Rhombencephalosynapsis as a cause of aqueductal stenosis: an under-recognized association in hydrocephalic children.

BACKGROUND: Rhombencephalosynapsis is a rare genetic aberration characterized by variable vermian hypoplasia/aplasia in conjunction with united cerebellar hemispheres. Genetic defects in the isthmic organizer at the mesencephalic-metencephalic junction are presumably responsible for the associated aqueductal stenosis. OBJECTIVE: We performed a retrospective review of 20 children with rhombencephalosynapsis to evaluate for and emphasize the association of aqueductal stenosis and hydrocephalus. MATERIALS AND METHODS: We retrospectively reviewed the MR and CT images of 20 children (0-11 years old) with rhombencephalosynapsis encountered at two academic children's hospitals. Rhombencephalosynapsis spectrum severity was graded based on pre-existing literature. We analyzed examinations for ventriculomegaly and degree of aqueductal stenosis. The collicular distances were measured from the collicular apices. Imaging studies were also analyzed for malformations of cortical and cerebellar development. RESULTS: Thirteen of the 20 children (65%) with rhombencephalosynapsis presented with clinical or imaging evidence of hydrocephalus and aqueductal stenosis, principally involving the caudal cerebral aqueduct. All children with aqueductal stenosis had collicular fusion. All six children with complete rhombencephalosynapsis had aqueductal stenosis. The cerebral aqueduct varied from normal to stenotic in children with incomplete rhombencephalosynapsis. Corpus callosum dysgenesis was present in four children. CONCLUSION: Aqueductal stenosis in the setting of rhombencephalosynapsis is an under-recognized cause of noncommunicating hydrocephalus. Our findings support the hypothesis that a defect involving the common gene(s) responsible for the differentiation and development of both the roof plate and midline cerebellar primordium at the mesencephalon/first rhombomere junction may be responsible for the association of aqueductal stenosis and rhombencephalosynapsis.

Síndrome de Joubert: a propósito de cuatro hermanos adultos afectados / Joubert syndrome: report of four adult siblings affected

Introducción. El síndrome de Joubert es una rara enfermedad de transmisión genética autosómica recesiva. Hasta el momento se han descubierto 10 genes asociados. Todos ellos codifican para proteínas ciliares primarias, de ahí que seconsidere al síndrome de Joubert dentro de las ‘ciliopatías’. Las cilias primarias están implicadas en la proliferación celular neuronal y migración axonal en el cerebelo y el tallo cerebral, siendo indispensables para su correcto desarrollo. La primera descripción fue realizada por Joubert et al en 1968, comunicando cuatro casos de individuos con agenesia parcial o total del vermis cerebeloso, síndrome de apnea-hiperapnea episódica neonatal, movimientos oculares anormales, ataxia y retraso mental. Uno de ellos presentaba también meningoencefalocele occipital. Casos clínicos. Se describen cuatro individuos adultos afectados por la enfermedad, hermanos biológicos entre sí, de 24 a 35 años de edad, presentando la evolución clínica y neuroimágenes con el ‘signo del molar’ del mesencéfalo, característico de la entidad, imagen formada por la agenesia o hipoplasia del vermis cerebeloso, pedúnculos cerebelosos superiores estrechos, horizontalizados, engrosados y elongados con falta de decusación, y fosa interpeduncular profunda en losistmos y puentes superiores. Conclusiones. Se pone de manifiesto la necesidad de un diagnóstico precoz de la enfermedad para lograr un correcto seguimiento, abordaje terapéutico y consejo genético familiar, así como también el papel del cerebelo en funciones cognitivasy desarrollo de la inteligencia (AU)

Introduction. Joubert syndrome is a rare, autosomal recessive genetic transmission illness, with ten associated genes discovered at the time. They code for primary ciliary proteins; that is why Joubert syndrome is considered a ‘ciliopathie’.The primary cilia are involved in cell proliferation and neuronal migration in cerebellum and axonal brain, being essential for their proper development. The first description was made in 1969 by Marie Joubert and colleagues. They reportedfour cases with partial or total agenesis of the cerebellar vermis, apnea-hyperpnea neonatal episodic, abnormal eye movements, ataxia and mental retardation. One of them also showed occipital meningoencephalocele. Case reports. Four adult individuals affected by the disease are described. All of them biological siblings, within 24-35 yearsold, and presenting the ‘sign of the molar’ midbrain in their clinical and neuroimaging. It is an entity characteristic, with the image formed by agenesis or hypoplasia of the cerebellar vermis, superior cerebellar peduncle narrow, flatten, thickened and elongated with a lack of decussation and deep interpeduncular fossa at the level of the isthmus and upper bridges. Conclusions. This study shows the need for early disease diagnosis to ensure proper monitoring, therapeutic approach and family genetic counseling, as well as the role of the cerebellum in cognitive functions and intelligence development (AU)

Cerebellar dentate dysplasia.

Dysplasia of the cerebellar dentate nucleus is a state of apparent maturational arrest that involves the cerebellar dentate nucleus. Origins include Joubert syndrome, other disorders of axon guidance and dentato-olivary dysplasia. An overview is given, linking the diverse etiologies.

Hypoplasia of deep cerebellar nuclei in joubert syndrome.

Abnormalities of deep cerebellar nuclei in Joubert syndrome have been previously reported only in rare autopsy cases. Epilepsy in association with Joubert syndrome is also rarely reported. In two new cases of patients with Joubert syndrome, bilateral hypoplasia of deep cerebellar nuclei was detected in vivo by magnetic resonance imaging. One of the patients had drug-resistant epilepsy. Both patients received clinical examination, electroencephalography, neuropsychologic testing, and high-resolution magnetic resonance imaging (1.5 T). Patient 1, a 7-year-old boy, had muscular hypotonia, periodic tachypnea, mild ataxia, global developmental delay, exotropia, and polydactyly. Patient 2, a 23-year-old woman, had muscular hypotonia, epilepsy with pharmacoresistant generalized tonic-clonic seizures, learning disability, esotropia, and mild gait ataxia. Abnormalities of deep cerebellar nuclei might contribute to the pathophysiology of epilepsy in patients with Joubert syndrome.

Congenital brainstem disconnection associated with a syrinx of the brainstem.

We report a case of congenital brainstem disconnection including the second detailed autopsy. A full-term newborn presented with irreversible apnoea and died on the fifth day. MRI revealed disconnection of the brainstem. The autopsy included a series of transverse sections of the mesencephalon, medulla oblongata and bridging tissue fragments. A fragile tube walled by mature brainstem tissue could be reconstructed. It enveloped a cylinder of fluid within the ventral pons extending to the mesencephalon and the lower brainstem. The aqueduct was patent and outside the lesion. The basilar artery was represented by a tiny median vessel. The ventral and lateral parts of the posterior brainstem were surrounded by heterotopic glial tissue. The olivary nucleus was absent and the cerebellar dentate nucleus was dysplastic. Considering the maturity of the remaining parts of the pons, the onset of structural decline is likely to be close to the time of birth. Probable causes are progressively insufficient perfusion through an hypoplastic basilar artery, and obstructed venous drainage through an abnormal glial barrier surrounding the posterior brainstem. The morphological findings can be characterized as a syrinx, known from disorders in which brainstem or spinal cord are damaged by a combination of mechanical and circulatory factors.

Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip.

The deep cerebellar nuclei (DCN) are the main output centers of the cerebellum, but little is known about their development. Using transcription factors as cell type-specific markers, we found that DCN neurons in mice are produced in the rhombic lip and migrate rostrally in a subpial stream to the nuclear transitory zone (NTZ). The rhombic lip-derived cells express transcription factors Pax6, Tbr2, and Tbr1 sequentially as they enter the NTZ. A subset of rhombic lip-derived cells also express reelin, a key regulator of Purkinje cell migrations. In organotypic slice cultures, the rhombic lip was necessary and sufficient to produce cells that migrate in the subpial stream, enter the NTZ, and express Pax6, Tbr2, Tbr1, and reelin. In later stages of development, the subpial stream is replaced by the external granular layer, and the NTZ organizes into distinct DCN nuclei. Tbr1 expression persists to adulthood in a subset of medial DCN projection neurons. In reeler mutant mice, which have a severe cerebellar malformation, rhombic lip-derived cells migrated to the NTZ, despite reelin deficiency. Studies in Tbr1 mutant mice suggested that Tbr1 plays a role in DCN morphogenesis but is not required for reelin expression, glutamatergic differentiation, or the initial formation of efferent axon pathways. Our findings reveal underlying similarities in the transcriptional programs for glutamatergic neuron production in the DCN and the cerebral cortex, and they support a model of cerebellar neurogenesis in which glutamatergic and GABAergic neurons are produced from separate progenitor compartments.

Oromotor and communication findings in joubert syndrome: further evidence of multisystem apraxia.

This study provides descriptive information in the areas of oromotor abilities and communication to better understand the spectrum of disability in individuals with Joubert syndrome. Participants included 21 individuals with the diagnosis of Joubert syndrome (mean age 10.45 years). Participants completed oromotor and receptive language measures. In addition, all of the participants' speech and gesture communication from a narrative task was coded and analyzed from videotape. Caregivers reported the participants' level of fine and gross motor function. The results show that individuals with Joubert syndrome exhibit a distinct oromotor pattern consistent with verbal and lingual apraxias. Despite significant motor skills deficits and oculomotor apraxia, persons with Joubert syndrome produced gestures when communicating, and those whose speech was less intelligible used a higher rate of gesture compared with those with greater verbal output. These findings suggest a new form of apraxia not previously described in the condition and are consistent with previous research that suggests that persons with Joubert syndrome typically do not exhibit classic symptoms of autism spectrum disorder.

Neonatal rigid-akinetic syndrome and dentato-olivary dysplasia.

This report describes a male infant who presented since birth with rigidity and hypokinesia. Severe developmental delay, episodic central hypoventilation, and drug-resistant epilepsy progressively added to the extrapyramidal signs in the following months and led to the patient's death at 10 months of age. Neuroradiologic and neurometabolic evaluations were negative. Normal cerebrospinal metabolites excluded a defect in dopamine metabolism, and treatment with levodopa failed to improve his motor symptoms. Neuropathologic findings demonstrated dentato-olivary dysplasia. While isolated dentato-olivary dysplasia has been described in a few cases of Ohtahara syndrome, to our knowledge, the association with infantile parkinsonism has not been previously reported.

Arthrogryposis multiplex congenita with callosal agenesis and dentato-olivary dysplasia.

We report the autopsy case of a boy with arthrogryposis multiplex congenita, associated with callosal agenesis and dentato-olivary dysplasia. The patient manifested with dysmorphic facial features and suffered from intractable epilepsy during the neonatal period. These sets of complications suggest that a common molecular mechanism may be involved in the development of corpus callosum and the folding of the dentate and inferior olivary nuclei. Deep brain structures, including the brainstem and the cerebellum, may be involved in the pathophysiology of symptomatic generalized epilepsy. The differential diagnoses for the clinical and pathological characteristics of this patient are discussed.

A rare cerebellar malformation: rhombencephalosynapsis.

Rhombencephalosynapsis is a rare cerebellar malformation characterized by absence of the vermis and midline fusion of hemispheres. It is easily recognized by MRI. No specific syndrome has been described in association with this cerebellar anomaly. Early diagnosis is possible especially when coexisting brain anomalies are present. We report a symptomatic case of rhombencephalosynapsis with moderate hydrocephalus.

Evidence that the loss of Purkinje cells and deep cerebellar nuclei neurons in homozygous weaver is not related to neurogenetic patterns.

To determine whether the neurogenetic patterns of Purkinje cells and deep cerebellar nuclei neurons were normal in weaver homozygotes and whether the degeneration of those neuronal types was linked to their time of origin, [3H] thymidine autoradiography was applied on sections of homozygous weaver mice and normal controls on postnatal day 90. The experimental animals were the offspring of pregnant dams injected with [3H] thymidine on embryonic days 11-12, 12-13, 13-14 and 14-15. The results show that the onset of neurogenesis, its pattern of peaks and valleys, and its total span were similar between wild type and homozygous weaver in the cerebellar areas analyzed, indicating that the loss of Purkinje cells and deep cerebellar nuclei neurons is not related to neurogenetic patterns. In weaver homozygotes, the loss of Purkinje cells and deep cerebellar nuclei neurons followed a lateral to medial gradient of increasing severity. Thus, the vermis and the fastigial nucleus, which are medially located, presented the most important neuron loss, whereas in the lateral hemisphere and the dentate nucleus, neuron loss was spared.

A case of Ohtahara syndrome with olivary-dentate dysplasia and agenesis of mamillary bodies.

We report a patient with early infantile epileptic encephalopathy (EIEE) with suppression-burst (Ohtahara syndrome) associated with olivary-dentate dysplasia and agenesis of mamillary bodies is reported. Although those with Ohtahara syndrome are a heterogeneous group, virtually all reported cases are secondary to neuronal migrational disorders, sometimes only identified by detailed neuropathologic examination, as in this case report, which describes mamillary body agenesis as a not-yet-recognized anomaly associated with Ohtahara syndrome. All children with Ohtahara syndrome should have high-resolution magnetic resonance imaging (MRI) and detailed postmortem neuropathologic examinations.

Rhombencephalosynapsis.

A case report of rhombencephalosynapsis in a 34-year-old female is presented and the clinical features and possible pathogenesis of this disorder are reviewed.

Rhombencephalosynapsis diagnosed in childhood: clinical and MRI findings.

Rhombencephalosynapsis is an unfrequent malformation of the posterior fossa essentially characterized by vermian agenesis or hypogenesis, fusion of the cerebellar hemispheres and fusion of the dentate nuclei. Supratentorial abnormalities are usually associated. No specific clinical syndrome can be described in relation with this disorder. We report a case diagnosed by MRI in a living patient.

Rhombencephalosynapsis associated with hand anomalies.

A case of rhombencephalosynapsis, a very rare disorder characterized by agenesis or hypogenesis of the cerebellar vermis and fusion of the cerebellar hemispheres, is reported with magnetic resonance imaging features. Radiographs showed anomalies in both hands; namely phalangeal hypoplasia and occult polydactyly in the right hand and syndactyly in the left, previously unreported in association with this disorder.

Isolated choroid plexus lipomas.

Seven patients with isolated choroid plexus lipomas were found during the consecutive evaluation of 5351 CT and 1542 MR examinations of the brain during approximately 9 months, from the diagnosis of the first case up to the last one. Five patients were adults and two were children (one neonate). The lesions were unilateral in six patients, and bilateral in one (the neonate). Their sizes ranged from 2mm to 1 cm, and they were nodular or curvilinear. The lesions were bright on spin-echo T1-weighted and water saturation MR images, and were dark on spin-echo T2-weighted and fat saturation MR images. Relatively smaller lesions (five cases) were not seen on the CT scan. We noted an approximately 0.04% frequency on the CT scan (two in 5351 CT examinations), and 0.45% frequently on the MR images (seven in 1542 MR examinations) for isolated choroid plexus lipomas.