Agenesis of the corpus callosum: What to tell expecting parents?

Agenesis of the corpus callosum (ACC) is one of the most common brain malformations, with an incidence estimated to range from 0.5 to 70 in 10,000 among the general population. Prenatal diagnosis is made via ultrasound; however, fetal MRI is useful to confirm or exclude the presence of associated cerebral abnormalities–mostly cortical malformations–that may affect postnatal prognosis. When no additional central nervous system (CNS) or extra CNS anomalies are identified and no genetic cause is found, an isolated ACC is diagnosed. Overall, in cases of ACC, an underlying genetic cause can be identified in up to 12.5% with chromosomal microarray (CMA) and up to 47% with whole exome sequencing (WES). In cases where ACC is the only anomaly detected, the yield of WES is 30%. Postnatal outcomes are variable and depend on whether the condition is isolated or not. In truly isolated ACC, outcomes range from normal in 65% of cases through mild to severe neurodevelopmental impairments in 35% of cases. An interdisciplinary team of medical experts is key in guiding parents toward informed decision‐making in pregnancies complicated by ACC. Considering current and expected advancements in genetic testing and imaging technologies in upcoming years, we herein summarize current recommendations for the management and prenatal counseling of expecting parents of fetuses with ACC. Our review pertains primarily to expecting parents of fetuses with complete ACC.


| INTRODUCTION
The corpus callosum (CC) is the largest white matter structure in the brain, serving as the bridge between the two cerebral hemispheres. 1 It begins to form in a bidirectional manner at 6 weeks of gestation, 2 completes formation between 18 and 20 weeks' gestation, and continues to thicken and grow posteriorly throughout pregnancy and infancy. 3Five parts of the CC can be recognized in its complete form: rostrum, genu, body, isthmus, and splenium (Figure 1).Multiple glial cell populations as well as migratory neurons in the brain are responsible for proper formation of the CC. 1 Disruption to the migratory processes of these cells during fetal development can result in either complete or partial agenesis (also referred to as dysgenesis or hypogenesis) of the CC. 1 Primary ACC is a morphological disorder not defined by functional or behavioral abnormalities, although linked to the potential development of neurological symptoms. 1It can be defined as either Type 1 or Type 2 agenesis. 4Type 1 primary ACC occurs when white matter fibers of the CC develop but cannot cross between the two hemispheres, leaving Probst bundles, or aberrant longitudinal fiber bundles, along the medial surfaces of the hemispheres. 4Type 2 ACC is defined by the lack of formation of white matter fibers to bridge the two hemispheres, with absent Probst bundles. 4Partial or complete ACC may also arise secondarily as a component of symptoms related to another neurological disorder, or degenerative process in the brain. 4C is typically detected at routine antenatal screening at 18-20 weeks' gestation. 3Prior to this gestational age, detection of ACC with fetal ultrasound is possible but not entirely reliable, given the developmental timeframe of this structure. 3

| EPIDEMIOLOGY AND RISK FACTORS
ACC is a fairly common fetal brain malformation, affecting up to 1:4000 live births. 5The exact prevalence of this disorder remains unknown, given the selection bias in reporting studies. 6Recognized risk factors for this condition include maternal alcohol consumption, 7 and rarely, maternal phenylketonuria, maternal infections with cytomegalovirus, toxoplasmosis, rubella, or influenza during pregnancy and vascular/hypoxic insults to the mother. 3Alcohol is considered a destructive agent to CC development, 8 and as such, it is highly recommended that maternal alcohol consumption is avoided in all trimesters of pregnancy. 9Advanced maternal age, associated with an increased probability of chromosomal anomalies, may increase the risk of ACC. 3 Fetuses with other cerebral abnormalities such as malformations of cortical development are at a greater risk of ACC. 10 Additionally, ACC can accompany multiple genetic syndromes as well as inborn errors of metabolism 1 (Table 1). 11In up to 20% of cases, ACC is due to chromosomal anomalies, including trisomies 18 and 13, and deletions or duplications. 12If the chromosomal microarray is normal, whole exome sequencing (WES) during the prenatal period can help to identify an underlying genetic cause for ACC. 3 Many cases of ACC are sporadic and it is possible that a majority of individuals have ACC as a consequence of de novo dominant mutations. 3

| DIFFERENTIAL DIAGNOSIS
In ACC, there will be an absent CSP.The only differential diagnosis to an absent CSP is early, albeit physiological obliteration of the cavum.
In the latter, the CC will be normal.An absent CSP should not be confused with an absent septum.In the case of absent septal leaflets resulting in communication of the anterior horns, the differential diagnosis includes malformations (holoprosencephaly or malformations of cortical development) or destructive processes (septal rupture secondary to hydrocephalus or septo-optic dysplasia). 12wever, the screening trans-ventricular axial plane of the fetal head will be key to the diagnosis, depicting either an absent cavum, thus raising the suspicion of ACC, or an absent septum, raising suspicion of alternative diagnoses.
In approximately 60% of cases, malformations of the CC are found alongside other major morphological disorders of the fetal brain 3-5,12-18 (Table 2).These co-occurring conditions must be

| Fetal imaging
ACC can be identified prenatally on ultrasound, after 18 weeks' gestation when the CC assumes its final shape. 3However, ACC can be suspected earlier as parts of the CC can already be identified with high resolution probes and a transvaginal approach.Recently, diagnosis of the CC has been demonstrated by fetal ultrasound as early as 13 weeks and nomograms for its length have been devised. 19[22] During a midgestation neurosonographic screening examination of the brain, the anterior complex should be visualized in the axial plane (Figure 2).This complex demonstrates the interhemispheric fissure, the callosal sulcus, the body of the CC and the anterior horns of the lateral ventricles. 23A normal anterior complex is evidence to the presence of the CC, visualized in the midsagittal plane by 18 weeks (Figure 2).At this time, indirect signs of ACC should be visible in the axial plane and include an absent CSP, dilation and elevation of the third ventricle, widely spaced parallel lateral ventricles with small and narrow frontal horns (which assume a bull horn shaped appearance in a coronal plane), colpocephaly, or dilation of the posterior horns of the lateral ventricles, with a teardrop appearance 3,24 and a widened interhemispheric fissure (Figure 3).
Additional indirect signs include absence/abnormal course of the pericallosal artery in the sagittal plane and radiating sulci in the third trimester (Sunburst sign). 25,26A "hairy" midline in axial plane can also be noted at this time (Figure 4).Direct visualization of the absence of the CC is best obtained in the midsagittal plane (Figure 3).When detected, a detailed neurosonographic assessment Findings on MRI that suggest or confirm ACC are similar to those seen on ultrasound and include 1 a racing car sign, where a top-down view of the lateral ventricles appears similar to a Formula One car, 2 moose head appearance, where anterior to posterior views of the frontal horns resemble a moose's head, 3 sunray appearance, where midline imaging show gyri radiating outwards from the ventricles, 4 lateral ventricles that are parallel to each other, 5 colpocephaly, 6 inverted Probst bundles along the superomedial lateral ventricle surfaces, and 7 a high riding third ventricle. 27,28According to a recent meta-analysis, MRI detected additional anomalies beyond detailed neurosonography in 5.7% of cases.Most commonly missed anomalies were of the and posterior fossa, that frequently accompany ACC. 29At times, malformations of cortical development may develop or become more evident later in pregnancy, emphasizing the importance of ongoing sonographic surveillance if pregnancy continues and adequate timing of MRI. 30 Nonetheless, in some countries, there are time limit restrictions on pregnancy termination, and this should be considered as well.
It should be noted that in cases of presumed isolated ACC prenatally, additional structural anomalies are detected postnatally in 15% of cases. 6These may include abnormalities of the posterior fossa, interhemispheric cysts, and other neuronal migration disorders. 6re specialized imaging techniques such as high-resolution diffusion tensor tractography are expected to become widely available in ACC diagnosis in future years. 3In addition, structural connectome analyses can point to abnormal white matter connectivity in the brain with malformations such as ACC. 31 Connectome analyses may elucidate biomarkers of ACC in the brain that are associated with cognitive or behavioral symptoms, thus guiding our understanding of the pathophysiology of this condition. 32

| Genetic testing
The diagnostic yield of chromosomal microarray analysis (CMA) in cases of apparently isolated ACC ranges from 11.1% to 12.5%, 42,43 but the relatively small numbers of cases in these studies should be acknowledged.
Prenatal WES is much more informative, and is thought to have a diagnostic yield of up to 47% (95% CI 37%-57%) for all cases of ACC.
In cases of isolated ACC its yield is 30% (95% CI 18%-41%), while in cases of non-isolated ACC it rises to 49% (95% CI 37%-60%) when additional non-CNS anomalies are present and 50% (95% CI 33%-67%) when additional CNS anomalies are present. 44rrently, genetic screening tests such as non-invasive prenatal testing (NIPT) are also available.However, this approach is of limited value because it would have a very low yield and would not detect most of the chromosomal abnormalities or any of the single gene mutations associated with ACC. 42 all cases, pre-and post-test genetic counseling by an experienced provider is recommended, and the variability in neurodevelopmental outcomes expected even when a genetic cause is identified should be explained to parents. 18

| Pregnancy and delivery
Throughout the prenatal period, it is highly recommended that all pregnancies complicated by ACC are monitored by an interdisciplinary team, including maternal fetal medicine specialists, midwives, genetic counselors, social workers, neuroradiologists, fetal pathologists, pediatricians, pediatric neurologists, clinical geneticists, and neonatologists. 3,45 after birth, the treatment options, and what their child's quality of life can be.The key point in counseling is the differentiation between isolated and non-isolated ACC, as the prognosis changes significantly with each diagnosis.The challenge is that isolated ACC can only be confirmed postnatally, since even if no additional anomalies are detected prenatally by US and MRI and WES is done and is normal, there is still a 15% chance of additional anomalies detected only postnatally. 6stetric complications in pregnancies involving ACC vary depending on whether other cerebral abnormalities exist, and the severity of the disorders together. 46In ACC, the ventriculomegaly is ex-vacuo and will typically not result in macrocephaly.Therefore, a vaginal delivery will likely be possible.This may not be the case in fetuses with a dysgenetic CC, where hydrocephalus and macrocephaly may appear and a Caesarean delivery may be required. 46Couples may elect for termination of pregnancy, especially in circumstances where additional anomalies with unfavorable prognoses are detected through genetic testing or diagnostic imaging. 3Parents often also choose the termination of pregnancy in cases of isolated ACC in the absence of other cerebral abnormalities, when concerned about uncertain or poor postnatal neurodevelopmental outcomes. 3Rarely, intrauterine fetal death may occur. 30The majority of pregnancies involving ACC can be brought to term without any complications. 3,5,47ans for delivery should take into consideration the complexity of ACC.In apparently isolated cases with normal genetic workup, delivery can occur in a community center.However, in complex cases with additional anomalies or in cases in which an underlying genetic cause is identified, delivery should be planned in advance with prior consultation with the pediatric team and take place at a tertiary facility that can accommodate for the supportive resources that may be required. 45Postnatally, plans should be made for developmental and neurological follow up.Neonatal neurological examinations should be undertaken within the first month of life, and postnatal MRI is mandatory to confirm findings from fetal imaging or exclude the presence of other cerebral abnormalities. 45Of note, MRI does not harm either the fetus or neonate if contrast agent is avoided. 48,49A particular challenge for postnatal MRI imaging is the requirement for the neonate to remain still, and so scans can be performed during natural sleep. 49

| Neurodevelopment and quality of life
The severity and complexity of ACC may vary widely, depending on whether the condition is isolated or associated with other cerebral or extra-cerebral abnormalities or underlying genetic condition.As such, postnatal outcomes are also highly variable. 5The core neuropsychological syndrome of primary ACC includes 1 delayed cognitive processing, 2 reduced interhemispheric transfer of sensory-motor information, and 3 decreased complex information analysis and unacquainted task performance, with increased vulnerability to more demanding cognitive tasks. 50A systematic review assessing neurodevelopmental outcomes after prenatal diagnosis of isolated ACC confirmed at birth found normal outcomes in 83/128 children (64.8%), and either borderline, moderate, or severe neurodevelopmental complications in 45/128 children (33.6%). 30Other symptoms can include vision problems (up to 33% of cases), delayed speech development (up to 29%), seizures (up to 25%), feeding problems (up to 20%), impaired hand-eye coordination, and socio-behavioral disorders such as attention-deficit-hyperactivity disorder (ADHD). 12Apart from these symptoms, those born with isolated ACC may have normal intelligence quotients with some cognitive deficits, including those noted in the core syndrome. 50Subtle cognitive deficits can however be revealed later in life. 45Generally, studies assessing neurodevelopmental outcomes in patients with ACC vary with respect to the definition of the mental disability, sample size studied, consideration of socio-cultural, economic, and educational factors contributing to neurocognitive performance, and lack a standardized pre-and postnatal medical workup protocol. 30Therefore, consultation with an interdisciplinary medical team is strongly recommended prior to decision-making for any case of prenatally diagnosed ACC.

| OPTIONS FOR THERAPY
Treatment for ACC is symptom-dependent, and supportive rather than curative. 12It can involve 1 anti-epileptic medications, 2 special education, 3 physiotherapy, 4 ventriculoperitoneal shunt (for cases where hydrocephalus is present) 5 genetic counseling for family members, 6 surgeries for associated morphological abnormalities, 7 speech and visual rehabilitation, and 8 psychological and psychiatric therapies. 12In some cases of ACC in which an interhemispheric cyst is also present, hydrocephalus may occur.In these cases, imaging surveillance is important, since neurosurgery may be required. 17,51,52ese surgeries do not treat the underlying ACC, but rather target the co-occurring abnormality. 17,51,52

| FUTURE RECURRENCE RISK AND PREVENTION
Genetic counseling is especially important for educating parents about the potential future recurrence risk.Whether there is a risk of future recurrence in subsequent pregnancies depends largely upon whether an underlying genetic etiology has been identified and what the specific finding is.De novo CNVs and de novo single gene pathogenic mutations have a low risk of recurrence estimated at 1% based on the possibility of germ line mosaicism. 53Some CNVs can be inherited from an affected parent, such as an inverted duplication deletion 8p and would have a risk of approximately 50%. 54The identification of an autosomal dominant condition would have a 50% risk of recurrence, while an autosomal recessive condition or an Xlinked recessive condition where the mother is shown to be a carrier would have a 25% risk of recurrence.
WES during the prenatal or postnatal period can identify high recurrence risk mutations that are not detected with karyotyping or 1532 -TSAI and SHINAR CMA. 55The results of WES along with the expertise of genetic counselors enable parents and family members to make informed decisions regarding how to proceed with future pregnancies. 56

F I G U R E 2 F I G U R E 3 1530 -
is warranted in search of additional CNS anomalies, and extra CNS anomalies.While MRI is not required to detect ACC, it is recommended for the potential detection of additional, namely cortical, Normal appearance of the anterior complex and corpus callosum at 21 þ 3 weeks (A) Axial view of a normal CSP (white arrow) (B) Midsagittal view of the corpus callosum through the anterior fontanelle, demonstrating all its parts (C) Coronal view of the genu of the corpus callosum (white arrowhead) and callosal sulcus (white arrow).[Colour figure can be viewed at wileyonlinelibrary.com]Signs of agenesis of the corpus callosum at 21 þ 2 weeks (A) Absent CSP and laterally displaced anterior horns (white arrows) with (B) anterior colpocephaly (tear drop shape, white arrow) and elevation of the third ventricle (C, white arrow) (D) Absent corpus callosum in the midsagittal plane.[Colour figure can be viewed at wileyonlinelibrary.com]TSAI and SHINAR anomalies,3,5 which may be more challenging for ultrasound detection.
the time of prenatal diagnosis, parents should be told what the diagnosis means for their pregnancy and their baby, the prognosis F I G U R E 4 Indirect signs of agenesis of the corpus callosum at 31 þ 6 weeks (A) Bullhorn-shaped anterior horns in coronal plane (white arrows) (B) Absent CSP and elevated third ventricle (star) in axial plane (C) "Hairy" midline in axial plane (multiple white arrows).[Colour figure can be viewed at wileyonlinelibrary.com]

1
All parts of the corpus callosum in a midsagittal plane.[Colour figure can be viewed at wileyonlinelibrary.com]Some genetic conditions associated with agenesis of the corpus callosum.
Tubulinopathies ACC, cerebellar hypoplasia/dysplasia, dysplastic basal ganglia, brainstem abnormalities, ventriculomegaly, microlissencephaly, pachygyria and polymicrogyria, distorted inetrhemispheric fissure Inborn errors of metabolism ACC; if present hypoplastic CC; periventricular pseudocysts; hindbrain anomalies; ventriculomegaly; increased extra-axial cerebrospinal fluid; cortical malformations Abbreviation: ACC, Agenesis of the corpus callosum.T A B L E 2 Examples of anomalies associated with ACC.CNS abnormalities CNS findings Some CNS developmental abnormalities associated with CC malformation Holoprosencephaly Atypical CC dysgenesis; absent anterior portions of the CC Septo-optic dysplasia Optic nerve hypoplasia, absent or hypoplastic septum pellucidum, hypoplastic CC Chiari II malformation Herniation of the cerebellum and medulla into the foramen magnum; noncommunicating hydrocephalus; ACC or CC dysplasia Lissencephaly Absent folds in the cerebral cortex; microcephaly; ACC Hydrocephalus with or without aqueduct of Sylvius stenosis Enlarged ventricles with excess cerebrospinal fluid, ACC Dandy-Walker malformation Agenesis of the cerebellar vermis and cystic enlargement of the fourth ventricle, ACC Encephalocele Neural tube defect, sac containing brain, meninges, and cerebrospinal fluid forms outside of the skull, ACC CC lipoma Fat-containing asymptomatic lesion; dysgenesis of CC; cerebral ectopic calcifications Cerebellar hypoplasia Underdevelopment of the cerebellum, ACC Periventricular nodular heterotopia Gray matter neurons cluster in and around the ventricles, ACC Interhemispheric cysts Mass effect on surrounding brain parenchyma; hydrocephalus; ACC Abbreviations: ACC, agenesis of the corpus callosum; CC, corpus callosum; CNS, central nervous system.TSAI and SHINAR considered when determining if ACC or partial ACC (PACC) is isolated or not.Here (Table 2) we highlight only several of these conditions.
If an underlying genetic cause has been identified, prenatal diagnosis via CVS or amniocentesis or prevention through preimplantation genetic testing are options in future pregnancies.If no underlying etiology is found, recurrence risk cannot be assessed but is thought to be low.Future pregnancies should be monitored by ultrasound.CONCLUSIONS ACC is a relatively common fetal brain malformation that can lead to neurodevelopmental complications, and cognitive and sociobehavioral difficulties.The severity of prognosis largely depends upon whether ACC is isolated or associated with other cerebral abnormalities.The etiology of ACC is highly variable, and includes malformative and destructive processes, as well as exposure to viral agents and teratogens.Prenatal screening with ultrasound is beneficial and MRI should be reserved to appreciate possible additional CNS anomalies, namely cortical malformations.Prenatal management and patient counseling should involve an interdisciplinary team.