Clinical features and genetic analysis of two Chinese pedigrees affected with Joubert syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome.@*METHODS@#Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2.@*RESULTS@#The proband of pedigree 1 was a fetus at 23+5 weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up.@*CONCLUSION@#The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.

Phenotype and genotype analysis of a pedigree affected with Joubert syndrome due to variant of TMEM237 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the pathogenesis of two siblings (including a fetus) from a pedigree affected with Joubert syndrome.@*METHODS@#Peripheral blood samples of the proband and his parents as well as amniotic fluid and abortion tissues of the fetus were collected. Part of the samples were used for the extraction of DNA, and whole exome sequencing (WES) was carried out to screen potential variants in the proband and his parents. Suspected variants were subjected to bioinformatics analysis with consideration of the clinical phenotype, and were verified by Sanger sequencing of the proband, fetus and their parents.The remainders were used for the extraction of RNA, and the mechanism of splicing variant was validated by reverse transcription-PCR (RT-PCR).@*RESULTS@#WES showed that both patients have carried c.175C>T (p.R59X) and c.553+1G>A compound heterozygous variants of the TMEM237 gene. Among these, c.175C>T was a nonsense mutation inherited from the asymptomatic mother, while c.553+1G>A was an alternative splicing mutation inherited from the asymptomatic father. RT-PCR showed that this variant has resulted in aberrant splicing by exon skipping.@*CONCLUSION@#The compound heterozygous variants of the TMEM237 gene probably underlay the etiology of Joubert syndrome in this pedigree. Above finding has enriched the phenotype and variant spectrum of the TMEM237 gene, and facilitated genetic counseling and prenatal diagnosis for the family.

Clinical and genetic analysis of a child with mental retardation and microcephaly with pontine and cerebellar hypoplasia / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and pathogenic variant in a child diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH).@*METHODS@#Clinical phenotype of the child was reviewed. Whole exome sequencing was carried out for the child. Candidate variant was verified by Sanger sequencing of the family member.@*RESULTS@#The proband manifested dyskinesia, development delay, cerebellar hypoplasia and bilateral hearing impairment. WES results revealed that the proband has carried a pathogenic c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene, which was verified by Sanger sequencing to be a de novo variant.@*CONCLUSION@#The c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene probably underlay the MICPCH in the proband. Above finding has provided a basis for genetic counseling. WES should be considered for the diagnosis of neurological dysplasia.

Severe Cerebellar Degeneration and Chiari I Malformation - Speculative pathophysiology based on a systematic review

SUMMARY BACKGROUND Symptomatic Chiari Type I Malformation (CM) is treated with posterior fossa decompression with or without duroplasty. We have noticed some cases with concomitant severe cerebellar ataxia due to cerebellar atrophy. The aim of this study is to review the literature of CM associated with severe cerebellar atrophy and discuss its potential physiopathology. METHODS A systematic literature review in the Pubmed Database was performed using the following key-terms: "cerebellar atrophy Chiari", and "cerebellar degeneration Chiari". Articles reporting the presence of cerebellar degeneration/atrophy associated with CM were included. RESULTS We found only six studies directly discussing the association of cerebellar atrophy with CM, with a total of seven cases. We added one case of our own practice for additional discussion. Only speculative causes were described to justify cerebellar atrophy. The potential causes of cerebellar atrophy were diffuse cerebellar ischemia from chronic compression of small vessels (the most mentioned speculative cause), chronic raised intracranial pressure due to CSF block, chronic venous hypertension, and association with platybasia with ventral compression of the brainstem resulting in injury of the inferior olivary nuclei leading to mutual trophic effects in the cerebellum. Additionally, it is not impossible to rule out a degenerative cause for cerebellar atrophy without a causative reason. CONCLUSIONS Severe cerebellar atrophy is found in some patients with CM. Although chronic ischemia due to compression is the most presumed cause, other etiologies were proposed. The real reasons for cerebellar degeneration are not known. Further studies are necessary.

RESUMO OBJETIVO A Malformação de Chiari (MC) tipo I sintomática é tratada através da descompressão da fossa posterior com ou sem duroplastia. Observamos alguns casos com ataxia cerebelar grave concomitante devido à atrofia cerebelar. O objetivo deste estudo é revisar a literatura sobre MC associada à atrofia cerebelar grave e discutir sua possível fisiopatologia. METODOLOGIA Conduzimos uma revisão sistemática da literatura no banco de dados Pubmed utilizando as seguintes palavras-chave: "cerebellar atrophy Chiari", e "cerebellar degeneration Chiari". Artigos sobre a presença de degeneração/atrofia cerebelar associada à MC foram incluídos. RESULTADOS Encontramos apenas seis estudos que discutiam diretamente a associação entre atrofia cerebelar e MC, com um total de sete casos. Nós adicionamos um caso da nossa própria prática para ampliar a discussão. Apenas causas especulativas foram descritas para justificar a atrofia cerebelar, entre elas: isquemia cerebelar difusa devido à compressão crônica de pequenos vasos (a causa especulativa mais citada), pressão intracraniana elevada crônica devido ao bloqueio de LCR, hipertensão venosa crônica e associação com platibasia com compressão ventral do tronco cerebral, resultando em lesão do núcleo olivar inferior e levando a efeitos tróficos mútuos no cerebelo. Além disso, não é possível descartar uma causa degenerativa para atrofia cerebelar sem motivos claros. CONCLUSÃO A atrofia cerebelar grave é encontrada em alguns pacientes com MC. A isquemia crônica causada por compressão é a causa mais apontada como suspeita, porém outras etiologias foram propostas. As reais causas da degeneração cerebelar não são conhecidas. Mais estudos são necessários.

Anestesia total intravenosa libre de opioides en un paciente con síndrome de Joubert: caso clínico / Opioid free total intravenous anesthesia in Joubert syndrome: Case report

Joubert syndrome (JS) is a rare autosomal recessive disorder characterized by abnormal eye movements, respiratory pattern abnormalities, anatomical airway alterations, mental retardation and hypoplasia/aplasia of the cerebellar vermis confirmed by magnetic resonance imaging. This case report describes the successful management of a patient with JS operated of cholesteatoma under 100% opioid-free total intravenous general anaesthesia. We also provide a brief review of JS, its anaesthetic implications and opioid-free anaesthesia (OFA) technique.

El síndrome de Joubert (SJ) es una enfermedad autosómica recesiva poco frecuente caracterizada por trastornos oculares, respiratorios, alteraciones anatómicas de la vía aérea, retraso mental e hipoplasia/aplasia del vermis cerebeloso constatada mediante resonancia magnética. Presentamos un caso exitoso de paciente con SJ operado de colesteatoma bajo anestesia general endovenosa total 100% libre de opioides. Asimismo, realizamos una breve revisión del SJ, sus implicaciones anestésicas y de la técnica de anestesia libre de opioides.

Lhermitte-Duclos Disease and Cowden Syndrome: A Case Report and Literature Review

Lhermitte-Duclos disease (LDD), also known as dysplastic gangliocytoma of the cerebellum, is a rare, usually benign, slow-growing tumor, that commonly affects patients aged 30 to 50 years-old. The manifestations of dysplastic cerebellar gangliocytoma are nonspecific and are related both to the mass effect produced by its growth and to the location of the lesion. Cerebellar symptoms such as ataxia are often present. In 40% of cases, the tumor is associated with Cowden syndrome, which is part of a group ofgenetic disorders called polypoid hamartoma complex. In this case report, the patient presented expansive lesion in the posterior fossa, compatible with LDD, associated with macrocephaly. These findings are consideredmajor criteria for Cowden syndrome. When together, they confirm the diagnoses. To our knowledge, this is the first report of the association of LDD and Cowden syndrome in Brazil.

Hidrocefalia Congénita: Síndrome de Gómez-López-Hernández, un síndrome subdiagnosticado. Caso clínico / Congenital Hydrocephalus: Gómez-López-Hernández syndrome. An underdiagnosed Syndrome. A clinical case

Resumen: Introducción: Las hidrocefalias son condiciones complejas influenciadas por factores genéticos y ambientales. Excluyendo las hidrocefalias adquiridas por infección o tumores encefálicos, las hidrocefalias congénitas de causa genética pueden ocurrir de forma aislada (hidrocefalia aislada, pura o no sindromática) o como componente de un síndrome genético definido (hidrocefalia sindromática). Objetivo: Presentar una hidrocefalia congénita sindromática con un diagnóstico co nocido, y realizar una revisión de la literatura. Caso clínico: Preescolar con diagnóstico prenatal de hidrocefalia y romboencefalosinapsis, cariotipo y estudio de TORCH normales. Al nacer se confirmaron los diagnósticos prenatales y se excluyó malformación del desarrollo cortical cerebral. En la primera semana de vida se realizó derivación ventrículo peritoneal. En una reevaluación a la edad de 4 años, la ausencia de reflejos corneales y alopecia parietal bilateral asociado a romboencefalosinapsis reunieron los criterios diagnósticos definitivos de una displasia cerebelo-trigémino dermal (Síndrome de Gómez, López-Hernández (SGLH)). Conclusiones: El SGLH es un síndro me neurocutáneo infrecuente, posiblemente una condición esporádica que está subdiagnostica da. Con las nuevas tecnologías imageneológicas y genéticas pre y post natales podemos acceder a un diagnóstico de precisión de las hidrocefalias de origen genético, en el cual la alta sospecha de equipos de especialistas clínicos es esencial. Sin el diagnóstico preciso no podemos acceder a un pronóstico a largo plazo, prevención de morbilidad agregada y un consejo genético adecuado, que son requeridos en la pediatría actual.

Abstract: Introduction: Hydrocephalus is defined as complex conditions influenced by genetic and environmental factors. Excluding hydrocephalus acquired from infection or brain tumors, congenital hydrocephalus with a genetic cause may occur isolated (hydrocephalus isolated, pure or non-syndromatic) or as a component of a genetic syndrome (syndromic hydrocephalus). Objective: To present a syndromic congenital hydrocephalus with a known diagnosis, in order to be considered in the study of this pathology and to perform a review of hydrocephaly with a genetic cause. Clinical case: Preschool with a prenatal diagnosis of hydrocephalus and rhombencephalosynapsis, karyotype and study of TORCH was normal. At the moment of birth, the prenatal diagnoses were confirmed and a malformation of cerebral cortical development was excluded. During the first week of life, perito neal ventricle shunt was performed. A reevaluation at age 4, the absence of corneal reflexes bilate ral parietal and congenital focal alopecia associated with rhombencephalosynapsis, meet definitive criteria for cerebello-trigeminal-dermal displasia or Gómez-López-Hernández syndrome (GLHS). Conclusions: GLHS is an uncommon neurocutaneous syndrome, possibly a sporadic condition that is underdiagnosed. Due to the new imaging and genetic technologies pre and post-natal, today it is possible to achieve a better and more accurate diagnosis of hydrocephalus with a genetic origin, in which the high suspicion of teams of clinical specialists is essential. Without accurate diagnosis, we can not access to a long-term prognosis, prevention of aggregate morbidity or an adequate genetic counseling, which are required in today's pediatrics.

A second reported malignancy in a patient with Morquio syndrome

Morquio syndrome is a rare lysosomal storage disease that affects multiple organ systems. However, it is rarely associated with malignancy. We present the case of a 30-year old man with Morquio syndrome associated with gastric adenocarcinoma. This case also demonstrates two other findings that have not been previously described in patients with Morquio syndrome - malrotation of brainstem and cerebellum, without clinical neurologic deficit, and persistence of fetal lobulation in the kidneys.

Linguagem, comportamento e neurodesenvolvimento na Síndrome de Joubert: relato de caso / Language, behavior and neurodevelopment in Joubert syndrome: a case report

RESUMO A síndrome de Joubert (SJ) é uma condição genética heterogênea, rara, do grupo das ciliopatias. Mais de 20 genes foram identificados relacionados com este fenótipo. As principais manifestações incluem hipotonia, ataxia, atraso psicomotor, apraxia oculomotora e anormalidades respiratórias neonatais. O objetivo deste artigo foi apresentar achados de linguagem e neurodesenvolvimento de um indivíduo com diagnóstico da SJ. Foi realizada a anamnese, avaliação genética clínica, observação do comportamento comunicativo, avaliação da linguagem, o Teste de Screening de Desenvolvimento Denver-II (TSDD-II) e a Early Language Milestone Scale (ELMS). Os principais achados da Ressonância Magnética do encéfalo mostraram grave hipoplasia do vérmis cerebelar, “sinal do dente molar”, tronco cerebral hipoplásico, atrofia dos hemisférios cerebelares. A avaliação da linguagem mostrou ausência de oralidade, prejuízo na recepção da linguagem, confirmando o diagnóstico de transtorno de linguagem, com grau de comprometimento grave. O TSDD-II e a ELMS comprovaram a observação e avaliação clínica e indicaram atraso grave nos domínios motor, autocuidados e de linguagem receptiva e expressiva. Diante da presença de hipotonia, ataxia, atraso psicomotor e anormalidades respiratórias neonatais é imprescindível a realização de exame por imagem e avaliação genética para o diagnóstico desta condição, tão complexa, com necessidades terapêuticas peculiares. Este conjunto de achados, associado à história familial e características fenotípicas peculiares reforçam o diagnóstico genético clínico da SJ. Esta síndrome genética é pouco reconhecida e merece ser apresentada para o reconhecimento da comunidade científica, visando o diagnóstico correto e planejamento terapêutico que minimize os efeitos deletérios desta condição.

ABSTRACT The Joubert syndrome (JS) is a rare, heterogeneous genetic condition among the ciliopathies. More than 20 genes have been identified associated with this phenotype. The main manifestations include hypotonia, ataxia, psychomotor retardation, ocular-motor apraxia and neonatal respiratory abnormalities. The objective of this paper was to present language and neurodevelopmental findings of an individual diagnosed with JS. The following procedures were performed: anamnesis, clinical genetic evaluation observation of communicative behavior, evaluation of language, the Denver Developmental Screening Test II (DDST-II) and the Early Language Milestone Scale (ELMS). The main findings of the MRI brain showed severe hypoplasia of the cerebellar vermis, “molar tooth sign”, hypoplastic brain stem and atrophy of the cerebellar hemispheres. The observation and evaluation of the language showed no oral, impaired reception of language, confirming the diagnosis of language disorder with severe degree of impairment. The DDST-II and the ELMS confirmed the observation and clinical assessment and indicated serious delay in motor domains, self-care and receptive and expressive language. Given the presence of hypotonia, ataxia, delayed psychomotor and neonatal respiratory abnormalities it is essential to carry out examination imaging and genetic evaluation for the diagnosis of this condition, so complex, with unique therapeutic needs. This set of findings, along with the familial history and unique phenotypic characteristics reinforce the clinical genetic diagnosis JS. This genetic syndrome is rarely recognized and deserves to be presented to the recognition of the scientific community, targeting the correct diagnosis and treatment planning that minimizes the deleterious effects of this condition.

Joubert Syndrome.

Joubert syndrome is a very rare condition seen in our country. Herein, we report a case of Joubert syndrome in a one year four months old, male baby from a consanguineous marriage presenting with delayed developmental milestone, hypotonia, abnormal respiratory pattern and nystagmus . Cranial MRI shows ‘‘Molar Tooth Sign’’.

Cerebellar vermis: topography and variations / Vermis cerebelar: topografía y variaciones

The vermis is described as the unpaired, median portion of the cerebellum to which the hemispheres are attached. Both the vermis and the hemispheres are formed by folia that, grouped together, are called lobules. The material analyzed consisted of a sample made up of 43 adult male cerebella fixed in 10 percent formaldehyde and sliced medially. The lingula was attached to the superior medullary velum in 100 percent (43) of the cerebella, varying only in size. In 80 percent (32) of the cerebella, the central lobe contained one folium; 7.5 percent (3) had two folia with the first larger than the second; 10 percent (4) had two folia with the second larger than the first; and 2.5 percent (1) had two folia of equal size. In 5 percent (2) of the cerebella, the folium of the vermis emerged from the declive; in 47.5 percent (19), the folium emerged from the central white matter; and in 42.5 percent (17), the folium emerged from the tuber. There was no variation in the lobules, culmen, pyramid, uvula or nodule in the sample studied. Contrary to what many believe, the folia of the cerebellum exhibit variations in form, number and arrangement. However, these variations are virtually unreported, which often hinders the determination of the limits of these structures by students of anatomy of the cerebellum.

El vermis se describe como la parte impar, mediana del cerebelo por la que los hemisferios están conectados. Tanto el vermis como los hemisferios están formados por folium que, de forma conjunta, se llaman lóbulos. El material analizado consistió en una muestra compuesta por 43 cerebelos de hombres, adultos, fijados en formol al 10 por ciento y cortados en rodajas en sentido medial. La língula se adjuntó al velo medular superior en 100 por ciento (43) del cerebelo, y sólo varían en tamaño. En el 80 por ciento (32) del cerebelo, el lóbulo central contenía un folium, 7,5 por ciento (3) había dos folium con el primero más grande que el segundo, 10 por ciento (4) tuvo dos folium con el segundo más grande que el primero, y 2,5 por ciento (1) tenía dos folium de igual tamaño. En el 5 por ciento (2) de los cerebelos, el folium del vermis surgido del declive, en el 47,5 por ciento (19), el folium surgido de la sustancia blanca central, y en el 42,5 por ciento (17), el folium surgido del tubérculo. No hubo, en la muestra estudiada, variación en los lóbulos, culmen, pirámide, úvula o nódulo. Contrariamente a lo que muchos creen, el folium del cerebelo presentan variaciones en la forma, número y disposición. Sin embargo, estas variaciones son virtualmente inadvertidas, lo que a menudo dificulta la determinación de los límites de estas estructuras del cerebelo, por los estudiantes de la anatomía.

Joubert syndrome: large clinical variability and a unique neuroimaging aspect / Síndrome de Joubert: grande variabilidade clínica e uma neuroimagem característica

Joubert syndrome (JS) is an autosomal recessive inherited disorder characterized by hypotonia, cerebellar vermis hypoplasia, ocular abnormalities (e.g, pigmentary retinopathy, oculomotor apraxia and nystagmus), renal cysts and hepatic fibrosis. Respiratory abnormalities, as apnea and hyperpnea, may be present, as well as mental retardation. At least seven JS loci have been determined and five genes identified. Herein, we report five children, belonging to independent families, with JS: they shared the same typical MRI abnormality, known as molar tooth sign, but had an otherwise quite variable phenotype, regarding mostly their cognitive performance, visual abilities and extra-neurological compromise.

A síndrome de Joubert (SJ) é uma doença hereditária, autossômica recessiva, caracterizada por hipotonia, hipoplasia do vermis cerebelar, anormalidades oculares (p.ex., retinite pigmentar, apraxia oculomotora e nistagmo), cistos renais e fibrose hepática. Anormalidades respiratórias tais como apnéia e hiperpnéia podem estar presentes, assim como deficiência mental. Pelo menos sete loci e cinco genes diferentes associados à SJ já foram identificados. Este artigo relata cinco crianças com SJ, pertencentes a diferentes famílias. Todos os pacientes compartilham a mesma anormalidade típica da RM, conhecida como sinal do dente molar, e apresentam ampla variabilidade clínica em relação ao desempenho cognitivo, comprometimento visual e alterações extra-neurológicas.

Tecto-cerebellar dysraphia manifesting as occipital meningocoele associated with congenital melanocytic nevi and pectus excavatum

Only few reported cases of tectocerebellar dysraphia with occipital encephalocele have been reported in the literature. Three month baby boy, the first child of healthy, consanguineous parents presented with a small swelling over the occipital region since birth. The child also used to have apneic spells without cyanosis and spontaneous recovery. CT scan showed absence of the cerebellar vermis, absence of tectum and the 4[th] ventricle communicating with the occipital menigocoele sac and an occipital bone defect. The excision of the encephalocoele sac was performed, however the child continued to have apneic spells and did not do well. In our child irregular respiration probably was the manifestation of the tectocerebellar dysraphia syndrome complex and associated shunt malfunction followed by seizures decompensated the physiology of the child leading to fatal outcome

MRI findings in Joubert syndrome.

Joubert syndrome is a very rare autosomal recessive disorder with only 200 cases reported worldwide.Here we report 4 cases of this rare disorder with MRI findings.

A severe illness of a congenital cytomegalovirus infection

Congenital cytomegalovirus [CMV] infection occurs in about 1 per cent of newborns and 10 per cent of them exhibit symptomatic infection. Nervous system damage influences prognosis and newborns management. We report the case of a newborn with a s6vere and progressive congenital CMV infection. He was admitted because of petechiae and thrombocytopenia. Investigations of the newborn showed a bilateral optic atrophy, severe nervous system damage with hydrocephalus, enormous periventricular pseudocysts and cerebellum hypoplasia. No brain calcifications were found. Diagnosis relied on blood CMV viral load measurement in both the newborn and his mother. The newborn received Ganciclovir. Hydrocephalus progressed and required ventriculoperitoneal shunt placement. This case illustrates that pseudocysts and progressive hydrocephalus must suggest CMV congenital infection even not associated to brain calcifications. Nervous system damage is serious in congenital CMV infection and requires a systematic screening during pregnancy

Rhombencephalosynapsis: association with single umbilical artery.

A 6-year-old girl who presented with developmental delay and non-progressive ataxia is described. MRI of brain showed agenesis of cerebellar vermis with fusion of cerebellar hemispheres and dentate nuclei. MRI findings were characteristic of rhombencephalosynapsis. Partial agenesis of corpus callosum and absent septum pellucidum were also seen. The child had also been noted to have a single umbilical artery at birth: a hitherto undescribed association.

Tectocerebellar dysraphia and occipital encephalocele: an unusual association with abdominal situs inversus and congenital heart disease.

Tectocerebellar dysraphia is a rare constellation of malformations comprising of occipital encephalocele, aplasia of the cerebellar vermis and deformity of the tectum. We describe a 7 month old infant who presented with tectocerebellar dysraphia associated with double outlet right ventricle, pulmonary stenosis and abdominal situs inversus. This association has not been reported in the literature, to the best of our knowledge.