Congenital Anomalies of the Brain and Spinal Cord

Congenital anomalies of the central nervous system (CNS) represent a diverse spectrum of structural and functional pathologies resulting from disruptions in embryonic and fetal neurodevelopment. As the leading causes of chronic disability and neonatal mortality, these malformations encompass a range of defects from lethal conditions such as anencephaly to complex structural disorders like holoprosencephaly and myelomeningocele. The clinical significance of these anomalies is underscored by their prevalence—approximately 1 to 2 per 1,000 births—and their lifelong impact on neurodevelopmental, motor, and autonomic functions. Recent advancements in the late 2024 and early 2026 period have transformed the diagnostic and therapeutic landscape, shifting from a model of postnatal symptom management to one of prenatal genetic precision and intrauterine surgical intervention.

Embryological Foundations of CNS Morphogenesis

The ontogeny of the brain and spinal cord is a highly regulated spatio-temporal sequence beginning in the third week of gestation. This process is largely defined by neurulation, the formation of the neural tube from the embryonic ectoderm. Primary neurulation involves the folding of the neural plate and its subsequent closure, which proceeds in both rostral and caudal directions. The rostral neuropore typically closes by day 24, giving rise to the brain, while the caudal neuropore closes by day 26 to day 28, forming the majority of the spinal cord. Failures in this primitive closure lead to open neural tube defects (ONTDs), where neural tissue remains exposed to the external environment or amniotic fluid.

Following the completion of primary neurulation, secondary neurulation occurs, involving the canalization of the caudal cell mass to form the sacral and coccygeal segments of the spinal cord. Disruptions during this phase, occurring around day 26 of gestation, are typically associated with closed spinal dysraphisms, as the defect is already covered by surface ectoderm. Simultaneously, the prosencephalon, or forebrain, undergoes a series of cleavage and midline development stages to form the telencephalon and diencephalon. This cleavage is essential for the separation of the cerebral hemispheres and the formation of midline structures such as the corpus callosum and septum pellucidum.

The subsequent stages of development involve neuronal proliferation, where neuroblasts are generated in the periventricular germinal zones, followed by neuronal migration along radial glial fibers to form the six-layered cerebral cortex. This complex migratory process, primarily occurring between the 7th and 20th weeks of gestation, is the foundation for cortical organization. Post-migrational organization and myelination continue well into the postnatal period, and disruptions at any point in this continuum result in distinct classes of malformations.

Developmental Chronology and Pathological Correlations

Gestational Age	Developmental Process	Potential Clinical Anomaly
Days 17–24	Primary Neurulation (Cranial)	Anencephaly, Craniorachischisis
Days 17–28	Primary Neurulation (Spinal)	Myelomeningocele, Myeloschisis
Day 26–Wk 8	Secondary Neurulation	Tethered Cord, Filum Terminale Lipoma
Wks 5–10	Prosencephalic Cleavage	Holoprosencephaly Spectrum
Wks 7–20	Neuronal Migration	Lissencephaly, Heterotopia
Wks 8–18	Callosal Development	Agenesis of the Corpus Callosum (ACC)

The implications of this chronology are profound; the timing of an environmental or genetic insult dictates the morphology of the resulting malformation. For instance, an insult at day 22 will likely result in a cranial defect, whereas an insult at the 12th week of gestation may disrupt the formation of the corpus callosum or cortical lamination.

Etiology and Multifactorial Risk Landscape

The etiology of CNS anomalies is characterized by a multifactorial model involving a complex interplay of genetic susceptibility, environmental exposures, and nutritional status. While approximately 50% of cases occur without a clearly identifiable single cause, recent genomic research has begun to unravel the underlying drivers of these defects.

Nutritional Factors and Folate Metabolism

Folic acid deficiency is the most significant preventable risk factor for neural tube defects. Periconceptional supplementation with 400 \mu g of folic acid per day has been demonstrated to reduce the incidence of NTDs by up to 70% in the general population. For women with a prior history of an NTD-affected pregnancy, a higher dose of 4,000 \mu g (4 mg) is recommended, which research shows can reduce recurrence risk by 72%. The physiological mechanism of folate is tied to its role in DNA synthesis and methylation; a deficiency disrupts the rapid cellular proliferation required for neural tube closure. Genetic polymorphisms in the MTHFR gene, particularly the C677T variant, further compound this risk by impairing the enzyme’s ability to process folate, thus increasing susceptibility even in the presence of moderate intake.

Environmental and Teratogenic Risks

Maternal metabolic health is a critical determinant of fetal neurodevelopment. Poorly controlled pregestational diabetes and maternal obesity are strongly associated with increased rates of NTDs and holoprosencephaly. Furthermore, exposure to specific pharmaceutical agents can be highly detrimental. Valproic acid, commonly used for epilepsy and mood disorders, is a potent teratogen that increases the risk of spina bifida approximately 10-fold. Other environmental factors include maternal infections—specifically the TORCH group (Toxoplasmosis, Rubella, Cytomegalovirus, and Herpes) and the Zika virus—which can cause destructive brain lesions, microcephaly, and cortical migration disorders.

Genomic Foundations and De Novo Mutations

The genetic landscape of CNS anomalies has shifted from a focus on large chromosomal aneuploidies, such as Trisomy 13 (Patau syndrome) and Trisomy 18 (Edwards syndrome), to the identification of specific molecular pathways. Holoprosencephaly is frequently linked to mutations in the Sonic Hedgehog (SHH), BMP, and FGF signaling pathways, which are vital for prosencephalic cleavage. Disorders of cortical development, such as megalencephaly and hemimegalencephaly, are often driven by overactivation of the PI3K/AKT/mTOR pathway, leading to dysregulated cell growth.

In a landmark study published in early 2025, researchers at the Rady Children’s Institute for Genomic Medicine utilized advanced sequencing to demonstrate that nearly 25% of spina bifida cases are influenced by de novo mutations—genetic changes present in the child but not the parents. These mutations often cluster in functional modules that regulate how embryonic cells adhere and communicate during the critical phases of neurulation. This discovery suggests that many isolated NTDs, previously thought to be purely environmental, may have a discrete monogenic basis, potentially paving the way for targeted gene therapies or personalized nutritional interventions.

Neural Tube Defects: Morphological Classification and Clinical Presentation

Neural tube defects are broadly categorized into open and closed dysraphisms, depending on whether the neural tissue is exposed to the environment.

Open Neural Tube Defects of the Cranium

Anencephaly represents the most severe cranial NTD, characterized by the absence of the cranial vault and the majority of the cerebral hemispheres, although the brainstem may be variably present. It results from a failure of the rostral neuropore to close by approximately the 24th day of gestation. Affected infants exhibit a “frog eye” appearance on imaging due to bulging orbits in the absence of a forehead. The condition is incompatible with life, and infants are typically stillborn or die shortly after birth. Polyhydramnios is a common secondary complication due to the fetus’s inability to swallow amniotic fluid.

Encephalocele involves the herniation of the brain or its coverings through a defect in the skull. These can occur anywhere from the nasal cavity to the occipital region. Occipital encephaloceles are the most common in Western populations, while anterior (nasal) encephaloceles are more prevalent in Southeast Asia. The clinical outcome depends on the amount of herniated brain tissue and the presence of associated hydrocephalus; large encephaloceles containing functional cortex often lead to significant neurological impairment and visual deficits.

Spina Bifida and Spinal Dysraphism Spectrum

Spina bifida refers to a defective fusion of the vertebral posterior elements. It is the most common CNS malformation surviving into infancy.

Spina Bifida Occulta (Closed Spinal Dysraphism)

This is the mildest form, where the vertebral defect is covered by skin and there is no protrusion of neural elements. It is frequently asymptomatic and may be discovered incidentally during radiographic examination for other conditions. However, cutaneous markers such as a hairy patch, a deep dimple, or a fatty mass over the lower spine (lipoma) can be clinical clues to an underlying occult spinal dysraphism, which may lead to cord tethering later in life.

Spina Bifida Aperta (Open Spinal Dysraphism)

This category includes more severe defects where neural tissue and meninges communicate with the external environment.

• Meningocele: A sac of fluid and meninges protrudes through a vertebral opening, but the spinal cord remains within the canal. Neurological damage is typically minimal, though the sac requires surgical closure to prevent infection.
• Myelomeningocele (MMC): The most common and debilitating form, involving the protrusion of the spinal cord, nerves, and meninges through the vertebral defect. This leads to permanent neurological damage below the level of the lesion, including paraplegia, sensory loss, and neurogenic bowel and bladder dysfunction.
• Myeloschisis: A variant where the spinal cord is exposed as a flat neural placode without an overlying sac.

Comparative Features of Spina Bifida Types

Feature	Spina Bifida Occulta	Meningocele	Myelomeningocele
External Sac	Absent	Present (fluid only)	Present (neural tissue + fluid)
Skin Coverage	Intact	Often thinning	Absent/Exposed
Spinal Cord	Normal position	Normal position	Herniated/Displaced
Neuro Deficits	Usually none	Minimal/Variable	Severe (paralysis, incontinence)
Hydrocephalus	Rare	Uncommon	Very common (70-90%)

The presence of myelomeningocele is almost always associated with the Chiari II malformation—a downward displacement of the cerebellum and brainstem into the spinal canal—which blocks the flow of CSF and leads to hydrocephalus. This “second hit” of brain dysfunction significantly impacts cognitive and autonomic outcomes.

Forebrain Malformations and Midline Defects

Disruptions in the cleavage and differentiation of the prosencephalon result in a spectrum of midline brain anomalies that profoundly affect facial morphology and cognitive function.

Holoprosencephaly (HPE)

Holoprosencephaly is characterized by the failure of the prosencephalon to divide into two distinct cerebral hemispheres. It is strongly associated with chromosomal anomalies (Trisomy 13) and maternal diabetes. The condition is classified into four subtypes in declining order of severity:

• Alobar HPE: The most severe form, with a completely undivided forebrain, a single primitive ventricle, and fused thalami. It is often associated with cyclopia or ethmocephaly and is typically fatal.
• Semilobar HPE: Partial separation of the hemispheres posteriorly, but fused anteriorly. Facial features may include hypotelorism or cleft lip/palate.
• Lobar HPE: The hemispheres are mostly separate, but the anterior horns of the lateral ventricles and the cingulate gyri remain fused. The septum pellucidum is universally absent.
• Middle Interhemispheric Variant (MIHV): The mildest form, where only the posterior frontal and parietal lobes are fused.

The neurological manifestations of HPE include severe developmental delay, intractable epilepsy, and hypothalamic-pituitary dysfunction.

Agenesis of the Corpus Callosum (ACC)

The corpus callosum is the primary white matter structure connecting the left and right cerebral hemispheres. Agenesis can be complete or partial (dysgenesis/hypoplasia) and is often caused by a disruption in neuronal migration or axon guidance during the 12th to 22nd weeks of pregnancy. While isolated ACC can sometimes be asymptomatic or present with mild learning challenges, it is frequently associated with other syndromes such as Aicardi syndrome (specific to females, involving ACC, retinal lesions, and infantile spasms). Clinical symptoms often involve clumsiness, poor bilateral motor coordination, and impairments in social and mental processing that overlap with the autism spectrum.

Septo-optic Dysplasia (De Morsier Syndrome)

This rare triad consists of a defect in the midline forebrain structures (absent septum pellucidum), hypoplasia of the optic nerves, and pituitary insufficiency. It results in a constellation of symptoms including nystagmus, vision loss, and hormonal imbalances such as growth hormone deficiency. The condition is linked to mutations in HESX1 and other genes involved in midline patterning.

Disorders of Cortical Development (MCD)

Malformations of cortical development occur when the processes of neuronal proliferation, migration, or organization are perturbed.

• Lissencephaly (Agyria): A failure of neuronal migration resulting in a smooth brain without normal folds (gyri) and a thickened four-layered cortex. It is characterized by severe intellectual disability and early-onset epilepsy. Mutations in LIS1 and DCX (X-linked) are the most common genetic causes.
• Megalencephaly and Hemimegalencephaly: Conditions of increased brain size due to over-proliferation of cells or lack of apoptosis. Hemimegalencephaly involves only one hemisphere and is a common cause of intractable seizures in infancy.
• Polymicrogyria: A disorder of late migration or cortical organization characterized by an excessive number of small, fused gyri. It can be focal or diffuse and is often associated with prenatal vascular insults or cytomegalovirus infection.
• Heterotopia: Clusters of neurons that “stalled” in the wrong location during migration, often along the ventricular walls (periventricular nodular heterotopia). These nodules are highly epileptogenic.

Posterior Fossa and Hindbrain Anomalies

Anomalies of the posterior fossa often disrupt the flow of CSF and the development of motor coordination and balance.

Chiari Malformation Spectrum

Chiari malformations are defined by the herniation of hindbrain structures through the foramen magnum.

Type	Anatomy Involved	Primary Associations
Chiari I	Cerebellar tonsils >5mm below foramen magnum	Syringomyelia, Scoliosis, adult-onset headaches
Chiari II	Cerebellum + Brainstem + 4th Ventricle	Myelomeningocele, Hydrocephalus
Chiari III	Cerebellum/Brainstem in high cervical encephalocele	Severe neuro deficits, Rare
Chiari IV	Cerebellar Hypoplasia/Aplasia	No herniation, severe coordination loss
Chiari 0	Syringohydromyelia with minimal/no herniation	Disrupted CSF flow at craniocervical junction

Symptoms of Chiari II in infants are often life-threatening, including vocal cord paralysis, sleep apnea, and difficulty swallowing (dysphagia) due to brainstem compression.

Dandy-Walker Malformation (DWM)

DWM is characterized by a triad: cystic dilation of the fourth ventricle, hypoplasia of the cerebellar vermis, and enlargement of the posterior fossa. Hydrocephalus occurs in approximately 90% of cases. While 50% of patients have a normal IQ, many suffer from balance difficulties (ataxia) and poor fine motor control. A rare but significant complication is the development of syringomyelia associated with DWM, which requires individualized surgical fenestration.

Secondary Spinal Pathology: Syringomyelia and Tethered Cord

Many congenital CNS anomalies lead to secondary pathologies that may not manifest until later in childhood or even adulthood.

Syringomyelia

Syringomyelia is the development of a fluid-filled cyst (syrinx) within the spinal cord. The syrinx expands over time, compressing neural tissue and causing a “cap-like” sensory loss across the shoulders, muscle wasting in the hands, and chronic pain. The most common cause is the Chiari I or II malformation, which alters CSF pressure dynamics. Treatment often involves posterior fossa decompression to restore normal CSF flow.

Tethered Cord Syndrome (TCS)

TCS occurs when the spinal cord is abnormally attached to surrounding tissues—such as a thickened filum terminale, an intradural lipoma, or scar tissue from a previous surgery—preventing it from moving freely within the spinal canal. As the child grows, this attachment stretches the cord, leading to progressive neurological deficits including leg weakness, foot deformities (clubfoot), and worsening bladder control.

Recent clinical trials in 2025 and 2026 have explored the efficacy of “spinal column shortening” versus traditional detethering surgery for recurrent TCS in adults. While detethering directly addresses the attachment, it carries a high risk of CSF leakage; spinal column shortening, which reduces tension on the cord by removing a vertebral segment, has emerged as a promising alternative with lower complication rates and significant pain reduction.

Visual Hallmarks and Radiological Patterns in Diagnostic Imaging

The diagnosis and characterization of CNS anomalies are driven by distinct visual patterns identified through advanced neuroimaging. These pathognomonic “signs” serve as critical clinical evidence for early intervention.

• The Lemon Sign: Observed on transverse cranial sonography, this sign refers to a scalloping or biconcavity of the frontal bones, giving the fetal skull a lemon-like configuration. It is a strong indirect marker for open spina bifida, particularly before 24 weeks of gestation.
• The Banana Sign: This hallmark describes the shape of the cerebellum when it is flattened and curved anteriorly around the brainstem due to downward herniation through the foramen magnum. This wrapping appearance is diagnostic of the Chiari II malformation associated with myelomeningocele.
• The Molar Tooth Sign (MTS): Pathognomonic for Joubert syndrome, the MTS is visualized on axial MRI at the midbrain-pons junction. It is formed by the combination of an abnormally deep interpeduncular cistern and thickened, elongated superior cerebellar peduncles that resemble the crown and roots of a molar tooth.
• Craniofacial Markers in Holoprosencephaly: Severe brain malformations often mirror dramatic facial phenotypes visible on ultrasound. These include cyclopia (a single centrally placed eye), ethmocephaly (a proboscis located between closely spaced eyes), and cebocephaly (a combination of a single-nostril nose and ocular hypotelorism).
• The Tail Sign: In Dandy-Walker malformations, modern T2-weighted MRI can identify a specific “tail sign,” which appears as a hypointense linear structure at the inferior aspect of the cerebellar vermis.

Evolution of Diagnostic Paradigms

The diagnosis of CNS anomalies has transitioned from simple ultrasound to a complex integrated framework of prenatal imaging and genomics.

Prenatal Screening and Neuroimaging

Maternal serum alpha-fetoprotein (MSAFP) remains a critical screening tool; elevated levels (typically >2.5 MoM) are highly suggestive of an open neural tube defect. Ultrasound is the first-line diagnostic modality, capable of detecting major anomalies like anencephaly as early as 11 weeks. For spina bifida, the presence of the “lemon sign” and “banana sign” provides a high degree of diagnostic certainty.

Fetal Magnetic Resonance Imaging (MRI) is increasingly used to complement ultrasound. Fetal MRI offers superior soft-tissue contrast, allowing for the identification of “sonographically occult” anomalies such as cortical heterotopias, subtle callosal dysgenesis, and detailed anatomy of the posterior fossa. In pregnancies at high risk for genetic syndromes, fetal MRI is performed even if the ultrasound appears normal, as brain malformations can be difficult to detect via sonography alone.

The Genomic Revolution: WES and WGS

While chromosomal microarray analysis (CMA) has replaced karyotyping as the first-tier genetic test, Next-Generation Sequencing (NGS) technologies have significantly increased diagnostic yield. Prenatal Exome Sequencing (pES) and Genome Sequencing (pGS) are now routinely offered when structural anomalies are detected by imaging.

Diagnostic Modality	Incremental Yield in BAs*	Clinical Utility
Karyotype	Baseline	Detection of large aneuploidies
CMA	~3.5% over Karyotype	Detection of CNVs (deletions/duplications)
Exome Sequencing	~26.5% to 38% over CMA	Detection of pathogenic SNVs (single genes)
Genome Sequencing	~36% to 40%	Comprehensive (introns + exons + CNVs)
*BAs: Brain Anomalies

Meta-analyses in 2025 confirm that for complex brain malformations, the diagnostic yield of exome sequencing is significantly higher (38%) than for isolated anomalies (22%), providing crucial data for clinical management and parental decision-making.

The Fetal Surgery Revolution: Myelomeningocele Repair

One of the most profound advancements in pediatric neurosurgery is the development of in-utero repair for spina bifida. The Management of Myelomeningocele Study (MOMS) demonstrated that prenatal repair reduces the need for postnatal shunting for hydrocephalus and improves independent ambulation at 30 months and into school age.

Open vs. Fetoscopic Surgical Techniques

Initially, fetal surgery was performed via an open hysterotomy, requiring a large uterine incision. However, the field has rapidly moved toward minimally invasive fetoscopic repair.

• Open Fetal Surgery: The spinal defect is accessed through a 7 cm incision across the mother’s uterus. Risks include preterm birth, uterine rupture, and the requirement for Cesarean delivery in all subsequent pregnancies.
• Fetoscopic Fetal Surgery: The repair is performed through two to three 4 mm incisions using a fetoscope and tiny instruments. This approach permits vaginal delivery and carries a significantly lower risk of uterine rupture.

As of November 2025, centers like Texas Children’s have completed over 220 fetoscopic repairs, demonstrating that the outcomes for the infant—specifically the reduction in shunting and improved leg function—are equivalent to open surgery, with vastly reduced maternal risk.

Regenerative and Cellular Innovations (2025-2026)

The “CuRe Trial” at UC Davis, active in 2025, represents the first treatment combining fetal surgery with stem cell therapy. In this approach, a patch seeded with mesenchymal stem cells is applied to the neural placode during repair to promote tissue regeneration and prevent further chemical damage from amniotic fluid. Similarly, UTHealth Houston is conducting efficacy trials using a cryopreserved human umbilical cord (HUC) patch as a meningeal scaffold. This HUC patch has shown zero CSF leakage at birth and has resulted in a 46% rate of vaginal delivery, redefining the standard for fetal wound healing.

Multidisciplinary Care and Neuro-Intensive Rehabilitation

The management of children with CNS anomalies requires a lifelong, interdisciplinary approach that integrates surgical precision with innovative rehabilitative technologies.

The Neuro-Intensive Care Paradigm

Neonatal Intensive Care Units (NICUs) have undergone a “conceptual revolution,” moving toward neuro-intensive care. This involves continuous video-EEG monitoring to detect silent seizures and the use of therapeutic hypothermia for neuroprotection in high-risk neonates. Predictive algorithms based on large omics databases are now used to individualize treatment and provide more accurate outcome predictions for families.

Technological Advances in Rehabilitation

Rehabilitation for congenital spinal dysfunction now incorporates robotic and digital tools to maximize independent function.

• Robotic Exoskeletons: Devices such as the ERIGO and wearable exoskeletons allow for early verticalization and gait training, reducing complications like muscle atrophy and autonomic decline.
• Virtual Reality (VR): Immersive and semi-immersive VR systems create stimulating environments for both motor and cognitive therapy, allowing SCI patients to practice daily living activities in a safe, controlled setting.
• Brain-Computer Interfaces (BCI): As of early 2026, clinical research into invasive BCIs has begun to offer hope for restoring communication in patients with severe motor deficits resulting from high cervical spinal cord injury or brainstem anomalies.

Future Frontiers: AI, Precision Medicine, and Gene Delivery (2026 and Beyond)

As we look toward the remainder of 2026, the integration of artificial intelligence (AI) and novel gene delivery systems is poised to transform the field.

AI-Driven Diagnostics and Phenotyping

AI is emerging as a potent tool for early detection and personalized medicine. Next-generation phenotyping tools like “Brain2Gene” use AI to analyze MRI patterns and predict genetic diagnoses with high accuracy. AI-enhanced seizure prediction algorithms and robotics are also increasing the safety and precision of cranial and spinal neurosurgeries.

Precision Gene Delivery Systems

The NIH’s BRAIN Initiative has recently pioneered “delivery truck” systems—modified adeno-associated viruses (AAVs)—that can deliver genetic packages to specific neighborhoods of cells in the brain and spinal cord. This platform allows researchers to activate or silence specific neural circuits without the need for transgenic animal models. For patients with rare loss-of-function genetic diseases, such as those within the lissencephaly or holoprosencephaly spectra, these delivery systems offer the hope of disease-modifying gene replacement therapy rather than just symptomatic management.

Breakthrough Drug Approvals and Trials

The 2026 neurology landscape is marked by a wave of new therapeutic approvals. Key expected decisions include tolebrutinib for progressive multiple sclerosis and new formulations of nimodipine (GTx-104) for managing aneurysmal subarachnoid hemorrhage—advancements that, while focused on adults, represent the accelerating pace of neuro-pharmacological innovation that will eventually extend to neonatal neuro-intensive care. In the rare pediatric disease space, convection-enhanced gene therapy is now entering clinical practice for specific enzyme deficiencies that lead to severe neurodevelopmental delay.

Conclusion: Synthesis and Clinical Implications

Congenital anomalies of the brain and spinal cord represent a significant challenge that requires a paradigm shift from reactive treatment to proactive, personalized care. The synthesis of embryological understanding, high-resolution fetal imaging, and genomic sequencing has enabled the identification of these defects at earlier gestational stages, providing a “window of opportunity” for intervention.

The success of fetoscopic myelomeningocele repair and the emergence of in-utero stem cell treatments signal a new era where anatomical repair is coupled with biological regeneration. Furthermore, the application of AI and precision gene delivery systems promises a future where the natural course of even the most debilitating CNS disorders can be fundamentally modified. For the clinician, the priority remains the integration of these advanced technologies into multidisciplinary care pathways that prioritize accuracy, personalization, and the ultimate goal of ensuring that every child born with a CNS anomaly can thrive.