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Infantile hydrocephalus: A review of epidemiology, classification and causes
Abstract
Hydrocephalus is a common but complex condition caused by physical or functional obstruction of CSF flow that leads to progressive ventricular dilatation. Though hydrocephalus was recently estimated to affect 1.1 in 1,000 infants, there have been few systematic assessments of the causes of hydrocephalus in this age group, which makes it a challenging condition to approach as a scientist or as a clinician. Here, we review contemporary literature on the epidemiology, classification and pathogenesis of infantile hydrocephalus. We describe the major environmental and genetic causes of hydrocephalus, with the goal of providing a framework to assess infants with hydrocephalus and guide future research.
... Натомість, рання діагностика та лікування прогресуючої гідроцефалії здатні повністю відновити стан дитини [1]. Саме «рання діагностика» гідроцефалії є найскладнішим завданням дитячого невролога, оскільки патогномонічних клінічних ознак вказаного захворювання не існує [1][2][3][4]. ...
... The term «early diagnosis» of hydrocephalus is the most difficult task for a pediatric neurologist. There are no pathognomonic clinical signs of this disease [1][2][3][4]. ...
... Гідроцефалія є досить важким захворюванням, яке зустрічається у всіх вікових групах. Популяційні дослідження поширення та етіології гідроцефалії ми знайшли у базі MEDLINE, EMBASE, Cochrane, та Google Scholar [1][2][3][4][5][6][7][8][9][10]. У 2018 році сформовано глобальний світовий реєстр з обробкою 2460 статей та проведенням 52 мета-аналізів, згідно з яким поширення гідроцефалії становить у середньому 85/100 000 загальної популяції: у дітей -88/100 000, у дорослих -11/100 000 та в людей похилого віку -175/100 000 [1]. ...
Hydrocephalus is a severe disease in children of all age groups. Failure to treat hydrocephalus in a timely manner can lead to progressive neurological deficits and death. Instead, early diagnosis and treatment of progressive hydrocephalus can completely recover the child. The term «early diagnosis» of hydrocephalus is the most difficult task for a pediatric neurologist. There are no pathognomonic clinical signs of this disease. Detection of electrophysiological signs of hydrocephalus progression in the early stages of the disease could significantly affect on treatment outcomes. The aim of our work is to establish early electrophysiological predictors of the progression of hydrocephalus in children with epilepsy. Materials and methods. 28 children with epilepsy were examined at the Transcarpathian Regional Children’s Hospital and the Medical Center «Diamed» in Uzhhorod from 2018 to 2022. All children were examined prospectively using video-EEG monitoring with sleep fixation, magnetic resonance imaging (MRI), multispiral computer tomography (MSCT). Results. The electrical status epilepticus during slow-wave sleep (ESES) was registered in 35 % of examined patients (8 children). The average duration from detection of the electrical status of sleep to the establishment of shunt system in the brain is 37 days (from 15 to 60 days). The ESES disappeared in 6 children during the first month after the implantation of the shunt system in the brain, in 2 children during the next 3 and 6 months of observation. We have developed our own algorithm for examining children with hydrocephalus and epilepsy up to 1 year and older than 1 year. Conclusion. An intense increase of epileptiform activity and appearance of electrical status of slow-wave sleep may be one of the predictors of the progression and decompensation of hydrocephalus and requires dynamic control. Further randomized trials are needed to assess the significance of these changes. The developed algorithm will increase the effectiveness of the use of additional examination methods for early detection of the progression of hydrocephalus in children with epilepsy.
... Hydrocephalus is the pathologic accumulation of excess cerebrospinal fluid (CSF) within the calvaria, brain parenchyma, or intraventricularly [1]. The divergence in anatomical designation among existing literature can be further elucidated with the following definition: "Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation" [2]. ...
... This broader classification mirrors the variation in the clinical picture of hydrocephalus. On presentation, patients can assume an array of symptoms, with underlying etiologies including increased CSF production, decreased CSF absorption, or obstructed flow from the ventricles to the subarachnoid space [1][2][3]. This great variability can elicit further complexity for clinicians and researchers managing and studying this condition. ...
Hydrocephalus represents a significant burden of disease, with more than 383,000 new cases annually worldwide. When the magnitude of this condition is considered, a centralized archive of pertinent literature is of great clinical value. From a neurosurgical standpoint, hydrocephalus is one of the most frequently treated conditions in the field. The focus of this study was to identify the top 100 journal articles specific to hydrocephalus using bibliometric analysis. Using the Journal of Citation Report database, 10 journals were identified. The Web of Science Core Collection was then searched using each journal name and the search term “hydrocephalus.” The results were ordered by “Times Cited” and searched by the number of citations. The database contained journal articles from 1976 to 2021, and the following variables were collected for analysis: journal, article type, year of publication, and the number of citations. Journal articles were excluded if they had no relation to hydrocephalus, mostly involved basic science research, or included animal studies. Ten journals were identified using the above criteria, and a catalog of the 100 most cited publications in the hydrocephalus literature was created. Articles were arranged from highest to lowest citation number, with further classification by journal, article type, and publication year. Of the 100 articles referenced, 38 were review articles, 24 were original articles, 15 were comparative studies, 11 were clinical trials, six were multi-center studies, three were cross-sectional, and three were case reports with reviews. Articles were also sorted by study type and further stratified by etiology. If the etiology was not specified, studies were instead subcategorized by treatment type. Etiologies such as aqueductal stenosis, tumors, and other obstructive causes of hydrocephalus were classified as obstructive (n=6). Communicating (n=15) included idiopathic, normal pressure hydrocephalus, and other non-obstructive etiologies. The category “other” (n=3) was assigned to studies that included etiologies, populations, and/or treatments that did not fit into the classifications previously outlined. Through our analysis of highly cited journal articles focusing on different etiologies and the surgical or medical management of hydrocephalus, we hope to elucidate important trends. By establishing the 100 most cited hydrocephalus articles, we contribute one source, stratified for efficient referencing, to facilitate clinical care and future research on hydrocephalus.
... Pediatric hydrocephalus has historically been linked to high morbidity and mortality rates due to the presence of other medical conditions. However, some studies suggest that these comorbidities may be more lethal than hydrocephalus itself [24,25,26,27]. The mortality rate is higher in pediatric patients with untreated hydrocephalus because the cerebral cortex is not fully developed yet. ...
... The mortality rate is higher in pediatric patients with untreated hydrocephalus because the cerebral cortex is not fully developed yet. In addition, severe hydrocephalus that compresses the cortex may cause brain atrophy and thinning [25,26,27]. Patients with longer follow-up periods had a higher mortality rate, indicating that the duration of exposure increases the risk of death. ...
... Obstructive hydrocephalus refers to obstruction of CSF in the ventricles most commonly due to occlusion of the cerebral aqueduct, colloid cysts, and tumors. [16][17][18] The obstruction may be proximal (aqueduct or third ventricle) or distal (fourth ventricle and its outflow tracts or foramen magnum). 17 Clinically, the symptoms of hydrocephalus are nonspecific and are not necessarily related to the etiology. ...
... [16][17][18] The obstruction may be proximal (aqueduct or third ventricle) or distal (fourth ventricle and its outflow tracts or foramen magnum). 17 Clinically, the symptoms of hydrocephalus are nonspecific and are not necessarily related to the etiology. In children, clinical presentations mainly involve headache, nausea, developmental delay, drowsiness, lethargy, and behavioral changes, while in adults, papilledema also has clinical importance. ...
Endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) are surgical methods for treating obstructive hydrocephalus. However, there is still disagreement regarding the most effective technique, in terms of both operative success and postoperative complications. Therefore, we performed a systematic review and meta-analysis to compare the efficacy and safety of these two methods in patients with obstructive hydrocephalus. We performed a systematic search of the PubMed, Scopus, and Cochrane Library databases. Randomized clinical trials (RCTs) comparing ETV and VPS in pediatric or adult patients with obstructive hydrocephalus were included. The outcomes included were operative success, postoperative cerebrospinal fluid leak, postoperative infection, postoperative or intraoperative bleeding, blockage rate, and mortality. The risk ratio (RR) was calculated with a 95% confidence interval (CI). Heterogeneity was evaluated with I 2 statistics. We used a fixed-effects model for outcomes with I 2 < 25% and DerSimonian and Laird random-effects model for other conditions. The Cochrane collaboration tool for assessing the risk of bias in randomized trials was used for risk-of-bias assessment. R, version 4.2.1, was used for statistical analyses. Of the 2,353 identified studies, 5 RCTs were included, involving 310 patients with obstructive hydrocephalus, of which 163 underwent ETV. There was a significant difference in favor of ETV for postoperative infection (risk ratio [RR]: 0.11; 95% confidence interval [CI]: 0.04–0.33; p < 0.0001; I 2 = 0%) and blockage rate (RR: 0.15; 95% CI: 0.03–0.75; p = 0.02; I 2 = 53%). Meanwhile, there was no significant difference between groups for the postoperative or intraoperative bleeding (RR: 0.44; 95% CI: 0.17–1.15; p = 0.09; I 2 = 0%), postoperative cerebrospinal fluid leak (RR: 0.65; 95% CI: 0.22–1.92; p = 0.44; I 2 = 18%), operative success (RR: 1.18; 95% CI: 0.77–1.82; p = 0.44; I 2 = 84%), and mortality (RR: 0.19; 95% CI: 0.03–1.09; p = 0.06; I 2 = 0%). Three RCTs had some concerns about the risk of bias and one RCT had a high risk of bias due to the process of randomization and selection of reported results. Thus, this meta-analysis of RCTs evaluating ETV compared with VPS demonstrated that although there is no superiority of ETV in terms of operative success, the incidence of complications was significantly higher in patients who underwent VPS. Our results suggest that the use of ETV provides greater benefits for the treatment of obstructive hydrocephalus. However, more RCTs are needed to corroborate the superiority of ETV.
... It is also often discussed and taught to students, patients, and caregivers. In hydrocephalus, the fact that the work of Dandy is the paradigm of science in hydrocephalus is supported by the fact that all of the classifications of hydrocephalus discussed here are based on Dandy's work [6][7][8][9][10][11][12][13][14]. ...
... The discussion dealt primarily to genetics and problems that began within the uterus or soon after birth. The classification is done well with the intention that it will lead to prospective trials of treatment and outcome [14]. 2. Professor Oi updated his extensive discussion of the classification and has now given it the name of "Multicategorical hydrocephalus classification." ...
Purpose:
The purpose of this review is to assess the early work of Walter Dandy leading to a paradigm or model that led to the first classification of hydrocephalus and resulted in the development of treatments.
Methods:
The modern understanding of hydrocephalus begins with the works of Walter Dandy. The purpose of this review is to discuss what was changed in the second decade of the 20th century and how the outcome is useful today. As a result of his experiments during that time he was able to recognize the role of the choroid plexus in the production of cerebrospinal fluid (CSF) within the cerebral ventricles. He then identified the role of obstruction blocking the flow of CSF from the ventricles to the absorption of CSF to the systemic vascular. As a result of those findings he showed that there were two forms of hydrocephalus and therefore the first classification of hydrocephalus into obstructive hydrocephalus and communicating hydrocephalus. Very soon after the publication of the experiments there was general agreement of this work by neurosurgeons working on hydrocephalus. The findings published in "experimental hydrocephalus" became a paradigm useful for all or the vast percentage of those neurosurgeons.
Results:
Dandy was the first to create a classification of hydrocephalus into obstructive and communicating hydrocephalus. He developed treatments for hydrocephalus such as removal of the choroid plexuses that remained in use until effective valved shunts became available in the 1950s. Essentially all subsequent classifications begin with this paradigm.
Conclusion:
Over time there have been new classifications primarily focused on specific uses. It is important that classifications in the sciences be reviewed periodically to include new findings and new ideas. Since the expectation that hydrocephalus can be treated or even cured new classifications tend to focus on the physics of CSF, the choice of treatment and the outcome in specific subgroups. These thoughts should be seen as additions to the paradigm.
... Pediatric hydrocephalus is historically associated with high morbidity and mortality rates due to the presence of associated medical conditions. Nevertheless, studies demonstrate that other comorbidities may be the main cause of death rather than hydrocephalus itself [27,28,29]. The mortality rate is higher in pediatric patients with untreated hydrocephalus since the cerebral cortex is not yet fully developed. ...
... The mortality rate is higher in pediatric patients with untreated hydrocephalus since the cerebral cortex is not yet fully developed. Moreover, severe hydrocephalus that compresses the cortex may reduce overall brain mass and thickness [28,29]. Patients with longer follow-up periods demonstrated a higher proportion of mortality, indicating that the time at risk raises mortality rates. ...
PURPOSE
Pediatric hydrocephalus is a significant challenge in neurosurgery, particularly in resource-limited settings. This study focuses on the landscape of pediatric hydrocephalus neurosurgery in Brazil, a developing country, over the past 13 years.
METHODS
Data were collected from the Brazilian Hospital Information System, Live Birth Information System, and Mortality Information System records in the DATASUS (Departamento de Informática do SUS) database among January 2008 and the July 2021. Various health indicators were analyzed, including hospitalizations, treatment options, costs, and mortality rates.
RESULTS
During the period of study, Brazil recorded 8,493 new diagnoses of congenital hydrocephalus in live births, with 1,123 cases associated with spina bifida. The prevalence of congenital hydrocephalus was 241 cases per 100,000 live births, and 210 cases per 100,000 live births were attributed to congenital hydrocephalus not related to spina bifida. A total of 730 perinatal mortality cases related to congenital hydrocephalus were reported, with no clear trend over the 12-year period. The average number of perinatal mortality cases was 60.83 ± 13.98 per year. There were 1,063 infant mortality cases associated with hydrocephalus and 3,122 cases associated with congenital hydrocephalus, with no clear trend observed. The highest mortality rates for both diagnoses occurred between 3 to 5 months of age. Ethnicity and age were found to have significant relationships with mortality rates. A total of 217,900 hydrocephalus-related procedures were performed, with an increase in mean hospitalization cost and procedure numbers over the 13-year period. Mean cost per procedure had a significant negative effect on mean length of stay, while average professionals' salary did not have a significant effect.
CONCLUSION
Pediatric hydrocephalus in Brazil's public health system is a significant burden. Congenital hydrocephalus prevalence and mortality rates emphasize the need for better diagnosis and treatment. Early diagnosis, prenatal care, and adequate resources are crucial. This study offers insights into pediatric hydrocephalus in a developing country, highlighting challenges and future directions for improved care.
... Hydrocephalus without an obvious extrinsic cause is usually referred as congenital hydrocephalus, which is often present at birth. Other types of hydrocephalus are known as acquired hydrocephalus (Tully and Dobyns, 2014). Growing evidence indicates that genetic factors have a crucial role in the development of hydrocephalus (Zhang et al., 2006). ...
... Children with hydrocephalus have a significant medical condition, with a prevalence of 1.1 per 1000 births (Tully and Dobyns, 2014;Munch et al., 2012). As it is one of the most challenging pediatric diseases, surgical treatments for fetal-onset hydrocephalus, such as cerebrospinal fluid shunting and endoscopic third ventriculostomy have been tried but are insufficient. ...
Coil-coiled domain containing 85c (Ccdc85c) is a causative gene for congenital hydrocephalus and subcortical heterotopia with frequent brain hemorrhage. We established Ccdc85c knockout (KO) rats and investigated the roles of CCDC85C and intermediate filament protein expression, including nestin, vimentin, GFAP, and cytokeratin AE1/AE3 during the lateral ventricle development in KO rats to evaluate the role of this gene. We found altered and ectopic expression of nestin and vimentin positive cells in the wall of the dorso-lateral ventricle in the KO rats during development from the age of postnatal day (P) 6, whereas both protein expression became faint in the wild-type rats. In the KO rats, there was a loss of cytokeratin expression on the surface of the dorso-lateral ventricle with ectopic expression and maldevelopment of ependymal cells. Our data also revealed disturbed GFAP expression at postnatal ages. These findings indicate that lack of CCDC85C disrupts the proper expression of intermediate filament proteins (nestin, vimentin, GFAP, and cytokeratin), and CCDC85C is necessary for normal neurogenesis, gliogenesis, and ependymogenesis.
... At a rate of approximately 0.7-1 every 1,000 live births, infantile hydrocephalus is not uncommon [1,2]. In infants, hydrocephalus without an obvious extrinsic cause is referred to as congenital hydrocephalus [3]. Hydrocephalus occurring as a complication of another condition is called acquired hydrocephalus. ...
... Research into different adverse outcomes of specific etiologies for these patients is urgently required. Previous studies have found that the common causes of acquired hydrocephalus in infants are hemorrhage, neoplasm, and infection, usually bacterial meningitis [1,3]. The reasons for the difference may be the selection bias of the inclusion criteria for the neonatal units and the high rate of critical disease at our referral center. ...
Aim
To assess the etiologies and adverse outcomes of infantile acquired hydrocephalus and predict prognosis.
Methods
A total of 129 infants diagnosed with acquired hydrocephalus were recruited from 2008 to 2021. Adverse outcomes included death and significant neurodevelopmental impairment which was defined as Bayley Scales of Infant and Toddler Development III score < 70, cerebral palsy, visual or hearing impairment, and epilepsy. Chi-squared was used to evaluate the prognostic factors of adverse outcomes. A receiver operating characteristic curve was calculated to determine the cutoff value.
Results
Of 113 patients with outcome data, 55 patients (48.7%) had adverse outcomes. Late surgical intervention time (13 days) and severe ventricular dilation were associated with adverse outcomes. The combination of surgical intervention time and cranial ultrasonography (cUS) indices was a better predictive marker compared with any of them (surgical intervention time, P = 0.05; cUS indices, P = 0.002). Post-hemorrhage (54/113, 48%), post-meningitis (28/113, 25%), and hydrocephalus arising from both hemorrhage and meningitis (17/113, 15%) accounted for a large proportion of the etiologies in our study. Hydrocephalus occurs secondary to post-hemorrhage and had a favorable outcome compared with other etiologies in both preterm and term groups. A significant difference in adverse outcomes between the inherited error of metabolism as a cause and other etiologies (P = 0.02).
Conclusion
Late surgical treatment times and severe ventricular dilation can predict adverse outcomes in infants with acquired hydrocephalus. It is crucial to identify the causes of acquired hydrocephalus to predict the adverse outcomes. Research into measures of improving adverse outcomes following infantile acquired hydrocephalus is urgently necessary.
... It is characterized by an abnormal accumulation of CSF, which may cause alterations in intracranial pressure [2]. Occurring across all age groups, hydrocephalus stands as a significant cause of mortality and morbidity worldwide [3], with an estimated prevalence of 1.1 per 1,000 infants [4]. Non-communicating hydrocephalus occurs due to a blockage in the flow of CSF within the ventricular system [5], leading to increased pressure within the ventricles and subsequent hydrocephalus [6]. ...
This case report presents the physiotherapy intervention of a one-year-old male child diagnosed with non-communicating hydrocephalus primary to developmental delay. Hydrocephalus is marked by an accumulation of cerebrospinal fluid and often leads to significant developmental delays and neurological impairments in affected infants. The physiotherapy intervention aimed to achieve head and trunk control, improve sensory awareness, and enhance overall body coordination and balance. Various techniques, including neurodevelopmental techniques, sensory stimulation, hippotherapy, and sensory integration therapy, were utilized to target specific developmental milestones and functional abilities. Outcome measures, including the Gross Motor Function Measure, Infant Neurological International Battery, Hammersmith Infant Neurological Examination, and New Ballard Score, were used to assess the patient's progress pre-and post-intervention. Significant improvements were observed across all outcome measures following four months of physiotherapy rehabilitation. The patient demonstrated substantial gains in gross motor function, neurological examination scores, and overall developmental milestones. These findings underscore the effectiveness of physiotherapy rehabilitation in addressing developmental delays associated with non-communicating hydrocephalus. This case underscores the significance of early physiotherapy intervention, which plays a vital role in enhancing outcomes and improving the quality of life for affected children.
... Particularly noticeable is the predilection for the male gender and the predominance in the early infancy months, aligning with previous studies that elucidate a similar trend in demographic distributions. [15,16] ...
Background: Congenital hydrocephalus, characterized by the abnormal accumulation of cerebrospinal fluid within the brain, presents a significant challenge in pediatric neurosurgery. Early intervention and proper management are vital for improving the clinical outcomes in affected infants. This study aimed to analyze the clinical presentations and surgical outcomes of shunt surgery in congenital hydrocephalus patients. Methods: A meticulous two-year analysis was conducted at the Department of Neurosurgery at Gauhati Medical College and Hospital, involving 50 patients who underwent shunt surgery. The parameters analyzed encompassed demographic details, clinical presentations, etiologies, and surgical outcomes. Results: The majority of the patients were aged between 2-4 months (50%) and had a male predominance (60%). Clinical presentations were marked by increased head circumference (90%), developmental delays (70%), and motor deficits (50%). Aqueductal stenosis (26%) and meningomyelocele (24%) emerged as the primary etiological factors. Ventriculoperitoneal shunt was the preferred surgical intervention, utilized in 70% of cases, with an 80% success rate involving the standard technique. The post-operative period witnessed a 52% complication rate, predominantly characterized by shunt obstruction (14%) and infection (12%). Encouragingly, 70% of the patients did not require revision surgeries, indicating initial surgical success. Conclusion: The study highlights the critical need for early detection and intervention in congenital hydrocephalus, emphasizing the significance of monitoring head circumference as a potential early indicator. The findings underscore the necessity for continued advancements in surgical techniques and post-operative care to further enhance the successful outcomes.
... Macrocephaly with increased brain size is frequently associated with ASD and neurodevelopmental disorders [1,2]. Macrocephaly in ASD can involve hydrocephalus [3,4], wherein ventricular cavities containing the cerebrospinal fluid (CSF) are abnormally enlarged [5,6]. Hydrocephalus can arise from various causes; among them are impairments in the circulation of CSF across ventricular structures, which is facilitated by the synchronous beating of the motile cilia belonging to ependymal cells lining ventricular walls [7][8][9][10][11]. ...
Autism spectrum disorders (ASD) frequently accompany macrocephaly, which often involves hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-regulatory protein strongly linked to ASD, but it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule- and ASD-related molecular, synaptic, brain, and behavioral phenotypes. We found that Katnal2-KO mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements. The latter involves increased length and beating frequency of motile cilia on ependymal cells lining ventricles. Katnal2-KO hippocampal neurons surrounded by enlarged lateral ventricles show progressive synaptic deficits that correlate with ASD-like transcriptomic changes involving synaptic gene down-regulation. Importantly, early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, suggesting a causal relationship and a potential treatment. Therefore, Katnal2 negatively regulates ependymal ciliary function and its deletion in mice leads to ependymal ciliary hyperfunction and hydrocephalus accompanying ASD-related behavioral, synaptic, and transcriptomic changes.
... Чим раніше у немовляти починає підвищуватися внутрішньочерепний тиск, тим раніше з'являється шовний діастаз. Якщо широкі черепні шви спричинені дефектом або уповільненим скостенінням, лікування зазвичай не показано, оскільки з віком скостеніння покращиться, а ширина шва зменшиться [36,37]. ...
The purpose of the work is to find out the embryological prerequisites and the time of the possible occurrence of malformations and congenital deformations of the human skull.Results. The growth and enlargement of the neurocranium is largely determined by the growth of the brain due to their close syntopy. By the end of the second year, the bones are connected by sutures. The neurocranium is embryologically divided into the vault, which is formed by membranous ossification, and the basis cranii, the bones of which are formed by cartilaginous osteogenesis. The initial development of the neurocranium depends on the formation of the brain and its surrounding membranes. The source of the germ of the outer layer is the mesoderm and ectomesenchyme of the neural crest, soon it is divided into the inner layer – endomeninx and outer – ectomeninx. The latter is further divided into the outer osteogenic layer, in which the ossification centers form the bones of the skull, and the inner layer of the dura mater. The centers of ossification form the frontal, parietal, occipital and temporal bones, and the intermediate areas form fibrous sutures and fontanelles. Usually, the sutures are joined at the end of the second year of life. Conclusions. Congenital deformities of the cerebral part of the skull are morphological manifestations of numerous hereditary syndromes and/or metabolic, teratogenic effects, lysosomal storage diseases, brain malformations, unfavorable factors during the fetal period of development: restriction of the intrauterine environment, weak muscle tone, torticollis, clavicle fracture, cervical spine anomalies, multiple pregnancy and bone mineralization disorders. For the differential diagnosis of congenital defects of the skull, along with the use of diagnostic three-dimensional medical imaging, it is necessary to carry out genetic screening.
... It might also be ongoing, happening over several months or years. In addition to being a standalone ailment, hydrocephalus can also be linked to a wide range of other neurological disorders and illnesses (Tully & Dobyns, 2014). According to Srivatsan et al., (2020), it may then be categorized as communicative or non-communicating. ...
... The L1 cell adhesion molecule, a member of the immunoglobulin adhesion protein superfamily, is composed of six immunoglobulin-like domains and fibronectin type III-like repeats in the extracellular region and a short cytoplasmic tail [27,28]. Most reported mutations include missense, nonsense, small insertions, or deletions and splice-site alterations that are distributed throughout the large extracellular domain of the L1 gene. ...
We present the case of a 35-year-old pregnant woman who visited our department for a routine ultrasonography screening scan for fetus anatomy during the 22nd week of gestation. Our report revealed a male fetus with marked hydrocephalus and severe intrauterine growth retardation. After extensive counseling, the couple decided to proceed with an invasive diagnosis via amniocentesis. The cytogenetic analysis showed findings related to clinical history and ultrasound findings related to the presence of a nucleotide change in c.578T>C with an amino acid change in p.Leu198Pro of the L1CAM gene. The result was reported as a hemizygote missense L1CAM gene variant of unknown significance. After extensive parental counseling, the couple decided on pregnancy termination. We report the present case of L1CAM mutation in p.Leu198Pro to add to the limited knowledge regarding the clinical presentation of mutations of the L1CAM gene with emphasis on prenatal diagnosis.
... Periventricular axons undergo primary destruction in a hydrocephalic brain (Del Bigio, 2001), accompanying white matter damage due to ventricular expansion causing physical stretching and compression as brain damage progresses (Del Bigio, 2010;McAllister & Chovan, 1998). Hydrocephalus impairs neuronal maturation and enlarges the extracellular space in the white matter adjacent to the ventricles impairing neuronal function (Del Bigio, 1993;Kahle et al., 2016;Tully & Dobyns, 2014). ...
Infantile hydrocephalus considerably impacts neurodevelopment, warranting attention to potential long-term consequences on visuomotor functions. The current study investigated the impact of infantile hydrocephalus on functional connectivity within the posterior cortex. Fourteen patients, who were treated for infantile hydrocephalus, were matched for age and sex with 14 typically-developing controls. Both groups had a mean age of 9 years old. Resting-state functional MRI was used to conduct a functional connectivity analysis within the visuomotor integration network, including the inferior frontal occipital fasciculus, superior longitudinal fasciculus, and frontal aslant tract. Patients had reduced functional connectivity in visuomotor pathways compared to typically-developing children with notable impact on the left and right fusiform gyrus and precuneus. Children with infantile hydrocephalus also performed significantly lower in tasks involving visuomotor integration, visual processing, visuospatial skills, motor coordination, and fine motor manipulation. This study enhances our understanding of the multifaceted impact of infantile hydrocephalus on both neural connectivity and considering behavioral outcomes.
... In communicating hydrocephalus, although there is an intact communication pathway between the ventricular system and the subarachnoid space, CSF is often overproduced or poorly absorbed, leading to insufficient venous drainage. CH can be caused by various factors, including congenital malformations, viral infections, inflammation, bleeding, tumors, metabolic abnormalities, and genetics [69,70]. ...
The brain’s ventricles are filled with a colorless fluid known as cerebrospinal fluid (CSF). When there is an excessive accumulation of CSF in the ventricles, it can result in high intracranial pressure, ventricular enlargement, and compression of the surrounding brain tissue, leading to potential damage. This condition is referred to as hydrocephalus. Hydrocephalus is classified into two categories: congenital and acquired. Congenital hydrocephalus (CH) poses significant challenges for affected children and their families, particularly in resource-poor countries. Recognizing the psychological and economic impacts is crucial for developing interventions and support systems that can help alleviate the distress and burden faced by these families. As our understanding of CSF production and circulation improves, we are gaining clearer insights into the causes of CH. In this article, we will summarize the current knowledge regarding CSF circulation pathways and the underlying causes of CH. The main causes of CH include abnormalities in the FoxJ1 pathway of ventricular cilia, dysfunctions in the choroid plexus transporter Na+-K+-2Cl- contransporter isoform 1, developmental abnormalities in the cerebral cortex, and structural abnormalities within the brain. Understanding the causes of CH is indeed crucial for advancing research and developing effective treatment strategies. In this review, we will summarize the findings from existing studies on the causes of CH and propose potential research directions to further our understanding of this condition.
... A large amount of cerebrospinal fluid (CSF) causes the ventricle to expand and results in a significant increase in ventricular pressure, which gradually aggravates the compression of brain tissue. This results in brain dysfunction, with high incidences of disability and mortality (2,3). Surgery is an effective method to treat hydrocephalus. ...
Background
Hydrocephalus with intracranial infection (HII) may cause pathological changes in brain tissue structure and irreversible damage to the nervous system. However, intracranial infection is a contraindication to ventriculo-peritoneal (VP) shunt surgery, and the prognosis is improved by early infection control and intracranial pressure reduction. This study evaluated the safety and efficacy of the Ommaya reservoir vs. modified external ventricular drainage (M-EVD) in the management of HII in pediatric patients.
Methods
This retrospective controlled study included 45 pediatric patients with HII treated with an Ommaya reservoir (n = 24) or M-EVD (n = 21) between January 2018 and December 2022. Clinical outcomes, cerebrospinal fluid (CSF) test results, complications, and outcomes were compared between the Ommaya reservoir and M-EVD groups.
Results
No patient died during the follow-up period. The two groups were similar regarding age, sex, admission temperature, weight, preoperative serum protein and albumin concentrations, CSF analysis (white blood cell count, glucose concentration, and protein content), and clinical symptoms (P > 0.05). Both groups had significant changes in the CSF test results postoperatively compared with preoperatively (P < 0.05). In the M-EVD group, the median days for 13 children to remove the external drainage tube and receive VP shunt was 19 days. The longest drainage tube retention time was 61 days, and there was no intracranial infection or serious complication related to the drainage tube. After the placement of the Ommaya, the median time required for CSF to return to normal was 21 days, and a total of 15 patients underwent VP shunt surgery.
Conclusion
The Ommaya reservoir and M-EVD are safe and effective for pediatric patients with HII. Both methods reduce the intracranial pressure and alleviate the symptoms of hydrocephalus, although there are differences between the two methods.
... Other classifications include acquired versus developmental (congenital) and syndromic versus non-syndromic. 5 Diagnosis is by clinical examination and neuroimaging techniques like; ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) and intracranial pressure monitoring techniques. 6 Various treatments for this condition include surgical and non-surgical management. ...
Background: Hydrocephalus is a disorder of cerebrospinal fluid (CSF) physiology, resulting in an abnormal enlargement of the ventricles due to excessive accumulation of CSF. Although neurosurgical treatment has evolved over time with ventriculoperitoneal shunt (VPS) as the standard of care, procedure-related complications and poor long-term cognitive and motor milestone outcomes are still considerable, justifying the need for safer alternatives. Endoscopic third ventriculostomy (ETV) has emerged as a promising prospect especially in non-communicating hydrocephalus (NCH). Aims and Objectives: To compare the beneficial effects of ETV versus ventriculoperitoneal shunt in patients of NCH. Materials and Methods: The present prospective study was conducted at the Department of Neurosurgery, Bangur Institute of Neurosciences, IPGMER and SSKM Hospital, Kolkata from July 2021 to December 2022 among 60 patients admitted with NCH. Out of 60 patients; 30 patients underwent ETV and the remaining 30 patients VP shunting. All included patients had their history taken and relevant clinical and radiological examination done pre-operatively. They were discharged on the third post-operative day or later depending on their clinical condition and recovery. Results: Aqueductal stenosis was the most common etiology for NCH in both the groups. Post-intervention, complications and reoperation rate were reported more in VP group as compared to ETV group. Overall 3 subjects died, out of which 2 belonged to VP group and 1 to ETV group. Success was found in 70% and 86.67% of the subjects in VP and ETV group respectively. Conclusion: In patients with non-communicating or obstructive hydrocephalus, ETV was reported to be superior to VPS in terms of reoperation and complication rate at 4th, 12th, and 24th weeks after the treatment.
... 3 CH is a primary (idiopathic) disease and, by definition, lacks an identifiable clinical antecedent. 4,5 Although clinical causes are unclear, the hallmark pathogenic cerebrospinal fluid accumulation can be associated with cerebral malformations such as aqueductal stenosis. 1,6 Recent efforts to elucidate genetic factors have contributed to evidence of rare associated genetic variants in CH. 7,8 Genetic factors are thought to contribute to both syndrome-associated and nonsyndromic (sporadic) CH 1 ; however, although variants in more than 100 genes have been associated with syndromic forms of hydrocephalus, few have been associated with nonsyndromic forms. ...
Importance
Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH).
Objective
To determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH
Data Sources
PubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023. The following search terms were used to identify studies: congenital hydrocephalus , ventriculomegaly , cerebral ventriculomegaly , primary ventriculomegaly , fetal ventriculomegaly , prenatal ventriculomegaly , molecular analysis , genetic cause , genetic etiology , genetic testing , exome sequencing , whole exome sequencing , genome sequencing , microarray , microarray analysis , and copy number variants .
Study Selection
Eligible studies included those with at least 10 probands with the defining feature of CH and/or severe cerebral ventriculomegaly that had undergone ES. Studies with fewer than 10 probands, studies of mild or moderate ventriculomegaly, and studies using genetic tests other than ES were excluded. A full-text review of 68 studies was conducted by 2 reviewers. Discrepancies were resolved by consensus.
Data Extraction and Synthesis
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology guidelines were used by 2 reviewers to extract data. Data were synthesized using a random-effects model of single proportions. Data analysis occurred in April 2023.
Main Outcomes and Measures
The primary outcome was pooled diagnostic yield. Additional diagnostic yields were estimated for specific subgroups on the basis of clinical features, syndromic presentation, and parental consanguinity. For each outcome, a 95% CI and estimate of interstudy heterogeneity ( I ² statistic) was reported.
Results
From 498 deduplicated and screened records, 9 studies with a total of 538 CH probands were selected for final inclusion. The overall diagnostic yield was 37.9% (95% CI, 20.0%-57.4%; I ² = 90.1). The yield was lower for isolated and/or nonsyndromic cases (21.3%; 95% CI, 12.8%-31.0%; I ² = 55.7). The yield was higher for probands with reported consanguinity (76.3%; 95% CI, 65.1%-86.1%; I ² = 0) than those without (16.2%; 95% CI, 12.2%-20.5%; I ² = 0).
Conclusions and Relevance
In this systematic review and meta-analysis of the diagnostic yield of ES in CH, the diagnostic yield was concordant with that of previous recommendations for other neurodevelopmental disorders, suggesting that ES should also be recommended as a routine diagnostic adjunct for patients with CH.
... 15 AQP1 specifically resides in the choroid plexus thought, by far, has contribution to the process of CSF production. 16 The fundamental role of AQPs is to enable the transportation of water across the cellular plasma membrane. Each AQP channel consists of six alpha-helices that span the membrane and form a central pore specifically designed for the transport of water molecules. ...
... Hydrocephalus affects 1.1 out of every 1000 infants, according to recent estimates. 1 Infants often have progressive macrocephaly, while children over the age of two usually have signs and symptoms of intracranial hypertension. There are numerous causes of hydrocephalus. ...
A 1‐year‐old girl presented with an overly enlarged head for 5 months. Negligence of parents regarding treatment for this enlarged head is concerning. Early treatment can avoid a lot of complications. Hydrocephalus secondary to aqueductal stenosis was diagnosed after a thorough history, examination, and investigations. Endoscopic third ventriculostomy was performed.
... 1,2 Prevalence of congenital and acquired hydrocephalus is 0.5 -1 and 3 -5 respectively, per 1000 live-born infants, in developed countries. 3,4 The occurrence of idiopathic NPH has been stated to be 200 per 100000 people. 5 Characteristics of iNPH are, gradual gait ataxia, urinary incontinence, and cognitive impairment, also known as Hakim-Adams syndrome and approximately 50% of cases show this clinical trial. ...
Introduction:
Objective: To compare functional outcomes in terms of INPGHS score and overall improvement in patients of iNPH treated with ETV vs. VP shunting.
Materials & Methods: A Randomized control trial was conducted for 6 months at the Department of Neurosurgery, Rawalpindi Medical University and Allied Hospitals, Rawalpindi. 62 patients (31 in each group) were enrolled & allocated into two groups. In group A patients ETV was done and in group B VP shunting. Post-operatively, Patients were followed up for 1 month.
Results: The mean age of the patients in the ETV & VP shunting groups was 63.19 ± 6.95 & 63 ± 6.82 years respectively. Males were 64.5% (n = 20) in both groups. Improvement was noted in 9 (29%) patients in the ETV group & 15 (48.4%) patients in the latter group (p-value = 0.118).
Conclusion: Ventriculoperitoneal shunts are superior to endoscopic third ventriculostomy in terms of functional neurological outcomes and improvement in symptoms.
... Hydrocephalus is a common disorder characterized by the superfluous accumulation of cerebrospinal fluid (CSF) within brain ventricles, which usually results in dilatation of brain ventricles and damage to brain parenchyma with various clinical symptoms. 1,2 The pathology of hydrocephalus is complicated and accumulating evidence has shown that one major cause is the dysfunction of motile cilia. [3][4][5][6][7] Motile cilia are complex and highly ordered organelles, which are lining on the multiciliated cells including ependymal cells in the brain. ...
Motile cilia lining on the ependymal cells are crucial for cerebrospinal fluid (CSF) flow and its dysfunction is often associated with hydrocephalus. Unc51‐like‐kinase 4 (Ulk4) was previously linked to CSF flow and motile ciliogenesis in mice, as the hypomorph mutant of Ulk4 (Ulk4tm1a/tm1a) developed hydrocephalic phenotype resulted from defective ciliogenesis and disturbed ciliary motility, while the underling mechanism is largely obscure. Here, we report that serine/threonine kinase 36 (STK36), a paralog of ULK4, directly interacts with ULK4 and this was demonstrated by yeast two‐hybrid (Y2H) in yeast and coimmunoprecipitation (co‐IP) assays in HEK293T cells, respectively. The interaction region was confined to their respective N‐terminal kinase domain. The hypomorph mutant of Stk36 (Stk36tmE4−/−) also developed progressive hydrocephalus postnatally and dysfunctional CSF flow, with multiple defects of motile cilia, including reduced ciliary number, disorganized ciliary orientation, defected axonemal structure and inconsistent base body (BB) orientation. Stk36tmE4−/− also disturbed the expression of Foxj1 transcription factor and a range of other ciliogenesis‐related genes. All these morphological changes, motile cilia defects and transcriptional dysregulation in the Stk36tmE4−/− are practically copied from that in Ulk4tm1a/tm1a mice. Taken together, we conclude that both Stk36 and Ulk4 are crucial for CSF flow, they cooperate by direct binding with their kinase domain to regulate the Foxj1 transcription factor pathways for ciliogenesis and cilia function, not limited to CSF flow. The underlying molecular mechanism probably conserved in evolution and could be extended to other metazoans.
... 1,2 Prevalence of congenital and acquired hydrocephalus is 0.5 -1 and 3 -5 respectively, per 1000 live-born infants, in developed countries. 3,4 The occurrence of idiopathic NPH has been stated to be 200 per 100000 people. 5 Characteristics of iNPH are, gradual gait ataxia, urinary incontinence, and cognitive impairment, also known as Hakim-Adams syndrome and approximately 50% of cases show this clinical trial. ...
Objective: To compare functional outcomes in terms of INPGHS score and overall improvement in patients of iNPH treated with ETV vs. VP shunting. Materials & Methods: A Randomized control trial was conducted for 6 months at the Department of Neurosurgery, Rawalpindi Medical University and Allied Hospitals, Rawalpindi. 62 patients (31 in each group) were enrolled & allocated into two groups. In group A patients ETV was done and in group B VP shunting. Post-operatively, Patients were followed up for 1 month. Results: The mean age of the patients in the ETV & VP shunting groups was 63.19 ± 6.95 & 63 ± 6.82 years respectively. Males were 64.5% (n = 20) in both groups. Improvement was noted in 9 (29%) patients in the ETV group & 15 (48.4%) patients in the latter group (p-value = 0.118). Conclusion: Ventriculoperitoneal shunts are superior to endoscopic third ventriculostomy in terms of functional neurological outcomes and improvement in symptoms. Keywords: Endoscopic Third Ventriculostomy, Ventriculoperitoneal Shunt, Idiopathic Normal Pressure Hydrocephalus Grading Scale (iNPHGS), Aqueductal CSF Stroke Volume (ACSV).
... Hydrocephalus is a common and often complex disease. In most of the patients, hydrocephalus leads to a progressive ventricular dilatation [34]. If left untreated, hydrocephalus leads to severe patient impairment or even death [14]. ...
Purpose:
The most frequent therapy of hydrocephalus is implantation of ventriculoperitoneal shunts for diverting cerebrospinal into the peritoneal cavity. We compared two adjustable valves, proGAV and proGAV 2.0, for complications resulting in revision surgery.
Methods:
Four hundred patients undergoing primary shunt implantation between 2014 and 2020 were analyzed for overall revision rate, 1-year revision rate, and revision-free survival observing patient age, sex, etiology of hydrocephalus, implantation site, prior diversion of cerebrospinal fluid, and cause of revision.
Results:
All data were available of all 400 patients (female/male 208/192). Overall, 99 patients underwent revision surgery after primary implantation. proGAV valve was implanted in 283 patients, and proGAV 2.0 valves were implanted in 117 patients. There was no significant difference between the two shunt valves concerning revision rate (p = 0.8069), 1-year revision rate (p = 0.9077), revision-free survival (p = 0.6921), and overall survival (p = 0.3232). Regarding 1-year revision rate, we observed no significant difference between the two shunt valves in pediatric patients (40.7% vs 27.6%; p = 0.2247). Revision operation had to be performed more frequently in pediatric patients (46.6% vs 24.8%; p = 0.0093) with a significant higher number of total revisions with proGAV than proGAV 2.0 (33 of 59 implanted shunts [55.9%] vs. 8 of 29 implanted shunts [27.6%]; p = 0.0110) most likely due to longer follow-up in the proGAV-group. For this reason, we clearly put emphasis on analyzing results regarding 1-year revision rate.
Conclusion:
According to the target variables we analyzed, aside from lifetime revision rate in pediatric patients, there is no significant difference between the two shunt valves.
... In cases of catch-down growth, possible underlying conditions such as malnutrition, endocrine, genetic or chronic diseases should be considered [11]. In a similar manner, concerning head circumference, both a downward and upward shift may mirror serious conditions that need prompt attention [12]. While the expected prevalence of being small (light) or tall (heavy) at a given age can be deduced from the reference curve (e.g. ...
Aims:
The overarching aim of this study was to evaluate the Norwegian guidelines for growth monitoring using routinely collected data from healthy children up to five years of age. We analysed criteria for both status (size for age) and change (centile crossing) in growth.
Methods:
Longitudinal data were obtained from the electronic health record (EHR) at the well-baby clinic for 2130 children included in the Bergen growth study 1 (BGS1). Measurements of length, weight, weight-for-length, body mass index (BMI) and head circumference were converted to z-scores and compared with the World Health Organization (WHO) growth standards and the national growth reference.
Results:
Using the WHO growth standard, the proportion of children above +2SD was generally higher than the expected 2.3% for all traits at birth and for length at all ages. Crossing percentile channels was common during the first two years of life, particularly for length/height. By the age of five years, 37.9% of the children had been identified for follow-up regarding length/height, 33% for head circumference and 13.6% for high weight-for-length/BMI.
Conclusions:
The proportion of children beyond the normal limits of the charts is higher than expected, and a surprisingly large number of children were identified for rules concerning length or growth in head circumference. This suggests the need for a revision of the current guidelines for growth monitoring in Norway.
... Secondary hydrocephalus is commonly caused by brain tumors, meningitis, or hemorrhage (Bondurant & Jimenez, 1995). Congenital hydrocephalus (CH, OMIM 617967) does not have a clear etiology or identifiable obstructive factors (Tully & Dobyns, 2014). Single gene variants are important factors in CH. ...
Background:
Primary ciliary dyskinesia (PCD) is a type of ciliary dyskinesia that is usually caused by autosomal recessive inheritance and can manifest as recurrent respiratory infections, bronchiectasis, infertility, laterality defects, and chronic otolaryngological disease. Although ependymal cilia, which affect the flow of cerebrospinal fluid in the central nervous system, have much in common with respiratory cilia in terms of structure and function, hydrocephalus is rarely associated with PCD. Recently, variants of Forkhead box J1 (FOXJ1) have been found to cause PCD combined with hydrocephalus in a de novo, autosomal dominant inheritance pattern.
Methods:
We performed DNA extraction, whole-exome sequencing (WES) analysis, and mutation analysis of FOXJ1 and analyzed the patient's clinical and genetic data.
Results:
The patient was a 4-year-old female exhibiting normal growth and development. At 3 years and 2 months of age, the patient experienced hand shaking and weakness in the lower limbs. Cardiac ultrasonography showed a right-sided heart, and cranial magnetic resonance imaging showed obstructive hydrocephalus. The nasal nitric oxide level was 54 nL/min. WES indicated a de novo, heterozygous variant of FOXJ1, c.734-735 ins20. This variant was novel, not included in the Human Gene Mutation and Genome Aggregation Database, and likely pathogenic according to the American College of Medical Genetics and Genomics, causing earlier termination of amino acid translation. The patient underwent a neuroendoscopic third ventriculostomy after the diagnosis of obstructive hydrocephalus. Six months after the operation, the patient's motor deficits had improved.
Conclusion:
This is the first report of a de novo, autosomal dominant pattern of FOXJ1 causing PCD combined with hydrocephalus in China. The patient's clinical symptoms were similar to those previously reported. WES confirmed that a novel variant of FOXJ1 was the cause of the PCD combined with hydrocephalus, expanding the spectrum of the genotypes associated with this condition. Physicians should be aware of the correlation of hydrocephalus and PCD and test for FOXJ1 variants.
... With an incidence of 1-2/1000 births, hydrocephalus is one of the most common conditions affecting the central nervous system in the pediatric population [1]. Ventriculoperitoneal shunting is still the mainstay of treatment. ...
Background
Clinical symptoms in children with suspected malfunction of ventriculoperitoneal shunt may not be specific and difficult to interpret. The presence or absence of ventricular enlargement on magnetic resonance imaging (MRI) does not reliably predict raised intracranial pressure (ICP) in these patients. Therefore, the aim was to investigate the diagnostic utility of 3D venous phase-contrast MR angiography (vPCA) in these patients.
Materials
The MR studies of two groups of patients at two different examination dates were retrospectively analyzed; one group without clinical symptoms on both examinations and one with symptoms of shunt dysfunction on one examination receiving surgery. Both MRI examinations had to have been performed including axial T2 weighted (T2-w) images and 3D vPCA. Two (neuro)radiologists evaluated T2-w images alone and in combination with 3D vPCA in terms of suspected elevated ICP. Interrater reliability, sensitivity and specificity were assessed.
Results
Compression of venous sinuses was seen significantly more often in patients with shunt failure (p = 0.00003). Consequently, evaluation of 3D vPCA and T2-w images increases sensitivity to 0.92/1.0 compared to T2-w images alone with 0.69/0.77, the interrater agreement for the diagnosis of shunt failure rises from κ = 0.71 to κ = 0.837. Concerning imaging markers, three groups could be identified in children with shunt failure.
Conclusion
In accordance with the literature, the results show that ventricular morphology alone is an unreliable marker for elevated ICP in children with shunt malfunction. The findings confirmed 3D vPCA as a valuable supplemental diagnostic tool improving diagnostic certainty for children with unchanged ventricular size in cases of shunt failure.
... Any obstruction to the cerebrospinal fluid flow that causes the ventricles to expand, results in hydrocephalus. 1 Infantile hydrocephalus can coexist with a number of developmental disorders that have an embryological or fetal basis. 2 An infant with hydrocephalus will typically have a head circumference that enlarges at an abnormal rate, which distinguishes hydrocephalus from macrocrania. 3 Meningitis is usually related to communicating hydrocephalus, unlike our case, where features of obstruction were developed. Only two children with obstructive hydrocephalus as a presenting feature of bacterial meningitis have been observed. ...
Obstructive infantile hydrocephalus may arise due to anatomic or functional obstruction of cerebrospinal fluid flow. Obstruction of the aqueduct of sylvius (aqueductal stenosis) causes dilation of the lateral and third ventricles, while the size of the fourth ventricle remains relatively normal. Obstructive infantile hydrocephalus with meningoventriculitis is a rare phenomenon, and literature with only 2 other children with similar findings have been reported. We hereby report a case of a 16-week-old infant who developed Escherichia coli meningoventriculitis, later complicated by the development of hydrocephalus, challenging the management. The diagnosis was based on the magnetic resonance imaging of the brain, which showed hydrocephalus, and the cerebrospinal fluid culture showing Escherichia coli meningoventriculitis. The case was managed with serial ventricular drainage along with antibiotics followed by staged ventriculoperitoneal shunting. Serial measurement of head circumference is essential to prompt diagnostic suspicion in the case of paediatric meningitis.
... Hidrosefali; beyin omurilik sıvısı (BOS) fizyolojisinin bozulması ve bununla ilişkili olan beyin ventriküllerinin anormal genişlemesi nedeniyle oluşur. 1 En yaygın çocukluk çağı beyin hastalıklarından biri olan hidrosefalinin prevalansı, gelişmiş ülkelerde 1.000 canlı doğumda 1, gelişmekte olan ülkelerde ise 1.000 canlı doğumda 3-4 olarak belirtilmektedir. [1][2][3][4][5] Sahra altı Afrika ülkelerinde bu oran yılda 200 binin üzerine çıkmaktadır. 6 Dünya Sağlık Örgütü, her yıl 380 binin üzerinde yeni hidrosefali tanısı konulduğunu belirtmektedir. ...
... Today, we know hydrocephalus to be "an active distension of the ventricular system resulting from inadequate passage of cerebrospinal fluid from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation." 2 Like in adults, hydrocephalus in pediatric patients can be the result of acquired insults like tumors, trauma, or infections, but may also be developmental or genetic. 3 It can be lethal if untreated and even with current standards of therapy though survival is high; survivors have frequent and severe sequelae. 4 Early diagnosis and therapy may mitigate some of this morbidity. ...
L1 syndrome, a neurological disorder with an X‐linked inheritance pattern, mainly results from mutations occurring in the L1 cell adhesion molecule ( L1CAM ) gene. The L1CAM molecule, belonging to the immunoglobulin (Ig) superfamily of neurocyte adhesion molecules, plays a pivotal role in facilitating intercellular signal transmission across membranes and is indispensable for proper neuronal development and function. This study identified a rare missense variant (c.1759G>C; p.G587R) in the L1CAM gene within a male fetus presenting with hydrocephalus. Due to a lack of functional analysis, the significance of the L1CAM mutation c.1759G>C (p.G587R) remains unknown. We aimed to perform further verification for its pathogenicity. Blood samples were obtained from the proband and his parents for trio clinical exome sequencing and mutation analysis. Expression level analysis was conducted using western blot techniques. Immunofluorescence was employed to investigate L1CAM subcellular localization, while cell aggregation and cell scratch assays were utilized to assess protein function. The study showed that the mutation (c.1759G>C; p.G587R) affected posttranslational glycosylation modification and induced alterations in the subcellular localization of L1‐G587R in the cells. It resulted in the diminished expression of L1CAM on the cell surface and accumulation in the endoplasmic reticulum. The p.G587R altered the function of L1CAM protein and reduced homophilic adhesion capacity of proteins, leading to impaired adhesion and migration of proteins between cells. Our findings provide first biological evidence for the association between the missense mutation (c.1759G>c; p.G587R) in the L1CAM gene and L1 syndrome, confirming the pathogenicity of this missense mutation.
Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.
Hydrocephalus is a heterogeneous disorder of cerebrospinal fluid (CSF) flow that leads to abnormal enlargement of the brain ventricles. The prevalence of infant hydrocephalus is approximately one case per 1,000 births. Hydrocephalus occurs due to an imbalance between the production and the absorption of CSF. The causes of hydrocephalus secondary to CSF overproduction are papilloma of the choroid plexus and rarely diffuse hyperplasia of the villi. All the other hydrocephalus forms are secondary to obstruction to normal CSF reabsorption and are also known as obstructive hydrocephalus. According to the location of obstruction, obstructive hydrocephalus can be defined as communicating, when caused by extraventricular obstruction of the CSF flow or decreased resorption of CSF distal to the fourth ventricle in the cisterns of the base or in the subarachnoid spaces, or as not communicating, in case of intraventricular obstruction to fluid flow. There is a third category, common in preterm infants, called external hydrocephalus which is secondary to delayed development of arachnoid function. Hydrocephalus leads to an increase in intraventricular pressure because of the lack of the mechanism regulating the homeostasis of the CSF flow. Increased intraventricular pressure is responsible for the clinical symptoms in affected child. Clinical presentation varies with age. In the neonatal period, prolonged or frequent apneic or bradycardic events, increasing head circumference, presence of sunsetting eyes or upward gaze palsy, evidence of full or tense anterior/posterior fontanelle, and splayed cranial sutures are signs of increased intracranial pressure. In infants, the most common signs are progressive macrocephaly, irritability, nausea/vomiting, headache, gait changes, and regression of developmental milestones. The extent of brain damage depends on the cause that led to hydrocephalus, the patient's age, and the rapidity of onset. The surgical treatment modalities consist of endoscopic ventriculostomy of the third ventricle and ventriculoperitoneal or ventriculoatrial CSF shunt.
Hydrocephalus is caused by an overproduction of cerebrospinal fluid (CSF), an obstruction of fluid movement, or improper reabsorption. CSF accumulation in the brain’s ventricles causes ventriculomegaly, increased intracranial pressure, inflammation, and neural cell injury. Hydrocephalus can arise from brain trauma, hemorrhage, infection, tumors, or genetic mutations. Currently, there is no cure for hydrocephalus. Treatments like shunting and endoscopic third ventriculostomies are used, but, unfortunately, these therapeutic approaches require brain surgery and have high failure rates. The choroid plexus epithelium (CPe) is thought to be the major producer of CSF in the brain. It is a polarized epithelium that regulates ion and water movement from a fenestrated capillary exudate to the ventricles. Despite decades of research, control of electrolyte movement in the CPe is still not fully understood. This review discusses important transporters on the CPe, how some of these are regulated, and which of them could be potential targets for hydrocephalus treatment. To advance the development of hydrocephalus treatments, physiologically relevant preclinical models are crucial. This review covers some of the current animal and cell culture methods used to study hydrocephalus and highlights the need to develop standardized preclinical models that are used by multiple investigators in order to replicate critical findings and resolve controversies regarding potential drug targets.
OBJECTIVE
Hydrocephalus is a neurological disorder with an incidence of 80–125 per 100,000 births in the United States. The most common treatment, ventricular shunting, has a failure rate of up to 85% within 10 years of placement. The authors aimed to analyze the association between ventricular catheter (VC) tissue obstructions and shunt malfunction for each hydrocephalus etiology.
METHODS
Patient information was collected from 5 hospitals and entered into a REDCap (Research Electronic Data Capture) database by hydrocephalus etiology. The hardware samples were fixed, and each VC tip drainage hole was classified by tissue obstruction after macroscopic analysis. Shunt malfunction data, including shunt revision rate, time to failure, and age at surgery, were correlated with the degree of tissue obstruction in VCs for each etiology.
RESULTS
Posthemorrhagic hydrocephalus was the most common etiology (48.9% of total cases). Proximal catheter obstruction was the most frequent cause of hardware removal (90.4%). Myelomeningocele (44% ± 29%), other congenital etiologies (48% ± 40%), hydrocephalus with brain tumors (45% ± 35%), and posthemorrhagic hydrocephalus (41% ± 35%) showed tissue aggregates in more than 40% of the VC holes. A total of 76.8% of samples removed because of symptoms of obstruction showed cellular or tissue aggregates. No conclusive etiological associations were detected when correlating the percentage of holes with tissue for each VC and age at surgery, shunt revision rates, or time between shunt implantation and removal.
CONCLUSIONS
The proximal VC obstruction was accompanied by tissue aggregates in 76.8% of cases. However, the presence of tissue in the VC did not seem to be associated with hydrocephalus etiology.
OBJECTIVE
The optimal timing of ventricular shunt placement in low-weight and preterm infants remains an unresolved topic in modern pediatric neurosurgery. Shunt placement for hydrocephalus is performed over a wide range of infant weights, and the standard weight threshold for shunt placement can vary substantially across institutions. The aim of this study was to investigate shunt outcome in infants of low body weight.
METHODS
An IRB-approved retrospective analysis of 76 infants (29 females, 47 males) who received primary shunt placement between 2003 and 2018 was performed. Uniform criteria were used over the entire dataset to determine the safety for ventriculoperitoneal (VP) shunt placement: 1) weight near or above 1500 g, 2) feeding tolerance, and 3) lack of necrotizing enterocolitis or active systemic infection. Infants were classified into a low-weight (LW) (< 2000 g) or standard weight (SW) (2000–3000 g) group based on their body weight at the time of initial shunt placement. Shunt survival was compared between the groups. The threshold weight separating the LW and SW groups and outcomes was additionally varied and systematically reanalyzed.
RESULTS
Shunts were placed in 24 LW infants and 52 SW infants over the inclusion period. Etiologies for hydrocephalus were similar across groups: predominantly intraventricular hemorrhage (54%) (p = 0.13) and open neural tube defect (29%) (p = 0.61). Both LW and SW groups had 58% 1-year shunt survival rates. Overall, 46% of shunts failed in the LW group compared with 54% in the SW group over a median follow-up of 47 months (range 0–170 months). A log-rank test comparing shunt survival rates did not show significance (p = 0.43). Groups were repartitioned using a range of threshold weights (1600–2400 g) to divide LW from SW infants. The lack of association between VP shunt placement in LW infants and time frame of revision was consistently observed over the full range of varied threshold weights.
CONCLUSIONS
There was no significant difference in overall time to shunt revision between infants weighing < 2000 g and infants weighing 2000–3000 g. No correlation between weight and shunt survival was detected. Combined with other clinical features pertinent to the management of hydrocephalus in the neonatal population, this investigation provides insight toward clinical decision-making regarding infants of low birth weight and suggests that further multi-institutional study on this topic is warranted.
INTRODUÇÃO: A hidrocefalia é caracterizada pelo enchimento de líquido cefalorraquidiano nos ventrículos e os sintomas clínicos de elevação da pressão intracraniana. Diante disso, as orientações em relação aos procedimentos as crianças que serão submetidas e a assistência técnica e cientifica empregada pela equipe de enfermagem são fundamentais para a família, principalmente para a continuidade dos cuidados no ambiente domiciliar. METODOLOGIA: Trata-se de um estudo descritivo, do tipo relato de experiência sobre a abordagem humanizada da assistência a pacientes com hidrocefalia. DISCUSSÃO: Tratando-se da enfermagem, utilizou-se como guia o processo de enfermagem para prover o acompanhamento das necessidades do paciente. Devido a presença constante do enfermeiro em todas as fases do tratamento da hidrocefalia, a capacitação profissional constante é oportuna para uma prestação de mais habilidosas, pois os profissionais precisam entender as necessidades de cada cliente com o diagnóstico e fazer as intervenções necessárias para o desenvolvimento do paciente e da família CONCLUSÃO: Fica evidente a importância da disseminação do conteúdo para o aperfeiçoamento das intervenções e consequentemente a melhora do paciente.
Significance
Shuntodynia is patient reported pain at the site of the implanted ventriculoperitoneal (VP) shunt. Pediatric hydrocephalus requiring shunt placement is a chronic and prevalent standard of care treatment and requires lifetime management. Shuntodynia is a subjective measure of shunt dysfunction. Quantitative, white-light tissue spectroscopy could be used to objectively identify this condition in the clinic.
Aim
Pediatric subjects were recruited for optical sensing during routine clinical follow-up visits, post-VP shunt implantations. Acquired optical signals were translated into skin-hemodynamic signatures and were compared between subjects that reported shuntodynia versus those that did not.
Approach
Diffuse reflectance spectroscopy (DRS) measurements were collected between 450 and 700 nm using a single-channel fiber-optical probe from (N=35) patients. Multiple reflectance spectra were obtained by the attending physician from regions both proximal and distal to the VP shunt sites and from a matched contralateral site for each subject. Acquired reflectance spectra were processed quantitatively into functional tissue optical endpoints. A two-way, repeated measures analysis of variance was used to assess whether and which of the optical variables were statistically separable, across subjects with shuntodynia versus those without.
Results
Analyses indicated that intrapatient differences in vascular oxygen saturation measured between shunt sites relative to that obtained at the scar or contralateral sites was significantly lower in the pain group. We also find that the total hemoglobin concentrations at the shunt site were lowest relative to the other sites for subjects reporting pain. These findings suggest that shuntodynia pain arises in the scalp tissue around the implanted shunts and may be caused due to hypoxia and inflammation.
Conclusions
Optically derived hemodynamic variables were statistically significantly different in subjects presenting with shuntodynia relative to those without. DRS could provide a viable mode in routine bedside monitoring of subjects with VP shunts for clinical management and assessment of shuntodynia.
Aim
We aimed to evaluate the occurrence of, and risk factors for precocious and early puberty in a retrospective cohort study of girls with shunted infantile hydrocephalus.
Methods
The study population comprised 82 girls with infantile hydrocephalus, born between 1980 and 2002, and treated with a ventriculoperitoneal shunt. Data were available for 39 girls with myelomeningocele and 34 without. Medical records were analysed regarding clinical data and timing of puberty. Precocious and early puberty was defined as the appearance of pubertal signs before 8 years and 0 months and 8 years and 9 months, respectively.
Results
Median age at last admission was 15.8 years (range 10.0–18.0). In total, 15 girls (21%) had precocious puberty, and another 21 (29%) had early puberty. Three or more shunt revisions had been performed in 26/36 girls with early or precocious puberty and in 3/37 girls without ( p = 0.01). The number of shunt revisions correlated negatively with age at the start of puberty in the girls with myelomeningocele (Spearman's correlation coefficient = −0.512, p = 0.001).
Conclusion
Girls with shunted infantile hydrocephalus have a high risk of precocious or early puberty. Repeated shunt revisions seemed to be associated with early puberty.
OBJECTIVE
Hydrocephalus is a highly significant global public health concern. In infants, it may be associated with a potentially deleterious increase in intracranial pressure (ICP). Currently, the gold standard for accurate monitoring of ICP is an intraventricular ICP monitor, but this method is invasive and expensive. Transorbital ultrasound measurement of the optic nerve sheath diameter (ONSD) may provide a noninvasive and cost-effective alternative method for monitoring ICP. The goal of the study was to determine the extent of the correlation between ultrasonographic ONSD and ICP in infants.
METHODS
A prospective observational study of 47 children with hydrocephalus aged ≤ 18 months was performed. The ONSD was measured with a transorbital ultrasound scan, while the intraventricular CSF opening pressure was assessed using a manometer during ventriculoperitoneal shunt insertion. Data were analyzed using SPSS software. The ONSD and ICP measurements were correlated, the receiver operating characteristic (ROC) curve was evaluated, and a sensitivity analysis was performed. Inferences were made using the 0.05 alpha level of significance.
RESULTS
The mean age of the study cohort was 4.8 ± 4.3 months, and 93.6% of patients were infants. The mean ONSD was 4.5 ± 0.7 mm (range 2.9–6.0 mm), and the mean ICP was 19.9 ± 6.5 mm Hg (range 5.2–32.4 mm Hg). Both ONSD and ICP increased with increasing age. The Pearson correlation coefficient revealed a strong positive correlation between ONSD and ICP (r = 0.77, p < 0.001). The ONSD cutoff points were 3.2 mm, 4.0 mm, and 4.6 mm for patients with ICPs of 10 mm Hg, 15 mm Hg, and ≥ 20 mm Hg, respectively. The sensitivity of ONSD was 97.7% (area under the ROC curve 0.99), and for every 14.3–mm Hg increase in ICP, the ONSD increased by 1.0 mm holding age constant.
CONCLUSIONS
ONSD has a strong positive correlation with ICP. Correspondingly, ONSD is highly sensitive in estimating ICP.
Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus.
To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016–23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term ‘SMARCC1-associated developmental dysgenesis syndrome’, characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a ‘neural stem cell’ paradigm of congenital hydrocephalus pathogenesis.
These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.
Background
Congenital hydrocephalus (CH) is a life‐threatening neurological condition that results from an imbalance in production, flow, or absorption of cerebrospinal fluid. Predicted outcomes from in utero diagnosis are frequently unclear. Moreover, conventional treatments consisting primarily of antenatal and postnatal surgeries are often unsuccessful, leading to high mortality rates. Causes of CH can range from secondary insults to germline pathogenic variants, complicating diagnostic processes and treatment outcomes. Currently, an updated summary of CH genetic etiologies in conjunction with clinical testing methodologies is lacking. This review addresses this need by generating a centralized survey of known genetic causes and available molecular tests for CH.
Methods
The scoping review protocol was registered with the Open Science Framework and followed the Arksey and O'Malley framework and the Joanna Briggs Institute methodology. The Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) was utilized to define search guidelines and screening criteria.
Results
Our survey revealed a high number of genetic etiologies associated with CH, ranging from single gene variants to multifactorial birth defects, and additionally uncovered diagnostic challenges that are further complicated by changes in testing approaches over the years. Furthermore, we discovered that most of the existing literature consists of case reports, underscoring the need for studies that utilize CH patient research cohorts as well as more mechanistic studies.
Conclusions
The pursuit of such studies will facilitate novel gene discovery while recognizing phenotypic complexity. Addressing these research gaps could ultimately inform evidence‐based diagnostic guidelines to improve patient care.
Background
Congenital hydrocephaly, an abnormal accumulation of fluid within the ventricular spaces at birth, can cause disability or death if untreated. Limited information is available about survival of infants born with hydrocephaly in Texas. Therefore, the purpose of the study was to calculate survival estimates among infants born with hydrocephaly without spina bifida in Texas.
Methods
A cohort of live‐born infants delivered during 1999–2017 with congenital hydrocephaly without spina bifida was identified from the Texas Birth Defects Registry. Deaths within 1 year of delivery were identified using vital and medical records. One‐year infant survival estimates were generated for multiple descriptive characteristics using the Kaplan–Meier method. Crude hazard ratios (HRs) for one‐year survival among infants with congenital hydrocephaly by maternal and infant characteristics and adjusted HRs for maternal race and ethnicity were estimated using Cox proportional hazard models.
Results
Among 5709 infants born with congenital hydrocephaly without spina bifida, 4681 (82%) survived the first year. The following characteristics were associated with infant survival: maternal race and ethnicity, clinical classification (e.g., chromosomal or syndromic), preterm birth, birth weight, birth year, and maternal education. In the multivariable Cox proportional hazards model, differences in survival were observed by maternal race and ethnicity after adjustment for other maternal and infant characteristics. Infants of non‐Hispanic Black (HR: 1.28, 95% CI: 1.04–1.58) and Hispanic (HR: 1.31, 95% CI: 1.12–1.54) women had increased risk for mortality, compared with infants of non‐Hispanic White women.
Conclusions
This study showed infant survival among a Texas cohort differed by maternal race and ethnicity, clinical classification, gestational age, birth weight, birth year, and maternal education in infants with congenital hydrocephaly without spina bifida. Findings confirm that mortality continues to be common among infants with hydrocephaly without spina bifida. Additional research is needed to identify other risk factors of mortality risk.
BACKGROUND AND OBJECTIVES
To improve the outcomes of minimally invasive, endoscopic, intracranial procedures, steerable robotic tools have been developed but still require thorough evaluation before use in a clinical setting. This paper compares a novel steerable robotic neuroendoscope tool against a standard rigid tool.
METHODS
Seventeen participants, 8 nonmedical and 9 medical (neurosurgery residents and fellows), were recruited. The evaluation trial consisted of a task that was completed using either a rigid tool or the steerable tool, followed by the completion of a qualitative survey. Target reach time and tool movement volume (TMV) were recorded for each trial and analyzed. The tools were evaluated within a realistic phantom model of the brain.
RESULTS
Preclinical evaluation of both tools showed that average target reach time for the steerable tool among medical personnel (15.0 seconds) was longer than that of the rigid tool (5.9 seconds). However, the average TMV for the steerable tool (0.178 cm ³ ) was much lower than that of the rigid tool (0.501 cm ³ ) for medical personnel, decreasing the TMV by 64.47%.
CONCLUSION
The steerable tool required more training and practice in comparison with the standard rigid tool, but it decreased the overall endoscope movement volume, which is a source of parenchymal injury associated with endoscopic procedures.
Third ventriculostomy is the preferred treatment for obstructive hydrocephalus, but the biomechanics of brain tissue damage caused by fiber endoscopes remains unclear. In this study, brain tissue material parameters were tested based on the Ogden model to simulate needle puncture mechanics, and replicated the entire fiber endoscope advancement process during third ventriculostomy. It was found that a smaller diameter fiber endoscope, a perpendicular puncture angle, and a faster puncture speed would decrease the damage of brain tissue caused by the fiber endoscope. This study provides valuable insights for optimizing the instrumentation and surgical process of third ventriculostomy.
The most common cause of acquired hydrocephalus in infants is hemorrhage, most often as a consequence of prematurity. Other important causes include neoplasm and infection, usually bacterial meningitis. Hypoxic ischemic encephalopathy (HIE) in term infants usually results in secondary microcephaly. We report an infant with severe HIE at birth treated by therapeutic hypothermia who developed progressive acquired hydrocephalus over 2 months, although no cause of the hydrocephalus was identified. Although hydrocephalus, even intraventricular hemorrhage, is uncommon in term infants with HIE, careful follow-up of the head circumference is important, even if no findings indicating possible causes of hydrocephalus, such as hemorrhage, are detected on ultrasound or magnetic resonance imaging.
Hydrocephalus is a common pediatric disorder of cerebral spinal fluid physiology resulting in abnormal expansion of the cerebral ventricles. However, the underlying molecular mechanisms remain unknown.
Materials and Methods: We performed proteomic analyses of cerebrospinal fluid (CSF) from 7 congenital hydrocephalus and 5 arachnoid cyst patients who underwent surgical treatment. Differentially expressed proteins (DEPs) were identified by label-free Mass Spectrometry followed by differential expression analysis. The GO and GSEA enrichment analysis was performed to explore the cancer hallmark pathways and immune-related pathways affected by DEPs. Then, network analysis was applied to reveal the location of DEPs in the human protein-protein interactions (PPIs) network. Potential drugs for hydrocephalus were identified based on drug-target interaction.
Results: We identified 148 up-regulated proteins and 82 down-regulated proteins, which are potential biomarkers for clinical diagnosis of hydrocephalus and arachnoid cyst. Functional enrichment analysis revealed that the DEPs were significantly enriched in the cancer hallmark pathways and immune-related pathways. In addition, network analysis uncovered that DEPs were more likely to be located in the central regions of the human PPIs network, suggesting DEPs may be proteins that play important roles in human PPIs. Finally, we calculated the overlap of drug targets and the DEPs based on drug-target interaction to identify the potential therapeutic drugs of hydrocephalus.
Conclusion: The comprehensive proteomic analyses provided valuable resources for investigating the molecular pathways in hydrocephalus, and uncovered potential biomarkers for clinical diagnosis and therapy.
CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid β, in a pathway that we have termed the "glymphatic" system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ∼50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ∼60%. When paravascular CSF-ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF-ISF exchange, while dobutamine increased the rate of paravascular CSF-ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.
The choroid plexus epithelium is a cuboidal cell monolayer, which produces the majority of the cerebrospinal fluid. The concerted action of a variety of integral membrane proteins mediates the transepithelial movement of solutes and water across the epithelium. Secretion by the choroid plexus is characterized by an extremely high rate and by the unusual cellular polarization of well-known epithelial transport proteins. This review focuses on the specific ion and water transport by the choroid plexus cells, and then attempts to integrate the action of specific transport proteins to formulate a model of cerebrospinal fluid secretion. Significant emphasis is placed on the concept of isotonic fluid transport across epithelia, as there is still surprisingly little consensus on the basic biophysics of this phenomenon. The role of the choroid plexus in the regulation of fluid and electrolyte balance in the central nervous system is discussed, and choroid plexus dysfunctions are described in a very diverse set of clinical conditions such as aging, Alzheimer's disease, brain edema, neoplasms, and hydrocephalus. Although the choroid plexus may only have an indirect influence on the pathogenesis of these conditions, the ability to modify epithelial function may be an important component of future therapies.
L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.
MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.European Journal of Human Genetics advance online publication, 12 June 2013; doi:10.1038/ejhg.2013.135.
Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system occurring at an average rate of 1 per 1,000 human pregnancies worldwide. Numerous genetic and environmental factors are discussed to be relevant in their etiology. In mice, mutants in >200 genes including the planar cell polarity (PCP) pathway are known to cause NTDs, and recently, heterozygous mutations in the human VANGL1 gene have been described in a small subset of patients with NTDs. We performed a VANGL1 mutation analysis in 144 unrelated individuals with NTDs from Slovakia, Romania and Germany and identified 3 heterozygous missense mutations: c.613G>A (p.Gly205Arg) with an open spina bifida (lumbosacral meningomyelocele), c.557G>A (p.Arg186His) with a closed spina bifida (tethered cord and spinal lipoma) and c.518G>A (p.Arg173His) with an unknown NTD. The c.613G>A mutation was also found in a healthy sibling. None of the mutations were described previously. Findings support that heterozygous VANGL1 mutations represent hypomorphs or conditional mutants predisposing to NTDs and occur at a frequency of approximately 2.1% of open and closed spinal NTDs. The mutations (p.Arg173His, p.Arg186His, p.Gly205Arg) modified conserved regions of the VANGL1 protein and shared similarities with previously described mutants, providing further evidence for the presence of mutational hot spots in these patients.
Hydrocephalus describes an expansion of the cerebral ventricles that is associated with decreased cerebral volume and compromised neurological function. Although hydrocephalus mostly occurs sporadically, it is frequently associated with diseases caused by defective cilia function, including Bardet-Biedl syndrome (BBS). A new study reveals that hydrocephalus in a mouse model of BBS is related to defective proliferation and apoptosis of neural progenitor cells (NPCs) and can be rescued with lithium treatment (pages 1797-1804).
Background:
Human congenital non-syndromic hydrocephalus is a vastly heterogeneous condition. A subgroup of cases are not secondary to a specific cause (eg, a neural tube defect), and within this subgroup, autosomal recessive inheritance has been described. One homozygous mutation in the DAPLE (Dvl-associating protein with a high frequency of leucine residues) protein-encoding gene CCDC88C (coiled-coil domain containing 88C) has recently been reported in a single family. The role of this gene has not been validated in another family, and no other autosomal recessive gene has been reported.
Methods:
We used homozygosity mapping and whole exome sequencing in two families with primary, non-syndromic congenital hydrocephalus from two different ethnic backgrounds.
Results:
In each family, we identified a novel homozygous mutation of CCDC88C. One mutation produced a premature stop codon at position 312 of the protein, while the second mutation induced a frameshift in the last exon, producing a stop codon that truncated the extreme C-terminus of DAPLE, including the 2026-2028 Gly-Cys-Val motif known to bind the post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) (PDZ) domain of Dishevelled.
Conclusions:
Our data validate CCDC88C as causing autosomal recessive, primary non-syndromic congenital hydrocephalus, suggesting this gene may be an important cause of congenital hydrocephalus, and underscore the important role of the C-terminal PDZ domain-binding motif in the DAPLE protein.
OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.
The objective of the study was to investigate familial aggregation of primary congenital hydrocephalus in an unselected, nationwide population. Based on the Danish Central Person Register, we identified all children born in Denmark between 1978 and 2008 and their family members (up to third-degree relatives). Information on primary congenital hydrocephalus was obtained from the National Patient Discharge Register. Using binomial log-linear regression, we estimated recurrence risk ratios of congenital hydrocephalus. An alternative log-linear regression model was applied to quantify the genetic effect and the maternal effect. Of 1 928 683 live-born children, 2194 had a diagnosis of idiopathic congenital hydrocephalus (1.1/1000). Of those, 75 (3.4%) had at least one other family member with primary congenital hydrocephalus. Significantly increased recurrence risk ratios of primary congenital hydrocephalus were observed for same-sex twins, first- and second-degree relatives as follows: 34.8 (95% confidence interval: 16.4-74.0), 6.2 (95% confidence interval 4.3-8.9) and 2.2 (95% confidence interval 1.6-3.1), respectively. Recurrence risk ratio for third-degree relatives was 1.5 (95% confidence interval 0.8-2.7). A maternal component was supported by the facts that recurrence risk ratios for opposite-sex twins (37.3, 95% confidence interval 11.9-116.7) were significantly higher than other first-degree relatives and that recurrence risk ratios for maternal half-siblings (8.4, 95% confidence interval 3.7-18.7) were significantly higher than for paternal half-siblings (3.0, 95% confidence interval 0.8-12.2). This population-based study found strong evidence of familial aggregation of primary congenital hydrocephalus, which supports the existence of a genetic component to the aetiology. In addition, the pattern of association suggests that a strong maternal component contributes to the familial aggregation.
Dishevelled is the common mediator of canonical and non-canonical Wnt signalling pathways, which are important for embryonic development, tissue maintenance and cancer progression. In the non-canonical Wnt signalling pathway, the Rho family of small GTPases acting downstream of Dishevelled has essential roles in cell migration. The mechanisms by which the non-canonical Wnt signalling pathway regulates Rac activation remain unknown. Here we show that Daple (Dishevelled-associating protein with a high frequency of leucine residues) regulates Wnt5a-mediated activation of Rac and formation of lamellipodia through interaction with Dishevelled. Daple increases the association of Dishevelled with an isoform of atypical protein kinase C, consequently promoting Rac activation. Accordingly, Daple deficiency impairs migration of fibroblasts and epithelial cells during wound healing in vivo. These findings indicate that Daple interacts with Dishevelled to direct the Dishevelled/protein kinase λ protein complex to activate Rac, which in turn mediates the non-canonical Wnt signalling pathway required for cell migration.
Rhombencephalosynapsis is a midline brain malformation characterized by missing cerebellar vermis with apparent fusion of the cerebellar hemispheres. Rhombencephalosynapsis can be seen in isolation or together with other central nervous system and extra-central nervous system malformations. Gómez-López-Hernández syndrome combines rhombencephalosynapsis with parietal/temporal alopecia and sometimes trigeminal anaesthesia, towering skull shape and dysmorphic features. Rhombencephalosynapsis can also be seen in patients with features of vertebral anomalies, anal atresia, cardiovascular anomalies, trachea-oesophageal fistula, renal anomalies, limb defects (VACTERL) association. Based on a comprehensive evaluation of neuroimaging findings in 42 patients with rhombencephalosynapsis, we propose a spectrum of severity, ranging from mild (the partial absence of nodulus, anterior and posterior vermis), to moderate (the absence of posterior vermis with some anterior vermis and nodulus present), to severe (the absence of posterior and anterior vermis with some nodulus present), to complete (the absence of the entire vermis including nodulus). We demonstrate that the severity of rhombencephalosynapsis correlates with fusion of the tonsils, as well as midbrain abnormalities including aqueductal stenosis and midline fusion of the tectum. Rhombencephalosynapsis is also associated with multiple forebrain abnormalities including absent olfactory bulbs, dysgenesis of the corpus callosum, absent septum pellucidum and, in rare patients, atypical forms of holoprosencephaly. The frequent association between rhombencephalosynapsis and aqueductal stenosis prompted us to evaluate brain magnetic resonance images in other patients with aqueductal stenosis at our institution, and remarkably, we identified rhombencephalosynapsis in 9%. Strikingly, subjects with more severe rhombencephalosynapsis have more severely abnormal neurodevelopmental outcome, as do subjects with holoprosencephaly and patients with VACTERL features. In summary, our data provide improved diagnostic and prognostic information, and support disruption of dorsal-ventral patterning as a mechanism underlying rhombencephalosynapsis.
Joubert syndrome (JS) is a ciliopathy characterised by a distinctive brain malformation (the 'molar tooth sign'), developmental delay, abnormal eye movements and abnormal breathing pattern. Retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly are variably present, resulting in significant phenotypic heterogeneity and overlap with other ciliopathies. JS is also genetically heterogeneous, resulting from mutations in 13 genes. These factors render clinical/molecular diagnosis and management challenging. CC2D2A mutations are a relatively common cause of JS and also cause Meckel syndrome. The clinical consequences of CC2D2A mutations in patients with JS have been incompletely reported.
Subjects with JS from 209 families were evaluated to identify mutations in CC2D2A. Clinical and imaging features in subjects with CC2D2A mutations were compared with those in subjects without CC2D2A mutations and reports in the literature.
10 novel CC2D2A mutations in 20 subjects were identified; a summary is provided of all published CC2D2A mutations. Subjects with CC2D2A-related JS were more likely to have ventriculomegaly (p<0.0001) and seizures (p=0.024) than subjects without CC2D2A mutations. No mutation-specific genotype-phenotype correlations could be identified, but the findings confirm the observation that mutations that cause CC2D2A-related JS are predicted to be less deleterious than mutations that cause CC2D2A-related Meckel syndrome. Missense variants in the coiled-coil and C2 domains, as well as the C-terminal region, identify these regions as important for the biological mechanisms underlying JS.
CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A-related JS should be monitored for hydrocephalus and seizures.
Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352 kb to 20.5 Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929 kb region for metopic craniosynostosis, a 1.08 Mb region for obstructive hydrocephalus, and a 1.84 Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions.
The cerebrospinal fluid (CSF) is contained in the brain ventricles and the cranial and spinal subarachnoid spaces. The mean CSF volume is 150 ml, with 25 ml in the ventricles and 125 ml in subarachnoid spaces. CSF is predominantly, but not exclusively, secreted by the choroid plexuses. Brain interstitial fluid, ependyma and capillaries may also play a poorly defined role in CSF secretion. CSF circulation from sites of secretion to sites of absorption largely depends on the arterial pulse wave. Additional factors such as respiratory waves, the subject's posture, jugular venous pressure and physical effort also modulate CSF flow dynamics and pressure. Cranial and spinal arachnoid villi have been considered for a long time to be the predominant sites of CSF absorption into the venous outflow system. Experimental data suggest that cranial and spinal nerve sheaths, the cribriform plate and the adventitia of cerebral arteries constitute substantial pathways of CSF drainage into the lymphatic outflow system. CSF is renewed about four times every 24 hours. Reduction of the CSF turnover rate during ageing leads to accumulation of catabolites in the brain and CSF that are also observed in certain neurodegenerative diseases. The CSF space is a dynamic pressure system. CSF pressure determines intracranial pressure with physiological values ranging between 3 and 4 mmHg before the age of one year, and between 10 and 15 mmHg in adults. Apart from its function of hydromechanical protection of the central nervous system, CSF also plays a prominent role in brain development and regulation of brain interstitial fluid homeostasis, which influences neuronal functioning.
KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.
The maintenance of adequate blood flow to the brain is critical for normal brain function; cerebral blood flow, its regulation and the effect of alteration in this flow with disease have been studied extensively and are very well understood. This flow is not steady, however; the systolic increase in blood pressure over the cardiac cycle causes regular variations in blood flow into and throughout the brain that are synchronous with the heart beat. Because the brain is contained within the fixed skull, these pulsations in flow and pressure are in turn transferred into brain tissue and all of the fluids contained therein including cerebrospinal fluid. While intracranial pulsatility has not been a primary focus of the clinical community, considerable data have accrued over the last sixty years and new applications are emerging to this day. Investigators have found it a useful marker in certain diseases, particularly in hydrocephalus and traumatic brain injury where large changes in intracranial pressure and in the biomechanical properties of the brain can lead to significant changes in pressure and flow pulsatility. In this work, we review the history of intracranial pulsatility beginning with its discovery and early characterization, consider the specific technologies such as transcranial Doppler and phase contrast MRI used to assess various aspects of brain pulsations, and examine the experimental and clinical studies which have used pulsatility to better understand brain function in health and with disease.
The etiology of non-syndromic hydrocephalus is poorly understood. Via positional cloning in a consanguineous family with autosomal recessive hydrocephalus we have now identified a homozygous splice site mutation in the CCDC88C gene as a novel cause of a complex hydrocephalic brain malformation. The only living patient showed normal psychomotor development at the age of 3 years and 3 months and her deceased aunt, who was assumed to suffer from the same condition, had mild mental retardation. The mutation in the affected patients, a homozygous substitution in the donor splice site of intron 29, resulted in a shorter transcript due to exclusion of exon 29 and loss of functional protein, as shown by Western blotting (p.S1591HfsX7). In normal human tissue panels, we found CCDC88C ubiquitously expressed, but most prominently in the fetal brain, especially in pons and cerebellum, while expression in the adult brain appeared to be restricted to cortex and medulla oblongata. CCDC88C encodes DAPLE (HkRP2), a Hook-related protein with a binding domain for the central Wnt signalling pathway protein Dishevelled. Targeted quantitative RT-PCR and expression profiling of 84 genes from the Wnt signalling pathway in peripheral blood from the index patient and her healthy mother revealed increased mRNA levels of CCDC88C indicating transcriptional upregulation. Due to loss of CCDC88C function β-catenin (CTNNB1) and the downstream target LEF1 showed increased mRNA levels in the patient, but many genes from the Wnt pathway and transcriptional target genes showed reduced expression, which might be explained by a complex negative feedback loop. We have thus identified a further essential component of the Wnt signalling pathway in human brain development.
Ependymal cells form the epithelial lining of cerebral ventricles. Their apical surface is covered by cilia that beat in a coordinated fashion to facilitate circulation of the cerebrospinal fluid (CSF). The genetic factors that govern the development and function of ependymal cilia remain poorly understood. We found that the planar cell polarity cadherins Celsr2 and Celsr3 control these processes. In Celsr2-deficient mice, the development and planar organization of ependymal cilia are compromised, leading to defective CSF dynamics and hydrocephalus. In Celsr2 and Celsr3 double mutant ependyma, ciliogenesis is markedly impaired, resulting in lethal hydrocephalus. The membrane distribution of Vangl2 and Fzd3, two key planar cell polarity proteins, was disturbed in Celsr2 mutants, and even more so in Celsr2 and Celsr3 double mutants. Our findings suggest that planar cell polarity signaling is involved in ependymal cilia development and in the pathophysiology of hydrocephalus, with possible implications in other ciliopathies.
Wnt signalling regulates multiple aspects of brain development in vertebrate embryos. A large number of Wnts are expressed in the embryonic forebrain; however, it is poorly understood which specific Wnt performs which function and how they interact. Wnts are able to activate different intracellular pathways, but which of these pathways become activated in different brain subdivisions also remains enigmatic.
We have compiled the first comprehensive spatiotemporal atlas of Wnt pathway gene expression at critical stages of forebrain regionalisation in the chick embryo and found that most of these genes are expressed in strikingly dynamic and complex patterns. Several expression domains do not respect proposed compartment boundaries in the developing forebrain, suggesting that areal identities are more dynamic than previously thought. Using an in ovo electroporation approach, we show that Wnt4 expression in the thalamus is negatively regulated by Sonic hedgehog (Shh) signalling from the zona limitans intrathalamica (ZLI), a known organising centre of forebrain development.
The forebrain is exposed to a multitude of Wnts and Wnt inhibitors that are expressed in a highly dynamic and complex fashion, precluding simple correlative conclusions about their respective functions or signalling mechanisms. In various biological systems, Wnts are antagonised by Shh signalling. By demonstrating that Wnt4 expression in the thalamus is repressed by Shh from the ZLI we reveal an additional level of interaction between these two pathways and provide an example for the cross-regulation between patterning centres during forebrain regionalisation.
To investigate the associations between isolated congenital hydrocephalus (CHC) and maternal characteristics, maternal medical diseases, and medicine intake during pregnancy as well as birth characteristics of the child in a retrospective, register-based, nationwide cohort study. Furthermore, to identify the risk factors unique for isolated CHC as compared to syndromic CHC.
We established a cohort of all children born in Denmark between 1978 and 2008. Information on CHC and maternal medical diseases were obtained from the National Patient Discharge Register, maternal intake of medicine during pregnancy from the National Prescription Drug Register, and birth characteristics of the child from the Danish National Birth Register. Rate ratios (RR) of isolated and syndromic CHC with 95% CI were estimated using log-linear Poisson regression.
In a cohort of 1 928 666 live-born children, we observed 1193 cases of isolated CHC (0.062/1000) born children. First-borns had an increased risk of isolated CHC compared to later-borns (1.32 95% CI 1.17 to 1.49) (0.72/1000 born children). First trimester exposure to maternal use of antidepressants was associated with a significantly increased risk of isolated CHC compared to unexposed children (RR 2.52, 95% CI 1.47 to 4.29) (1.5/1000 born children). Risk factors also found for syndromic CHC were: Male gender, multiples and maternal diabetes.
The higher risk for isolated CHC in first-born children as well as behavioural aspects and comorbidities associated with maternal use of antidepressants, should be the targets for future research. Potential biological pathways by which antidepressants may cause hydrocephalus remain to be elucidated.
MUPP-1 (multi-PDZ domain protein-1) and PATJ (PALS-1-associated tight junction protein) proteins are closely related scaffold proteins and bind to many common interactors including PALS-1 (protein associated with Lin seven) a member of the Crumbs complex. Our goal is to understand how MUPP-1 and PATJ and their interaction with PALS-1 are regulated in the same cells. We have shown that in MCF10A cells there are at least two different and co-existing complexes, PALS-1/MUPP-1 and PALS-1/PATJ. Surprisingly, MUPP-1 levels inversely correlated with PATJ protein levels by acting on the stabilization of the PATJ/PALS-1 complex. Upon MUPP-1 depletion, the increased amounts of PATJ are in part localized at the migrating front of MCF10A cells and are able to recruit more PAR3 (partition defective 3). All together these data indicate that a precise balance between MUPP-1 and PATJ is achieved in epithelial cells by regulating their association with PALS-1.
Background:
Congenital hydrocephalus is a condition characterized by accumulation of cerebrospinal fluid in the ventricles of the brain. Prenatal infections are risk factors for some birth defects. This pilot study investigated whether residual dried blood spots (DBS) could be used to assess infections as risk factors for birth defects by examining the associations between prenatal infection with Toxoplasma gondii (T. gondii) or cytomegalovirus (CMV) with congenital hydrocephalus.
Methods:
Case-infants with hydrocephalus (N=410) were identified among live-born infants using birth defects surveillance systems in California, North Carolina, and Texas. Control-infants without birth defects were randomly selected from the same geographic areas and time periods as case-infants (N=448). We tested residual DBS from case- and control-infants for T. gondii immunoglobulin M and CMV DNA. When possible, we calculated crude odds ratios (cORs) and confidence intervals (CIs).
Results:
Evidence for prenatal T. gondii infection was more common among case-infants (1.2%) than control-infants (0%; p=0.11), and evidence for prenatal CMV infection was higher among case-infants (1.5%) than control-infants (0.7%; cOR: 2.3; 95% CI: 0.48, 13.99).
Conclusions:
Prenatal infections with T. gondii and CMV occurred more often among infants with congenital hydrocephalus than control-infants, although differences were not statistically significant. This pilot study highlighted some challenges in using DBS to examine associations between certain infections and birth defects, particularly related to reduced sensitivity and specimen storage conditions. Further study with increased numbers of specimens and higher quality specimens should be considered to understand better the contribution of these infections to the occurrence of congenital hydrocephalus.
Numerous methods have been suggested for the treatment of internal hydrocephalus, none of which have been productive of satisfactory results. So long as the etiology of this condition remains obscure, the treatment must necessarily be only symptomatic. In the hope of clarifying its etiology and thus affording a rational working basis for its relief, we have undertaken this investigation.The present communication, which is presented as a preliminary report, includes observations on dogs after the production of experimental hydrocephalus, together with observations on patients suffering from the disease. We have also considered the manner and the place of formation and of absorption of the normal cerebrospinal fluid and the relation of these factors in the production of this pathologic condition.HYDROCEPHALUS EXPERIMENTALLY PRODUCED
From a survey of the literature we have been unable to find any record of hydrocephalus having been produced experimentally. In our experiments an obstruction has been
In vertebrate development, the body plan is determined by primordial morphogen gradients that suffuse the embryo. Retinoic acid (RA) is an important morphogen involved in patterning the anterior-posterior axis of structures, including the hindbrain and paraxial mesoderm. RA diffuses over long distances, and its activity is spatially restricted by synthesizing and degrading enzymes. However, gradients of endogenous morphogens in live embryos have not been directly observed; indeed, their existence, distribution and requirement for correct patterning remain controversial. Here we report a family of genetically encoded indicators for RA that we have termed GEPRAs (genetically encoded probes for RA). Using the principle of fluorescence resonance energy transfer we engineered the ligand-binding domains of RA receptors to incorporate cyan-emitting and yellow-emitting fluorescent proteins as fluorescence resonance energy transfer donor and acceptor, respectively, for the reliable detection of ambient free RA. We created three GEPRAs with different affinities for RA, enabling the quantitative measurement of physiological RA concentrations. Live imaging of zebrafish embryos at the gastrula and somitogenesis stages revealed a linear concentration gradient of endogenous RA in a two-tailed source-sink arrangement across the embryo. Modelling of the observed linear RA gradient suggests that the rate of RA diffusion exceeds the spatiotemporal dynamics of embryogenesis, resulting in stability to perturbation. Furthermore, we used GEPRAs in combination with genetic and pharmacological perturbations to resolve competing hypotheses on the structure of the RA gradient during hindbrain formation and somitogenesis. Live imaging of endogenous concentration gradients across embryonic development will allow the precise assignment of molecular mechanisms to developmental dynamics and will accelerate the application of approaches based on morphogen gradients to tissue engineering and regenerative medicine.
Craniofacial and neural tissues develop in concert throughout prenatal and postnatal growth. FGFR-related craniosynostosis syndromes, such as Apert syndrome (AS), are associated with specific phenotypes involving both the skull and the brain. We analyzed the effects of the FGFR P253R mutation for AS using the Fgfr2(+/P253R) Apert syndrome mouse to evaluate the effects of this mutation on these two tissues over the course of development from day of birth (P0) to postnatal day 2 (P2). Three-dimensional magnetic resonance microscopy and computed tomography images were acquired from Fgfr2(+/P253R) mice and unaffected littermates at P0 (N = 28) and P2 (N = 20).Three-dimensional coordinate data for 23 skull and 15 brain landmarks were statistically compared between groups. Results demonstrate that the Fgfr2(+/P253R) mice show reduced growth in the facial skeleton and the cerebrum, while the height and width of the neurocranium and caudal regions of the brain show increased growth relative to unaffected littermates. This localized correspondence of differential growth patterns in skull and brain point to their continued interaction through development and suggest that both tissues display divergent postnatal growth patterns relative to unaffected littermates. However, the change in the skull-brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other. © 2013 Wiley Periodicals, Inc.
Background:
It is suggested that disturbed CSF dynamics are involved in the pathophysiology of idiopathic normal pressure hydrocephalus (INPH). The pulsatility curve describes the relationship between intracranial pressure (ICP) and the amplitude of cardiac related ICP pulsations. The position of baseline ICP on the curve provides information about the physiological state of the CSF dynamic system. The objective of the study was to investigate if shunt surgery modifies the pulsatility curve and the baseline position on the curve, and how this relates to gait improvement in INPH.
Methods:
51 INPH patients were investigated with lumbar CSF dynamic investigations preoperatively and 5 months after shunt surgery. During the investigation, ICP was measured at baseline, and then a CSF sample was removed, resulting in pressure reduction. After this, ICP was regulated with an automated infusion protocol, with a maximum increase of 24 mm Hg above baseline. The pulsatility curve was thus determined in a wide range of ICP values. Gait improvement was defined as a gait speed increase ≥0.1 m/s.
Results:
The pulsatility curve was unaltered by shunting. Baseline ICP and amplitude were reduced (-3.0±2.9 mm Hg; -1.1±1.5 mm Hg; p<0.05, n=51). Amplitude reduction was larger for gait improvers (-1.2±1.6 mm Hg, n=42) than non-improvers (-0.2±0.5 mm Hg, n=9) (p<0.05) although mean ICP reduction did not differ.
Conclusions:
The pulsatility curve was not modified by shunt surgery, while the baseline position was shifted along the curve. Observed differences between gait improvers and non-improvers support cardiac related ICP pulsations as a component of INPH pathophysiology.
Congenital hydrocephalus is an important birth defect that is heterogeneous in aetiology and clinical presentation. Although genetics is believed to play an important role in the aetiology of non-syndromic congenital hydrocephalus, the overwhelming majority of cases lack mutations in L1CAM, the only disease gene identified to date. The purpose of this study is to identify a novel genetic cause of congenital hydrocephalus.
Families with congenital hydrocephalus were phenotyped clinically and, in one family, autoyzogisty mapping and linkage analysis were pursued. Sequencing of the genes within the candidate locus was followed by targeted sequencing of the likely candidate gene in two other families.
We have identified a family in which severe congenital hydrocephalus of the communicating type follows an autosomal recessive mode of inheritance. Linkage analysis and autozygosity mapping narrowed the critical interval to 6.9 Mb on 9p24.1-p22.3 spanning just six genes. Direct sequencing of these genes revealed a truncating mutation in MPDZ, encoding a tight junction protein. Remarkably, we have also identified the same founder mutation in a stillbirth with massive congenital hydrocephalus from another family.
Our data strongly support the candidacy of MPDZ as a novel congenital hydrocephalus disease gene.
Objective:
Fetal pathology aims to recognize syndromal patterns of anomalies for goal-directed mutation analyses, genetic counseling, and early prenatal diagnosis in consecutive pregnancies. Here, we report on five fetuses with Peters' plus syndrome (PPS) from two distinct families aborted after prenatal ultrasound diagnosis of hydrocephaly.
Method:
We performed fetal autopsies and molecular analyses.
Results:
Among 44 fetuses with prenatally diagnosed hydrocephaly, four fetuses of 16 to 21 gestational weeks presented with additional cleft lip/palate and/or agenesis of the corpus callosum. Other features were growth retardation, hypertelorism, anomalies of the eyes, in part consistent with Peters' anterior chamber anomalies, mild brachymelia, brachydactyly, and also internal anomalies. Suspected PPS was confirmed by detection of B3GALTL mutation in these four fetuses and in one additional sib fetus, revealing homozygosity for the common c.660 + 1G > A donor splice site mutation in intron 8.
Conclusions:
Autosomal-recessive PPS has not yet been diagnosed prenatally. We want to alert ultrasonographers to the diagnosis of this disorder in growth-retarded fetuses with (recurrent) hydrocephaly, agenesis of the corpus callosum, and cleft lip/palate and stress the more severe fetal manifestation, describing a first such case with additional Dandy-Walker cyst and occult meningoencephalocele.
Object:
McLone and Knepper's unified theory of Chiari malformation Type II (CM-II) describes how the loss of CSF via the open posterior neuropore fails to create adequate distending pressure for the developing rhomboencephalic vesicle. The authors of the present article describe the relationship between the posterior fossa volume and intracranial cerebellar volume as being related to the distance from the obex of the fourth ventricle to the myelomeningocele lesion using a common mathematical model, the Hagen-Poiseuille law.
Methods:
All newborns who required closure of a myelomeningocele at the authors' institution between 2008 and 2011 and who were between 4 weeks premature and 2 months, corrected gestational age, at the time of MRI were included in this study. Volumes and measurements were obtained from axial and sagittal T2-weighted MR images of the brain and spine.
Results:
A total of 56 newborn infants met the inclusion criteria. There was a direct linear relationship between both posterior fossa volume and cerebellar volume and the spinal level of the myelomeningocele lesion (p = 0.0012 and p = 0.0041, respectively). There was a negative linear relationship between the cerebellar descent, the spinal level of the lesion, and posterior fossa volume and cerebellar volume. These relationships strengthen in patients with no syringomyelia and are not significant in those groups with syringomyelia. The results of a 1-way ANOVA for the 3 groups did not reach significance.
Conclusions:
Using a linear equation derived from the Hagen-Poiseuille law that describes pressure in the fourth ventricle as being directly related to the length of the central canal from the obex to the myelomeningocele lesion, the authors were able to explain the directly observed linear relation between posterior fossa volume, intracranial cerebellar volume, and cerebellar descent to the level of the spinal lesion. As this model assumes a uniform radius of the central canal they were able to validate this model when they observed a strengthening in relationships in the no syringomyelia group and statistically insignificant correlations in the groups with syringomyelia. They therefore propose that the spinal level of the lesion is one of the major determinants of posterior fossa volume, intracranial cerebellar volume, and cerebellar ectopia.
Central nervous system anomalies in Pfeiffer syndrome (PS) due to mutations in the FGFR2 gene are poorly understood, even though PS is often associated with serious cognitive impairment. The aim of this study is to describe the neuropathological phenotype in PS. We present four severe fetal cases of sporadic PS with FGFR2 mutations who underwent termination followed by fetopathological and neuropathological examination. We studied the expression pattern of Fgfr2 in the mouse brain using radioactive fluorescence in situ hybridization. PS is associated with brain deformations due to the abnormal skull shape, but FGFR2 mutations also induce specific brain developmental anomalies: megalencephaly, midline disorders, amygdala, and hippocampus malformations, and ventricular wall alterations. The expression pattern of Fgfr2 in mice matches the distribution of malformations in humans. The brain anomalies in PS result from the combination of mechanical deformations and intrinsic developmental disorders due to FGFR2 hyperactivity. Several similarities are noted between these anomalies and the brain lesions observed in other syndromes due to mutations in FGF-receptor genes. The specific involvement of the hippocampus and the amygdala should encourage the precise cognitive screening of patients with mild forms of PS. © 2012 Wiley Periodicals, Inc.
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. © 2012 Wiley Periodicals, Inc.
Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
To verify if any of the 15 congenital defects already reported in association with misoprostol can be found within an epidemiological registry of congenital defects.
Case-control study including case-sick and case-health controls.
Comparison of misoprostol exposure for each specific defect, using the exposure for the rest of defects as a reference group.
Four thousand six hundred seventy-three consecutive newborn infants with malformations of unknown aetiology, in the Latin American Collaborative Study of Congenital Malformation.
There was no difference in exposure rate between the malformed (34/4,673) and nonmalformed (23/4,980) newborns. Four of the five more frequently cited defects in the literature were found to be in excess: constriction ring, terminal transverse-limb defects, hydrocephalus, and arthrogryposis. Equinovarus feet had a normal frequency in our study. Thirteen different defects not described in the literature were seen in our misoprostol exposed cases, but only holoprosencephaly and bladder exstrophy significantly exceeded the expected number.
The confirmation from an epidemiological registry of an association for four of the five more commonly observed congenital defects among misoprostol exposed children described in the literature seems indicative of a real teratogenic effect. The defects are of vascular disruption type. However, additional attempts to achieve abortion could not be excluded as a concurrent contribution.
The Gorlin (naevoid basal cell carcinoma) syndrome is an autosomal dominant disorder consisting principally of naevoid basal cell carcinomas, odontogenic keratocysts, skeletal abnormalities, and intracranial calcification. We report the prenatal detection of the Gorlin syndrome by ultrasonography in a fetus with macrocephaly and mild ventriculomegaly.
Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss. Homozygosity mapping and whole-exome sequencing of DNA from affected individuals in eight families (including the family in the first report of CMS) revealed four molecular variations (two single-base deletions, a nonsense mutation, and a canonical splice-site mutation) in the G protein-signaling modulator 2 gene, GPSM2, that underlie CMS. Mutations in GPSM2 have been previously identified in people with profound congenital nonsyndromic hearing loss (NSHL). Subsequent brain imaging of these individuals revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a CMS diagnosis, but no ventriculomegaly. The gene product, GPSM2, is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development.
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
The diagnosis of Pallister-Hall syndrome is based on family history and the clinical findings of hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus, and renal abnormalities. Molecular genetic testing of GLI3, the only gene in which mutations are known to cause Pallister-Hall syndrome, is available clinically.
Treatment of manifestations: Urgent treatment for endocrine abnormalities, especially cortisol deficiency; management of epiglottic abnormalities depending on the abnormality and the extent of respiratory compromise; bifid epiglottis, the most common abnormality, typically does not need treatment. Standard treatment of anal atresia or stenosis; symptomatic treatment of seizures; elective repair of polydactyly; developmental intervention or special education for developmental delays. Prevention of secondary complications: Biopsy or resection of hypothalamic hamartoma may result in complications and lifelong need for hormone replacement; seizures may begin or worsen with use of stimulants for attention deficit disorder. Surveillance: During childhood, annual developmental assessment and annual medical evaluation to assess growth and monitor for signs of precocious puberty.
Pallister-Hall syndrome is inherited in an autosomal dominant manner. Individuals with PHS may have an affected parent or may have the disorder as the result of a de novo mutation. About 25% of cases are caused by a de novo gene mutation. The de novo cases are generally more severe than the familial cases. The risk to offspring of an affected individual is 50%. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. The reliability of ultrasound examination for prenatal diagnosis is unknown.
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true ocular hypertelorism, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
The diagnosis of GCPS is based on clinical findings and family history. Standard Giemsa-banding cytogenetic studies can detect translocations or gross cytogenetic deletions involving 7p13. FISH analysis detects deletions in the estimated 5%-10% of individuals with large deletions involving band 7p13; comparative genomic hybridization array may become an alternative to FISH in the future. GLI3 is the only gene known to be associated with GCPS; GLI3 alterations (i.e., cytogenetic abnormalities involving GLI3 or mutations of GLI3) can be identified in more than 75% of typically affected individuals. Testing for GLI3 sequence alterations is clinically available.
Treatment of manifestations: elective surgical repair of polydactyly with greatest priority given to correction of preaxial polydactyly of the thumbs; evaluation and treatment as needed for hydrocephalus or other CNS abnormalities in individuals showing signs of increased intracranial pressure, developmental delay, loss of milestones, and/or seizures. Surveillance: monitoring for evidence of OFC increasing faster than normal.
GCPS either is inherited in an autosomal dominant manner (either as a mutation in GLI3 or as a deletion of 7p13 involving GLI3) or occurs as the result of a de novo or inherited chromosomal rearrangement. Individuals with GCPS as the result of a GLI3 mutation may have an affected parent or may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with a GLI3 mutation has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the underlying genetic cause in the family (i.e., deletion of 7p13, balanced chromosomal rearrangement, or GLI3 mutation) has been identified. The reliability of ultrasound examination for prenatal diagnosis is unknown.
Neural tube defects (NTDs), including anencephaly and spina bifida, have a complex etiology. Defects in the planar cell polarity (PCP) signaling pathway have been strongly associated with NTDs in animal models and human cohorts. In this genetic study, we examined the core PCP gene CELSR1 in NTDs and caudal agenesis cases to determine whether mutations at this gene predispose to these defects.
We sequenced the coding region and the exon-intron junctions of CELSR1 in a cohort of 473 patients affected with various forms of open and closed NTDs (412) or caudal agenesis (61). Novel and rare variants (<1%) were genotyped in a cohort of 639 ethnically-matched individuals. The effect of novel missense mutations absent in controls and in public databases on protein function was predicted in silico.
We identified in our cohort one nonsense mutation in exon 1 of CELSR1 that truncates the majority of the protein in one patient with NTD and one in-frame 12 bp deletion that removes a putative PKC phosphorylation "SSR" motif in one caudal agenesis patient. We also detected a total of 13 novel missense variants in 12 patients (11 NTDs and 1 caudal agenesis) that were predicted to be pathogenic in silico.
We detected novel CELSR1 mutations predicted to be pathogenic in 2.9% of our NTD cohort and 3.3% of our caudal agenesis cohort. Our findings implicate CELSR1 as a risk factor for NTDs or caudal agenesis and provide additional evidence for a pathogenic role of PCP signaling in these malformations.
We report a female patient with situs inversus, dextrocardia, a complex heart malformation, hydrocephalus due to aqueductal stenosis, and abnormal ultrastructure of the respiratory epithelium cilia. Several animal models of this disorder implicate abnormal ciliary function in the genesis of hydrocephalus, and 11 patients were previously reported with hydrocephalus and the syndrome of primary ciliary dyskinesia. Primary ciliary dyskinesia-associated aqueductal stenosis should be considered as a possible cause for fetal or neonatal hydrocephalus if heterotaxy, heart malformations, and/or a probable genetic etiology are present.
The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia.
Arachnoid cysts are fluid-filled duplications or splittings of the arachnoid layer with a content which is similar but not equal to the cerebrospinal fluid. Arachnoid cysts are not actual neurodegenerative disorders, rather the underlying defect of the texture of the arachnoid layer is probably congenital in nature. They can occur sporadically or can be associated with other malformations or diseases. Arachnoid cysts may be discovered in early childhood. However, they can develop de novo, grow or decrease in size. They may be diagnosed by ultrasound screening in the fetal period or be discovered during childhood or adulthood. Many arachnoid cysts are asymptomatic.
Treatment strategies are discussed controversially. If they are diagnosed incidentally or are correlated with only very mild symptoms, a conservative management with follow-up imaging may be favored. If they grow, they can cause headaches, seizures or other neurological symptoms and require neurosurgical treatment. This chapter addresses aspects of pathogenesis, clinical symptoms, indication for neurosurgical treatment and treatment options.
Hydrocephalus is a complex pathophysiology with disturbed cerebrospinal fluid (CSF) circulation. There are numerous numbers of classification trials published focusing on various criteria, such as associated anomalies/underlying lesions, CSF circulation/intracranial pressure patterns, clinical features, and other categories. However, no definitive classification exists comprehensively to cover the variety of these aspects. The new classification of hydrocephalus, "Multi-categorical Hydrocephalus Classification" (Mc HC), was invented and developed to cover the entire aspects of hydrocephalus with all considerable classification items and categories.
Ten categories include "Mc HC" category I: onset (age, phase), II: cause, III: underlying lesion, IV: symptomatology, V: pathophysiology 1-CSF circulation, VI: pathophysiology 2-ICP dynamics, VII: chronology, VII: post-shunt, VIII: post-endoscopic third ventriculostomy, and X: others. From a 100-year search of publication related to the classification of hydrocephalus, 14 representative publications were reviewed and divided into the 10 categories.
The Baumkuchen classification graph made from the round o'clock classification demonstrated the historical tendency of deviation to the categories in pathophysiology, either CSF or ICP dynamics.
In the preliminary clinical application, it was concluded that "Mc HC" is extremely effective in expressing the individual state with various categories in the past and present condition or among the compatible cases of hydrocephalus along with the possible chronological change in the future.
X-linked VACTERL-hydrocephalus syndrome (X-linked VACTERL-H) is a rare disorder caused by mutations in the gene FANCB which underlies Fanconi Anemia (FA) complementation group B. Cells from affected males have increased chromosome breakage on exposure to DNA cross-linking agents. Only five FANCB mutations found in six affected males, including an affected uncle and nephew, have been reported. We have identified FANCB mutations in a further four affected families. The VACTERL-H phenotype segregates as an X-linked recessive trait in three of these. Each mutation is predicted to truncate the FANCB open reading frame and results in highly skewed X-inactivation in unaffected carrier females. Phenotypic data were available on six affected males. Comparison of the clinical findings in our patients with published clinical data (total 12 patients) shows that ventriculomegaly, bilateral absent thumbs and radii, vertebral defects, renal agenesis, and growth retardation are the major phenotypic signs in affected males. Less frequent are brain, pituitary, ear and eye malformations, gastrointestinal atresias (esophageal, duodenal and anal), tracheoesophageal fistula, lung segmentation defects, and small genitalia. Three of six of our patients survived the perinatal period. One boy lived up to 2 years 10 months but developed aplastic anemia and died of renal failure. These data show that loss-of-function FANCB mutations result in a recognizable, multiple malformation phenotype in hemizygous males for which we propose clinical criteria to aid diagnosis.
To identify the defective gene in the sex-linked, recessively inherited retinal dysplasia and degeneration (rdd) chicken and to search for the human equivalent disease.
Microsatellites from chicken chromosome Z were genotyped in 77 progeny of a carrier male (rdd/+) and an affected female (rdd/W), and candidate genes were sequenced. Retinal cross-sections from rdd and wild-type birds were analyzed by immunohistology. The human orthologous gene was screened in a panel of archival DNAs from 276 patients with retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA) using melting curve analysis and DNA sequencing.
The rdd locus was refined to an approximately 3-Mb region on chromosome Z. Sequence analysis identified a C→T change in the mpdz gene that created a premature stop codon (c.1372C→T, p.R458X), which segregated with the disease phenotype. As expected, the full-length mpdz protein was absent in rdd retinas, but in wild-type birds, it localized to the retinal outer limiting membrane, where it may have a role in the interactions between photoreceptors and Müller glia cells. The screen to identify the human equivalent disease found 10 heterozygous variants in the orthologous gene in patients with RP (three missense and two null alleles) and LCA (four missense and one null allele).
These findings reveal that MPDZ is essential for normal development of the retina and may have a role in maintaining photoreceptor integrity. The identification of human mutations suggests that MPDZ plays a role in human retinal disease, but the precise nature of this role remains to be determined.
Neural tube defects (NTDs) are a heterogeneous group of common severe congenital anomalies which affect 1-2 infants per 1000 births. Most genetic and/or environmental factors that contribute to the pathogenesis of human NTDs are unknown. Recently, however, pathogenic mutations of VANGL1 and VANGL2 genes have been associated with some cases of human NTDs. Vangl genes encode proteins of the planar cell polarity (PCP) pathway that regulates cell behavior during early stages of neural tube formation. Homozygous disruption of PCP genes in mice results in a spectrum of NTDs, including defects that affect the entire neural axis (craniorachischisis), cranial NTDs (exencephaly) and spina bifida. In this paper, we report the dynamic expression of another PCP gene, Fuzzy, during neural tube formation in mice. We also identify non-synonymous Fuzzy amino acid substitutions in some patients with NTDs and demonstrate that several of these Fuzzy mutations affect formation of primary cilia and ciliary length or affect directional cell movement. Since Fuzzy knockout mice exhibit both NTDs and defective primary cilia and Fuzzy is expressed in the emerging neural tube, we propose that mutations in Fuzzy may account for a subset of NTDs in humans.
Congenital hydrocephalus is a common and often disabling disorder. The etiology is very heterogeneous. Little is known about the genetic causes of congenital hydrocephalus. A retrospective survey was performed including patients with primary congenital hydrocephalus referred to the Department of Clinical Genetics between 1985 and 2010 by perinatologists, (child) neurologists or pediatricians. Patients with hydrocephalus secondary to other pathology were excluded from this survey. We classified patients with primary congenital hydrocephalus into two main groups: non-syndromic hydrocephalus (NSH) and syndromic hydrocephalus (SH). Seventy-five individuals met the inclusion criteria, comprising 36% (27/75) NSH and 64% (48/75) SH. In 11% (8/75) hydrocephalus was familial. The cause of hydrocephalus was unknown in 81% (61/75), including all patients with NSH. The male-female ratio in this subgroup was 2.6:1, indicating an X-linked factor other than the L1CAM gene. In the group of SH patients, 29% (14/48) had a known cause of hydrocephalus including chromosomal abnormalities, L1 syndrome, Marden-Walker syndrome, Walker-Warburg syndrome and hemifacial microsomia. We performed this survey in order to evaluate current knowledge on the genetic etiology of primary congenital hydrocephalus and to identify new candidate genes or regulatory pathways for congenital hydrocephalus. Recommendations were made concerning the evaluation and genetic workup of patients with primary congenital hydrocephalus. We conclude that further molecular and functional analysis is needed to identify new genetic forms of congenital hydrocephalus.
Costello syndrome is a rasopathy caused by germline mutations in the proto-oncogene HRAS. Its presentation includes failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. In a systematic review we found absolute or relative macrocephaly (100%), ventriculomegaly (50%), and other abnormalities on brain and spinal cord imaging studies in 27/28 individuals. Posterior fossa crowding with cerebellar tonsillar herniation (CBTH) was noted in 27/28 (96%), and in 10/17 (59%) with serial studies posterior fossa crowding progressed. Sequelae of posterior fossa crowding and CBTH included hydrocephalus requiring shunt or ventriculostomy (25%), Chiari 1 malformation (32%), and syrinx formation (25%). Our data reveal macrocephaly with progressive frontal bossing and CBTH, documenting an ongoing process rather than a static congenital anomaly. Comparison of images obtained in young infants to subsequent studies demonstrated postnatal development of posterior fossa crowding. This process of evolving megalencephaly and cerebellar enlargement is in keeping with mouse model data, delineating abnormal genesis of neurons and glia, resulting in an increased number of astrocytes and enlarged brain volume. In Costello syndrome and macrocephaly-capillary malformation syndrome disproportionate brain growth is the main factor resulting in postnatal CBTH and Chiari 1 malformation.
Raised intracranial pressure (ICP) in infants with hydrocephalus may cause (ir)reversible damage to the brain parenchyma but can be present without clinical signs and/or symptoms. Therefore, new, favorably noninvasive, detection methods are needed to distinguish between compensated hydrocephalus with normal intracranial pressure and slowly progressive hydrocephalus with increased intracranial pressure. Because early ischemic changes in the brain parenchyma are associated with increased intracranial pressure, transcranial Doppler (TCD) indices may be useful to detect increased intracranial pressure in infants with hydrocephalus. Twenty-four infants with hydrocephalus underwent noninvasive ICP measurement, magnetic resonance imaging and TCD before and after cerebrospinal fluid (CSF) diversion. The TCD indices were paired to the anterior fontanelle pressure findings and compared for correlation. After CSF diversion, ICP decreased significantly from 21.8 cm H2O to 7.7 cm H2O (p < 0.005). The transsystolic time (TST) as measured with TCD increased significantly from 176 to 221 ms (p < 0.005), whereas the pulsatility index (PI) decreased significantly from 1.3 to 1.0 (p < 0.05). The resistance index (RI) decreased significantly from 0.73 to 0.63 (p < 0.05). Mean bloodflow velocity through the middle cerebral artery increased significantly from 55.5 to 75.8 cm/s (p < 0.005). TST has a strong correlation with the ICP (p < 0.005). Measuring TST with TCD can be helpful in the decision-making process about whether to perform CSF diversion in infants with hydrocephalus. Because TST is related solely to the relative changes in the flow velocity caused by intracranial physical properties, it has a closer relation to ICP than the PI and the RI. (E-mail: [email protected]
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