Overview of neonatal brain malformations of the cortex

INTRODUCTION — When managing brain malformations, one should have a basic understanding regarding the developmental process disrupted, the potential causes, the imaging features, and the clinical implications for the child, family, and caregivers. This topic will review these issues, including relevant factors in brain development, magnetic resonance imaging (MRI) sequences for brain malformations, specific types of brain malformations, and their clinical manifestations. Brain malformations will be discussed as isolated, distinct clinical entities. However, patients may have multiple different brain malformations, indicating a more diverse pathological process.

The evaluation of brain malformations in the prenatal period is reviewed separately. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly".)

NORMAL AND ABNORMAL BRAIN DEVELOPMENT — A brief outline of cerebral cortical development, greatly simplified, is presented here [1], which may be helpful in understanding how specific malformations develop.

●Regionalization – The neural tube is induced from neuroectoderm by the signaling protein sonic hedgehog (SHH), which is secreted by the notochord. Retinoic acid (RA) and SHH are produced from the ventral region of the spinal cord, while other signaling proteins (Wnt and BMP family proteins) are produced by the dorsal spinal cord, thereby generating chemical gradients. Spinal cord precursors start expressing specific transcription factors based upon the relative amounts of ventralizing signals (SHH) and dorsalizing signals (Wnt and BMP proteins) and differentiate into different classes of neurons [2]. A similar, although less completely understood, process occurs in telencephalon cerebral cortical development. For instance, SHH is expressed at the base of the future cerebral cortex, Wnt and BMP in the ventral region, and fibroblast growth factor 8 (FGF8) at the very anterior portion of the brain [3].

●Neuronal development – Neuronal precursors of the cerebral cortex proliferate with logarithmic growth during early development and prior to neuronal differentiation. This logarithmic growth is important to produce enough neurons later during cerebral cortical development. Once a cell becomes a neuron (terminal differentiation), it can no longer divide. During cerebral cortical development, precursor cells divide near the inner surface adjacent to the ventricle (the ventricular zone), while the future cerebral cortex (the cortical plate) with terminally differentiated neurons is adjacent to the outer portion (the pial surface). Neuronal precursor proliferation is more complex than described here [4].

●Neuronal migration – Upon terminal differentiation, neurons migrate from the ventricular zone (which lines the inside of the developing ventricles) to the future cerebral cortex at the pial surface. As the brain grows during development, this distance becomes very large relative the size of the neuron. Newly differentiated neurons climb along a scaffold of other neuronal precursors, known as radial glia, that extend from ventricular to pial surface in a process known as radial migration. The neurons stop within the cortical plate using signals found at the pial surface. Neurons of the cerebral cortex terminally differentiate between approximately 8 and 20 weeks of gestation, and they complete migration by approximately 28 weeks of gestation. These processes outline the development of most glutamatergic neurons, which are the most common excitatory neurons of the cerebral cortex.

Gamma-aminobutyric acid (GABA)ergic neurons, the most common inhibitory neurons, have a somewhat different pathway [5]. Most GABAergic neurons originate in the medial and lateral ganglionic eminence and migrate tangentially within the subventricular zone (adjacent to the ventricular zone) or the marginal zone (the outermost layer of the developing cortex) to reach their final location within the cortex [6].

●Axonal pathfinding – During development, axons grow by reacting to proteins within their environment, either attracted or repelled (and sometimes both depending on context) to be guided to their proper postsynaptic targets [7-9]. Axonal pathfinding involves specialized growth cones at the tip of extending axons and numerous chemical cues and receptors that mediate growth cone movement.

●Genetic mechanisms of malformations – Understanding genetic mechanisms of brain malformations is reasonably straightforward. A gene encodes for a protein that plays a role in cell proliferation, neuronal migration, axonal pathfinding, or other processes that are critical for brain development. Pathogenic variants differ in relative severity, leading to variability in phenotype. Identifying pathogenic variants that lead to brain malformations is important for future family and caregiver counseling. A thorough but negative genetic evaluation does not necessarily rule out genetic causes, as rare genetic pathogenic variants leading to brain malformations continue to be identified.

●Environmental insults – Environmental insults are injuries to the brain. Insults such as TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes simplex virus)/Zika infections, hemorrhage, ischemia, toxins, radiation, and other injuries will vary based upon the severity of the injury and the stage of brain development at the time the injury occurs. Different types of nongenetic injuries can lead to the same types of brain malformations. Most types of nongenetic injury are one-time events and have little risk of recurrence (with some exceptions such as teratogenic drug exposure). An insult early in development that destroys neuronal precursors will affect all neurons that would have been produced by those precursors. Injury during neuronal migration can lead to various malformations. Injury that occurs later in development on differentiated neurons is limited to the affected neurons. Therefore, the same injury early in brain development is often more severe than if it were to occur later in development.

MALFORMATIONS — We discuss brain malformations as isolated, distinct clinical entities. However, some patients have multiple different brain malformations, indicating a more diverse pathological process.

Holoprosencephaly — Holoprosencephaly is reviewed here briefly and discussed in greater detail separately. (See "Overview of craniofacial clefts and holoprosencephaly", section on 'Holoprosencephaly'.)

●Description and forms – Holoprosencephaly results from lack of separation of the forebrain, with the result that the two hemispheres remain fused. It occurs in a spectrum of severity:

•Alobar is the most severe, with the frontal regions fused and the posterior region absent with a large single ventricle in its place.

•Semilobar has posterior regions separated, while frontal cortical regions remain fused, which can include cerebral cortex and basal ganglia.

•Lobar is less severe, with only a small amount of nonfused cerebral cortex, typically in the frontal region, with basal ganglia that may or may not be fused.

Alobar, semilobar, and lobar forms have abnormalities that are more pronounced at the base of the brain, with olfactory nerves typically small to absent, while optic nerves are often small as well.

•Middle-interhemispheric (syntelencephaly) holoprosencephaly has fusion higher in the middle portions of the brain (posterior frontal and parietal lobes), not at the base of the brain, and it is usually less severe. The olfactory bulbs are not typically involved.

●Etiology – There are many causes of holoprosencephaly. Chromosomal anomalies (with abnormal karyotypes or chromosomal microarrays) are the most common causes, particularly trisomy 13. Other causes include point variants and deletions in specific genes, including SHH (sonic hedgehog), SIX3, and ZIC2 [10,11]. Pathogenic variants in the SHH gene, genes involved in SHH signaling, and other genes involved in forebrain induction indicate that holoprosencephaly results from failure of proper forebrain induction.

●Epidemiology and risk factors – Holoprosencephaly is one of the most common brain malformations in utero (up to 1:250). It often leads to spontaneous miscarriages and therefore is significantly less common in newborns (approximately 1:10,000) [12].

Nongenetic risk factors for holoprosencephaly include maternal diabetes (strongest association), hypertension, fetal infections, salicylate, antiseizure medications, statins, retinoids, fetal alcohol exposure, and assisted reproductive technologies [13,14]. Folic acid supplementation during pregnancy may reduce risk [14].

●Associated conditions – Malformations in the face correspond to severity of brain malformations. Severe eye abnormalities include cyclopia, and less severe abnormalities include narrow-spaced eye with optic nerve hypoplasia. Nose malformations and cleft palate can also occur [15,16]. (See "Overview of craniofacial clefts and holoprosencephaly", section on 'Craniofacial clefts'.)

●Clinical aspects and prognosis – The severity of symptoms is correlated with the severity of brain malformations; alobar is typically more severe than semilobar, while lobar and interhemispheric are the least severe.

Infants with severe forms may not survive long after birth and often do not survive beyond one year of life, but patients with milder cases can survive into adulthood. Affected infants can have feeding difficulties, arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus), other endocrine abnormalities, seizures, hydrocephalus, temperature instability, or central apnea. Children who survive early childhood typically have motor and speech delays and can have vision and hearing issues [17,18].

Microcephaly and microencephaly — Microcephaly (small head) is largely correlated with microencephaly (small brain), such that head circumference is a marker of relative brain size.

●Etiology – The causes of microcephaly (table 1) include destructive injuries during the pre-, peri-, or postnatal periods. Microcephaly is found in many genetic disorders; searching "microcephaly" in OMIM.org yields over 1800 results. Microcephaly is often present with other brain malformations as well as degenerative brain conditions and recognizable genetic disorders such as Angelman and Rett syndromes.

Primary microcephaly (also known as microcephaly vera, or true microcephaly) is present at birth and uncomplicated by systemic anomalies. Most of the genes associated with primary microcephaly appear to play a role in centriole function [4,19]. The mechanism is not fully understood, but there is evidence that abnormal centriole function in neuronal precursors leads to premature terminal differentiation of precursors into neurons, reducing overall number of neurons produced due to inadequate proliferation [20]. Most of brain volume and growth during development is dependent upon synaptogenesis and axonal outgrowth. Fewer neurons produced early in development leads to less of these other processes and smaller brains as children grow. In addition to centriole genes, some DNA (deoxyribonucleic acid) repair genes have been associated with microcephaly [4,19].

●Clinical aspects – Children with head circumference between 2 and 3 standard deviations (SD) below the mean (borderline microcephaly) can have normal development, while those with head circumference <3 SD (99.7th percentile) below the mean (moderate microcephaly) should be evaluated for microcephaly. Reassuring factors include normal development in children with stable head circumference growth curves that are consistently no lower than 2.5 SD below the mean, in conjunction with parents with a small head and no other abnormalities. Falling further below the mean head circumference curves over time implies lack of proper growth. Delayed milestones should prompt evaluations and interventions, while loss of milestones typically requires more urgent evaluations. The differential diagnoses for microcephaly require accounting for neuroimaging, dysmorphology, developmental history, and neurologic and systemic findings [21]. (See "Microcephaly in infants and children: Etiology and evaluation" and "Microcephaly: A clinical genetics approach".)

Profound microcephaly without any clear structural abnormalities can be associated with primary microcephaly; affected patients do not typically have any other neurologic findings besides developmental delay, which often involves severe motor and language delay. Head circumference at birth can be a low percentile or just below the bottom of the curve. However, the relative degree of microcephaly worsens over time due to lack of normal brain growth, not to worsening of disease (primary microcephaly is not a destructive process). The relative microcephaly is often profound, with head circumference up to 6 to 8 SD below the mean as children reach their later teens. Therefore, the relative level of microcephaly will worsen over time in patients with microcephaly vera. The SD above or below reference standards for normal head growth in infants according to age and sex can be determined using the World Health Organization infant head circumference calculator (calculator 1).

Children with a pathogenic DNA repair gene variant can have seizures, ataxia, neuropathy, or immune deficiency. However, there are rare pathogenic variants that lead to moderate levels of primary microcephaly with milder delays or even normal developmental outcomes.

Macrocephaly and megalencephaly — Macrocephaly (large head) is frequently associated with hydrocephalus but can be due to megalencephaly (large brain), also called macrencephaly (table 2). Head circumference greater than 3 SD (99.7th percentile) above the mean is typically concerning, as head circumference 2 to 3 SD above the mean are reasonably common in normal individuals. However, a rapidly growing head circumference affecting infants can be concerning for worsening hydrocephalus.

●Etiology and associated conditions – Megalencephaly can result from brain overgrowth or metabolic disorders that enlarge the brain.

•Metabolic disorders include organic acid processing disorders, lysosomal storage disorders, and leukodystrophies. Metabolic disorders are typically associated with developmental regression, abnormal imaging on MRI, or systemic abnormalities that will point towards these diagnoses [22].

•Autism spectrum disorder has been associated with increased head size [23]. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Macrocephaly'.)

•Fragile X in males is one of the more common causes of intellectual disability/autism frequently associated with macrocephaly. Physical characteristics typically associated with Fragile X may not be present in younger children. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)

•Macrocephaly is common in patients with neurofibromatosis 1 (NF1). (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Macrocephaly'.).

•Deletion or loss-of-function variants of the overgrowth suppressor gene PTEN, a negative regulator of the mechanistic target of rapamycin (mTOR) pathway, leads to different clinical phenotypes collectively known as PTEN hamartoma tumor syndromes [24]. In addition to macrocephaly, symptoms can include autism, hamartomas, various cancers, various mucocutaneous lesions, and other features. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)

•Activating pathogenic variants in the mTOR pathway (PI3K-AKT-mTOR) also lead to macrocephaly [25]. Examples include the megalencephaly-capillary malformation and megalencephaly-polymicrogyria-hydrocephalus syndromes that involve macrocephaly, polymicrogyria, capillary malformations of the nose/lip, and polydactyly (pathogenic variants can also involve the cell cycle-related gene CCND2). Hemimegalencephaly (ie, enlargement of one side of the brain, often associated with various malformations) typically results from somatic pathogenic variants within the mTOR pathways [26]. Clinical outcomes vary according to the pathogenic variant and typically correlate with severity and extent of brain malformations, with developmental delays and seizures common.

●Clinical aspects – Evaluation for macrocephaly should be initiated when a single head circumference (accurately measured) is abnormal or if serial measurements reveal progressive enlargement. Additionally, for infants age <6 months, evaluation is warranted when there is an increase in head circumference of >2 cm/month (>0.8 inches/month). (See "Macrocephaly in infants and children: Etiology and evaluation", section on 'Evaluation of postnatal macrocephaly'.)

Neuroimaging, preferably with MRI, should be obtained in infants and children suspected of having an expanding lesion. Imaging is necessary to determine if the volume increase is due to hydrocephalus, mass effect from cysts/tumor, enlarged bone thickness, or larger than normal brain tissue volume. (See "Macrocephaly in infants and children: Etiology and evaluation", section on 'Neuroimaging'.)

Ultrasound can be used in infants up to approximately three months of age depending upon the size of anterior fontanelle. While not as good as MRI, it can typically determine if the cause is hydrocephalus and provide clues as to other causes. Computed tomography (CT) scans expose children to radiation and have suboptimal resolution compared with MRI, but they can determine if hydrocephalus is present.

Cortical migration disorders

Lissencephaly — Lissencephaly means "smooth brain," with decreased or absent development of cortical gyri and sulci gyration. Lissencephaly may be complete (agyria) or incomplete (pachygyria). Lissencephaly results from lack of normal neuronal migration from the ventricular surface to the cortical plate.

Lissencephaly can be divided into type 1 and type 2, which is anatomically characterized by a cobblestone appearance of the brain. (See 'Cobblestone lissencephaly' below.)

Type 1 lissencephaly is often characterized by pachygyria, with a thickened, smoothened cerebral cortex. Genetic causes of type 1 lissencephaly include pathogenic variants in PAFAH1B1 (also known as LIS1), DCX, various tubulin genes, microtubule-associated proteins, and various other genes involved in cell motility. Pathogenic variants in some genes have been identified in a small number of families [27]. Point variants or small deletions within the LIS1 gene lead to lissencephaly and larger deletions of multiple genes in 17p13.2, including the LIS1 gene, which includes characteristic facial features associated with Miller-Dieker Syndrome. Pathogenic variants in the X-linked gene, ARX, lead to ambiguous genitalia in affected males. Variations in the pattern of microcephaly can suggest specific pathogenic variants; examples include greater severity of pachygyria affecting frontal or occipital regions, and the presence or absence of cerebellar hypoplasia [28,29].

Outcomes with lissencephaly vary with the severity of the condition and whether it is complicated by microcephaly. Significant lissencephaly is often associated with severe developmental delay and seizures. Epilepsy syndromes such as infantile spasms are common in the first year of life [30]. Epilepsy is frequently refractory. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis", section on 'CNS malformations' and "Infantile epileptic spasms syndrome: Clinical features and diagnosis" and "Infantile epileptic spasms syndrome: Management and prognosis".)

We advise a low threshold for the evaluation of possible or suspected seizures in neonates and children with lissencephaly, particularly those with concerns for developmental regression. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

Cobblestone lissencephaly — Cobblestone lissencephaly (type 2) has the appearance of smooth brain with small bumps on the surface of the cerebral cortex. Cobblestone lissencephaly results from neurons failing to stop at the cortical plate during migration. The "cobblestones" on the pial surface are groups of neurons that have migrated out and onto the outer surface of the brain [31-33].

Cobblestone lissencephaly is found in patients with muscular dystrophy-dystroglycanopathy, which is divided into different clinical phenotypes based upon the severity of the disease. The dystroglycanopathies are caused by abnormal glycosylation of the protein alpha-dystroglycan. They are both genetically and phenotypically heterogeneous; multiple different genes involving glycosylation can lead to the same phenotype. Affected patients typically have generalized weakness and hypotonia and can have eye abnormalities, including severe myopia, glaucoma, and optic nerve and retinal developmental issues. In addition to lissencephaly, associated developmental brain abnormalities include cerebellar cysts, pontine hypoplasia, and posterior concavity of the brainstem (bowing); these are best identified on MRI. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Dystroglycanopathies'.)

●Walker-Warburg syndrome is the most severe dystroglycanopathy and includes diffuse cobblestone lissencephaly, enlarged ventricles, and dramatic reduction of white matter. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Walker-Warburg syndrome'.)

●Muscle-eye-brain disease is moderately severe, with moderately severe cobblestone lissencephaly. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Muscle-eye-brain disease'.)

●Fukuyama congenital muscular dystrophy is most common in Japanese populations and has cobblestone lissencephaly predominately in the occipital region. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Fukuyama type'.)

Treatment is supportive. Life expectancy is correlated with severity of disease. Patients with Walker-Warburg syndrome often have limited life spans of only a few years. Patients with cobblestone lissencephaly can have motor regression due to worsening muscular dystrophy.

Band heterotopia (double cortex) — Patients with band heterotopia have a (reasonably) normal-appearing cerebral cortex with an abnormal subcortical band of neurons (gray matter) found within the white matter between the cerebral cortex and ventricle. Band heterotopia is considered a variant of lissencephaly because it is caused by aberrant neuronal migration and is linked to similar pathogenic variants [28,29].

Band heterotopia can be found in females with heterozygous pathogenic variants of the PAFAH1B1 gene or the X-linked DCX gene. Random inactivation of one X chromosome in females will lead to expression of the normal or the pathogenic DCX gene within a migrating neuron. Neurons expressing the normal X chromosome will migrate properly. Conversely, neurons expressing the mutant DCX will be arrested during migration, leading to a band of gray matter within the white matter. In males, a pathogenic DCX variant on their single X chromosome causes abnormal migration of all neurons and results in lissencephaly. Band heterotopia can also occur in patients with somatic mosaicism of pathogenic variants that would typically lead to lissencephaly. (See 'Lissencephaly' above.)

Developmental delay and seizures are the most common issues in patients with band heterotopia. Female carriers of X-linked DCX pathogenic variants can have mild cognitive abnormalities and normal MRIs while having a risk of seizures [34].

Periventricular heterotopia — Periventricular heterotopia are clusters of gray matter that are adjacent to the ventricle where only white matter is normally present. They are most commonly found in patients with epilepsy but can also be an incidental finding.

Periventricular heterotopia is the result of groups of neurons that fail to migrate out to the cerebral cortex from the ventricular zone during development. The causes of heterotopia cannot always be identified. In females, pathogenic variants in the X-linked FLNA gene lead to heterotopia as well as connective tissue and vascular abnormalities; in males, pathogenic FLNA variants are typically lethal at the embryonic stage [35]. FLNA pathogenic variants are relatively common in patients with bilateral periventricular heterotopia but less common in other forms [36]. Pathogenic variants in tubulin genes can lead to periventricular heterotopia and many other migration defects [37,38].

Environmental insults are another presumed cause of periventricular heterotopia, but they are not well understood.

Seizures are the most common clinical feature in patients with periventricular heterotopia. Patients with incidental heterotopia should be warned that they may be at increased risk for seizures, but there are no prospective studies determining what that risk might be. Any spells concerning for seizures should be evaluated.

The exact mechanism of focal seizures is a matter of debate, but they could be caused by the heterotopia itself or by abnormal connections formed between the heterotopia and the overlying normal gray matter. Surgical evaluation may be an option for refractory focal epilepsy [39]. (See "Seizures and epilepsy in children: Classification, etiology, and clinical features", section on 'Neurodevelopmental lesions'.)

Polymicrogyria — Polymicrogyria is one the most common brain malformations affecting children and one of the hardest to learn to recognize.

Polymicrogyria is characterized by very small, irregular gyri and abnormal cortical structure and lamination [40]. The gyri are visible via microscopy but are often smaller than the spatial resolution of conventional MRI sequences and field strengths; multiple small gyri visualized within a single MR image results in blurring, which can lead to the illusion of an abnormally thickened cortex and be misinterpreted as pachygyria. In addition, because the gyri are smaller than the resolution of the MRI, the gray-white border is not clearly seen. The fuzzy, irregular nature of the cortex along with the lack of a distinct gray-white border on MRI distinguishes polymicrogyria from pachygyria, even though the individual gyri may not be visualized.

Schizencephaly is a cleft in the cerebral cortex connecting the ventricular and pial surfaces that is lined with polymicrogyria [41].

The causes of polymicrogyria are diverse and include environmental and genetic etiologies [41]. Polymicrogyria has been associated with utero vascular insults, TORCH infections (especially CMV, but also toxoplasmosis and syphilis), and multiple metabolic disorders including neonatal adrenal leukodystrophy, Zellweger syndrome, mitochondrial disorders, and maple syrup urine disease. It is associated with chromosomal deletions such as 22q11 and 1p36, autosomal dominant pathogenic variants in tubulin genes, autosomal recessive pathogenic variants such as GPR56, and others.

The cellular pathological processes leading to polymicrogyria are not completely understood and likely vary based upon etiology. Derangements at the end of migration involve the pial surface, such that gyri might abnormally fuse or that the process of gyration itself is disrupted. However, the mechanisms that result in normal gyral formation are not well understood, so this remains speculative. Pathogenic variants in GPR56 lead to abnormal neuronal migration that passes through the cerebral cortex and breaches the pial membrane, resulting in the appearance of polymicrogyria [42-44]. Since this is the same mechanism that leads to cobblestone lissencephaly, polymicrogyria is pathologically classified with that disorder [42,43].

The outcomes of polymicrogyria vary according to severity and location. Perisylvian polymicrogyria is often associated with oral motor dysfunction (such as inability to stick out the tongue), swallowing and speech delays, and other motor delays. Seizures are common with polymicrogyria and can be either focal or generalized [45].

Cortical dysgenesis — Cortical malformations that cannot be classified into a specific category due to imaging ambiguity are typically called cortical dysgenesis. If initial imaging was performed prior to the time of near myelination completion (around two years of age), repeat imaging might yield clearer results.

Agenesis of corpus callosum — The corpus callosum (CC) is a large white matter bundle of axons that carry information between the cerebral hemispheres. The CC is divided into portions including the rostrum, genu, body, and splenium.

●Agenesis – Complete agenesis of corpus callosum (ACC) means that no CC is present, while partial ACC indicates that the CC is shorter in its anterior-posterior length as a result of missing segment(s) such as the splenium and/or the rostrum. The posterior segments of the CC are usually absent in partial ACC [46]. Other abnormalities of the CC include dysgenesis (abnormal shape) or hypoplasia.

●Etiology – Proper development of the CC requires many steps. The brain must fuse after it has separated, requiring that the proper induction of midline structures occurs prior to neurons crossing. Specific neurons will project through the CC starting around week 13 of gestation, and they must be specified via signaling and transcription factors. Axons receive extracellular guidance cues that help to lead them along the proper pathway in addition to other critical steps, resulting in a formed CC by week 20, but neurons continue to grow afterward [47-49].

Since there are so many steps required for proper CC development, there as many likely potential causes of agenesis. The cause of the disruption may be genetic, infectious (eg, TORCH infections, Zika virus), vascular, or toxic (eg, fetal alcohol syndrome) [50,51]. Genetic factors are believed to be the most common; ACC has been associated with over 200 genetic syndromes and chromosomal abnormalities [52]. Among the various causes, ACC may occur as an isolated abnormality or may be a component of different syndromes that present with neuroanatomic pathologies [51]. The precise mechanisms that lead to partial versus complete agenesis are not clear.

●Epidemiology – The prevalence of ACC in the general population ranges from 1:4000 to 1:5000 but may be underestimated because the course is often asymptomatic [51,53,54]. Among patients with impaired neurodevelopment, the prevalence is estimated to be between 1 and 3 percent [47,55].

●Clinical correlates – ACC has variable clinical manifestations ranging from asymptomatic to severe neurodevelopmental impairment. The degree of symptomatic involvement depends in part upon whether ACC is complete or partial and whether it is isolated or associated with other abnormalities [51,56,57].

●Evaluation – Suspicion of ACC is often raised, or the diagnosis is confirmed, in the prenatal period during routine ultrasound screening for fetal anomalies at 20 to 22 weeks of gestation. Fetal MRI (after week 20 of gestation) is useful to look for associated brain anomalies that may be missed on ultrasound. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Disorders of the corpus callosum'.)

A postnatal MRI will provide further anatomic information compared with the fetal imaging study. The CC can be visualized in any plane of imaging with MRI but is usually best seen on sagittal imaging in midline regions.

Chromosome microarray analysis can detect pathogenic or likely pathogenic findings, since copy number variants are relatively common in ACC [58-61]. Gene panel testing may be diagnostic if the clinical pattern fits a specific syndrome or disease-specific gene. Increasingly, whole exome sequencing is used.

●Outcomes – The outcomes in isolated ACC are extremely variable. Approximately 70 to 75 percent of patients with isolated ACC (complete and partial) have normal neurodevelopment, while the remainder have motor and cognitive deficits that range from moderate to severe [56]. Although many patients with ACC have normal developmental milestones, they lack normal connections that allow information to be transmitted between hemispheres. This can lead to specific educational issues, such as reduced information processing speed and impaired complex reasoning and problem-solving skills [62]. Some children with isolated ACC appear to be asymptomatic but develop learning difficulties and struggles in school with deficits in higher language function, cognitive information process, and social difficulties [52,63,64]. These problems warrant neuropsychologic testing and interventions to optimize the educational program and social function of children with isolated ACC.

Septo-optic dysplasia — Septo-optic dysplasia (also known as de Morsier syndrome) is typically defined as two of the three following, any of which indicate defects in midline brain formation:

●Absent septum pellucidum or ACC

●Optic nerve hypoplasia

●Endocrine deficiencies due to hypothalamic-pituitary abnormalities

The septum pellucidum is a membrane found between the two hemispheres of the cerebral cortex within the ventricles. It is best visualized in either axial or coronal planes. Its absence does not appear to have any clear neurologic consequences. However, absent septum pellucidum can be a marker of failure of midline induction and is a sign of possible septo-optic dysplasia.

For infants and very young children, the finding of an absent septum pellucidum on imaging is an indication for referral to ophthalmology and endocrinology for evaluations, since vision and endocrine issues may not have been identified in that age group. In older children with normal vision and growth, an absent septum pellucidum is typically a benign finding that requires no further investigation. There are rare pathogenic variants that can lead to septo-optic dysplasia, but the majority of cases are sporadic and without a clear genetic cause, although vascular abnormalities are possible [65,66]. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Congenital abnormalities'.)

GENERAL CLINICAL ISSUES

MRI and other imaging modalities — Abnormal fetal ultrasound can identify concerns for different types of brain malformations. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly".)

Ultrasound can be used in infants up to approximately three months of age depending upon the size of anterior fontanelle. While not as good as MRI, it can typically determine if the cause is hydrocephalus and provide clues as to other causes. CT scans expose children to radiation and have suboptimal resolution, but they can determine whether hydrocephalus is present.

Traditional MRIs typically require sedation until children are at least school age depending upon their ability to hold still. In the newborn period, many institutions are able to obtain a good-quality rapid MRI via a "feed and swaddle" method. Babies are fed and then wrapped in a blanket, which may allow the babies to sleep through the MRI without sedation. The author has found that this strategy is less effective as the child ages and typically does not work after three months. For infants older than three months of age, sedation is typically required for full MR imaging until the child is old enough to cooperate with holding still for a traditional MRI.

Some centers are able to obtain a rapid MRI evaluation that does not require sedation to look for hydrocephalus. These studies can have institution-dependent names such as Turbo T2 or MRI shunt series; they were first developed to replace CT scans to prevent repeated radiation exposures for patients with ventricular shunts (but requiring resetting adjustable magnetic flow valves if present). At the author's institution, T2 images are used along with gradient echo/susceptibility sequences (to detect blood) and can take as little as four minutes of scanning time. The goal is to get the best-quality imaging possible given patient cooperation, but it is not always successful if the child moves too much. The studies optimize visualization of the cerebrospinal fluid and parenchyma, so gray/white imaging can be less distinct than traditional MRI but can visualize white matter and parenchyma when successful. Since it requires neither sedation nor radiation, it can be a good option depending upon the clinical scenario.

Some malformations are identified on postnatal CT or ultrasound studies. Fetal head ultrasound and postnatal head CT have lower resolution than postnatal MRI. If possible, it is best to wait until a good MRI is obtained before providing a definitive diagnosis to families, as that provides the most complete and accurate assessment of brain changes.

Optimal MRI sequences — Optimal MRI sequences for identification may differ by age. Newborn imaging is preferable to imaging later in infancy because of myelination changes. For subtle changes, such as possible gray matter heterotopia within the white matter, re-imaging with MRI after 24 months may be required.

In older children and adults, white matter should be largely myelinated, making myelinated axons appear darker than gray matter on T2 sequences (gray matter has a higher water content than myelinated axons, and water is brighter on T2 sequences). In the newborn period, axons within the cerebral cortical areas are largely unmyelinated, and axonal tracks are brighter on T2 sequences compared with gray matter. Consequently, the distinction between gray and white matter is often unclear on T1 MRI sequences, making assessments of brain malformations more difficult. Therefore, this author typically relies on T2 sequences in the newborn period. However, MRI scanners and programming differences could produce different results at different institutions.

After a few months of age and extending to 18 to 24 months, axonal myelination occurs. During this time, partially myelinated axons might have the characteristics of gray or white matter, making interpretations more difficult. Clinical circumstances may dictate whether imaging is needed within the period of myelination. However, subtle changes, such as possible gray matter heterotopia within the white matter, are likely to be more apparent after 24 months when white matter myelination is relatively advanced.

In older children, T1 sequences are often best for detecting structural changes. On T1 sequences, fully myelinated white matter is brighter then gray matter, while cerebrospinal fluid is very dark. Magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequences are high-resolution, T1-like sequences. They are not routinely done for standard MRI studies but are often done for seizure protocols. MPRAGE sequences have thinner sections and are optimal for identifying subtle changes such as gray matter heterotopia (hence their use for the evaluation of seizures). However, good T1 imaging should be able to identify all malformations discussed here.

Uncertainties in prognosis — Families and caregivers will want to know the long-term prognosis of a child with a brain malformation, but outcome is often hard to predict. Nearly all brain malformations occur on a severity spectrum, so the malformation type alone is not predictive. If more severe, the prognosis is more concerning. Furthermore, some malformations (eg, focal cortical dysplasia) can have changes that cannot be seen on MRI but have deleterious effects. The occurrence and severity of epileptic seizures is generally associated with worse outcomes, regardless of the type of malformation.

Developmental regression and seizures — Brain malformations develop in utero and do not progress as children age. Thus, affected children may be delayed in development but should not have developmental regression. However, some brain malformations have a high risk for seizures. Any loss of development in a child should prompt an evaluation for seizures in addition to the typical workup for loss of developmental milestones. High seizure burden can lead to epileptic encephalopathy with developmental regression in children, and parents and caregivers should be counseled about this possibility if their child has a high risk for seizures. Seizures may be controlled with appropriate antiseizure therapies, so it is important to recognize epileptic encephalopathy. (See "Overview of infantile epilepsy syndromes", section on 'Developmental and epileptic encephalopathies' and "Epilepsy syndromes in children", section on 'Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS)' and "Lennox-Gastaut syndrome".)

Seizure-like events should be investigated by child neurology/epilepsy, with concerns for infantile spasms requiring immediate evaluation. (See "Infantile epileptic spasms syndrome: Clinical features and diagnosis".)

Multidisciplinary management — Children with significant brain malformations will require a multidisciplinary approach for their medical and developmental needs. The family and caregivers should be reassured that they will have help and guidance meeting their child's long-term care needs. In infancy, the child may be cared for by pediatrics/family medicine for their general medical needs and pediatric neurology or developmental pediatrics for their developmental needs. Early physical, speech, and occupation therapy and/or early intervention for patients with developmental delays is helpful. Children with suspicion for seizures/epilepsy should be evaluated by child neurology, ideally by clinicians or centers with expertise in pediatric epilepsy.

Swallowing issues should always be considered and addressed. Concerns for choking when drinking or eating should be evaluated by speech therapy and/or modified barium swallow with appropriate interventions to prevent aspirations. (See "Aspiration due to swallowing dysfunction in children".)

Delays in eye tracking should be investigated by ophthalmology. (See "Vision screening and assessment in infants and children".)

As children age, their needs will change based upon their cognitive and neuromuscular issues. (See "Intellectual disability (ID) in children: Management, outcomes, and prevention".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital malformations of the central nervous system".)

SUMMARY

●Mechanisms – Normal cortical brain development requires a sequence of molecular mechanisms that guide neuronal maturation, migration, and axonal pathfinding. Disruption of these mechanisms caused by pathogenic variants or environmental insults (eg, infections, ischemia, hemorrhage, toxins, or other injuries) can lead to brain malformations. (See 'Normal and abnormal brain development' above.)

●Holoprosencephaly – Holoprosencephaly results from lack of separation of the forebrain so that the two hemispheres remained fused. It occurs on a spectrum of severity ranging from alobar (most severe), semilobar, lobar, and middle-interhemispheric (syntelencephaly). Holoprosencephaly is commonly associated with midfacial defects. The most severe forms are incompatible with life, and survival beyond early infancy is rare. Affected infants can have feeding difficulties, endocrine abnormalities, seizures, hydrocephalus, temperature instability, or central apnea. Children who survive early childhood typically have neurodevelopmental delays and can have vision and hearing issues. (See 'Holoprosencephaly' above and "Overview of craniofacial clefts and holoprosencephaly", section on 'Holoprosencephaly'.)

●Microcephaly – Microcephaly (small head) is largely correlated with microencephaly (small brain), such that head circumference is a marker of relative brain size. Primary microcephaly (also known as microcephaly vera) is present at birth and uncomplicated by systemic anomalies; affected patients do not typically have any other neurologic findings besides developmental delay. The causes of microcephaly (table 1) include genetic disorders and destructive injuries during the pre-, peri-, or postnatal periods. (See 'Microcephaly and microencephaly' above and "Microcephaly in infants and children: Etiology and evaluation" and "Microcephaly: A clinical genetics approach".)

●Macrocephaly – Macrocephaly (large head) is frequently associated with hydrocephalus but can be due to megalencephaly (large brain), also called macrencephaly. Megalencephaly can result from brain overgrowth or metabolic disorders that enlarge the brain (table 2). (See 'Macrocephaly and megalencephaly' above and "Macrocephaly in infants and children: Etiology and evaluation".)

●Cortical migration disorders – Cortical migration disorders include lissencephaly, cobblestone lissencephaly, band heterotopia, periventricular heterotopia, and polymicrogyria.

•Lissencephaly – Lissencephaly means "smooth brain," with decreased or absent development of cortical gyri and sulci gyration. Lissencephaly may be complete (agyria) or incomplete (pachygyria). Lissencephaly results from lack of normal neuronal migration from the ventricular surface to the cortical plate. Significant lissencephaly is often associated with severe developmental delay and seizures. Epilepsy syndromes such as infantile spasms are common in the first year of life. (See 'Lissencephaly' above.)

•Cobblestone lissencephaly – Cobblestone lissencephaly has the appearance of smooth brain with small bumps on the surface of the cerebral cortex. Cobblestone lissencephaly results from neurons failing to stop at the cortical plate during migration. Cobblestone lissencephaly is found in patients with muscular dystrophy-dystroglycanopathy. The dystroglycanopathies are caused by abnormal glycosylation of the protein alpha-dystroglycan. They are both genetically and phenotypically heterogeneous. (See 'Cobblestone lissencephaly' above.)

•Band heterotopia – Band heterotopia (double cortex) is characterized by an abnormal subcortical band of neurons (gray matter) found within the white matter between the cerebral cortex and ventricle. Band heterotopia is most often found in females with heterozygous pathogenic variants of the X-linked DCX gene. Developmental delay and seizures are the most common issues in patients with band heterotopia. (See 'Band heterotopia (double cortex)' above.)

•Periventricular heterotopia – Periventricular heterotopia are clusters of gray matter that are adjacent to the ventricle where only white matter is normally present. They are most commonly found in patients with epilepsy but can also be an incidental finding. (See 'Periventricular heterotopia' above.)

•Polymicrogyria – Polymicrogyria is characterized by very small irregular gyri and abnormal cortical structure and lamination. Polymicrogyria can be challenging to recognize because the gyri are often smaller than the resolution of conventional MRI sequences and field strengths, and the gray-white border is not clearly seen. The causes of polymicrogyria are diverse and include environmental and genetic etiologies. The outcomes of polymicrogyria vary according to severity and location. Perisylvian polymicrogyria is often associated with oral motor dysfunction, swallowing and speech delays, and other motor delays; seizures are common. (See 'Polymicrogyria' above.)

●Agenesis of corpus callosum – Agenesis of corpus callosum (ACC) ranges from complete to partial. The cause may be genetic, infectious, vascular, or toxic. ACC may occur as an isolated abnormality or may be a component of different syndromes that present with neuroanatomic pathologies. Clinical manifestations range from asymptomatic to severe neurodevelopmental impairment, and they depend in part upon whether ACC is complete or partial and whether ACC is isolated or associated with other abnormalities. (See 'Agenesis of corpus callosum' above.)

●Septo-optic dysplasia – Septo-optic dysplasia is typically defined as two of the three following: absent septum pellucidum or ACC, optic nerve hypoplasia, and/or endocrine deficiencies due to hypothalamic-pituitary abnormalities. These are caused by defects in midline brain formation. (See 'Septo-optic dysplasia' above.)