The Conundrum of Mechanics Versus Genetics in Congenital Hydrocephalus and Its Implications for Fetal Therapy Approaches: A Scoping Review.

Recent advances in gene therapy, particularly for single-gene disorders (SGDs), have led to significant progress in developing innovative precision medicine approaches that hold promise for treating conditions such as primary hydrocephalus (CH), which is characterized by increased cerebrospinal fluid (CSF) volumes and cerebral ventricular dilation as a result of impaired brain development, often due to genetic causes. CH is a significant contributor to childhood morbidity and mortality and a driver of healthcare costs. In many cases, prenatal ultrasound can readily identify ventriculomegaly as early as 14-20 weeks of gestation, with severe cases showing poor neurodevelopmental outcomes. Postnatal surgical approaches, such as ventriculoperitoneal shunts, do not address the underlying genetic causes, have high complication rates, and result in a marginal improvement of neurocognitive deficits. Prenatal somatic cell gene therapy (PSCGT) promises a novel approach to conditions such as CH by targeting genetic mutations in utero, potentially improving long-term outcomes. To better understand the pathophysiology, genetic basis, and molecular pathomechanisms of CH, we conducted a scoping review of the literature that identified over 160 published genes linked to CH. Mutations in L1CAM, TRIM71, MPDZ, and CCDC88C play a critical role in neural stem cell development, subventricular zone architecture, and the maintenance of the neural stem cell niche, driving the development of CH. Early prenatal interventions targeting these genes could curb the development of the expected CH phenotype, improve neurodevelopmental outcomes, and possibly limit the need for surgical approaches. However, further research is needed to establish robust genotype-phenotype correlations and develop safe and effective PSCGT strategies for CH.

Congenital hydrocephalus: a review of recent advances in genetic etiology and molecular mechanisms.

The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual's genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner's fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.

Congenital hydrocephalus and ligneous conjunctivitis in two children with severe type I plasminogen deficiency: A case report and literature review.

Type I plasminogen (PLG I) deficiency is a genetic disorder inherited in an autosomal recessive mode and carries high mortality and morbidity. This case report discusses two babies, aged 2 and 3 months, who were diagnosed with ligneous conjunctivitis and congenital hydrocephalus. They had progressive macrocephaly, which led to the insertion of a ventriculoperitoneal shunt. However, there was no significant improvement. During the course of the disease, they underwent genetic testing and were diagnosed with PLG I deficiency. One of the babies underwent ventriculocholecystic shunt insertion as part of palliative care and management, since this disease has poor absorption in the peritoneal cavity. Unfortunately, there was no improvement observed, and he died at 18 months. The other baby received intravenous plasma (10 ml/kg) three times a week, plus using several eye drops daily, with moderate improvement. Promising results are expected with the approved plasminogen, human-tvmh, by the Food and Drug Administration. However, access to the newly approved drug in developing countries is challenging, often hindered by cost or supply issues, necessitating the use of alternative treatments.

Quality of life and functional vision in adolescents with surgically treated hydrocephalus in infancy.

AIM: To evaluate health- and vision-related quality of life (HR- and VR-QoL) and perceptual visual dysfunction (PVD) in adolescents with hydrocephalus surgically treated in infancy. METHODS: In total, 23 adolescents (15 males and 8 females; median age 14.9 years) with hydrocephalus and 31 controls were evaluated using validated instruments to measure HR-QoL and VR-QoL. PVDs were reported by history taking in five areas: recognition, orientation, depth, movement and simultaneous perception. RESULTS: Adolescents with hydrocephalus and the parent proxy reports showed lower mean total Paediatric Quality of Life Inventory 4.0 scores (75.8 and 63.7, respectively) compared with controls (87.6 and 91.5), p = 0.016 and p < 0.0001. Parent-reported scores were lower than self-reported scores (p = 0.001). Adolescents with myelomeningocele (n = 10) showed lower physical health scores (p = 0.001). No VR-QoL difference was found between groups. PVDs were reported in ≥1 area by 14/23 hydrocephalus participants and 2/31 controls (p < 0.0001). Associations were found in the hydrocephalus group between VR-QoL and HR-QoL (rs = 0.47, p = 0.026) and number of PVD areas (rs = -0.6, p = 0.003). CONCLUSION: Adolescents with hydrocephalus and their parents reported lower HR-QoL and more PVDs. These problems indicate the need for not only ophthalmological follow-ups but also evaluation of QoL and PVDs in individuals with infantile hydrocephalus.

Atresia of the Aqueduct of Sylvius as a cause of congenital hydrocephalus.

Hydrocephalus is defined as an anomaly in the flow of cerebrospinal fluid, with multiple and varied etiologies, both acquired and congenital. The most dominant etiology in the congenital aspect is the stenosis or atresia of the Sylvian Aqueduct, whether isolated or associated with other malformations. We report a case of congenital hydrocephalus due to a stenosis of the Aqueduct of Sylvius in a 2 and a half-year-old child, which was unrecognized in the neonatal period, and the importance of imaging, especially MRI, in the rapid diagnosis of this pathology.

A Review of Cerebrospinal Fluid Circulation and the Pathogenesis of Congenital Hydrocephalus.

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.

CCDC88C variants are associated with focal epilepsy and genotype-phenotype correlation.

CCDC88C gene, which encodes coiled-coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole-exome sequencing (trio-based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in the gnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult-onset epilepsy, whereas patients with biallelic variants displayed infant-onset epilepsy. They all responded well to anti-seizure medications and were seizure-free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non-classical splicing and a variant located at crucial domain, suggesting a sub-molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy-associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus-associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.

Abdominal pseudocyst complicating ventriculoperitoneal shunt: A rare indication for ventriculopleural shunt conversion.

Key Clinical Message: Abdominal pseudocyst is a rare complication of ventriculoperitoneal (VP) shunt placement. Ventriculopleural shunt (VPL) can be an effective treatment option for the recurrent complications of VP shunt failure. Abstract: Abdominal pseudocyst (APC) is a rare complication of ventriculoperitoneal (VP) shunt placement for the treatment of congenital hydrocephalus. This case report presents a two-and-a-half-year-old male child who underwent VP shunt placement for aqueductal stenosis-related hydrocephalus. The patient subsequently developed recurrent shunt failure and an APC, which was managed initially by surgical excision of the cyst and repositioning of the catheter. However, shunt failure recurred. The patient underwent ventriculopleural (VPL) shunt conversion as a more viable option for recurrent blockage. Postoperatively, the patient developed respiratory distress with massive pleural effusion, which was treated with chest tube insertion. This case highlights the complexity of managing congenital hydrocephalus and its rare complication, APC. Prompt recognition and appropriate management of APC can lead to improved outcomes and minimize the need for invasive procedures. VPL shunt conversion can be considered an alternative treatment option when other treatments have failed. Further research is needed to establish guidelines for the management of APC and determine the long-term effectiveness of VPL shunting.

Effect of tolvaptan on hyponatremia in a dog with syndrome of inappropriate secretion of antidiuretic hormone.

A 1-year-old spayed female Miniature Schnauzer had chronic hyponatremia, accompanied by polyuria and polydipsia. Blood tests and urinalysis revealed severe hyponatremia, low plasma osmolality with euvolemia, and increased sodium excretion in urine. Hypothyroidism and hypoadrenocorticism were ruled out as causes. These findings led to the diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Magnetic resonance imaging (MRI) showed dilation of the lateral ventricles, indicating severe hydrocephalus. Tolvaptan, a vasopressin V2 receptor antagonist commonly used in human SIADH, was administered along with water restriction. This treatment resulted in a consistent increase in plasma sodium levels without any adverse effects. This case report represents the first documented evidence of the therapeutic efficacy of tolvaptan in treating SIADH in a dog.

A case report of hydrocephalus due to diffuse villous hyperplasia of the choroid plexus: surgical treatment by combination a flexible videoscope with a rigid endoscope.

PURPOSE: Diffuse villous hyperplasia of the choroid plexus (DVHCP) and choroid plexus papilloma (CPP) are rare benign tumors usually diagnosed as a result of progressive hydrocephalus, especially in childhood. We present the case of a Japanese boy diagnosed with progressive hydrocephalus due to DVHCP. METHODS: Case: A 2-year and 3-month-old Japanese boy was found to have delayed motor development (equivalent to 1 year and 2 months old), an enlarged head circumference of 51 cm within + 1.5 standard deviation (S.D.), and incomplete closure of the anterior fontanel. The magnetic resonance imaging (MRI) showed lobular enlargement of the bilateral choroid plexuses extending from the trigone to the body and inferior horn of the lateral ventricle. The endoscopic choroid plexus coagulation surgery was performed to reduce the CSF formation rate. RESULTS: DVHCP was diagnosed both pathologically and clinically. Postoperatively, the patient progressed without complications, such as cerebrospinal fluid leakage. Although ventricular enlargement persisted, the anterior fontanel recessed, and the expansion of the head circumference stopped. CONCLUSION: Few cases of bilateral DVHCP and CPP have been reported in the literature. We encountered a case in which effective choroid plexus coagulation was performed for hydrocephalus due to DVHCP using less invasive endoscopic technique. It also represented an association between DVHCP and the gain of chromosome 9p.

Convergence of multiple RNA-silencing pathways on GW182/TNRC6.

The RNA-binding protein TRIM71/LIN-41 is a phylogenetically conserved developmental regulator that functions in mammalian stem cell reprogramming, brain development, and cancer. TRIM71 recognizes target mRNAs through hairpin motifs and silences them through molecular mechanisms that await identification. Here, we uncover that TRIM71 represses its targets through RNA-supported interaction with TNRC6/GW182, a core component of the miRNA-induced silencing complex (miRISC). We demonstrate that AGO2, TRIM71, and UPF1 each recruit TNRC6 to specific sets of transcripts to silence them. As cellular TNRC6 levels are limiting, competition occurs among the silencing pathways, such that the loss of AGO proteins or of AGO binding to TNRC6 enhances the activities of the other pathways. We conclude that a miRNA-like silencing activity is shared among different mRNA silencing pathways and that the use of TNRC6 as a central hub provides a means to integrate their activities.

Endoscopic Third Ventriculostomy in a 12-Year-Old With Recurrent Failure of Ventriculoperitoneal Shunts.

With a success rate of about 80%, ventriculoperitoneal (VP) shunts are widely used for the treatment of hydrocephalus. Whether congenital or acquired, hydrocephalus is not a single disease entity. It can be caused by abnormal cerebrospinal fluid (CSF) reabsorption, obstruction along the ventricular pathways, or, very rarely, increased production of CSF itself. This case presents a patient with a history of congenital hydrocephalus with multiple failed VP shunts. Through various clinical examinations and diagnostic measures, an endoscopic third ventriculostomy was eventually performed. This case highlights the rare complications, yet a large possibility, that can lead to failure of VP shunts in more than one way and when it is appropriate for shunt reversal versus removal.

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance.

BACKGROUND: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. MATERIALS AND METHODS: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. RESULTS: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. CONCLUSION: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla.

Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (ß-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell-cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.

Risk factors of congenital hydrocephalus: a case-control study in a lower-middle-income country (Egypt).

OBJECTIVE: Hydrocephalus is the most common brain disorder in children and is more common in low- and middle-income countries. Research output on hydrocephalus remains sparse and of lower quality in low- and middle-income countries compared with high-income countries. Most studies addressing hydrocephalus epidemiology are retrospective registry studies entailing their inherent limitations and biases. This study aimed to investigate child-related, parental, and socioeconomic risk factors of congenital hydrocephalus (CH) in a lower-middle-income country. METHODS: An investigator-administered questionnaire was used to query parents of patients with CH and controls who visited the authors' institution from 2017 until 2021. Patients with secondary hydrocephalus and children older than 2 years of age at diagnosis were excluded. Uni- and multivariable logistic regression was performed to identify the factors affecting CH development. RESULTS: Seven hundred forty-one respondents (312 cases and 429 controls) were included in this study. The authors showed that maternal diseases during pregnancy (OR 3.12, 95% CI 1.96-5.03), a lack of periconceptional folic acid intake (OR 1.92, 95% CI 1.32-2.81), being a housewife (OR 2.66, 95% CI 1.51-4.87), paternal illiteracy (OR 1.65, 95% CI 1.02-2.69), parental consanguinity (OR 3.67, 95% CI 2.40-5.69), a history of other CNS conditions in the family (OR 2.93, 95% CI 1.24-7.34), conceiving a child via assisted fertilization techniques (OR 3.93, 95% CI 1.57-10.52), and the presence of other congenital anomalies (OR 2.57, 95% CI 1.38-4.87) were associated with an independent higher odds of a child having CH. Conversely, maternal hypertension (OR 0.22, 95% CI 0.09-0.48), older maternal age at delivery (OR 0.93, 95% CI 0.89-0.97), and having more abortions (OR 0.80, 95% CI 0.67-0.95) were negatively correlated with CH. CONCLUSIONS: Multiple parental, socioeconomic, and child-related factors were associated with higher odds for developing CH. These results can be utilized to guide parental counseling and management, and direct social education and prevention programs.

A novel pathogenic deletion in ISPD causes Walker-Warburg syndrome in a Chinese family.

BACKGROUND: Walker-Warburg syndrome (WWS) is a genetically heterogeneous disease that often presents with complex brain and eye malformations and congenital muscular dystrophy. Mutations of the ISPD gene have been identified as one of the most frequent causes of WWS. OBJECTIVE: The current study aimed to identify the cause of severe congenital hydrocephalus and brain dysplasia in our subject. METHODS: Genomic DNA was extracted from the fetus's umbilical cord blood and peripheral venous blood of the parents. The genetic analysis included whole-exome sequencing and qPCR. Additionally, in silico analysis and cellular experiments were performed. RESULTS: We identified a novel homozygous deletion of exons 7 to 9 in the ISPD gene of the fetus with WWS. In silico analysis revealed a defective domain structure in the C-terminus domain of the ISPD. Analysis of the electrostatic potential energy showed the formation of a new binding pocket formation on the surface of the mutant ISPD gene (ISPD-del ex7-9). Cellular study of the mutant ISPD revealed a significant change in its cellular localization, with the ISPD-del ex7-9 protein translocating from the cytoplasm to the nucleus compared to wild-type ISPD, which is mostly present in the cytoplasm. CONCLUSION: The present study expands the mutational spectrum of WWS caused by ISPD mutations. Importantly, our work suggests that whole-exome sequencing could be considered as a diagnostic option for fetuses with congenital hydrocephalus and brain malformations when karyotype or chromosomal microarray analysis fails to provide a definitive diagnosis.

A congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation.

Congenital hydrocephalus (CH) is a major cause of childhood morbidity. Mono-allelic mutations in Trim71, a conserved stem-cell-specific RNA-binding protein, cause CH; however, the molecular basis for pathogenesis mediated by these mutations remains unknown. Here, using mouse embryonic stem cells as a model, we reveal that the mouse R783H mutation (R796H in human) alters Trim71's mRNA substrate specificity and leads to accelerated stem-cell differentiation and neural lineage commitment. Mutant Trim71, but not wild-type Trim71, binds Lsd1 (Kdm1a) mRNA and represses its translation. Specific inhibition of this repression or a slight increase of Lsd1 in the mutant cells alleviates the defects in stem cell differentiation and neural lineage commitment. These results determine a functionally relevant target of the CH-causing Trim71 mutant that can potentially be a therapeutic target and provide molecular mechanistic insights into the pathogenesis of this disease.

Early Regressive Development of the Subcommissural Organ of Two Human Fetuses with Non-Communicating Hydrocephalus.

Hydrocephalus is a central nervous system condition characterized by CSF buildup and ventricular hypertrophy. It is divided into two types: communicative and non-communicating hydrocephalus. Congenital hydrocephalus has been linked to several changes in the subcommissural organ (SCO). However, it is unclear whether these changes occur before or as a result of the hydrocephalic illness. This report presents three cases of human fetuses with hydrocephalus: one non-communicating case, two communicating cases, and two controls. Hematoxylin-Eosin (H&E) or cresyl violet and immunohistochemistry with anti-transthyretin were used to analyze SCO morphological and secretory changes. We conclude that in the cases presented here, there could be an early regression in the SCO of the communicating cases that is not present in the non-communicating case.

Left Ventricular Non-compaction in a 40-Year-Old Male With Congenital Hydrocephalus.

Left ventricular non-compaction (LVNC) is a rare type of cardiomyopathy resulting from ineffective embryogenesis and is typically recognized shortly after birth. Here, we report a case of LVNC in a 40-year-old male with a history of congenital hydrocephalus who presented in overt heart failure. To date, there have been few reported cases of LVNC associated with hydrocephalus in the pediatric population and the pathophysiology is poorly understood. This nonclassical presentation of LVNC illustrates a rare cause of heart failure that may be related to hydrocephalus. Recognition of LVNC and further elucidating its association with hydrocephalus is crucial for identifying risk factors of LVNC and preventing its progression to heart failure.

Successful conservative management of a large acute epidural hematoma in a patient with arrested hydrocephalus: A case report.

Background: Arrested hydrocephalus is a condition wherein congenital hydrocephalus spontaneously ceases to progress due to a balance between production and absorption of cerebrospinal fluid. These patients rarely present with pressure symptoms so conservative treatment may be instituted. There are, however, little data on the long-term outcomes of these patients and how they present in the presence of other intracranial pathologies as they transition into adulthood. We aim to add to the growing knowledge about the management of patients with arrested hydrocephalus who have sustained traumatic hematomas. Case Description: To the best of our knowledge, we present the only reported case of a 34-year-old female with arrested hydrocephalus who sustained an acute epidural hematoma secondary to a fall and underwent a conservative management. She was asymptomatic except for mild headache that started on the 3rd day postinjury and was thus treated conservatively with favorable outcomes. A review of literature showed that adults with arrested hydrocephalus may develop intracranial hematomas after head injuries despite them manifesting with little or no symptoms. The hydrocephalus may have provided them with a form of internal decompression thus delaying symptomatology. Conclusion: Clinicians should be vigilant as these patients will present with either delayed or completely without neurologic symptomology. Tailored and individualized management of other intracranial pathologies should be adapted in this subset of patients.