The corpus callosum (CC) connects the two brain hemispheres through axonal fiber tissues, being important for the functional integration of sensory, motor, visuomotor and cognitive processes, in addition to processing and management of social and emotional stimuli. Agenesis of the corpus callosum (ACC) is a congenital brain malformation defined by anatomy (complete or partial absence of the corpus callosum), rarely occurring in isolation and is a specific and relatively easy to detect phenotypic marker for developmental disorders. The prevalence of ACC in the general population is extremely variable and probably underestimated due to the asymptomatic course, the usual range is 0.020–0.025%, in individuals with neurodevelopmental impairment this defect has a prevalence of 1 to 3%. Etiology that varies, from maternal alcohol consumption, to prenatal infections, chromosomal errors or genetic mutations. Fetal alcohol syndrome (FAS) is the most important non-genetic congenital cause of ACC, with an incidence of approximately 7% in FAS cases, but the most frequent cause of ACC are genetic mutations related to axonal guidance pathways, ciliary development, cell adhesion, proliferation, differentiation and migration. Patients with ACC can be divided into three groups: the first including individuals with “syndromic” ACC who commonly present severe neurocognitive deficiency that obscures the deficiencies directly caused by the absence of CC generally associating cerebral malformations, non-cerebral structural defects, altered patterns of growth and development, in addition to progressive neurological symptoms and sensory impairment; the second presents with neurodevelopmental diseases in which ACC has been suggested to play a role; and the final includes patients with isolated complete or partial ACC who remain neurologically asymptomatic and have normal intelligence, however, in-depth neuropsychological screening can often reveal mild behavioral and cognitive deficits. In recent decades, magnetic resonance imaging (MRI) has been implemented, a tool that has increased the recognition of fetal diagnosis, which is performed in three planes and is useful in identifying associated anomalies. The use of MRI is essential and must be done together with a complementary fetal ultrasound exam, with the midsagittal plane parallel to the CC being ideal for evaluation. Multiplanar fetal neurosonography is the best imaging test to evaluate the fetus from the 20th week of gestation onwards. Most brain abnormalities remain undiagnosed until midway through the first trimester, and may go undetected due to small fetal brain structures. Between the 11th and 13th weeks, ultrasound can highlight changes that are incompatible with life. Multiplanar neurosonography is indicated in the middle of the first trimester of pregnancy, including non-axial plane scanning. The sonographer's knowledge of fetal anatomy and sonoembryology results in early diagnosis.

The corpus callosum is the largest of the interhemispheric white matter tracts that connect the cerebral hemispheres. It can be divided into four main parts: rostrum, genu, body and splenium.¹ “Complete agenesis of the corpus callosum” is the terminology used to describe its complete absence, while “partial agenesis of the corpus callosum” refers to a reduction in its anteroposterior length as a result of the absence of one or multiple segments, such as the splenium and the rostrum, there are also other abnormalities which include dysgenesis (abnormal shape) and hyper/hypoplasias.² The prevalence of agenesis of the corpus callosum in the general population ranges from 1:4,000 to 1:5,000, which may be underestimated due to the generally asymptomatic course.² Genetic factors have been described as the most common etiology, with agenesis being associated with more than 200 genetic syndromes and chromosomal abnormalities.³ It can occur in an isolated presentation or as a component of different syndromes that course with neuroanatomical malformations.² There is suspicion or the diagnosis is confirmed, in the prenatal period during routine ultrasound screening between 20 and 22 weeks of gestation, magnetic resonance imaging is useful after the 20th week of gestation to demonstrate associated brain anomalies that may go unnoticed.⁴ Approximately one-third of patients with isolated agenesis of the corpus callosum, whether complete or partial, have normal neurodevelopment, while the remainder have motor and cognitive deficits ranging from moderate to severe.⁵

This article aims to review the scientific literature in order to highlight the agenesis of the corpus callosum in its etiology, epidemiology, symptoms, pathophysiology and its intrauterine diagnosis. Furthermore, this study aims to encourage the development of new research on the topic, due to the scarce number of research papers surrounding the disease.

This narrative literature review adheres to the methodological guidelines stipulated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The investigation draws upon the following databases: Scientific Electronic Library Online (SciELO), Latin American and Caribbean Literature (Lilacs), and PubMed. The search strategy employed encompassed the utilization of the search descriptors "agenesis of the corpus callosum" and "corpus callosum agenesis, across all aforementioned databases. The inclusion criteria encompassed original articles, clinical trials or series, systematic and literature reviews, meta-analyses, and randomized controlled trials, published between the years 2012 to 2022 in either English or Portuguese, with free full text. These selected studies were constrained to the pediatric population and aligned with the research's defined objectives. Conversely, the exclusion criteria encompassed book chapters, duplicated abstracts, as well as studies focused on adult populations.

Following the implementation of the PRISMA framework, the outcomes revealed the following distribution across databases: PubMed produced 97 articles, SciELO 5 articles meeting the criteria, and Lilacs generated 8 articles. Subsequent scrutiny of the retrieved articles against the stipulated inclusion and exclusion criteria specified in the methodology resulted in: 14 from PubMed, 1 article from SciELO and only 1 article fulfilled the criteria from Lilacs, that pertinently discussed the isolated agenesis of the corpus callosum (Table 1, Figure 1).

Figure 1 Flowchart of search mechanism based on the PRISMA-P 2015.

The corpus callosum (CC) connects the two brain hemispheres through axonal fiber tissues, being important for the functional integration of sensory, motor, visuomotor and cognitive processes (language, abstract reasoning and integration of complex sensory information), in addition to processing and management of social and emotional stimuli.¹⁵ The CC can be anatomically divided into 4 regions: rostrum, genu, body and splenium. The rostrum and genu connect the frontal and premotor regions of the cerebral cortex, the body connects the motor, somatosensory, and parietal regions, while the splenium links the temporal and occipital cortices on both sides.³ At birth, the CC already has its characteristic shape, its thickness generally increases throughout childhood and adolescence, with growth in the anterior sections being more pronounced in the first 10 years of life, and posterior growth predominating during adolescence.⁷

Agenesis of the corpus callosum (ACC) is a congenital brain malformation defined by anatomy (complete or partial absence of the corpus callosum) and not by behavioral abnormalities. It rarely occurs in isolation and is a specific and relatively easy to detect phenotypic marker for developmental disorders.⁸ The prevalence of ACC in the general population is extremely variable and probably underestimated due to the asymptomatic course, the usual range is 1:4,000 to 1:5,000 live births (0.020–0.025%), whereas in individuals with neurodevelopmental impairment this defect has a prevalence of 1 to 3%.⁶

CC development begins around the 12th week of gestation and follows well-orchestrated events: neuronal and glial planning, neuronal migration and planning, midline patterning, axonal growth and orientation, and post-orientation refinement, becoming recognizable around the 14 to 15th week of gestation, while the splenium becomes predominant around the 18th to 19th week of gestation. This process is complex and involves several pathways, such as Semaphorin/Plexin/Neuropilin, Slit/Robo, Eph/Ephrin, Netrin/DCC/Unc5, Wnt/Ryk and FGF8/MAPK.³

ACC has an etiology that varies, from maternal alcohol consumption, to prenatal infections, chromosomal errors or genetic mutations. Fetal alcohol syndrome (FAS) is the most important non-genetic congenital cause of ACC, with an incidence of approximately 7% in FAS cases.⁸ The most frequent cause of ACC are genetic mutations related to axonal guidance pathways, ciliary development, cell adhesion, proliferation, differentiation and migration, which can present as an isolated anomaly or as a component of a complex disorder.²

Pânzaru et al.³ describes the existence of several genes associated with CC development events, which may contribute to a possible change in structure, density or quantity of CC commissure fibers. The described genetic alterations are grouped into chromosomal anomalies, monogenic alterations and those related to the isolated form of ACC. Among the chromosomal anomalies are trisomies 18, 13 and 21, mosaic 8, monosomy X, 8p inverted duplication/deletion syndrome, 1q43q44, 6q27 and 17q21.31 microdeletions, in addition to several other variations in the number of chromosomes which were reported in ACC cases. Among the monogenic alterations, which are found in 8 to 35% of the cases of ACC, are the acrocallosal syndrome (ACS), the tubulinopathies, the FOXG1 syndrome, the Andermann syndrome (ACC–neuropathy), the Aicardi syndrome, Proud syndrome (ACC-abnormal genitalia), pyruvate dehydrogenase complex (PDC) deficiency, pyridoxine-dependent epilepsy (PDE), congenital mirror movements (CMM), split-brain syndrome (horizontal gaze palsy with progressive scoliosis) and septo-optic dysplasia (SOD). Regarding the isolated presentation of ACC, heterozygous missense of the CDK5RAP2 gene and missense mutations of the DCC (deleted in colorectal cancer) gen are described, the latter with some emphasis.¹²

The DCC gene encodes the DCC receptor netrin-1 (NTN1), a transmembrane protein necessary for the orientation of commissural axons. Germinal mutations in this gene interrupt the development of the greater commissures causing loss of their physiological function leading to congenital mirror movements, isolated ACC or both. A significant, level-dependent increase in DCC gene expression is observed in testosterone-treated neural stem cells derived from human embryonic stem cells, suggesting that isolated ACC may occur when DCC gene expression is below a critical level during CC development.¹²

In general, patients with ACC can be divided into three groups according to their clinical and neurocognitive characteristics. The first group includes individuals with “syndromic” ACC who commonly present severe neurocognitive deficiency that obscures the deficiencies directly caused by the absence of CC. These patients generally associate cerebral malformations, non-cerebral structural defects, altered patterns of growth and development, in addition to progressive neurological symptoms and sensory impairment. A second group of patients presents with neurodevelopmental diseases in which ACC has been suggested to play a role. The final group includes patients with isolated complete or partial ACC who remain neurologically asymptomatic and have normal intelligence, however, in-depth neuropsychological screening can often reveal mild behavioral and cognitive deficits.⁸

The syndromic presentation results from a reduction in the interhemispheric transfer of sensorimotor information, an increase in cognitive processing time and a deficient processing of complex information and unknown tasks with a consequent greater vulnerability to increased cognitive demands. However, because these cognitive impairments are typically mild to moderate, they are often not easily recognized. The degree of involvement is directly related to the areas of deficient development and whether the malformation is partial or total, factors that affect quality of life and treatment. There is a change in social cognition, emotion recognition, mentalization and linguistic skills, in addition to a greater tendency towards the autism spectrum and attention deficit disorder.⁶

Guadarrama-Ortiz et al.⁸ reports a case in which an 8-year-old male patient with ACC was fully identified intrauterine by means of ultrasound (US), requiring a cesarean section at 36 weeks due to hydrocephalus, without perinatal complications or any other abnormality suggestive of the syndrome. congenital. Magnetic resonance imaging (MRI) of his brain at school age demonstrated, in addition to the total ACC, an enlargement of the lateral ventricles with dilated occipital horns (colpocephaly). During follow-up, he did not present any disturbances on neurological examination, behavioral/psychiatric disorders or intellectual disabilities.

In a quantitative analysis with clinical cases where the authors evaluated neuroplasticity in patients with ACC, there where described decision-making difficulties which occur due to impaired connection of the commissural fibers within the frontal lobes, with growth in the thickness of the anterior commissure being seen in patients with neuroplasticity when compared to controls.¹³ Although the increase in the size of the anterior commissure constitutes the main event of anatomical neuroplasticity in patients with ACC, no current evidence is available to recommend an efficient cognitive therapy to improve the quality of decision making, explaining the heterogeneity between patients. More experimental studies will be necessary, especially in the use of molecular markers to clarify this field of knowledge.¹

Since 1985, ACC has been diagnosed through fetal ultrasound. This assessment was incoherent and divergent, meaning that the evaluator, at that time, was unable to distinguish complete agenesis from the partial form.¹¹ In recent decades, magnetic resonance imaging (MRI) has been implemented, a tool that has increased the recognition of fetal diagnosis, which is performed in three planes and is useful in identifying associated anomalies. The use of MRI is essential and must be done together with a complementary fetal ultrasound exam, with the midsagittal plane parallel to the CC being ideal for evaluation.¹⁴

In a systematic literature review and meta-analysis study, in which 14 studies were included totaling 798 fetuses, evaluating the type of ultrasound evaluation (neurosonography versus standard axial evaluation), gestational age on fetal MRI and anomaly rates detected postnatally, in search of greater sensitivity and effectiveness in diagnosis. According to the type of ultrasound assessment, the rate of associated anomalies detected only on fetal MRI was 5.7% with dedicated neurosonography and 18.5% with standard axial assessment. In fetuses with isolated partial ACC, 13.4% and 16.2% of additional anomalies were detected by fetal or postnatal MRI, respectively. According to the type of ultrasound assessment, the rate of associated anomalies detected only on fetal MRI was 11.4% when dedicated neurosonography was performed. Cortical and posterior fossa anomalies are among the most common anomalies detected exclusively on MRI, thus confirming the crucial role of fetal MRI in determining prognosis. However, some anomalies still go unnoticed during prenatal care and this should be highlighted during parental counseling.⁴

Multiplanar fetal neurosonography is the best imaging test to evaluate the fetus from the 20th week of gestation onwards. Most brain abnormalities remain undiagnosed until midway through the first trimester, and may go undetected due to small fetal brain structures. Between the 11th and 13th weeks, ultrasound can highlight changes that are incompatible with life. Multiplanar neurosonography is indicated in the middle of the first trimester of pregnancy, including non-axial plane scanning. The sonographer's knowledge of fetal anatomy and sonoembryology results in early diagnosis (Figure 2).^10,16

Figure 2 Agenesis of corpus callosum in midsagittal ultrasound view in first trimester, showing increased ratio between diencephalon (D) and falx (F) diameters. In 80% of fetuses that had agenesis of the corpus callosum diagnosed later in gestation, there was an increased ratio between the diencephalon diameter (from midbrain to falx, including third ventricle and thalami) and the falx diameter. Adapted from Volpe et al. 2021.

ACC is a rare condition with a variety of causes, including genetic, environmental, and infectious factors. This malformation can be asymptomatic or cause a variety of symptoms, which vary depending on the severity of the malformation. The most common symptoms include developmental delay, seizures, learning and behavioral deficits, and physical and motor disabilities.

Dedicated ultrasound has high sensitivity for detecting malformations in the Central Nervous System during the prenatal period, so the diagnosis of ACC is usually made by fetal ultrasound. Magnetic resonance imaging should be used as a complementary method to detect associated anomalies and provide data for better perinatal care. The use of magnetic resonance imaging combined with neurosonography may result in a better prognosis for the patient.

None.

The authors declare no conflicts of interset.

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