Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct.

Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.

Endoscopic third ventriculostomy (ETV) or ventriculoperitoneal shunt (VPS) for paediatric hydrocephalus due to primary aqueductal stenosis.

PURPOSE: The purpose of this study was to compare outcomes of endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) in children with symptomatic triventricular hydrocephalus due to primary aqueductal stenosis. METHOD: This is a retrospective analytical study. Patients who underwent either ETV or VPS as the first procedure for hydrocephalus due to primary aqueductal stenosis were included in the study. RESULT: A total of 89 children were included in the study for analysis. The mean age was 8.4 years. Forty-four (49.4%) had their first surgery as ETV and 45 (50.6%) had their first surgery as VPS. Overall, 34 (38.2%) patients required a second surgery (either ETV or VPS) for persistent or recurrent hydrocephalus. The mean follow-up duration was 832.9 days. The overall complication rate was 13.5%. The mean timing of the second surgery after index surgery was 601.35 days. Factors associated with a second surgery were the presence of complications, high protein in cerebrospinal fluid, the relative change of frontal-occipital horn ratio (FOHR) and Evans' index. The survival of the first surgery was superior in ETV (751.55 days) compared to VPS (454.49 days), p = 0.013. The relative change of fronto-occipital horn index ratio (FOIR) was high in the VPS (mean 7.28%) group compared to the ETV (mean 4.40%), p = 0.001 group. CONCLUSION: Overall procedural survival was better after ETV than VPS for hydrocephalus due to aqueductal stenosis. VPS causes more reduction in linear indices of ventricles as compared to ETV, however, is not associated with the success or complication of the procedure.

Advanced cerebrospinal fluid flow MRI findings of aqueductal stenosis caused by web.

BACKGROUND: The aqueductal web (AW) is one of the causes of aqueductus stenosis (AS). Recent advances in Magnetic resonance (MR) imaging have enabled us to better reveal the cerebrospinal fluid (CSF) flow dynamics and aqueductal anatomy. PURPOSE: The aim of this study is to evaluate the CSF flow dynamics of patients with AW with phase contrast Magnetic resonance imaging (MRI) and compare them with the imaging findings. MATERIALS AND METHODS: We evaluated 23 patients under 65-year-old age. On constructive interference in steady-state (T2 CISS) images, the width of prepontine cistern (PPC) and the width of Sylvian aqueduct (SA) were measured. Localization and number of webs were evaluated. The existence of flow at the aqueduct and the presence of spontaneous third ventriculostomy (STV) were evaluated on sagittal Sampling Perfection with Application optimized Contrast (SPACE) sequences. RESULTS: Of the 23 patients included in the study, 11 were male and 12 were female. The mean age was 34.02 (0.5-64). A total of 31 AWs were detected in 23 patients. Six of 23 patients (26.1%) had STV and 17 of those not. Four of 23 patients (17.4%) had aqueductal flow on SPACE sequences. The PPC distance was significantly wider in patients with STV (median: 6.7-4.5, interquartile range (IQR): 1.35, p = 0.004). In the cases where artifact secondary to flow is observed in SPACE sequences in aqueduct, the Evan index (EI) was significantly lower (median: 0.2955-0.3900, IQR: 0.03-0.14, p < 0.001). CONCLUSION: In patients with a low EI, there may be flow in the SA even if there is a web. In patients with a wide PPC distance, it is necessary to consider the presence of STV and evaluate the presence of flow with the SPACE sequences.

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.

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.

Open-aqueduct LOVA, LIAS, iNPH: a comparative clinical-radiological study exploring the "grey zone" between different forms of chronic adulthood hydrocephalus.

PURPOSE: The definition of chronic adult hydrocephalus encompasses different pathological entities with overlapping characteristics, including long-standing overt ventriculomegaly in adults (LOVA), late-onset idiopathic aqueductal stenosis (LIAS) and idiopathic normal pressure hydrocephalus (iNPH). The aim of our study was to identify preoperative clinical and radiological features peculiar of these diseases providing some pathophysiology inferences on these forms of hydrocephalus. METHODS: Clinical and radiological preoperative records, type of surgical treatment and clinical outcome of patients with chronic adult hydrocephalus who were surgically treated between 2013 and 2019 were retrospectively reviewed. Univariate and multivariate analyses were performed to evaluate the contribution of each variable to the differential diagnosis. RESULTS: In total, 105 patients were included: 18 with LOVA, 23 with LIAS and 64 with iNPH. On multivariate analysis, an enlarged cisterna magna and a more severe ventriculomegaly were associated with the diagnosis of LOVA, while an older age and DESH with iNPH. LIAS patients tend to have an higher prevalence of raised ICP symptoms. Based on that, a clinical and radiological scoring system was developed to distinguish between iNPH and no iNPH cases. A precise cut-off value with a sensitivity of 95.1% and a specificity of 90.6% was identified. CONCLUSIONS: LOVA, LIAS and iNPH are different forms of chronic adulthood hydrocephalus and present different and peculiar clinical and radiological features, with an impact on the treatment and outcome prediction. The implementation of a clinical-radiological score for differential diagnosis may help the differentiation. Further studies are warranted.

Assessment of the prevalence and associated risk factors of pediatric hydrocephalus in diagnostic centers in Addis Ababa, Ethiopia.

BACKGROUND: Hydrocephalus (HCP) is a common disorder of cerebral spinal fluid (CSF) physiology resulting in abnormal expansion of the cerebral ventricles. Infants commonly present with progressive macrocephaly whereas children older than 2 years generally present with signs and symptoms of intracranial hypertension. Neither qualitatively nor quantitatively are there adequate data to determine the prevalence and incidence of HCP in the developing world. HCP is a treatable condition that when left untreated, has fatal consequences. OBJECTIVE: The objective of this study was to assess the prevalence of pediatric HCP and associated risk factors in diagnostic centers in Addis Ababa, Ethiopia. METHODS: This study was conducted using a cross-sectional facility-based study design over a two-time period, i.e. a 2-year retrospective data collection from January 2018 to January 2020 included 1101 patients and a prospective data collection from May 2019 to February 2020 included 99 patients. Children aged 5 years and below who came to the selected diagnostic centers for MRI/CT examination were studied. The collected data were analyzed using binary logistic regression. RESULT: The retrospective study included 639(58%) males and 462 (42%) females. The mean age calculated was 22.3 months. Infants aged younger than 24 months 753 (68.4%) were significantly associated with HCP development (P < 0.05). In the retrospective study, HCP etiologies; Aqueductal stenosis (17.9%), Neural Tube defects (NTDs) (35.7%), post-infectious (10.1%) were identified. In the prospective study, the gender and age distribution was 57(57.6%) males, 42 (42.4%) females, 60.6% infants aged younger than 24 months with a mean age of 24.9 months. Inadequate consumption of folic acid and development of HCP was found to be statistically significant (P < 0.05). In the prospective study, HCP etiologies; Aqueductal stenosis (26.1%), Neural Tube defects (26.08%), and post-infectious (8.69%) were identified. The 3 years prevalence of HCP calculated in both studies was 22% (223 per 1000 live births). CONCLUSION: The results of this study suggest that the high prevalence of HCP was due to the high prevalence of aqueductal stenosis and neural tube defects; with a small contribution of post-infectious causes. The majority of infants who present with HCP were aged younger than 24 months.

Agenesis of the right internal carotid artery and aqueductal stenosis in a child with hydrocephalus, the role of endoscopic third ventriculostomy: a case report.

Agenesis of the internal carotid artery (aICA) is a rare congenital vascular condition that can affect one or both sides of the patient. Most patients remain asymptomatic, but ischemic/hemorrhagic stroke, intracranial aneurysm, and other neurologic findings can occur. CT scan can demonstrate the absence of the bony carotid canal and helps to differentiate a complete aICA from aplasia or hypoplasia. The association of aICA and aqueductal stenosis (AS) has never been reported in the literature. We report the case of a 9-year-old with agenesis of the right ICA associated with AS and hydrocephalus, which was treated successfully with an endoscopic third ventriculostomy (ETV). We review the literature looking for the association of the clinical findings and the evolution of the patient.

X-linked partial corpus callosum agenesis with mild intellectual disability: identification of a novel L1CAM pathogenic variant.

Pathogenic variants in L1CAM, the gene encoding the L1 cell adhesion molecule, are responsible for a wide clinical spectrum including X-linked hydrocephalus with stenosis of the Sylvius aqueduct, MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), and a form of spastic paraplegia (SPG1). A moderate phenotype with mild intellectual disability (ID) and X-linked partial corpus callosum agenesis (CCA) has only been related to L1CAM in one family. We report here a second family, including 5 patients with mild to moderate ID and partial CCA without signs usually associated with L1CAM pathogenic variations (such as hydrocephalus, pyramidal syndrome, thumb adductus, aphasia). We identified a previously unreported c.3226A > C transversion leading to a p.Thr1076Pro amino acid substitution in the fifth fibronectin type III domain (FnIII) of the protein which co-segregates with the phenotype within the family. We performed in vitro assays to assess the pathogenic status of this variation. First, the expression of the novel p.Thr1076Pro mutant in COS7 cells resulted in endoplasmic reticulum (ER) retention and reduced L1CAM cell surface expression, which is expected to affect both L1CAM-mediated cell-cell adhesion and neurite growth. Second, immunoblotting techniques showed that the immature form of the L1CAM protein was increased, indicating that this variation led to a lack of maturation of the protein. ID associated with CCA is not a common clinical presentation of L1CAM pathogenic variants. Genome-wide analyses will identify such variations and it is important to acknowledge this atypical phenotype.

Central nervous system pathology in the amniotic rupture sequence.

AIMS: We delineate and review the central nervous system (CNS) pathology of amniotic rupture sequence (ARS) and its extraneural associations. MATERIALS AND METHODS: We review a consecutive 15-year fetal/neonatal autopsy series for cases of ARS to document its morphology and correlates. RESULTS: We retrieved 15 cases of ARS with complete dissection of the CNS. Seven lacked craniofacial abnormalities; in these the brain and spinal cord were normal. Eight had acalvaria or encephalocele, with facial clefts. All 8 had abnormal brains. Two cases demonstrated normal cerebral lobation with aqueductal stenosis/atresia (AS) and secondary changes. Two cases demonstrated holoprosencephaly and AS. Four other cases had large encephaloceles covered by amnion and extensive secondary change, 3 of which had absent olfactory bulbs, folded and thinned cerebral cortex, reduced thalami, and irregular ventricular systems with superimposed gliosis and hemorrhage. In these, the aqueduct or rostral 4th ventricle was either atretic or occluded by heterotopic neuronal masses. CONCLUSION: CNS pathology in ARS is strongly associated with craniofacial clefts. There is a non-random association between AS, holoprosencephaly, and ARS. Some of the anomalies may be due to abnormal induction events, vascular instability, and the mechanical effects of craniofacial maldevelopment.

A novel nonsense mutation in the L1CAM gene responsible for X-linked congenital hydrocephalus.

BACKGROUND: Congenital hydrocephalus is a descriptive diagnosis of symptoms, that are present for numerous reasons, including chromosomal disorders, genetic mutations, intrauterine infection and hemorrhage, amongst other factors. Mutation of L1CAM gene is the most frequent cause of congenital hydrocephalus, contributing to approximately 30% of X-linked congenital hydrocephalus. METHODS: In the present study, we used whole-exome sequencing and Sanger sequencing to investigate an aborted male fetus present with severe congenital hydrocephalus at 24 weeks of gestation, whose mother had a history of two previous voluntary terminations of pregnancies as a result of hydrocephalus. Magnetic resonance imaging, an autopsy and electron microscopy were performed and the phenotypic changes were described. RESULTS: Whole-exome sequencing in the fetus, as well as variant segregation analysis, revealed a novel maternally derived hemizygous nonsense mutation (c.2865G>A; p. Y955*) in exon 21 of the L1CAM gene (NM_000425.4). Severe hydrocephalus was observed along with marked dilatation of lateral ventricles. An electron micrograph of the surface of lateral ventricle walls revealed a lack of ependymal cilia. CONCLUSION: The present study suggests that L1CAM mutation screening should be considered for a male fetus with isolated hydrocephalus, especially with a family history, which could facilitate prenatal diagnosis in a subsequent pregnancy.

A new frameshift mutation in L1CAM producing X-linked hydrocephalus.

BACKGROUND: X-linked hydrocephalus (XLH), characterized by mental retardation and bilateral adducted thumbs, often come out to be a genetic disorder of L1CAM. It codes the protein L1 cell adhesion molecule (L1CAM), playing a crucial role in the development of the nervous system. The objective of the study was to report a new disease-causing mutation site of L1CAM, and gain further insight into the pathophysiology of hydrocephalus. METHODS: We collect the samples of a couple and their second hydrocephalic fetus. Then, the whole-exome sequencing and in-depth mutation analysis were performed. RESULTS: The variant c.2491delG (p.V831fs), located in the exon 19 of L1CAM (chrX:153131214), could damage the L1CAM function by producing a frameshift in the translation of fibronectin type-III of L1CAM. CONCLUSION: We identified a novel disease-causing mutation in L1CAM for the first time, which further confirmed L1CAM as a gene underlying XLH cases.

Prediction of endoscopic third ventriculostomy (ETV) success with preoperative third ventricle floor bowing (TVFB): a supplement to ETV success score.

Preoperative judgement of which children is likely to benefit from endoscopic third ventriculostomy (ETV) is still the most difficult challenge. This study aimed to compare the efficiency of third ventricular floor bowing (TVFB) and ETV success score (ETVSS) in selecting ETV candidates and achieve a better preoperative patient selection method for ETV based on our institutional experience. Children (≤ 16 years old) with newly diagnosed hydrocephalus treated with ETV between January 2013 and June 2018 were included in this prospective study. Patients with TVFB will receive ETV procedure in the pediatric subgroup of our department. ETVSS was calculated in every patient. The ETVSS predicted ETV success rate and the actual ETV success rate in our institution were compared and further analyzed. One hundred twenty-nine children with TVFB were enrolled in our study. The mean age at ETV was 5.84 ± 5.17 years (range, 0.04-16). Brain tumors, aqueductal stenosis, and inflammatory are the most common hydrocephalus etiologies. The most common complication was noninfectious fever (3.1%). During the average follow-up of 19.5 ± 14.95 months, twenty-five patients had depicted ETV failure. The actual ETV success rate (81%) in our study was higher than the success rate (69%) predicted by ETVSS. TVFB is a pragmatic, efficient, and simple model to predict the ETV outcome. We suggest that for hydrocephalic patients with preoperative third ventricular floor bowing, ETV should be the first-treatment choice regardless of the ETV success score. And for patients without such sign, ETVSS should be applied to select ETV candidates.

SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.

BACKGROUND: Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery. METHODS: WES of family members of a sporadic and familial form of severe L1CAM mutation-negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression. RESULTS: A novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K+ -Cl- cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion-transporting domain, and significantly reduces KCC3-dependent K+ transport. A novel de novo CNV (deletion) was identified in SLC12A7, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH. CONCLUSION: These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.

Low-field magnetic resonance imaging and computed tomography of a calf with aqueductal stenosis caused by web: comparison with normal calves.

A 6-day-old female Holstein displayed a dome-shaped skull and cardiac murmur on physical examination. Neurological abnormalities included progressive ataxia, decreased pupillary light reflex, and blindness soon after birth. On diagnostic imaging, CT identified expanded ventricles and thyroid hypoplasia on the left side. MRI detected expanded ventricles, especially in the rostral cerebrum at the mesencephalic aqueduct, compared with normal calves, so we suspected hydrocephalus causing stenosis of the mesencephalic aqueduct. Postmortem examination revealed a structure in the mesencephalic aqueduct resembling the "web" type of aqueductal stenosis described in humans. This case report indicates the utility of describing mesencephalic aqueductal stenosis by web and detection of other malformations on CT and MRI for antemortem diagnosis in calves.

Two novel pathogenic variants of L1CAM gene in two fetuses with isolated X­linked hydrocephaly: A case report.

Hydrocephalus due to aqueductal stenosis (HSAS; Online Mendelian Inheritance in Man #307000) is a rare X­linked, recessively­inherited disease characterized by severe hydrocephaly and occasionally adducted thumbs, in addition to intellectual disability and spasticity in surviving individuals. The present study described two fetuses with severely enlarged ventricles of the brain. The clinical diagnosis of HSAS was made on the basis of family history and sonographic findings. Molecular testing of the L1 cell adhesion molecule (L1CAM) gene revealed two novel hemizygous L1CAM variants, c.998C>T(p.Pro333Leu) and c.2362G>T(p.Val788Phe). The variants affect the highly conserved amino acids which are located in the key domains of the protein (the fourth Ig domain and second FnIII domain, respectively). The two variants were predicted to be 'disease causing' by a number of prediction tools, and have been classified as likely pathogenic following the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. The present study highlights the importance of combining family history, prenatal ultrasonography and molecular testing in the diagnosis of HSAS. The novel variants expand the mutational spectrum of L1CAM gene in the Chinese population, and could be used in genetic counseling, carrier testing of female relatives, and prenatal, as well as preimplantation genetic diagnosis.

Anterior skull base duplication requiring delivery via EXIT procedure: A case report.

Duplication of the anterior skull base structures is an extremely rare malformation of failed midline blastogenesis. We present the case of a child with an obstructive oral cavity mass diagnosed on prenatal imaging. The child was successfully delivered by EXIT procedure, a tracheotomy was performed, and postnatal imaging demonstrated an array of craniofacial malformations, including complete duplication of the maxilla, pituitary glands, aqueducts of Sylvius, and basilar arteries. The child underwent excision of the duplicate maxilla, resulting in a wide cleft palate that will be repaired at a future date.

A propósito de un caso; Hidrocefalia fetal ligada a cromosoma X (Síndrome de L1) / X-Linked Fetal hydrocephalus (L1 syndrome): Report of clinical case

Presentamos el caso de una paciente de 22 años que solicita interrupción de la gestación tras el diagnóstico de hidrocefalia fetal en la semana 34. Tras el estudio de necropsia fetal se evidencia ausencia de la vía piramidal por lo que se establece el diagnóstico de sospecha de hidrocefalia ligada a X con estenosis del acueducto de Silvio (hydrocephalus due to congenital stenosis of aqueduct of Sylvius HSAS). Se realiza estudio del gen L1CAM en ADN fetal detectándose la variante c.1484A > G (p.Tyr495Cys) en hemicigosis catalogada como de significado clínico incierto. El estudio de la variante genética en la gestante confirma su estado de portadora heterocigota. Dado estos hallazgos consideramos necesario elaborar una revisión bibliográfica sobre síndrome de hidrocefalia fetal ligada al cromosoma X9

We present the case of a 22 years old patient who requested interruption of pregnancy after the diagnosis of fetal hydrocephalus at week 34. After the fetal necropsy study the absence of the pyramidal tract is evidenced therefore the diagnosis of suspicion of X-linked hydrocephalus with stenosis of aqueduct of Sylvius (hydrocephalus due to congenital stenosis of aqueduct of Sylvius. HSAS) is established. A study of the L1CAM gene in fetal DNA was carried out detecting the variant c.1484A > G (p.Tyr495Cys) in hemicigosis cataloged as of uncertain clinical significance. The study of the genetic variant in the pregnant woman confirms its heterozygous carrier status. Because of these findings we consider necessary do a review of X-linked hydrocephalus syndrome 9

Congenital Aqueductal Stenosis: Findings at Fetal MRI That Accurately Predict a Postnatal Diagnosis.

BACKGROUND AND PURPOSE: Congenital aqueductal stenosis is a common cause of prenatal ventriculomegaly. An accurate diagnosis provides prognostic information and may guide obstetric management. The purpose of this study was to identify specific anatomic findings on prenatal MR imaging that can be used as predictors of congenital aqueductal stenosis. MATERIALS AND METHODS: Prenatal and postnatal MRIs of fetuses referred to our institution for ventriculomegaly between June 2008 and August 2015 were reviewed. Imaging findings in postnatally confirmed congenital aqueductal stenosis (disease group) were compared with those of ventriculomegaly cases from other causes (control group). Univariate analysis was performed using the Fisher exact test and the Wilcoxon rank test, and multivariate analysis, via the random forest method. RESULTS: Forty-three cases of ventriculomegaly had a confirmed postnatal diagnosis of congenital aqueductal stenosis. Thirty-two ventriculomegaly cases negative for congenital aqueductal stenosis were included in the control group. Dominant findings associated with an accurate prenatal diagnosis of congenital aqueductal stenosis on multivariate analysis included the following: enlarged inferior third ventricular recesses, enlargement of the lateral ventricles and third ventricle, and an abnormal corpus callosum. Findings that significantly increase the probability of congenital aqueductal stenosis (high positive predictive value) included the following: enlarged third ventricular recesses, aqueduct funneling, hemorrhage in the cerebral aqueduct, ventricular diverticulum, rhombencephalosynapsis, and dystroglycanopathy-related cerebellar dysplasia. CONCLUSIONS: Our study identified specific characteristics on fetal MR imaging that can be used as predictors of the diagnosis of congenital aqueductal stenosis. Most of these findings are secondary to the obstructive nature of the resulting hydrocephalus. Common associated malformations such as rhombencephalosynapsis and dystroglycanopathies should also increase the suspicion of congenital aqueductal stenosis when present with ventriculomegaly.