 cases RES was an element of a complex malformation. The additional anomalies were as follows: callosal hypoplasia in 3 children, abnormalities of gyration in 2, brainstem hypoplasia in 2, isolated fourth ventricle in 1, abnormal white matter signal intensity in 4 (in 2 cases in supratentorial compartment, in 1 in the cerebellum and in 1 in the pons), abnormally dilated extraaxial fluid collections in 2, syringohydromyelia in 2. In 5 cases RES was total, in 3 - partial. Rhombencephalosynapsis has a very characteristic appearance on magnetic resonance imaging which allows diagnosis of this malformation at any age, including prenatal period.

Rhombencephalosynapsis is a malformation deserving of further study

Rhombencephalosynapsis is a malformation deserving of further study

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.

Rhombencephalosynapsis with and without associated malformations

Pasquier et al. [3], in a recent morphological analysis of 40 fetuses from 14 to 35 weeks of gestation found rhombencephalosynapsis (RES) in 11 cases and diencephalo-mesencephalosynapsis in 24 cases, usually associated with other brain anomalies or malformations (agenesis or hypoplasia of corpus callosum, lobar holoprosencephaly, encephalocele, stenosis or forking of Sylvian aqueduct, ventricular dilatation; and extraneuronal anomalies, e.g., VACTERL + H syndrome, etc), while in only two cases of RES (#9, #11) no additional abnormalities were observed. Thus, separation between pure neurological phenotypes and those associated with other syndrome-anomalies were possible. These data can be conWrmed in a small personal series of four cases of RES (two published previously [1]). In a boy aged 7 years presenting with mental retardation and tetraparesis, in addition to typical RES no other CNS malformations were observed, while general autopsy revealed cardiac dilatation and pneumonia. In contrast, a girl aged 6 weeks, with deformation of the occipital cranium and keratomalacia but without neuro-psychiatric signs and symptoms, in addition to typical RES, showed a hypoplasia of the corpus callosum and pons, internal hydrocephalus and absence of the spinal trigeminal tracts. A boy aged 2 years with mental retardation, epileptic seizures and Xaccid paraparesis of the legs, but without extraneuronal malformations, revealed typical RES, diVuse atrophy of the cerebral hemispheres, and fusion of both thalami. The oldest patient, a woman aged 26 years, with severe mental retardation, blindness, incontinence, severe behavioral disturbances, dying from pulmonary embolism, in the absence of extraneuronal malformations, showed typical RES, associated with severe internal hydrocephalus due to stenosis of the Sylvian aqueduct and consecutive atrophy of the optic nerves. Since in the Wrst case of RES, reported by Obersteiner [2], no clinical data, general autopsy Wndings, nor exact data of the skull and brain are available, it cannot be further evaluated. Although no genetic examinations had been performed in our cases, together with those reported by Pasquier et al. [3], they suggest that the frequent combination of both telencephalic and hindbrain malformations in patients with RES may be due to disordered formation of the roof plate and development of midline cerebellar primordia at the junction of the mesencephalon and the Wrst rhombomere.

Reactivity to visual signals and the cerebellar vermis: Evidence from a rare case with rhombencephalosynapsis.

The modulatory role of the cerebellum was investigated in a case with rhombencephalosynapsis (RS), a rare dysplasia characterized by the absence of the cerebellar vermis. The visual psychophysical task involved localizing a target and ignoring a distractor appearing either before, at the same time as, or after the target. It allowed us to assess reactivity to warning signals, distraction, and reactivity to signals appearing during attentive processing. Compared with a control sample, the patient exhibited greater reactivity to warning signals and difficulties interrupting attentive processing, whereas distraction was not increased. Complementary analyses showed that these deficits did not reflect just delayed development of attentional processes. These results suggest that the cerebellum modulates responsiveness and commands attentional/exploratory flexibility in response to sensory signals.

Rhombencephalosynapsis associated with autosomal dominant polycystic kidney disease Type 1

Rhombencephalosynapsis (RES) is a rare congenital malformation of the cerebellum characterized by hypogenesis or agenesis of the vermis and fusion of the cerebellar hemispheres with or without fusion of the dentate nuclei and superior cerebellar peduncles. No genetic or chromosomal abnormalities have been identified for RES. Although the occurrence of RES is presumed to be sporadic, no clear pattern of inheritance has been identified. The authors report on a 17-year-old girl with autosomal dominant polycystic kidney disease Type 1 as well as RES.

Gomez–Lopez-Hernandez syndrome: An easily missed diagnosis

Gomez–Lopez-Hernandez syndrome (GLHS) is a rare syndrome comprising the triad rhombencephalosynapsis (RS), parietal alopecia, and trigeminal anesthesia. Other typical findings are skull abnormalities, craniofacial dysmorphic signs, and short stature. Intellectual impairment is typical but cases with normal cognitive functions have also been reported. Only 15 cases of GLHS have been described so far, all sporadic. We report four further patients with GLHS: one neonate, two children and a middle aged man. In all cases the diagnosis was made only in retrospect; one child died as neonate due to esophageal atresia. All patients presented RS and parietal alopecia, three intermittent head stereotypies, two had obvious trigeminal anesthesia, and one normal cognition. Alopecia and also trigeminal anesthesia can be very mild and can be easily missed. However, the dysmorphic signs including bilateral alopecia are already present in the neonatal period and are highly suggestive of GLHS. RS should be looked for in this situation. It is important to mention that neuroimaging does not allow distinguishing between isolated RS and GLHS. If RS is diagnosed the clinical signs of GLHS should be sought. The diagnosis of GLHS can only be made by the combination of the typical dysmorphic signs and neuroimaging in the neonatal period, but not prenatally.