Hydrocephalus is defined by the abnormal accumulation of cerebrospinal fluid (CSF) within the brain’s ventricles. CSF normally flows through the brain and spinal cord, protecting the central nervous system and removing waste. When the production, circulation, or absorption of CSF is disrupted, the resulting buildup causes the ventricles to enlarge and put pressure on brain tissue. The condition results from a combination of factors that are broadly classified as genetic or acquired.
The Role of Specific Genes
Genetic factors contribute significantly to a subset of hydrocephalus cases, particularly those that are congenital. While most cases are sporadic or acquired, an estimated 40% of congenital hydrocephalus may have a genetic component, often manifesting as part of a larger syndrome. The most common genetic cause of inherited congenital hydrocephalus is X-linked hydrocephalus, attributed to mutations in the L1CAM gene located on the X chromosome.
The L1CAM gene provides instructions for the L1 cell adhesion molecule, a protein integral to brain development. This molecule guides neuronal migration, facilitates cell-to-cell adhesion, and aids in the growth of axons. Disruptions in this gene impair these functions, often leading to a narrowing of the aqueduct of Sylvius. This narrowing blocks CSF flow and causes the ventricular enlargement characteristic of the condition. X-linked hydrocephalus is part of L1 syndrome, which can also include intellectual disability, spasticity, and adducted thumbs.
Hydrocephalus can also be a feature of several other genetic syndromes and single-gene defects.
Genetic Syndromes and Defects
Walker-Warburg syndrome, caused by autosomal recessive mutations involving brain development defects.
Genetic changes in the PI3K-AKT-mTOR pathway, such as mutations in AKT3 and CCND2.
Specific genes like MPDZ and CCDC88C identified in isolated cases.
These genes are involved in the planar cell polarity pathway that governs the function of ependymal cells lining the ventricles. These discoveries highlight that structural malformations or a failure of proper neurodevelopment are often the underlying mechanism.
Non-Genetic Causes
Hydrocephalus not tied to inherited genetic mutations is classified as acquired, developing due to environmental, disease-related, or traumatic factors. This category accounts for a substantial number of cases, occurring both before birth (congenital non-genetic) and later in life. One significant non-genetic cause of congenital hydrocephalus is prenatal infection with pathogens such as Toxoplasma gondii, the parasite responsible for toxoplasmosis.
In congenital toxoplasmosis, the parasite causes inflammation and tissue damage within the fetal brain. This inflammation often obstructs the aqueduct of Sylvius, preventing the normal flow of CSF. The resulting condition is associated with a classic triad of symptoms: hydrocephalus, chorioretinitis, and intracranial calcifications. Other pathogens like cytomegalovirus and rubella can also cause similar inflammatory responses leading to CSF blockage.
Acquired hydrocephalus in infants, children, and adults is commonly triggered by neurological events.
Common Acquired Causes
Intraventricular hemorrhage, particularly in premature infants.
Traumatic brain injury.
Brain or spinal cord tumors that obstruct fluid flow.
Central nervous system infections such as bacterial meningitis.
In these scenarios, scar tissue or inflammation interferes with the normal circulation and reabsorption of CSF.
Understanding Inheritance and Recurrence Risk
When hydrocephalus has a genetic basis, the pattern of inheritance dictates the probability of recurrence for future children. X-linked hydrocephalus presents the highest recurrence risk. Since the L1CAM gene is on the X chromosome, a mother who is a carrier has a 50% chance of passing the gene mutation to any child.
For male offspring, who inherit only one X chromosome, the recurrence risk for the condition is approximately 50%. Other genetic forms follow standard inheritance patterns. Autosomal dominant patterns carry a 50% recurrence risk, while autosomal recessive patterns carry a 25% risk. The autosomal recessive pattern is more likely when parents are related, increasing the chance of both carrying the same gene mutation.
In the majority of cases, a clear genetic cause is not identified, and the hydrocephalus is considered sporadic or multifactorial. In these situations, the empiric recurrence risk for future pregnancies is significantly lower, estimated to be less than 1% to 4%. Genetic counseling is important to accurately determine the cause, as a low empiric risk could be mistakenly given to families who unknowingly carry an X-linked mutation.
Genetic Counseling and Testing Options
Genetic counseling is a specialized resource for families concerned about the cause of hydrocephalus or the probability of recurrence. A genetic counselor reviews the family history, medical records, and imaging studies to determine if the hydrocephalus is isolated, syndromic, or part of a known genetic pattern. This process clarifies the mode of inheritance and provides a precise recurrence risk, allowing families to make informed reproductive decisions.
When a genetic cause is suspected, several testing options are available to confirm the diagnosis. The most common approach involves targeted gene panels, which use Next-Generation Sequencing (NGS) to simultaneously analyze multiple genes known to be associated with hydrocephalus, including L1CAM. If results are inconclusive, broader methods like whole exome sequencing may be employed to screen nearly all protein-coding genes for novel mutations.
Testing can be performed prenatally via amniocentesis or chorionic villus sampling if a familial mutation is already known. For example, if a mother is identified as an L1CAM carrier, prenatal testing can determine the status of a male fetus. Postnatal testing is often recommended when a congenital case has no obvious non-genetic cause, providing a definitive diagnosis that guides medical management and future family planning.