Agenesis of the Corpus Callosum — Genetic Basis and Clinical Approach

An abnormality of the principal interhemispheric commissure, isolated or part of more than two hundred chromosomal, monogenic, metabolic and teratogenic syndromes; prenatal and postnatal approaches, with dedicated boxes on Aicardi syndrome, hereditary motor and sensory neuropathy with agenesis of the corpus callosum (SLC12A6), the DCC-associated spectrum and Mowat–Wilson syndrome (ZEB2).

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

Agenesis of the corpus callosum (ACC) is an anatomical finding rather than a single disease; the approach to this finding and the four entities covered in boxes are summarised separately.

Table 0.1 — Agenesis and dysgenesis of the corpus callosum as a finding

Table 0.2 — Entities covered in boxes

1. Introduction

1.1. The Corpus Callosum: Function and Development

The corpus callosum is the largest fibre bundle in the human brain. It connects the two cerebral hemispheres, integrates motor and sensory information from both sides and participates in higher-order cognitive functions, such as executive function, social interaction and language [37]. Failure of this bundle to develop has become a model for studying brain connectivity, with neuropsychological, electroencephalographic and functional magnetic resonance investigations addressing the emotional, social and higher-order cognitive deficits accompanying agenesis, and with interest as a model for schizophrenia and autism [15].

Development of the cerebral commissures begins at around 6 weeks of gestation, when axons destined for the anterior commissure grow medially; the most important fibres cross the midline in the lamina terminalis. The first anterior commissural fibres cross at 10 weeks, and corpus callosum fibres begin crossing from 11 weeks, with rapid growth over the following weeks. Growth of the corpus callosum locally thins the lamina terminalis, which will form the septum pellucidum; this common origin explains why absence of the cavum septi pellucidi (CSP) is the main indirect sign of agenesis on axial screening views. By 18–20 weeks, the corpus callosum already has its adult shape and continues to thicken and grow caudally for several months [3]. The Society for Maternal-Fetal Medicine (SMFM) considers that all CC segments have developed by 20 weeks [1]. High-frequency transvaginal imaging can show the early CSP and anterior portions of the CC between 14 and 17 weeks [38].

CC formation depends on axon guidance ligands (netrins, ephrins, semaphorins and Slit proteins) and their receptors [31], and on a process of interhemispheric fissure remodelling that precedes callosal axon crossing in mouse models [39]; disruption of any of these steps may result in complete or partial absence of the commissure.

1.2. Definitions and Nomenclature

Agenesis of the corpus callosum is the complete or partial absence of the main commissural bundles connecting the hemispheres; in the partial form, the posterior segments are usually absent. CC abnormalities comprise complete or partial agenesis, dysgenesis (abnormal shape) and hypoplasia (reduced thickness) [1]. The 2025 international Delphi consensus defined partial agenesis as absence of a CC segment and considered that an excessively short CC with heterogeneity, abnormal thickness or partial absence suggests dysgenesis (78.0% agreement), that an excessively thick or abnormally shaped CC suggests dysgenesis (100%), that a short CC with normal echogenicity, morphology and the remainder of the brain should be considered a variant of normal development (78.0%), and that an excessively long CC is not associated with pathology (96.6%) [2].

Midline abnormalities form a heterogeneous group resulting from abnormal ventral induction after primary neurulation; ultrasonography is the primary technique, and MRI confirms the findings and detects additional cortical abnormalities [40]. Isolated ACC, without other abnormalities, is distinguished from complex ACC, when other cerebral or extracerebral abnormalities coexist [41]. Classification is dynamic: a proportion of cases considered isolated on ultrasonography reveal additional abnormalities on fetal MRI, postnatal MRI, physical examination or during follow-up, and this reclassification is one of the determinants of prognosis (sections 5 and 11).

Nomenclature is more heterogeneous in prenatal than in postnatal literature. A systematic review of 24 studies with 1135 cases of fetal callosal abnormalities found complete agenesis in 49%, while the remaining cases were termed “partial agenesis” or described by nine other terms, five with more than one definition; the authors proposed a simplified categorisation aligned with postnatal classification [42]. In children, analysis of midsagittal MRI in 30 patients from 19 consanguineous families with more than one affected individual (validated in 10 sporadic cases) defined three classes: hypoplasia, hypoplasia with dysplasia and complete agenesis. Affected members of the same family showed the same class, or complete agenesis, suggesting that complete agenesis is a final phenotype shared by several developmental pathways [43].

1.3. Historical and Molecular Milestones

The sources consulted do not identify the first anatomical report of callosal agenesis. Fetal callosal abnormalities have been described in the prenatal imaging literature since 1985 [42]. In 1965, Jean Aicardi described the association of flexion spasms, callosal agenesis and ocular abnormalities that would come to bear his name; further signs were subsequently added as major criteria because they were frequent or specific [35]. In 1979, Schinzel described acrocallosal syndrome [44]. In the Charlevoix and Saguenay–Lac-Saint-Jean region of Quebec, severe motor and sensory neuropathy with CC agenesis was characterised in French Canadian clinical series in the 1980s and 1990s, including Mathieu's series of 64 patients (1990) [21], and in 2002 Howard and colleagues identified variants in SLC12A6, the gene encoding the potassium–chloride cotransporter KCC3 [45]. The clinical criteria for Aicardi syndrome, adapted by Sutton in 2005 from Aicardi (1999), remain the basis of diagnosis because the gene remains unknown [20].

The 2010s brought the first comprehensive classification of clinical and genetic syndromes associated with callosal agenesis, combining copy number variants (CNVs), single genes, mouse models and neuroimaging [37]. In 2011, KIF7 was associated with hydrolethalus and acrocallosal syndromes [46]. In 2017, two papers published side by side established DCC as the first genetic cause of isolated ACC, with dominant inheritance and incomplete penetrance, and biallelic loss-of-function variants in the same gene as the cause of developmental split-brain syndrome [31, 33]. In 2025, a French cohort of 352 fetuses undergoing prenatal exome sequencing confirmed DCC as the most frequent monogenic aetiology in fetal agenesis [5]. In 2026, reports described BHLHE22, with dominant and recessive inheritance and CC agenesis in 12 of 15 carriers [47], and CC thinning in ReNU syndrome, caused by variants in the non-coding gene RNU4-2, which conventional exome sequencing does not capture [48].

1.4. Included Entities and Cross-References

This article addresses agenesis of the corpus callosum as a finding, covering classification, chromosomal and monogenic causes, prenatal diagnosis and prognosis of the isolated form. Four entities in which ACC is cardinal or in which the gene was described through ACC receive dedicated boxes: Aicardi syndrome, hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC, SLC12A6), the DCC spectrum (autosomal dominant isolated ACC, congenital mirror movements and autosomal recessive split-brain syndrome) and Mowat–Wilson syndrome (ZEB2). Spastic paraplegias with a thin corpus callosum (SPG11, SPG15), BHLHE22-associated paraparesis, X-linked lissencephaly with abnormal genitalia and the other ARX-associated encephalopathies, and L1 syndrome (L1CAM) enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Mechanisms of Commissure Formation and Anatomical Consequences

Callosal axons cross the midline guided by attractive and repulsive signals. The transmembrane receptor DCC binds netrin-1 (NTN1) and guides axons across the midline; its loss simultaneously causes abnormal decussation of the corticospinal tract, with an ipsilateral tract explaining mirror movements, and failure of CC formation [6]. Biallelic DCC loss disorganises white matter tracts throughout the central nervous system and suppresses all commissures at several levels of the neuraxis, establishing DCC as a master regulator of midline crossing [33]. In a preclinical study published in November 2025, conditional Tcf4 inactivation in mouse guidepost neurons disrupted astroglial function and prevented closure and remodelling of the interhemispheric fissure, without which callosal axons cannot cross; semaphorin 7A emerged as a mediator of communication between neurons and astroglia [39]. The corresponding human gene, TCF4, causes Pitt–Hopkins syndrome, which includes CC aplasia or hypoplasia [49].

When axons fail to cross, they accumulate parallel to the midline, forming the longitudinal Probst bundles, which compress the frontal horns medially and give them a pointed or slit-like appearance. Reduced posterior white matter disproportionately dilates the occipital horns (colpocephaly), and the lateral ventricles lie parallel to each other and to the midline; the roof of the third ventricle may extend upwards into the interhemispheric space [1]. Ventricular dilatation in ACC therefore results from configuration rather than hydrocephalus and belongs to the group of non-obstructive ventriculomegalies [50]. Associated meningeal dysplasia may give rise to echogenic midline lipomas or interhemispheric cysts [1]. At autopsy, patients with HMSN/ACC show a normal CC or partial or complete agenesis with preserved Probst bundles [21].

2.2. Aetiological Architecture

ACC has been described in more than 200 genetic syndromes and chromosomal abnormalities [1]. Genetic factors contribute in the vast majority of cases, whereas prenatal infections, vascular injuries and toxic agents are less frequent causes; interaction between modifier genes and environmental factors is considered in isolated ACC without an identified cause [4]. Chromosomal abnormalities were found in 17% of ACC cases in a clinical review and in 18% in a fetal meta-analysis combining isolated and complex forms [1, 41]. In a clinical review, between 20% and 35% of ACC cases had an identifiable monogenic cause, grouped into six sets of syndromes: those with craniofacial dysmorphism, neuroanatomical or neurological findings, ocular phenotypes, metabolic disorders, ciliopathies and others [32]. In prenatal exome sequencing of 352 French fetuses with callosal abnormalities, pathogenic or likely pathogenic (P/LP) variants were distributed across 49 different genes, most associated with disorders of intellectual development [5]; a meta-analysis of 288 prenatal cases investigated by exome sequencing after normal CMA described 116 variants in 83 genes [16].

2.3. Chromosomal Abnormalities and Copy Number Variants

The aneuploidies most associated with prenatal isolated ACC are trisomies 18 and 13 and mosaic trisomy 8 [1]. In trisomy 13, ACC is among the abnormalities present in fewer than half of cases, and in trisomy 18 the CC defect occurs in fewer than 10% [51, 52]. Mosaic trisomy 8 combines finger contractures (70%), vertebral deformity (65%), heart disease (25%), renal abnormalities, deep palmar and plantar creases (75%), small patellae and CC agenesis or hypoplasia; detection in chorionic villi is problematic because most mosaicism found there is confined to the placenta, and postnatal diagnosis may require a buccal smear or skin biopsy [7, 53]. In monosomy X, imaging studies describe a reduced CC genu, and ACC has been reported in two cases [54, 55]. Other abnormalities involving the CC include mosaic tetrasomy 12p (Pallister–Killian), with structural brain abnormalities in 77%, 9q34.3 microdeletion (Kleefstra), with central nervous system defects in 50–61%, 2q31.1 and 15q24 microdeletions, 11q deletion, 22q11.2 deletion and Xq28 duplication including MECP2, in which the frequency of callosal hypoplasia depends on the location of the distal breakpoint [56–61]. In cri du chat syndrome, caused by loss of part of the short arm of chromosome 5 (estimated incidence 1 in 15,000 to 1 in 50,000 live births; interstitial deletions in 3–5%, mosaicism in 1.4%, inversions and ring chromosomes in 0.5% each), CC hypoplasia or agenesis is among the neurological manifestations, alongside the cat-like cry, ID, periventricular leukomalacia, cerebral or cerebellar atrophy, hydrocephalus and myelination abnormalities; the first test is the karyotype, followed by array CGH, FISH or PCR if it is normal [62].

In a postnatal series of 149 patients with CC abnormalities and ID investigated using single nucleotide polymorphism (SNP) arrays, at least one probably contributory CNV was found in 20 (13%), with 66 variants of uncertain significance (VUS) in 57 patients. The most frequent rearrangement was inverted duplication with terminal deletion of 8p (3.2%); recurrent deletions involved 6qter, 18q21 (including TCF4), 1q43q44, 17p13.3, 14q12, 3q13, 3p26 and 3q26 (including SOX2); the critical regions of 8q21.1 deletion and 19p13.1 duplication were refined, and a 10p12 deletion including ZEB1, with a callosal abnormality and corneal dystrophy, and a 7q36 duplication including SHH were described. The authors concluded that microarray should be the first-line test [63]. Chinese prenatal series identified 1p36 deletions, 2q31.2, 2p16.3, 13q32.2q34, 18q21.2q21.31, 16p13.3 and 16p12.2 microdeletions, 17q12 microduplication, Xq26.3q27.1 microdeletion and derivative chromosomes resulting from unbalanced translocations [18, 64, 65]. In a series of 16 fetuses with isolated ACC investigated using CytoScan HD, pathogenic CNVs were found in 2 (12.5%) and VUS in 3 (18.75%); candidate genes proposed for one CNV derive from bioinformatic inference rather than functional demonstration [66]. An 11-Mb 1p36 deletion may reproduce the Aicardi phenotype without chorioretinal lacunae [20].

2.4. DCC: Dominant Isolated Agenesis, Mirror Movements and Split-Brain Syndrome

DCC (18q21.2) encodes the transmembrane netrin-1 receptor required for commissural axon guidance [6, 24]. Monoallelic missense or predicted loss-of-function variants cause congenital mirror movements, isolated ACC or both; biallelic loss-of-function variants cause developmental split-brain syndrome (DSBS). By 2018, 26 variants associated with abnormal central nervous system development had been described (14 missense and 12 predicted loss-of-function variants) and deposited in a locus-specific database [24, 67]. The common mechanism is reduced or disrupted netrin-1 signalling [24].

In the founding series, DCC variants were found in four families and five sporadic individuals with isolated ACC without ID [31]. Combining 88 carriers from the literature and the study, excluding index cases, estimated penetrance was 42% for mirror movements and 26% for ACC (19 of 39 carriers with imaging had ACC). Mirror movements were more frequent in males (31 versus 19; ratio 1.8; p=0.0027), and among carriers of truncating variants, ACC was more frequent in females (7 versus 1). In human neural stem cells, testosterone (10 and 100 nM) increased DCC expression in a dose-dependent manner, leading the authors to propose sex-related modification of the phenotype. Truncating variants act through haploinsufficiency, and ACC would arise when the quantity of DCC falls below a threshold; missense variants at the DCC/netrin-1 interface, such as p.(Val793Gly) and p.(Gly805Glu), were predicted to be the most disruptive [31]. Variants at this interface may predispose to CC abnormalities with or without mirror movements; NTN1 and RAD51, the other causes of congenital mirror movements, have no reported CC abnormalities [6].

Variants in the founding families were published against NM_005215.3; the current MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript is NM_005215.4, with the same c. numbering, and normalisation was performed using VariantValidator on GRCh38 [31, 68].

Table 2.1 — DCC variants in the founding families, normalised to the MANE Select transcript

Source: [31, 68]. The presence of p.Val754Met in 19 alleles in a population database illustrates the difficulty of interpreting missense variants in a gene with incomplete penetrance.

The biallelic form (OMIM 617542, familial horizontal gaze palsy with progressive scoliosis and ID) manifests as absence of commissures between the hemispheres, ID, horizontal gaze palsy and scoliosis; MRI and tractography show extensive white matter disorganisation and loss of all commissural tracts [6, 33]. Somatic DCC variants in sporadic tumours (colorectal, oesophageal) are unrelated to the inherited disease [6].

2.5. SLC12A6 and KCC3

SLC12A6 (15q14) encodes the potassium–chloride cotransporter KCC3, with 12 transmembrane helices and an extracellular loop between segments 7 and 8 containing five N-glycosylation sites. The protein regulates axonal volume and participates in paranodal action potential propagation; loss of function leads to neuronal degeneration [21]. The Slc12a6−/− mouse shows locomotor impairment, neuropathy and impaired sensorimotor control [45], but the CC appears normal [21]. The mechanism of HMSN/ACC is biallelic loss of function [21].

The French Canadian founder variant was published in 2002 as “2436delG, Thr813fsX813”; the truncated protein is glycosylated and reaches the membrane but does not transport, indicating a functional rather than a trafficking defect [45, 69]. In GeneReviews, the variant appears as NM_133647.1:c.2436+1delG, with the alternative designation c.2436delG [21]. VariantValidator normalisation shows that, applying the 3′ alignment rule, the G deletion corresponds to NM_133647.1:c.2436+1del, an intronic splice donor variant; in the MANE Select transcript it is written NM_001365088.1:c.2436+1del, NP_001352017.1:p.?, NC_000015.10:g.34240661del. The historical protein notation p.Thr813fs describes the reported functional effect rather than current HGVS nomenclature [68]. More than 99% of French Canadian patients have this variant [21].

The allelic disorders section of the 2020 GeneReviews states that there are no other phenotypes, but its pathogenesis section itself mentions that KCC3 gain of function causes peripheral neuropathy without CC abnormalities [21]. In 2020, the de novo heterozygous missense variants NM_001365088.1:c.620G>A p.(Arg207His) and NM_001365088.1:c.2036A>G p.(Tyr679Cys) were described in three unrelated patients with early-onset intermediate Charcot–Marie–Tooth disease (CMT), both axonal and demyelinating, with spasticity in one patient, normal cognition and brain MRI, and reduced potassium influx in Xenopus oocytes [23, 69]. The gene is thus associated with a recessive disease with ACC and a de novo dominant disease without ACC. Published data are insufficient for genotype–phenotype correlations in HMSN/ACC [21].

2.6. ZEB2 and Mowat–Wilson Syndrome

Classic Mowat–Wilson syndrome (MWS) results from ZEB2 haploinsufficiency (2q22.3) [70]: an intragenic pathogenic variant in approximately 84% of patients, a heterozygous 2q22.3 deletion including ZEB2 in approximately 15%, and a chromosomal rearrangement disrupting the gene in approximately 1% [22]. In one patient, the cause was a de novo Alu insertion in exon 8, detected by long-read genome sequencing [22]. Missense, splice or in-frame variants account for fewer than 2% of classic MWS cases and are often associated with milder or different phenotypes [22]. In a cohort of 87 patients, severity correlated with variant type: locus deletions accompanied severe phenotypes, while rare, non-missense intragenic variants preserving some function accompanied milder presentations [71]. In the MRI series of 54 patients, variants leading to synthesis of a defective protein were associated with better psychomotor development but also CC agenesis [34]. A ZEB2 methylation episignature has been described [72].

2.7. Aicardi Syndrome: A Gene Yet to Be Identified

Aicardi syndrome has no known gene; the leading hypothesis is de novo variants in an X-linked gene subject to inactivation, with male lethality. At least six discordant twin pairs (five confirmed dizygotic) argue against a prenatal toxic exposure or disruption as the cause. In a study of 35 patients, X-inactivation was non-random in 11 of 33 informative individuals and extremely skewed in 6 (18%). The syndrome is not allelic to microphthalmia with linear skin defects or Goltz syndrome. Arrays, exome sequencing and X-chromosome sequencing by at least three groups have not identified the gene [20].

The 2019 French National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé (HAS) considers as a hypothesis an event outside the coding regions, which would explain the negative results of the exomes and genomes analysed to date. Fewer than ten affected boys have been described, all with Klinefelter syndrome (47,XXY), which is consistent with the hypothesis of an X-linked gene that is lethal in hemizygous males. Microphthalmias with ACC associated with interstitial Xp22.3 deletions were for some time considered candidates for the gene's location; because no deletion at this locus has been found in Aicardi syndrome and the associated encephalopathies did not show all the signs, they are now treated as differential diagnoses [35].

2.8. Other Genes with Corpus Callosum Abnormalities

Table 2.2 lists diagnostically relevant genes not covered in boxes (AD, autosomal dominant; AR, autosomal recessive); the clinical differential diagnosis is in section 6.

Table 2.2 — Other genes associated with corpus callosum abnormalities

The table illustrates a central feature of the genetic architecture: the same callosal finding results from defects in axon guidance (DCC, L1CAM), neuronal migration and cytoskeleton (tubulins, ARX), transcriptional and chromatin regulation (ZEB2, FOXG1, TCF4, SWI/SNF complex), the primary cilium (KIF7), cellular trafficking (EPG5, SNAP29) and energy metabolism.

2.9. Inborn Errors of Metabolism

CC agenesis or hypoplasia occurs in many metabolic diseases: non-ketotic hyperglycinaemia (NKH), pyruvate dehydrogenase complex (PDHC) deficiency, respiratory chain defects, defects in complex molecule synthesis and most cellular trafficking disorders; a thick CC, conversely, points towards neurofibromatosis, syndromes involving PI3K/AKT3/mTOR pathway hyperactivation or MAST1 [97]. Two practical rules accompany Saudubray's malformation table: all amino acid synthesis defects may present with CC hypoplasia, and any disease involving hypomyelination or white matter abnormalities may show it [97].

In PDHC deficiency, almost always X-linked (PDHA1), hemizygous boys present with neonatal lactic acidosis (frequently with cerebral dysgenesis, such as ACC), Leigh encephalopathy or intermittent ataxia; in girls, almost all with seizures in the first six months, MRI frequently shows severe cortical and subcortical atrophy, dilated ventricles and partial to complete CC agenesis [98, 99]. In the neonatal acidosis group, some patients had cortical cysts at autopsy and several had ACC [100], and protein X (E3BP) deficiency may combine severe lactic acidosis and absence of the CC [101]. ECHS1, HIBCH and FBXL4 produce phenocopies with CC dysgenesis or agenesis [99].

Sources disagree on the relationship between NKH and ACC. In 1989, Dobyns described a two-week-old infant with myoclonic encephalopathy and CC agenesis on computed tomography and, reviewing 15 published patients, found ACC in 6/15, gyral malformation in 6/14, ventriculomegaly in 5/15 and cerebellar hypoplasia in 2/16 [102]; the Oxford Desk Reference and Nyhan's Atlas retain ACC among the manifestations of NKH [103, 104]. Conversely, the 2019 GeneReviews states that the CC may be thin and short but is not absent, and that gyral malformations and true CC absence are not features of NKH, having been observed in variant forms and pyridoxal phosphate disorders [105]. In an MRI series cited by Nyhan, the CC was abnormally thin in all patients with NKH, with progressive atrophy and delayed myelination [106, 107]. The difference is explained by the period, imaging technique (1989 computed tomography versus MRI) and definition; in current practice, a short, thin CC with deficient growth is the expected finding in severe classic NKH, and true absence should prompt consideration of an alternative or associated diagnosis [105, 108].

Other metabolic diseases with ACC or a thin CC include D-2-hydroxyglutaric aciduria (CC absence in at least three published patients, one with neonatal intracranial haemorrhages and another with optic nerve hypoplasia) [109, 110], asparagine synthetase deficiency and SLC1A4 serine transporter deficiency (thin CC) [111], AMPD2 deficiency with pontocerebellar hypoplasia type 9 (callosal hypoplasia or agenesis) [112], the Zellweger spectrum (hypoplastic CC) [113], fumarase deficiency, glutaric aciduria type II, MOCS2, EPG5, CDK5RAP2 and dystroglycanopathies [97]. Because optical character recognition of the original table merged the columns for gyration abnormalities and CC hypoplasia or agenesis, this list does not assign each disease to one of the two findings.

2.10. Teratogens, Infections and Acquired Causes

Prenatal alcohol exposure produces CC abnormalities on neuropathology and quantitative MRI, more frequent and severe when facial dysmorphism is present; partial or complete CC agenesis is among the structural central nervous system criteria for fetal alcohol spectrum disorder, and the critical period encompasses the entire pregnancy [114–116]. Warfarin between 14 and 20 weeks, mycophenolate and congenital Zika virus infection, with agenesis or dysgenesis and marked CC thinning, complete this group [117–120]. Cytomegalovirus and toxoplasma may cause subtle callosal changes, particularly a heterogeneous CC [2].

3. Clinical Spectrum and Manifestations by System

3.1. Isolated Agenesis: A Spectrum from Incidental Findings to Learning Difficulties

ACC is a much less specific finding than generally assumed and is sometimes discovered incidentally in children with normal development [3]. In families with DCC variants, for example, agenesis in the female proband and her sister was discovered on MRI requested for headaches, and other female carriers had normal intelligence with mild learning difficulties in language and mathematics [31]. At the other extreme, population-based series and prospective cohorts show that a minority of children with apparently isolated ACC have severe ID, frequently due to a syndrome diagnosed only after birth (section 11).

The natural history of the isolated form is characterised by deficits that become more apparent with age. SMFM summarises these as epilepsy in 7–16%, abnormal fine and gross motor control in approximately 10%, and deficits in higher-order language, complex information processing and social functioning, together with learning difficulties emerging predominantly at school age [1]. In a meta-analysis, epilepsy occurred in 6.8% of isolated cACC and 16.1% of isolated pACC cases, and fine motor skills were impaired in 10.98% and 11.74%, respectively [121]. In an Italian cohort of 38 school-aged children with isolated cACC on fetal MRI, motor deficits affected 58%, executive deficits 37%, language deficits 61%, memory deficits 58% and academic performance deficits 53%, with behavioural difficulties in 21%; deficits were more apparent in the second decade [14]. Neuropsychological studies also describe deficits in emotional and social functioning and higher-order cognition even with normal intelligence [4, 15].

In the first year of life, a prospective North American study using the Vineland Adaptive Behavior Scales compared infants with isolated ACC with children with fragile X syndrome, Down syndrome, siblings at high risk of autism spectrum disorder (ASD) and typically developing children. Communication was affected from 6 months, motor skills at 12 months and daily living skills at 18 months, whereas socialisation was equivalent to that in typically developing children; by 24 months, 29% of children with ACC were delayed in at least one domain. This was a convenience sample recruited through social media and family associations, with diagnosis confirmed from clinical records in only a subset [122]. Sleep disturbances are frequent, particularly early in life, and have a plausible basis because the CC participates in interhemispheric synchronisation of slow waves during sleep; the evidence comes from a narrative review [123]. Three of 34 children in a French cohort with prenatally “isolated” ACC had hypopituitarism, all with additional abnormalities on postnatal MRI [124].

3.2. Complex and Syndromic Forms

Complex forms have a poorer prognosis. In a 20-year retrospective cohort of 161 North American children with ACC confirmed on postnatal MRI, complex forms were associated with more motor delay, assistive device use, cerebral palsy, ventriculoperitoneal shunting, epilepsy and language and cognitive delay; approximately half had genetic variants associated with neurodevelopmental disorders, and more than half of those with delays and more than 60% of children with assistive devices or cerebral palsy had genetic abnormalities [125]. In the California registry, callosal abnormalities were accompanied by chromosomal disease in 17.3%, musculoskeletal malformations in 33.5%, cardiac malformations in 27.6% and other central nervous system malformations in 49.5% [11]. In the Hungarian series of 38 patients, ACC was isolated in 18, associated with other central nervous system malformations in 5, with central nervous system and extracerebral malformations in 7, and with somatic abnormalities alone in 8; 5 of the 18 isolated cases were asymptomatic, all but one patient with combined forms had delay, ID or epilepsy, and 5 patients with multiple malformations died [12]. In fetuses, extracerebral abnormalities accompany ACC in approximately 60% (predominantly cardiac and genitourinary), and coexisting brain abnormalities in 46% — Dandy–Walker syndrome, vermian dysgenesis, migration disorders, polymicrogyria and grey matter heterotopia [1, 41].

Table 3.1 summarises the frequencies of callosal abnormalities recorded in the most relevant syndromes; denominators derive from published series and are not specified in the source references.

Table 3.1 — Frequency of corpus callosum abnormalities in selected syndromes

The three frequencies for MWS do not contradict each other: they measure different findings in series from different periods. The 35% figure comes from a 2003 series and refers to agenesis; the 79.6% figure from 2017 derives from systematic MRI and includes hypoplasia and partial agenesis; and GeneReviews summarises that approximately half of patients who have undergone imaging have central nervous system abnormalities, with CC abnormalities the most common [22, 34, 128].

3.3. Box — Aicardi Syndrome

Aicardi syndrome is a neurodevelopmental disorder occurring almost exclusively in females, defined by the triad of CC agenesis, central chorioretinal lacunae and infantile spasms; not all patients have the complete triad [20].

Table 3.2 — Frequency of manifestations in Aicardi syndrome

Source: GeneReviews, based on Wong and Sutton (2018) [20].

Seizures begin before 3 months in many patients and before 1 year in most, evolve into refractory epilepsy with multiple seizure types, and the electroencephalogram (EEG) shows asynchronous multifocal activity with burst suppression and interhemispheric dissociation [20]. Examination reveals microcephaly, axial hypotonia and appendicular hypertonia or spasticity, frequently unilateral, with hemiparesis. Moderate to severe delay is typical, but some patients have mild learning difficulties or normal development. On MRI, CC dysgenesis is usually complete and sometimes partial; associated findings include frontal and perisylvian polymicrogyria or pachygyria with underopercularisation, very common periventricular and intracortical heterotopia, cerebral asymmetry, choroid plexus papillomas, ventriculomegaly, intracerebral cysts (around the third ventricle and choroid plexus) and increasingly recognised posterior fossa and cerebellar abnormalities [20].

The lacunae are sharply demarcated, round, white or yellowish-white areas with depigmentation of the retinal pigment epithelium and choroid and pigmented margins, clustered at the posterior pole around the optic nerve. In a series of 40 patients with 75 assessable eyes, lacunae were present in all patients, colobomas in 39% of eyes, glial proliferation in 19%, severe dysplasia in 17% and pseudoadenomatous proliferation of the pigment epithelium in 14% [20]. Facial features may include a short philtrum, prominent premaxilla, upturned nasal tip, large ears and sparse lateral eyebrows; plagiocephaly occurs, and cleft lip and palate in 3%. Marked scoliosis affects up to one-third of patients, and hip dysplasia occurs. Gastrointestinal problems (constipation, gastro-oesophageal reflux, diarrhoea and feeding difficulties) are, according to parents, the second most difficult problem after seizures. Vascular malformations, pigmentary lesions and tumours are described: choroid plexus papillomas and lipomas and, among malignancies, angiosarcoma, hepatoblastoma, medulloblastoma, embryonal carcinoma and teratoma. Growth is normal until approximately 7 years for height and 9 years for weight, then falls below the general population; syndrome-specific growth charts are available, and puberty may be early or delayed [20].

The French PNDS adds data from published series and from the experience of the coordinating reference centre (Necker Hospital, Paris). Head circumference is usually normal at birth and progresses to moderate secondary microcephaly in the first years; spastic hemiparesis often affects the same side as the asymmetric spasms and the side opposite the EEG abnormalities. On MRI, agenesis is complete in 81% of described cases and partial in 18.9%, mainly posterior; choroid plexus cysts (more than 50%) range from millimetres to several centimetres, and intracranial cysts are preferentially located in the interhemispheric fissure and in the region of the third ventricle and pineal gland, sometimes large and compressive but rarely with hydrocephalus requiring shunting. Histology of the lacunae shows thinning of the choroid and sclera, hypopigmented pigment epithelium, degeneration of cones and rods and microcystic degeneration of the outer nuclear and inner plexiform layers, without an inflammatory component; the lacunae do not change in size with age, although pigment deposits may increase. Persistent fetal vasculature, persistent pupillary membrane, optic nerve aplasia or hypoplasia, partial aniridia and iris coloboma ipsilateral to the microphthalmia have also been described. In a family survey, one third of girls had unilateral blindness, and in a series of 14 children assessed with preferential looking tests and visual evoked potentials, visual function correlated with the appearance of the macula, being preserved when the fovea had no lacunae [35].

Among the systemic manifestations, the PNDS highlights orthopaedic deformities (40–55%), more frequent than in other forms of multiple disability because of asymmetric tone and vertebral malformations; scoliosis (Cobb angle greater than 10°) is early, long-sweeping and may include the pelvis. Among tumours, in addition to choroid plexus papillomas, whose management depends on their progression and on hydrocephalus, intestinal polyposis, embryonal carcinoma, hepatoblastoma, lipomas, angiosarcoma and a large-cell medulloblastoma have been described; a metastatic malignant sacrococcygeal teratoma responded to high-dose chemotherapy with autologous stem cell transplantation. Oral problems (caries, gingivitis, wear from bruxism, delayed shedding of deciduous teeth and eruption of permanent teeth, malocclusion) and pain (expressed mainly through facial expression and vocalisations, predominantly of gastrointestinal origin) are extrapolated from multiple disability, without dedicated studies. Sleep disorders are frequent in the centre's experience, whereas behavioural disorders are rare and should prompt a search for dental, bone or digestive pain. There are no validated motor or behavioural scales for this syndrome, nor quality-of-life studies; carers identify emotional stress, dependency and altered family dynamics as the main sources of burden [35].

Table 3.3 — Quantitative data on Aicardi syndrome compiled in the French PNDS (2019)

Source: [35].

3.4. Box — Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

HMSN/ACC, also called Andermann syndrome or Charlevoix disease, is both a neurodevelopmental and a neurodegenerative disease: it combines severe progressive motor and sensory neuropathy (hypotonia, areflexia and amyotrophy), variable degrees of CC dysgenesis, mild to severe ID and psychotic episodes from adolescence [21]. Sitting is achieved at a mean age of 2.1 years, standing after 2 years and walking at 3.8 years; walking is lost at a mean age of 13.8 years and death occurs at a mean age of 33 years, usually from respiratory failure [21]. On MRI, CC agenesis is complete in 60%, partial in 10%, and the CC is normal in 30%, with mild cortical or cerebellar atrophy later [21].

Table 3.4 — Manifestations of HMSN/ACC in 64 French Canadian patients (2–34 years)

Source: GeneReviews, based on Mathieu (1990) and subsequent series [21].

In the Taft classification used in these series, an intelligence quotient (IQ) above 75 is normal, 50–75 corresponds to mild ID (with 5–6 years of primary schooling and independent living), 25–50 to moderate ID and below 25 to severe ID. Psychotic episodes include paranoid delusions, depressive states, visual and auditory hallucinations and autistic-like traits. Cerebrospinal fluid (CSF) protein is mildly elevated, and sural nerve biopsy, now unnecessary when molecular testing is available, shows near absence of large myelinated fibres, axonal loss and enlarged axons with reduced neurofilament density. Autopsy reveals swollen axons in cranial nerves (III and VII) and nerve roots [21].

3.5. Box — The DCC Spectrum

In heterozygous DCC carriers, phenotypes vary within the same family. In one North African family, five females had complete (three) or partial (two) agenesis, one with mirror movements, and ACC was detected in female fetuses by ultrasonography; in an Australian family of European ancestry, the mother and three of four children had isolated cACC and mirror movements, with low-average to borderline intellectual functioning and mainstream schooling; in a third family, five members had mirror movements, the female index case had pACC with mild movements, one woman had cACC without movements and one male carrier had only a thin rostrum [31]. In a study of 12 carriers from three families, aged 8 to 50 years, five had ACC and mirror movements, two only mirror movements, three only ACC and two neither; neuropsychological performance ranged from extremely low to average, was poorer in the presence of mirror movements and/or ACC and better in carriers with neither, showing that the variant alone does not explain disability [135].

Mirror movements are involuntary movements on one side of the body that reproduce voluntary movements on the opposite side. Mild mirror movements are physiological in young children and usually disappear before age 7 years; their persistence and intensity beyond that age distinguish the pathological form [6]; GeneGuidance curation gives approximately 10 years as the limit [136]. In the congenital form, movements begin early, persist throughout life without worsening or improvement and are generally unaccompanied by other neurological manifestations; a subgroup of DCC carriers, particularly those with CC abnormalities, have cognitive or neuropsychiatric problems [6]. Developmental split-brain syndrome, caused by biallelic variants, combines horizontal gaze palsy, progressive scoliosis and ID [33].

3.6. Box — Mowat–Wilson Syndrome

Classic MWS is characterised by a distinctive face (widely spaced eyes, broad eyebrows with medial flaring, low-hanging columella, prominent or pointed chin, open mouth and uplifted earlobes with a central depression), congenital heart disease with a predilection for the pulmonary arteries and valves, Hirschsprung disease or chronic constipation, moderate to severe ID, epilepsy and genitourinary abnormalities [7, 22, 34].

Table 3.5 — Frequency of selected manifestations in classic Mowat–Wilson syndrome

Source: GeneReviews [22].

Epilepsy begins at a mean age of approximately 3 years (from 1 month to 11 years); the most frequent seizures are focal seizures and atypical absences, and the first is often a focal seizure with fever. Up to 25% of patients have difficult-to-control seizures, more commonly in childhood than in adolescence or adulthood. The initial EEG is often normal or shows only slowing, and repeated studies reveal diffuse spike-and-wave discharges with frontal predominance; in a study of 36 patients with epilepsy, 14 (39%) had electrical status epilepticus during sleep. Epileptic activity does not correlate with structural brain abnormalities [22]. In a cohort of 87 patients, epilepsy affected approximately 79%, microcephaly 78%, hypospadias 60% of boys, heart disease 58% and Hirschsprung disease 44% [71, 72]. The clinical case in section 10 illustrates prenatal presentation as apparently isolated ACC.

4. Clinical Recognition and Warning Signs

4.1. In the Prenatal Period

Complete ACC is usually suspected in the second trimester when the CSP is not visualised in the axial plane, because the septum pellucidum and CC share the same embryological origin [1]. The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guideline states that transabdominal imaging should always demonstrate the CSP between 17–20 and 37 weeks, or with a biparietal diameter of 44–88 mm; non-visualisation before 16 or after 37 weeks is normal. Non-visualisation or an abnormal appearance of the CSP is the indirect sign of callosal agenesis on screening views, usually accompanied by teardrop-shaped ventricles, and an abnormal CSP shape is described as a relatively reliable marker of partial agenesis [137]. Absence of the septal membranes raises suspicion of severe malformations, such as holoprosencephaly, severe hydrocephalus or septo-optic dysplasia [137].

In Aicardi syndrome, the French PNDS describes a third-trimester fetal MRI pattern that some teams use to raise suspicion: complete or partial ACC, usually asymmetric polymicrogyria, periventricular and subcortical heterotopias and cysts around the third ventricle or choroid plexus. The combination of choroid plexus and supratentorial cysts with ACC, interhemispheric asymmetry and posterior fossa abnormalities are the most suggestive signs, but the diagnosis can be confirmed only after birth, because chorioretinal lacunae are not visible on ultrasound or fetal MRI [35].

Other indirect signs are colpocephaly, ventricular walls parallel to one another and to the midline, widening of the interhemispheric fissure, an elevated and dilated third ventricle and comma-shaped or slit-like anterior horns; not all need to be present [1]. In partial agenesis, the CSP may appear normal, dysmorphic or short and wide, and a CSP length-to-width ratio below 1.5 has been proposed as a screening marker [1]. In a Chinese series of 118 fetuses with pACC, the CSP was abnormal in 86.4%, the interhemispheric fissure was widened in 77.1%, the third ventricle was dilated and elevated in 47.4%, and ventriculomegaly was present in 35.6%; among fetuses with a dilated third ventricle, 67.8% had a posteriorly displaced midline cystic mass communicating with the third ventricle, proposed as a new indirect sign [138]. In a Chilean and Spanish series of 22 fetuses with pACC, assessment of the posterior complex on basic axial views showed posterior widening of the interhemispheric fissure in 20 and absence of the callosal sulcus in 19, with interobserver agreement of 95–100% [139].

Ventriculomegaly is not necessary to suspect ACC: atrial width is usually below 10 mm before 24 weeks, and dilatation becomes more common with gestational age [1]. When ventriculomegaly is present, more than 60% of fetuses have another ultrasound abnormality, and in severe ventriculomegaly approximately two-thirds of these abnormalities are intracranial, particularly ACC [50, 140]. Atrial width remains constant from 14 weeks, with a mean of 7.6 ± 0.6 mm; ventriculomegaly is classified as mild (10–12 mm), moderate (12.1–15 mm) or severe (>15 mm), and in pooled data on isolated ventriculomegaly, outcomes were normal in 94%, 76% and 28%, respectively, with a small severe group owing to many pregnancy terminations. These figures refer to isolated ventriculomegaly and do not apply to ventriculomegaly resulting from the configuration of ACC [50, 141].

Table 4.1 — Indications for targeted neurosonography (ISUOG)

Source: [137].

4.2. After Birth, by Age and Context

In newborns, ACC emerges during investigation of abnormal neurological findings or seizures and is readily visible on transfontanellar ultrasonography [3]. In neonatal encephalopathy, MRI may reveal diagnoses other than hypoxic–ischaemic encephalopathy, such as NKH [103], and in neonatal hypoglycaemia, brain imaging investigates panhypopituitarism and ACC [142]. In a male infant with ACC and seizures, neonatal adrenoleukodystrophy should be considered (measurement of very-long-chain fatty acids) [3], and in a boy with lissencephaly, ACC, neonatal-onset epilepsy and ambiguous or underdeveloped genitalia, ARX [76].

In older children, ACC is found during investigation of developmental delay, ID, cerebral palsy and epilepsy [3, 143]. Some patterns point to specific entities: infantile spasms in a girl with ACC suggest Aicardi syndrome and require fundus examination [20]; in the neonatal period, in the absence of fetal signs, the syndrome is rarely recognised (birth measurements are normal in most cases and spasms usually appear after 2 months), but hypotonia, asymmetric tone, feeding difficulties, microphthalmia and subtle dysmorphism (round face, flat forehead, epicanthus, depressed nasal bridge with anteverted nares, large ears) warrant fundus examination and imaging [35]; hypotonia with areflexia and unrecordable sensory potentials in a French Canadian child or a child from a consanguineous family suggest HMSN/ACC [21, 45]; persistent mirror movements after age 7 years, in a carrier or relative with ACC, point to DCC [6, 31]; Hirschsprung disease or severe constipation with the characteristic face suggests MWS [22, 32]; a movement disorder with CC hypogenesis suggests FOXG1 [7]; polydactyly, macrocephaly and hypertelorism suggest acrocallosal or Greig syndrome [44]; and at school age, learning difficulties and progressive paraplegia with a thin CC point to SPG11 [144].

4.3. Warning Signs and Emergencies

Table 4.2 — Warning signs in a patient with ACC

There is no newborn screening for ACC or the entities covered in boxes.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Postnatal Imaging

ACC is visible on neonatal transfontanellar ultrasonography, computed tomography and MRI [3]. On the midsagittal T1-weighted MRI section, absence of the CC is accompanied by absence of the cingulate gyrus; on the axial section, the lateral ventricles are parallel, the anterior horns diverge and the posterior lateral ventricles are dilated (colpocephaly) [7]. Figure 2.39 of the Oxford Desk Reference compares a normal sagittal MRI of a 2-year-old girl with ACC in a 6-year-old girl with microcephaly and moderate learning difficulties, and shows axial computed tomography of the same patient [7]. MRI should be reviewed for other midline abnormalities (agenesis of the septum pellucidum), a generalised migration defect (tubulin-associated lissencephaly) or hydrocephalus (L1CAM) [3]. In tubulinopathy, dysmorphic basal ganglia, with bulbous caudate nuclei and thalami and a diffuse or absent anterior limb of the internal capsule, together with rounded frontal horns, are the key to diagnosis [73]. Hanna's three classes (hypoplasia, hypoplasia with dysplasia and complete agenesis) provide a framework for postnatal description [43].

5.2. Prenatal Ultrasonography: Screening and Neurosonography

The CC can be assessed from 18 weeks with serial ultrasound examinations; absence is generally detectable, whereas hypoplasia is harder to determine reliably [13]. In the median plane, the normal CC is a C-shaped anechoic structure with echogenic borders, with the pericallosal artery immediately above. Definitive diagnosis is made in the direct two-dimensional median plane or in the median plane reconstructed from a three-dimensional (3D) volume acquired axially. Colour Doppler of the pericallosal artery, with a very low pulse repetition frequency, supports assessment of presence or absence, but an abnormal arterial course alone is not conclusive; transvaginal imaging is useful when the fetus is in cephalic presentation [1].

ISUOG recommends assessing and documenting the distal atrium and presence of the CSP in the transventricular plane (good practice point, GPP); measuring atrial width from inner border to inner border, with a normal value below 10 mm throughout pregnancy (grade C); using transabdominal ultrasonography for screening low-risk pregnancies (GPP); and referring suspected cerebral or spinal abnormalities on screening for targeted neurosonography as a diagnostic examination (GPP). ISUOG screening does not include the sagittal CC plane [137]. Transvaginal imaging is preferred for targeted neurosonography; if impracticable (breech presentation, twins), transabdominal imaging with high-resolution linear or microconvex probes is used. The midsagittal plane is the reference plane for midline structures. Callosal biometry should be used cautiously to diagnose hypoplasia: a short, thin or thick CC is not necessarily abnormal, and qualitative assessment confirming that all four components (rostrum, genu, body and splenium) are visible and sonographically normal is more important than quantitative assessment (GPP). Three-dimensional ultrasonography is recommended in targeted neurosonography, particularly when two-dimensional imaging is difficult, and colour Doppler has a marginal role in CC assessment [38].

Ultrasound performance depends on the type of examination. A meta-analysis of 12 studies involving 544 fetuses with suspected central nervous system abnormalities, 143 with ACC confirmed by autopsy or postnatal imaging, estimated prenatal ultrasound sensitivity at 0.72 (95% confidence interval [95% CI] 0.39–0.91), specificity at 0.98 (0.79–1.00), positive likelihood ratio at 43.73 (3.42–558.74), negative likelihood ratio at 0.29 (0.11–0.74) and area under the curve at 0.94; neurosonography outperformed routine screening, with sensitivity of 0.84 versus 0.57 and specificity of 0.98 versus 0.89 [148]. The wide intervals indicate small, heterogeneous studies. A 2026 review of first-trimester neurosonography describes emerging markers, such as choroid plexus-to-ventricle ratios and pericallosal artery Doppler, for early identification of ventriculomegaly and ACC, and notes that cortical and vermian malformations may not be detectable at that stage [149].

5.3. The 2025 International Delphi Consensus

The Delphi consensus was developed over three rounds (data from January to October 2024), with a core group of nine experts and 61 statements in five domains; consensus was defined as agreement above 70%. Of 65 invitees, 55 responded in the first round and 43 completed the process; the panel was predominantly European (74.5%), with four experts from North America, four from South America (including one from Brazil), four from Oceania and one each from Africa and Asia, and predominantly from maternal–fetal medicine (78.2%), with five radiologists and two paediatric neurologists [2].

Table 5.1 — Statements in the final round of the 2025 Delphi consensus

Source: [2].

If the midsagittal CC plane cannot be obtained during the diagnostic examination, the examination should be rescheduled even if indirect assessment (CSP, transthalamic plane) is normal. Unlike ISUOG, the panel included the sagittal plane in screening, but flexibly: in settings with limited resources or expertise it should be attempted without being mandatory; if obtained, assessment is qualitative and without measurements; if it cannot be obtained and axial views are normal, the CC may be considered normal without repeating the examination. The ratio of CC length to the internal occipitofrontal skull dimension in the midsagittal plane is a potential metric for a short CC. A complete, isolated, homogeneous but short CC may be a benign variant, and longitudinal follow-up helps decision-making; when uncertainty between a variant and dysgenesis persists, parental MRI may reveal a familial pattern. Infectious investigation is reserved for a heterogeneous CC because cytomegalovirus and toxoplasma may cause subtle changes, whereas a short, thin or thick CC is more closely linked to genetic causes [2]. The panel itself acknowledges the consensus limitations: lack of agreed biometric references and cut-offs, with a risk of overdiagnosis or underdiagnosis, few radiologists, underrepresentation of Africa and Asia, development in high-resource settings and reliance on expert opinion rather than prospective data [2].

5.4. Fetal Magnetic Resonance Imaging

Fetal MRI reduces false positives, confirms ACC, distinguishes complete from partial agenesis and detects coexisting brain abnormalities; approximately 15% of cases considered isolated prenatally had associated abnormalities after birth [41]. MRI is superior to ultrasonography for abnormalities of callosal and gyral development, cerebellar hypoplasia, porencephaly, vermian cysts and subependymal nodules or cortical tubers; in one series, it changed the diagnosis in 45 of 145 cases, with better performance at later gestational ages [140].

The added value of MRI depends on the quality of the preceding ultrasound examination. In the British MERIDIAN study, in which ultrasonography was not necessarily specialist neurosonography and MRI was performed within two weeks, 79 fetuses with failed commissuration on ultrasonography (55 with agenesis and 24 with hypogenesis) had a diagnostic accuracy of 34.2% on ultrasonography and 94.9% on MRI (difference 60.7%; 95% CI 47.6–73.9); prognostic information changed in 45.6% of cases and management in 44.3%, and the authors recommended MRI for all pregnant women whose fetus has failed commissuration as the only intracranial finding [150]. In a meta-analysis of 14 studies involving 798 fetuses with isolated ACC on ultrasonography, MRI found additional abnormalities in 10.9% (95% CI 4.1–20.6) of cACC cases, and a further 4.3% (1.4–8.8) emerged only after birth; when ultrasonography consisted of dedicated neurosonography, MRI added 5.7% (0.5–16.0), versus 18.5% (7.8–32.4) after standard axial assessment. In pACC, MRI added 13.4% (4.0–27.0), with 16.2% (5.9–30.3) postnatal abnormalities. Cortical and posterior fossa abnormalities were those most often missed by ultrasonography [151]. In the multinational ENSO group study (14 centres in Italy, the United Kingdom, Portugal, Canada, Austria and Spain), involving 269 fetuses with apparently isolated callosal abnormalities after specialist multiplanar neurosonography and a normal karyotype, MRI performed within two weeks found additional central nervous system abnormalities in 11.2% (30/269), predominantly malformations of cortical development (11.6% in cACC and 9.7% in pACC); only maternal body mass index was independently associated with MRI detection (odds ratio 1.07; 95% CI 1.01–1.14), and 3.9% of abnormalities escaped both techniques and were detected only after delivery or at autopsy [152].

ISUOG considers that fetal MRI should be indicated by the findings of the expert performing neurosonography rather than solely by screening suspicion, because inappropriate referrals have inflated the rate of malformations “detected only by MRI” and MRI has false positives; MRI complements neurosonography and may replace it as a second-line assessment when neurosonography is unavailable or inadequate [38, 137]. SMFM considers MRI particularly useful in ACC that appears isolated on ultrasonography, because subtle abnormalities markedly worsen prognosis [1].

5.5. Prenatal Genetic Investigation

SMFM recommends offering amniocentesis with CMA when ACC is detected; depending on institutional policies, beginning with karyotyping or fluorescence in situ hybridisation (FISH), with reflex CMA if these are normal, is reasonable. If additional abnormalities, consanguinity or a specific family history are present, a gene panel or exome sequencing may be useful because CMA does not detect Mendelian disorders, with pre- and post-test counselling by a professional experienced in genomic sequencing. Cell-free fetal DNA is an option for those declining invasive diagnosis but detects only common aneuploidies. Cytomegalovirus or Zika serology is rarely useful without other findings [1]. The 2025 Delphi consensus is more emphatic: systematic amniocentesis with microarray for any CC abnormality (92.0%) and amniocentesis for isolated complete and partial agenesis (82.0%) [2].

Table 5.2 — Diagnostic yield of karyotyping, CMA and sequencing

These series are not directly comparable. They differ in selection (isolated or complex ACC, agenesis alone or all callosal abnormalities), prior testing (negative CMA or otherwise), design (trio or proband), period and population, and some include series selected for suspected monogenic disease. The 2024 meta-analysis concludes that exome sequencing should also be considered in isolated ACC but acknowledges small, heterogeneous and selected studies [16].

A 2025 review systematises the genetic diseases underlying fetal callosal abnormalities and prenatal testing options, with CMA for aneuploidies and CNVs and exome sequencing for monogenic diseases [156]. General position statements on prenatal genomic sequencing provide the context for exome sequencing in ACC. In 2022, the International Society for Prenatal Diagnosis (ISPD) cited an overall yield of 31% in pregnancies with ultrasound abnormalities and normal karyotype and CMA, 15% in unselected cohorts and 42% in selected series; it recommends trio sequencing, individualised pre-test counselling of both parents, separate consent from each for their sample (the pregnant woman alone consents to the invasive procedure), an explicit institutional policy on secondary and incidental findings, discussion of possible disclosure of non-paternity or consanguinity, post-test counselling for everyone, including those with negative results, and reanalysis when a new postnatal phenotype or a new pregnancy arises. Indications include a fetus with a major abnormality or multisystem abnormalities without a diagnosis after CMA and a phenotype suggesting a genetic cause, a pattern strongly suggesting a monogenic disorder (with CMA beforehand or in parallel, because prenatal exome sequencing is not validated for all CNVs), and recurrence of similar abnormalities; routine use in all pregnancies is not supported [157]. In 2020, the American College of Medical Genetics and Genomics (ACMG) published a points-to-consider document on fetal exome sequencing, the full text of which was inaccessible [158]. In Denmark, the 2026 national guidelines included central nervous system malformations among the indications for routine prenatal genome sequencing in the public health service [159].

5.6. Postnatal Aetiological Assessment

The objective is a specific laboratory-confirmed diagnosis, which forms the basis of counselling [7]. The history includes a three-generation pedigree assessing consanguinity, seizures and developmental milestones; examination looks for dysmorphic features and other malformations, measures head circumference, height and weight, and looks for gaze palsy, suggestive of tubulinopathy [3]. Genital examination is performed in male infants because of ARX [146].

Investigations recommended by the Oxford Desk Reference are genomic analysis (array, panel, exome or genome, according to availability); ophthalmological examination for optic nerve hypoplasia or chorioretinal lacunae (Aicardi syndrome and KIF11); MRI review; urinary amino acids and organic acids; CSF glycine (NKH) and lactate (PDHC deficiency) when seizures are present; very-long-chain fatty acids in a male infant; and complete hypothalamic–pituitary axis investigation when optic nerve hypoplasia or absence of the septum pellucidum is present [3]. In NKH, CSF glycine above 230 μM, hydrocephalus and a short, thin CC indicate the severe classic form; a CSF-to-plasma glycine ratio below 0.08, onset after 4 months, a normal-sized CC and absence of epilepsy indicate the attenuated form [108]. On long-echo-time MR spectroscopy, NKH shows a glycine peak at 3.5 ppm [108].

Microarray remains the first-line test in a child with a callosal abnormality and ID, with a yield of 13% in a series of 149 patients [63], followed by exome or genome sequencing when CMA is normal [3, 154]. In a Japanese series of 95 patients with a neurodevelopmental disorder and negative exome sequencing, genome sequencing identified the recurrent RNU4-2 variant NR_003137.3:n.64_65insT (genomic NC_000012.12:g.120291839_120291840insA, gene on the negative strand) in 5 (5.3%), all de novo; patients had severe ID, microcephaly, short stature, ventriculomegaly, CC thinning and a characteristic lip gestalt (tented upper lip with an exaggerated Cupid's bow, everted lower lip and horizontal philtrum) [48, 68].

5.7. Criteria and Tests for the Entities Covered in Boxes

Aicardi syndrome. There are no consensus criteria; Sutton's modified criteria (2005) consider the classic triad diagnostic and the presence of two triad elements with at least two major or supporting features strongly suggestive. Diagnosis is exclusively clinical [20]. The combination of ACC, cysts that do not communicate with the ventricles, subependymal heterotopia and polymicrogyria is relatively specific [20].

Table 5.3 — Modified criteria for Aicardi syndrome

Sources: [20, 35].

The PNDS confirms the diagnosis by combining ophthalmological and neuroradiological criteria and stresses that ACC, even when associated with epilepsy, is not sufficient. The lacunae, regarded as pathognomonic, are round or petal-shaped areas, whitish, pinkish or greyish, in the plane of the retina and without vessel deviation, measuring from 1/10 to several times the optic disc diameter; ring-shaped pigment deposits around a colobomatous disc may resemble the morning glory anomaly. Assessment should be performed by an experienced ophthalmologist; only one 8-month-old child has been studied with fluorescein angiography and optical coherence tomography. In the Barkovich classification of ACC with cysts, type 1 cysts are diverticula of the third or lateral ventricles and type 2 cysts do not communicate with the ventricular system; type 2b cysts, with falx defects, subependymal heterotopias and polymicrogyria, account for most cases of Aicardi syndrome. Genetic testing does not confirm the diagnosis, but genome-wide analysis is recommended to rule out differential diagnoses before counselling [35].

HMSN/ACC. There are no consensus criteria. Suspicion is based on severe progressive motor and sensory neuropathy with areflexia, developmental delay or mild to severe ID, and conduction studies: unrecordable sensory potentials in the median, ulnar and sural nerves even in the first year, reduced-amplitude motor potentials, variable conduction velocities and mild electromyographic signs of active denervation. Absence of a family history does not exclude the diagnosis. Diagnosis is established by biallelic P/LP SLC12A6 variants; two VUS, or one pathogenic variant with one VUS, neither establish nor exclude the diagnosis. In the targeted approach, SLC12A6 is sequenced and, if zero or one variant is found, deletion and duplication testing follows; in French Canadians with a typical phenotype, the founder variant is tested first. In the comprehensive approach, exome or genome sequencing is used, with exome array for exonic CNVs [21]. Sequencing detects more than 90% of known pathogenic variants, and only one gene deletion or duplication has been published [21]; this is the proportion of variants detectable by the technique, not the clinical sensitivity of the test in a patient with the phenotype.

DCC spectrum. Molecular diagnosis is made by an ACC or mirror movement panel, or by exome sequencing, with parental testing; GeneReviews recommends MRI to assess the CC in DCC carriers [6]. In a patient with mirror movements and diagnostic uncertainty, brain and cervical MRI may be considered [6].

Mowat–Wilson syndrome. No formal criteria have been published; diagnosis is established in a patient with the characteristic face and developmental delay or ID, or by identifying a heterozygous P/LP ZEB2 variant (approximately 84%), a 2q22.3 deletion including ZEB2 (approximately 15%, requiring CMA), or a chromosomal rearrangement disrupting the gene (approximately 1%) [22]. A ZEB2-associated methylation episignature has been described [72].

5.8. Test Limitations and Report Content

Each test has blind spots that a negative result does not eliminate. Karyotyping and FISH detect only aneuploidies and large rearrangements; CMA does not detect sequence variants or Mendelian disorders [1]; exome sequencing does not capture non-coding genes such as RNU4-2 [48], nor mobile element insertions such as the Alu insertion in ZEB2, detected only by long-read sequencing [22], and is not validated for all CNVs [157]. Cell-free DNA screens only for common aneuploidies [1]. Mosaicism is another limitation: in mosaic trisomy 8, detection in chorionic villi is problematic because of the frequency of confined placental mosaicism, and postnatal diagnosis may require tissue other than blood [7, 53]; in parents of children with MWS, leukocyte DNA analysis may not detect all somatic mosaicism and does not detect gonadal mosaicism [22]. Aicardi syndrome has no molecular test, and testing serves only to exclude differential diagnoses [20]. Finally, variant interpretation in a gene with incomplete penetrance is delicate: a missense DCC variant present in population databases does not exclude pathogenicity, and the variant's presence in an asymptomatic parent is expected [31].

A molecular test report should specify the gene, reference transcript with version (preferably MANE Select), HGVS variant nomenclature, zygosity, classification according to ACMG and Association for Molecular Pathology (ACMG/AMP) criteria, and the method and its limitations [21, 22]. VUS neither establish nor exclude the diagnosis; parental segregation studies and reanalysis in light of new clinical information help reclassify them [21, 157]. In prenatal trio sequencing, inheritance is assigned directly; if only the proband is sequenced, inheritance must be validated by targeted parental testing [157].

5.9. After Termination or Fetal Loss

If pregnancy is terminated, fetal DNA should be stored (for panel, exome or genome sequencing if autopsy suggests a monogenic disorder), and non-invasive autopsy, including brain MRI, or a detailed autopsy with neuropathology should be strongly recommended; the latter requires specific consent and time for brain fixation. Ultrasound appearances may not be confirmed at autopsy [140]. This sample is decisive for prenatal diagnosis in a future pregnancy, as illustrated by the case in section 10, in which a previous sibling with ACC had been terminated without genetic investigation or autopsy [32].

5.10. Practical Algorithm

Table 5.4 — Assessment sequence for a corpus callosum abnormality

5.11. Differences Between Guidelines

Table 5.5 — Points of divergence between recommendations on fetal callosal abnormalities

The main divergence concerns the place of exome sequencing: SMFM reserves it for contexts with additional signs, whereas the 2024 meta-analysis and 2025 French cohort show yields of 23–43%, including the isolated form, and Denmark already incorporates prenatal genome sequencing for central nervous system malformations [1, 5, 16, 159].

In Aicardi syndrome, the two diagnostic references also diverge: GeneReviews considers the presence of two triad elements with at least two major or supporting features strongly suggestive, whereas the French PNDS requires all three elements and classifies incomplete presentations as “variants”, with no consequence for the therapeutic approach (Table 5.3) [20, 35].

6. Differential Diagnosis

6.1. Imaging Differential Diagnosis

In the fetus, definitive diagnosis is possible only in the median plane. Dilated colpocephalic ventricles open the broad differential diagnosis of ventriculomegaly; a widened interhemispheric space also occurs in cerebral atrophy, accompanied by microcephaly; and a false CSP may be seen due to an interhemispheric cyst, a widened interhemispheric space with abnormal medial sulcation, or the columns of the fornix in the axial plane [1]. Holoprosencephaly frequently affects midline structures, including the CC: the semilobar form combines CC absence and frontal lobe fusion; approximately half of cases are chromosomal, with trisomy 13 the most common cause, and SHH is the most frequent gene [140, 160, 161]. Hydranencephaly and arachnoid or porencephalic cysts also enter the differential diagnosis [140].

Septo-optic dysplasia (De Morsier syndrome) is the main midline differential diagnosis. It is defined by two of three elements: optic nerve hypoplasia, agenesis of the septum pellucidum and hypothalamic–pituitary dysfunction; half of patients have a septum pellucidum. In one series, 80% had growth hormone (GH) deficiency, 60% corticotrophin (ACTH) deficiency, 40% gonadotrophin deficiency and 35% diabetes insipidus; seizures frequently result from hypoglycaemia, and approximately half of patients have moderate to severe delay. It is predominantly sporadic, with a low recurrence risk; HESX1 explains some cases, with phenotypes ranging from severe septo-optic dysplasia to isolated GH deficiency, and a multigenic origin with environmental interaction is considered [7, 145]. CC agenesis or hypoplasia is included in the spectrum of this sequence [162].

Arachnoid cysts are located in the midline in 40% of cases, are almost always sporadic and solitary, predominate in males (more than 2:1) and on the left, and are generally asymptomatic; without symptoms, management is conservative with neurosurgical consultation. Bilateral temporal arachnoid cysts should prompt investigation for glutaric aciduria type 1 [145].

Some rare callosal abnormalities have a significance of their own. In a meta-analysis of 33 studies with 604 fetuses, none had an abnormal karyotype, and development was abnormal in 9.7% with an obliterated CSP, 15.4% with isolated septal agenesis, 24.9% with a hypoplastic CC, 33% with a thin CC, 8.7% with a wide CSP and 0% with an isolated pericallosal lipoma or thick CC; data were insufficient for a thin CC and narrow CSP [163]. A thick CC should nevertheless be interpreted in context: the Delphi consensus considers an excessively thick CC suggestive of dysgenesis [2], and thickening is associated with neurofibromatosis type 1, megalencephaly–capillary malformation (PIK3CA) and other syndromes involving PI3K/AKT/mTOR pathway hyperactivation [97, 164, 165].

In a patient with a thin rather than absent CC, the differential includes severe classic NKH (a short, thin CC that does not grow) [105, 108], complicated spastic paraplegias SPG11 and SPG15, with learning difficulties and cognitive decline preceding paraplegia in the second decade [144], leukodystrophies and hypomyelinating disorders (RARS1, DDHD2/SPG54) [97], asparagine synthetase and SLC1A4 deficiencies [111], and ReNU syndrome [48].

6.2. Syndromes and Genes: Comparative Table

Table 6.1 — Aetiological differential diagnosis of ACC

The difference between Aicardi syndrome and its differential diagnoses is predominantly ophthalmological: Aicardi lacunae are central and the optic nerve is almost always involved, whereas in microcephaly with lymphoedema and retinopathy (KIF11, autosomal dominant), retinopathy is peripheral and the optic nerves are normal. FLNA-related periventricular heterotopia has no ophthalmological abnormalities; PLK4, TUBGCP4 and TUBGCP6 (autosomal recessive) cause microcephaly with chorioretinal retinopathy; PORCN causes Goltz syndrome; tuberous sclerosis complex (TSC1, TSC2) combines spasms, tubers and achromic retinal patches; and lacunae have been described in orofaciodigital syndrome type IX [20]. The French PNDS adds that microcephaly is generally more severe in microcephaly with lymphoedema and retinopathy than in Aicardi syndrome and that neuronal migration disorders, frequent in Aicardi syndrome, are almost absent in the former; that oculocerebrocutaneous (Delleman) syndrome, with no known molecular cause, has a pathognomonic malformation with tectal dysplasia, absent vermis, small cerebellar hemispheres and excess fluid in the posterior fossa; and that, in ACC (particularly partial) with ophthalmological abnormalities unrelated to Aicardi syndrome, low acuity, refractive errors and strabismus predominate, with developmental delay in 62% and epilepsy in 46% [35].

In HMSN/ACC, the differential includes autosomal recessive forms of CMT type 4 (EGR2, FGD4, FIG4, GDAP1, MTMR2, NDRG1, PRX, SBF1, SBF2, SH3TC2), with severe early neuropathy without ID or callosal dysgenesis; infantile neuroaxonal dystrophy (PLA2G6), with regression between 6 months and 3 years, spastic tetraparesis, optic atrophy and sometimes partial ACC; metachromatic leukodystrophy (ARSA), generally without ACC; giant axonal neuropathy (GAN), without ACC but with CC atrophy in some patients; SPG11, with upper-limb hyperreflexia and spasticity; and Krabbe disease (GALC), with a thin CC in some patients [21]. De novo dominant SLC12A6 variants cause intermediate CMT without ACC or ID [23]. In the same Quebec founder population, ARSACS (SACS) combines spastic ataxia and motor and sensory neuropathy with onset usually between 12 and 18 months, and MRI shows thinning of the posterior part of the CC body, without agenesis.

Congenital mirror movements may also result from NTN1 and RAD51, without reported callosal abnormalities [6], and occur in ANOS1-associated Kallmann syndrome [6]. Early-onset mirror movements also accompany congenital hemiplegia and several complex syndromes, in which associated findings dominate the presentation [6].

6.3. List of Syndromes in Smith's Appendix

Smith's differential diagnosis appendix lists ACC as a frequent finding in acrocallosal, cerebro-oculo-facio-skeletal, Curry–Jones, FG, Fryns, Gómez–López–Hernández, Marden–Walker and Meckel–Gruber syndromes, 2q31.1 and 15q24 microdeletions, microphthalmia with linear skin defects, Miller–Dieker, Neu–Laxova and Pitt–Hopkins syndromes, septo-optic dysplasia sequence, Toriello–Carey and Walker–Warburg syndromes, distal Xq duplication or disomy and Zellweger syndrome; and as an occasional finding in Apert, Baller–Gerold, Carpenter, cerebro-costo-mandibular and Coffin–Siris syndromes, microgastria–limb reduction complex, Crouzon syndrome, 11q deletion, Fanconi anaemia, fetal effects of alcohol and warfarin, 45,X, frontonasal dysplasia, Gorlin, Greig, hydrolethalus, Laurin–Sandrow and Lenz–Majewski syndromes, Lenz microphthalmia, Marshall–Smith syndrome, microcephalic primordial dwarfism, 22q11.2 deletion, Mowat–Wilson syndrome, oculo-auriculo-vertebral spectrum, Opitz G/BBB, orofaciodigital and Peters-plus syndromes, thrombocytopenia with absent radius and Rubinstein–Taybi syndrome [60]. Other syndromes with CC abnormalities described in Smith include Smith–Lemli–Opitz (agenesis or dysgenesis, with holoprosencephaly in 5%), Curry–Jones (craniosynostosis, polysyndactyly, ACC, plaque-like skin lesions, hemimegalencephaly and a porencephalic cyst), microphthalmia with linear skin defects (ACC and absence of the septum pellucidum), mosaic trisomy 8 (occasional ACC) and Xq28 duplication (callosal hypoplasia) [172–176]; in Cohen syndrome, conversely, the CC may be enlarged [177], and in Baraitser–Winter syndrome, a present CC is short and thick [178]. Figure 1 of the acrocallosal syndrome chapter shows a newborn with a broad forehead, hypertelorism, a broad nose with anteverted nostrils, abnormal auricles, redundant nuchal skin, broad thumbs and halluces with partial thumb duplication, nail hypoplasia and toe syndactyly [179]. In the Oxford Desk Reference polymicrogyria diagram, CC hypoplasia is associated with tubulinopathies and Goldberg–Shprintzen (KIAA1279/KIFBP), Joubert, SOX2, Zellweger and 22q11 deletion syndromes [180]. Nyhan's Atlas adds ACTH deficiency, mitochondrial diseases (particularly PDHC deficiency), NKH, peroxisomal disorders and Vici syndrome among metabolic and endocrine causes [104]. Walker–Warburg syndrome and muscle–eye–brain disease (POMT1, POMGNT1) combine type II lissencephaly, ocular abnormalities and congenital muscular dystrophy [140, 181].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no treatment that modifies the callosal abnormality, and no approved drugs or therapeutic trials target ACC [18]. A ClinicalTrials.gov database search on 10 October 2026, with 21 records for “agenesis of corpus callosum”, returned only observational or diagnostic studies or studies relating to other conditions; the European trial registry was not consulted, and a negative search does not prove that no studies exist [17, 182]. Management therefore addresses the identified cause and manifestations: epilepsy, development and learning, sleep, endocrine deficiencies associated with midline defects, orthopaedic problems and systemic comorbidities of the syndromes. None of the source references formulates specific treatment recommendations for isolated ACC [1, 3].

7.2. Pregnancy and Delivery Following a Fetal Diagnosis of ACC

Initial assessment includes detailed ultrasonography and neurosonography, fetal echocardiography and fetal MRI, with third-trimester follow-up ultrasonography for brain abnormalities that manifest late. Mode and place of delivery follow usual obstetric indications [1]. The SMFM section on ACC does not specifically address pregnancy termination [1]; in a French cohort, all couples with a fetal DCC variant continued the pregnancy, 73% of couples with another genetic diagnosis chose termination, and 17% without a genetic diagnosis did so [5]. Information on prognosis (section 11) and aetiology is therefore the main clinical tool in prenatal management.

7.3. Early Intervention, Rehabilitation and School

Deficits in isolated ACC appear early and become more pronounced at school age. The prospective North American study using the Vineland scales recommends multimodal intervention programmes from the first year of life, building on relatively preserved social skills, because communication is impaired from 6 months, motor skills at 12 months and daily living skills at 18 months [122]. In the Italian cohort with isolated cACC, almost half of the children underwent rehabilitation [14]. Given the occurrence of subtle neurological, social and learning deficits even with normal intelligence, the review by Palmer and Mowat recommends longitudinal neurocognitive follow-up for all children with ACC [4]. For DCC carriers with mirror movements, GeneReviews recommends educational accommodations (extra time in examinations, limiting handwriting), educating parents and teachers, reassuring them about the usual absence of ID in isolated mirror movements, avoiding stigmatisation and providing career guidance towards occupations not requiring complex bimanual movements, repetitive or sustained hand movements, or extensive writing; when neurodevelopmental deficits are present, usual treatment is provided, with specialist referral [6].

7.4. Epilepsy

Epilepsy follows the general principles of treatment of the genetic epilepsies. None of the sources identifies a specific antiseizure drug for isolated ACC. In Aicardi syndrome, epilepsy is treated with conventional antiseizure drugs by an experienced neurologist, and most patients require several drugs [20]. In HMSN/ACC, seizures are treated with the usual antiseizure drugs, without any drug having demonstrated specific efficacy; GeneReviews states that valproate may also benefit behavioural problems, without specifying a dose [21]. In MWS, up to 25% of patients have difficult-to-control seizures; vagus nerve stimulation reduced seizure frequency in at least two patients, and in one patient antiseizure drugs were discontinued in adulthood without recurrence [22]. Electrical status epilepticus during sleep has been described in several patients with MWS investigated with overnight EEG; in a study of 36 patients with epilepsy, 14 (39%) had this pattern [22]. In all these cases, conventional antiseizure drug doses are those for their general indications, and syndrome-specific doses were not described in the sources consulted.

For Aicardi syndrome, the French PNDS does not set out a specific regimen: the choice depends on seizure type; for spasms, one study suggested benefit from first-line vigabatrin, and corticosteroids and corticotropin (ACTH) are debated, given the lack of demonstrated efficacy in this syndrome and the risks in a context of multiple disability; in older children with persistent spasms, no study demonstrates the need to continue vigabatrin. If seizures persist after second-line treatment, choice and follow-up pass to a paediatric neurologist experienced in epileptology (or an epileptologist after 12 years of age); polytherapy is justified only by a significant and lasting benefit, with attention to interactions and to the risk of osteopenia, which is greater with polytherapy. The ketogenic diet has never had published efficacy in the syndrome, vagus nerve stimulation has no demonstrated specific efficacy, and palliative surgery has variable results without predictive factors: callosotomy controlled seizures in one patient with partial agenesis, resection of the polymicrogyric area failed in two patients and cyst surgery did not alter epilepsy in one case. Presurgical evaluation is the remit of teams specialised in surgery for rare and complex childhood epilepsies. Detailed characterisation of seizure types and the EEG serves mainly to avoid therapeutic escalation [35]. Reference doses are given in Table 7.3.

7.5. Cannabidiol in Aicardi Syndrome: Off-Label Use

Purified cannabidiol (CBD) (Epidiolex® in the United States, Epidyolex® in the European Union) is marketed as an oral solution. The Aicardi syndrome GeneReviews cites a reduction in median seizure frequency of up to 50% with CBD [20]. The source study was an open-label compassionate-use and expanded-access programme at 11 North American institutions (January 2014 to December 2016), involving patients aged 1 to 30 years with severe refractory epilepsy treated for at least 10 weeks: CDKL5 deficiency (n=20), Aicardi syndrome (n=19), 15q duplication (n=8) and Doose syndrome (n=8). In the efficacy group (n=46), the median percentage reduction in convulsive seizure frequency was 51.4% at week 12 (n=35; interquartile range 9–85%) and 59.1% at week 48 (n=27; interquartile range 14–86%), pooled values across the four syndromes rather than Aicardi-specific results. In the safety group (n=55), 15 patients (27%) withdrew by week 144, 4 because of adverse effects and 9 because of lack of efficacy. The authors classified the evidence as class III and recommended randomised controlled trials [183].

Table 7.1 — Cannabidiol study including patients with Aicardi syndrome

Source: [183]. IQR, interquartile range.

This study has no control group, combines four syndromes, loses patients over time (35 assessed at week 12 and 27 at week 48, favouring retention of responders) and provides no confidence intervals; the relative reduction in the median does not indicate the proportion of seizure-free patients. There is no randomised CBD trial in Aicardi syndrome, and the French PNDS classifies this study as class III evidence [35]; use in this syndrome is off-label in both jurisdictions.

The US label, in the version effective 29 May 2026, authorises Epidiolex® for seizures associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome and tuberous sclerosis complex (TSC) from age 1 year. In LGS and Dravet syndrome, the recommended starting dose is 2.5 mg/kg twice daily (5 mg/kg/day); after one week, this may be increased to the maintenance dose of 5 mg/kg twice daily (10 mg/kg/day), up to a maximum of 10 mg/kg twice daily (20 mg/kg/day). In TSC, the starting dose is the same, with weekly increases of 2.5 mg/kg twice daily up to the maintenance dose of 12.5 mg/kg twice daily (25 mg/kg/day). The label requires transaminase (ALT and AST) and total bilirubin measurements before initiation because of the risk of hepatocellular injury and provides for dose adjustment in moderate or severe hepatic impairment [36]. These doses are for the approved indications and do not constitute a validated recommendation for Aicardi syndrome.

Table 7.2 — Regulatory status of cannabidiol

Sources: [36, 184].

7.6. Endocrinology and Midline Defects

When ACC is associated with optic nerve hypoplasia or absence of the septum pellucidum, the entire hypothalamic–pituitary axis, including the posterior pituitary, should be investigated because of the risk of hypoglycaemia due to GH and ACTH deficiencies and of diabetes insipidus; MRI should include the chiasm and pituitary [3, 145]. In the cohort with prenatally isolated ACC from France, three children with hypopituitarism had additional abnormalities on postnatal MRI [124]. Hormone replacement follows the rules for each deficiency and is not addressed in the source references for this entry.

7.7. Sleep

Sleep disturbances are frequent in children with ACC, particularly early in life. A 2025 narrative review recommends systematic sleep assessment and investigation of interventions; no treatment trials exist [123].

7.8. Management of the Entities Covered in Boxes

Aicardi syndrome. Initial assessment includes biometry; neurological assessment with MRI and EEG; developmental assessment; neuropsychiatric assessment after 12 months (sleep, attention deficit hyperactivity disorder, anxiety, ASD); spinal radiographs (hemivertebrae, block vertebrae, ribs); physical and rehabilitation medicine, physiotherapy and occupational therapy; gastrointestinal and nutritional assessment (dysphagia, aspiration, need for gastrostomy); ophthalmology; pubertal assessment; dermatological examination of vascular malformations and pigmentary lesions because of the risk of malignant transformation; and genetic counselling, with testing to exclude differential diagnoses, particularly in non-classic presentations. Regular tumour screening is not recommended, but careful clinical surveillance is [20]. Treatment includes conventional antiseizure drugs, gastrostomy when necessary, physiotherapy and occupational therapy, orthopaedic care, constipation treatment (stool softeners, prokinetics, osmotic and stimulant laxatives), augmentative and alternative communication, behavioural intervention and, if necessary, medication for attention deficit hyperactivity disorder [20].

The French PNDS organises management as for multiple disability, coordinated by a paediatric neurologist (or neurologist) at a reference or competence centre, in liaison with the attending physician. The diagnosis should be disclosed at a dedicated consultation by the physician who established it, preferably with the department psychologist, including the follow-up plan, the multidisciplinary team and contact details for the patient association. Several drugs are used outside their marketing authorisation, which in France requires informing the family, stating the off-label prescription on the prescription form and justifying it in the medical record [35].

• Rehabilitation and orthoses. Early intervention with active and passive physiotherapy, changes of position, psychomotor therapy, stimulation of non-verbal communication, hydrotherapy, therapeutic horse riding and psychological support for parents, carers and siblings; in a patient who does not walk, the aim is to prevent hip dislocation and scoliosis and to preserve comfortable sitting and standing. Orthoses (seating brace, anti-equinus orthoses, scoliosis braces, standing frame, moulded mattress, night-time knee extension orthoses) are prescribed after orthopaedic assessment and reviewed to detect pressure sores and to adapt to growth [35].
• Oral skills and communication. Chopped or minced textures if chewing is weak without dysphagia, puréed and smooth textures if there is dysphagia or no chewing; speech and language therapy for perioral hypersensitivity and aspiration; assessment of communication by speech and language therapy and occupational therapy [35].
• Behaviour and sleep. First look for pain and its cause (change of environment, sensory loss, change of positioning); psychological or psychiatric assessment, behavioural therapy, psychotropic drugs for major agitation or anxiety, relaxation in a multisensory environment (Snoezelen). For sleep, sleep diary, actigraphy, screening for nocturnal seizures and obstructive sleep apnoea, and polysomnography if necessary; melatonin and neuroleptics are often required [35].
• Nutrition. Assessment of growth, oral skills and intake by the dietitian at diagnosis and at least annually, with a target BMI at the 25th centile; a high-calorie diet if growth slows, always enriched with calcium. Under the ESPGHAN criteria for children with multiple disability, a single criterion suffices to define malnutrition: physical signs (pressure sores, poor peripheral circulation), weight-for-age below −2 Z, triceps skinfold or mid-upper arm circumference below the 10th centile, or weight loss or a flat curve. Height is estimated from knee–heel length in a tetraplegic child. Gastrostomy is discussed at a multidisciplinary meeting in the presence of malnutrition despite a high-calorie diet, aspiration with pneumonia or excessively long meals; it shortens mealtimes and reduces aspiration pneumonia. Gluten-free or lactose-free diets do not improve growth [35].
• Bone. Vitamin D supplementation from diagnosis and throughout life, calcium intake adapted to age and mode of feeding, measures against immobility and good-quality puberty (treatments to limit menstrual cycles should maintain good oestrogenisation). Densitometry can be interpreted only from 5 years of age: the lumbar spine (L1–L4) is the most reliable measurement, but the femoral neck better predicts fractures in spastic tetraparesis and is used in severe scoliosis or after arthrodesis; values below −2 standard deviations are interpreted together with calcium–phosphate studies (vitamin D or calcium deficiency, hyper-resorption). A fracture with density below −2 standard deviations defines fragility-fracture osteoporosis and leads to consideration of intravenous bisphosphonates, discussing benefit and risk, particularly before orthopaedic surgery [35].
• Gastro-oesophageal reflux. Treat from the first direct signs (regurgitation, vomiting, grimacing or discomfort at meals) or indirect signs (bruxism, crying or night-time discomfort, sleep disturbance): a proton pump inhibitor (omeprazole, lansoprazole) as first line, combined with an H2 antagonist if this fails and, in severe refractory reflux, bethanechol (hospital pharmacy) introduced gradually, provided there is no unstable epilepsy or asthma; if this fails, endoscopy and possible anti-reflux surgery. Constipation is treated with laxatives, particularly polyethylene glycol [35]. The H2 antagonist named by the protocol, ranitidine, was suspended in the European Union in 2020 [185].
• Respiratory. Prevention of food aspiration and reflux, vaccination against seasonal influenza and pneumococcus and early detection of vertebral deformities. For salivary aspiration, head positioning, a hyoscine (scopolamine) patch and, under discussion, botulinum toxin injection into the salivary glands. In severe congestion or aspiration pneumonia, cessation of oral feeding, gastrostomy and a secretion suction device; inhaled anticholinergics or salbutamol (Ventolin®) and inhaled corticosteroids for bronchial hyperreactivity, without demonstrated efficacy; continuous or alternating antibiotic therapy (amoxicillin, co-amoxiclav, co-trimoxazole or macrolides) for recurrent infections; instrumental airway clearance techniques taught to parents (Cough Assist®, Percussionnaire®); nocturnal non-invasive ventilation or oxygen discussed case by case at a multidisciplinary meeting, with quality of life at the centre of the decision [35].
• Orthopaedics. Early diagnosis and treatment; surgery when the deformity progresses despite orthopaedic treatment or this is poorly tolerated. Before the pubertal peak, bracing or non-fusion instrumentation with growing rods, to reduce the number of procedures; with sufficient bone maturity and a painful deformity or one with respiratory or functional repercussions, definitive arthrodesis. Hip subluxation (femoral head migration ≥30%) requires clinical and radiological surveillance in younger patients, for early prevention with orthoses and physiotherapy [35].
• Therapeutic education. Programmes under development, with a care coordinator attached to the paediatric neurology clinic, an educational diagnosis and follow-up by telephone or email; sessions on feeding and digestive problems, constipation and dysmotility, seizure management, daily care, adaptation of equipment and transition to adulthood, and training in technical procedures (secretion suction, airway clearance manoeuvres, positioning) [35].

Table 7.3 — Doses in Aicardi syndrome: French protocol and comparison with labels

HMSN/ACC. Initial assessment includes neurological examination, EEG and MRI; orthopaedic and rehabilitation assessment (Achilles contractures, mobility, daily living activities); baseline orthopaedic assessment of scoliosis and pulmonary function because of the risk of restrictive lung disease; ophthalmology (ptosis, strabismus, gaze palsy, nystagmus); developmental assessment; psychiatric referral if there is a history of psychotic episodes; genetic counselling; and family support [21]. Treatment comprises regular physiotherapy, walking aids and orthoses; scoliosis generally requires surgical correction; psychosis warrants psychiatric assessment, and low-dose neuroleptics may be helpful (no drug or dose specified in the source); and care is provided by a multidisciplinary team including a paediatrician or paediatric neurologist, developmental paediatrician, psychiatrist, orthopaedic surgeon, physiotherapist and occupational therapist [21]. Early intervention is indicated from 0 to 3 years, followed by preschool programmes and individual education plans [21]. GeneReviews does not mention investigational therapies [21].

DCC spectrum. Treatment is supportive and educational; there is no specific clinical action according to GeneGuidance curation [136]. Botulinum toxin has been used successfully in one patient with mirror movements but is not usually proposed because the risk of inducing motor impairment generally outweighs the benefit; non-invasive modulation of interhemispheric communication is a future possibility [6]. Complex bimanual movements and repetitive or sustained manual activity should be limited to reduce upper-limb pain and discomfort [6].

Mowat–Wilson syndrome. Each problem is treated by the relevant specialist: dental abnormalities, seizures, ocular abnormalities, heart disease, chronic constipation and Hirschsprung disease (surgical treatment), genitourinary abnormalities and thoracic or foot deformities, with educational intervention and early assessment of language and alternative communication methods [22]. The case in section 10 illustrates neonatal surgery for Hirschsprung disease with ileostomy [32].

7.9. Agents and Circumstances to Avoid

In MWS, stimulants should be used cautiously because aggression worsened with a stimulant in one patient with tantrums and concentration difficulties [22, 72]. In DCC carriers with mirror movements, complex bimanual and repetitive manual activities should be limited [6]. In primary prevention, prenatal exposure to alcohol at any stage of pregnancy, warfarin between 14 and 20 weeks and mycophenolate is associated with CC abnormalities [116–118]. With off-label CBD use, liver function should be assessed before initiation, as required by the label [36]. In Aicardi syndrome there are no specific drug contraindications, but the patients' vulnerability requires weighing the benefit and risk of each prescription, with particular caution regarding respiratory depressants (benzodiazepines, opioids and derivatives); mucolytics are contraindicated in respiratory complications [35].

7.10. Perioperative Care, Pregnancy and Transition

In HMSN/ACC, scoliosis surgery is frequent and should be preceded by pulmonary function assessment because of restrictive lung disease associated with scoliosis and axonal loss affecting respiratory muscles [21]. In Aicardi syndrome, dysphagia, aspiration risk and respiratory failure are monitored at each visit [20]. According to the French PNDS, any surgery should take place in a hospital setting coordinated with the reference centre team: anaesthetic risk is higher because of respiratory complications, a high pain threshold may delay recognition of postoperative complications, malnutrition delays healing and favours infection, and scoliosis and hip surgery and percutaneous gastrostomy should be performed by teams trained in multiple disability and neuromuscular scoliosis. The same protocol calls for anticipation of emergency and decompensation situations (severe or prolonged seizures, sepsis, pain, shock, agitation), with a reasonable care plan discussed within the team and with the family [35]. Women with Aicardi syndrome theoretically have a transmission risk of up to 50% to their offspring, with possibly reduced fertility [20]; no offspring are known in patients with HMSN/ACC or MWS [21, 22]. In female DCC variant carriers, pregnancy predominantly raises the issue of prenatal diagnosis (section 8). Transition to adulthood is particularly demanding in HMSN/ACC, in which walking is lost at around 14 years and psychotic episodes emerge after 15 years [21], and in Aicardi syndrome, in which mortality risk peaks at around 16 years [30]. The French PNDS asks that transition be anticipated from the first signs of puberty, addressed between 12 and 14 years and prepared with a neurology appointment from 13 years; in adulthood, follow-up by a team experienced in multiple disability, gastroenterological and respiratory follow-up, the search for a suitable residential facility and a legal protection measure are maintained [35]. The sources consulted do not describe specific breastfeeding recommendations for these entities.

7.11. Registered Studies

Table 7.4 — Registered ACC studies (ClinicalTrials.gov, accessed 10 October 2026)

None of these registrations tests a therapeutic intervention, and none has results published in the registry itself. Registry summaries cite prognostic figures (favourable prognosis in 80% and ID in 20%; approximately 70% favourable cognitive outcome in the isolated form) that are statements by the sponsors rather than study results [194, 195].

7.12. Developments in the Last Twelve Months

Table 7.5 — Developments from October 2025 to October 2026

Predating this window but still recent are the 20-year cohort comparing complete and partial agenesis [125], the study of adaptive behaviour in the first year [122], the practical review for paediatric neurologists [196] and the series on ultrasound signs of pACC [138, 139]. No pharmacological trial, regulatory opinion or authorisation for ACC or the entities covered in boxes was identified during this period.

7.13. Summary of Guideline Recommendations

Existing formal recommendations concern obstetrics and diagnosis (ISUOG, SMFM, Delphi consensus, ISPD) and are summarised in Tables 5.1 and 5.5; differences centre on the sagittal screening view, biometry, infectious investigation and the place of exome sequencing. For postnatal follow-up, recommendations come from the GeneReviews chapters for each entity and clinical reviews, and the sources consulted do not include a professional society guideline dedicated to follow-up of isolated ACC [4, 196].

For Aicardi syndrome, the 2019 French PNDS is the only national guideline consulted that is dedicated to the entity; it is an expert consensus without levels of evidence, predating the most recent authorisations and withdrawals, and it diverges from GeneReviews on the points summarised in Table 7.6.

Table 7.6 — Divergences between the French PNDS for Aicardi syndrome and other sources

Sources: [35].

8. Reproductive Options and Family Counselling

8.1. A Specific Diagnosis as the Starting Point

Counselling is precise only when a specific laboratory-confirmed diagnosis is available; without one, isolated ACC may be sporadic or follow autosomal dominant, autosomal recessive or X-linked inheritance [7]. The sources consulted do not provide an empirical recurrence risk for isolated ACC without an identified cause, and this value should not be extrapolated from other malformations. Storing DNA from the proband or fetus and performing autopsy allow diagnosis to be revisited later; without a sample from the previous proband, ISPD proposes sequencing both parents to identify shared carrier status for autosomal recessive disorders, always preferring tissue from the previous fetus or child when available [140, 157]. In the clinical case in section 10, absence of genetic investigation in a previous pregnancy with ACC prevented prenatal diagnosis in the subsequent pregnancy [32].

8.2. Recurrence Risks by Scenario

Table 8.1 — Sibling recurrence risks according to cause

8.3. Family and Carrier Testing

In HMSN/ACC, carrier testing requires prior identification of the familial variants; founder variant carrier screening is offered to individuals with genealogical links to high-frequency regions of Quebec [21]. In a gene with incomplete penetrance such as DCC, parental testing is essential to interpret a variant found in a fetus or child, and carrier parents may be asymptomatic or have only mirror movements [6, 31]. When distinguishing an anatomical variant from dysgenesis is uncertain, parental MRI may show a familial pattern of callosal morphology [2]. In MWS, testing parents for the proband's alteration is recommended; leukocyte DNA analysis may not detect somatic mosaicism and does not detect gonadal mosaicism [22].

8.4. Prenatal Diagnosis and Preimplantation Genetic Testing

Once the familial variant or variants have been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible in HMSN/ACC, DCC-associated forms and MWS, in which they are offered because of the possibility of parental mosaicism or a balanced rearrangement [6, 21, 22]. In Aicardi syndrome, molecular prenatal diagnosis is impossible; ACC with intracranial cysts in a female fetus may raise suspicion, fetal MRI showing ACC and migration abnormalities is suggestive but not diagnostic, costovertebral defects and microphthalmia are difficult to detect, and definitive prenatal diagnosis in a low-risk pregnancy has not been reported: confirmation is made after birth through the lacunae and seizures [20]. In a subsequent pregnancy, the French PNDS proposes, instead of molecular diagnosis, close ultrasound surveillance at a multidisciplinary prenatal diagnosis centre [35].

In forms with incomplete penetrance, the prenatal result must be explained carefully. In the 2025 French cohort, all couples with a fetal DCC variant continued the pregnancy, whereas 73% of couples with another genetic diagnosis and 17% without a genetic diagnosis chose termination [5]. Prenatal isolated ACC has been described as a paradigm of “clinical uncertainty” for couples and teams, prompting a registered study of the decision-making process [194].

8.5. Content of Prenatal Counselling

Counselling following fetal ACC should address what imaging and genetics have already excluded and what remains to be excluded (abnormalities revealed only by MRI or later evolution, syndromes diagnosable only after birth), the distribution of outcomes in the isolated form and its limitations (section 11), testing options and their turnaround times (median 21.5 days for CMA and trio exome sequencing in a French series) [155], the possibility of VUS and secondary or incidental findings, and future reanalysis [157]. ISPD requires individualised pre-test counselling of both parents by a professional trained in genetics and post-test counselling for all results, including negative results [157].

8.6. Minors

The sources consulted contain no specific recommendations on testing asymptomatic minors for these entities. In practice, testing an asymptomatic child in the family of a DCC carrier does not change medical surveillance, and carrier testing for recessive diseases (HMSN/ACC, BHLHE22, KIF7) is predominantly of reproductive relevance, which weighs in the decision to perform it during childhood; a symptomatic child should be investigated like any proband [6, 21].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What Each Figure Measures

Estimates of ACC frequency differ by several orders of magnitude because they measure different populations and definitions and should not be combined.

Table 9.1 — Estimates of ACC frequency and their meaning

The two population-based studies, with diagnosis in the first year of life and inclusion of hypoplasia, converge on approximately 2 per 10,000 live births. Orphanet values, attributed to these same studies, are six to thirteen times lower and classified as isolated ACC; they do not match the principal published values, possibly because they refer only to isolated cases, but the entry does not explain the calculation, and they do not constitute an independent measure [8, 11, 12]. Values of 3–7/1000 and 0.3–0.7% come from imaging series in selected populations (referred fetuses, children with neurological symptoms) and do not represent prevalence in the general population [2, 3]. A birth registry underestimates terminated cases and those undiagnosed in the first year; an imaging series overestimates through referral. The sources consulted do not include EUROCAT data.

9.2. Sex, Prematurity and Parental Age

In the California registry, 52% of cases were male; ACC prevalence was almost four times higher in preterm infants than in those born at 37 weeks or later (relative risk 3.7; 95% CI 2.5–5.3); maternal age ≥40 years was associated with ACC and chromosomal disease (relative risk 5.9; 95% CI 1.8–19.3) and, with less precision, hypoplasia with chromosomal disease (3.5; 0.9–14.1), after adjustment for paternal age, which had no independent association [11]. In the Hungarian series, 26 of 38 were boys [12]. In DCC carriers, sex modifies the phenotype (mirror movements more frequent in males; ACC more frequent in females with truncating variants) [31]. Aicardi syndrome typically affects females and has been described in 47,XXY males and, very rarely, 46,XY males, possibly due to mosaicism [20].

9.3. Founder Populations and Geographical Distribution

HMSN/ACC exemplifies a founder effect: in Saguenay–Lac-Saint-Jean, Quebec, incidence is 1 in 2117 live births and carrier frequency 1 in 23 inhabitants; Orphanet records 47.0/100,000 in this population and fewer than 1/1,000,000 worldwide. Outside this region, the disease is extremely rare, with three sibling pairs of Italian, Mexican and Turkish origin molecularly confirmed at the time of the GeneReviews publication [21, 26]. Most hydrolethalus syndrome cases occur in Finland [167]. The homozygous BHLHE22 frameshift variant was found in consanguineous Punjabi, Caucasian, Syrian and Turkish families; the haplotype was not studied, so whether it is a founder or recurrent variant is unknown [47]. The founding DCC families were from North Africa and Australia, of European ancestry [31].

Aicardi syndrome occurs in all ethnic groups, with an estimated incidence of 1/105,000–1/167,000 in the USA and 1/93,000–1/99,000 in some European countries, a prevalence of at least 853 cases in the USA and more than 4000 worldwide (estimate) [20]. In the study of 408 cases, incidence was 1/105,000 in the USA and 1/93,000 in the Netherlands [30]; Orphanet records birth prevalences of 1.07/100,000 in the Netherlands and 0.95/100,000 in the USA from the same study, and a worldwide point prevalence of 0.4/100,000 [25]. The French PNDS reproduces the same incidence estimates but gives both 853 and 800 cases in the USA within the same document; in France, fewer than five adult patients had been recorded in 2019 [35]. MWS has an estimated prevalence of 1/50,000–70,000 live births [22].

The clinical and imaging cohorts cited in this article come from the USA (California and other centres), France (Lyon and a national cohort), Italy, the Netherlands, the United Kingdom, Austria, Spain and Chile, China and Japan [5, 11, 14, 48, 124, 125, 139, 147, 150, 153, 154, 197].

9.4. Portugal and Brazil

The multinational ENSO group study on the role of fetal MRI in isolated callosal abnormalities included Portuguese centres among its 14 participants [152]. A systematic review by Portuguese authors, published in 2021, included 8 studies involving 217 fetuses with isolated ACC [198]. The 2025 Delphi consensus panel included one Brazilian expert (Rio de Janeiro State University) [2]. The sources consulted contain no estimates of ACC prevalence in Portugal or Brazil, which does not demonstrate an absence of published data.

9.5. Reference Networks and Patient Associations

In Europe, the relevant reference network is ERN ITHACA, dedicated to rare malformation syndromes, ID and other neurodevelopmental disorders [19]. Among associations, the National Organization for Disorders of the Corpus Callosum (NODCC) in the USA brings families together and publicises research studies [21, 199]; Corpal in the United Kingdom supports people affected by ACC and Aicardi syndrome [200]; the Aicardi Syndrome Foundation and the Aicardi Syndrome International Registry focus on Aicardi syndrome [20]; the Hereditary Neuropathy Foundation and Muscular Dystrophy Canada support families with HMSN/ACC [21]; FOCUS Families focuses on optic nerve hypoplasia and septo-optic dysplasia [145]; and, in the British prenatal setting, Antenatal Results and Choices (ARC) supports couples facing fetal abnormalities and Shine supports families affected by hydrocephalus [141].

In France, Aicardi syndrome is managed by the reference centre for intellectual disabilities of rare causes and multiple disability (sponsor of the PNDS, Necker Hospital, Paris), the reference centre for rare eye diseases (Ophtara) and the reference centres for developmental anomalies and malformation syndromes, coordinated within the DéfiScience, SensGene and AnDDI-Rares health networks; the working group included the coordinator of ERN EpiCARE. The PNDS serves as the basis for the care protocol for exemption from the “ticket modérateur” (patient co-payment) as a condition outside the list of long-term illnesses and for benefit applications to the Maison départementale des personnes handicapées (MDPH); medico-social facilities (CAMSP, SESSAD, IME, MAS, FAM) provide early intervention and residential care. The Association syndrome Aicardi is the national patient association, and the protocol considers enrolment of patients in a European registry essential to understand the natural history [35].

10. Illustrative Clinical Case

The case was published by Şenbil and colleagues in 2021 and describes Mowat–Wilson syndrome presenting prenatally as isolated ACC [32].

History. The proband, a boy, was the third liveborn child of a 35-year-old mother in her fourth pregnancy. In the second pregnancy, a male fetus had ACC, congenital heart disease and absence of the nasal bone at 24 weeks, and the pregnancy was terminated without genetic testing or autopsy [32].

Pregnancy and neonatal period. In the proband's pregnancy, ultrasonography at 18 weeks showed isolated ACC. No fetal MRI was performed, and amniocentesis was limited to karyotyping, which showed 46,XY. Delivery was by caesarean section at 38 weeks, with a birthweight of 3820 g. The newborn passed no stool during the first three days; laparotomy with biopsies confirmed Hirschsprung disease, and an ileostomy was performed [32].

Assessment at 12 months. During an assessment for fever, weight was 8.4 kg (3rd percentile), height 74 cm (3rd percentile) and head circumference 46 cm (25th percentile). He had hypertelorism, uplifted earlobes with a central depression, frontal bossing, telecanthus, deep-set eyes, broad eyebrows with medial flaring, a rounded prominent nasal tip, low-hanging columella, open mouth, a thin M-shaped upper lip, prominent chin, short neck, widely spaced nipples, overlapping toes and flat feet. He made eye contact and smiled socially, had stereotyped hand movements and three unclear words; he was hypotonic, could not sit unsupported, and had bilateral extensor plantar responses and sustained ankle clonus. He developed acute pyelonephritis, and ultrasonography and cystourethrography showed grade 3 right hydronephrosis. Brain MRI revealed enlargement of the lateral and third ventricles, with enlarged occipital and temporal horns, bilateral incomplete hippocampal inversion, enlargement of the thalamus and caudate nucleus and complete CC agenesis [32].

Molecular diagnosis. A novel heterozygous ZEB2 variant was identified, published as c.646dupT p.(Cys216LeufsTer23), in exon 6, within the C2H2-1 zinc finger domain. VariantValidator normalisation confirms NM_014795.4(ZEB2, MANE Select):c.646dup, NP_055610.1:p.(Cys216LeufsTer23), NC_000002.12:g.144404077dup [32, 68].

Course. At 16 months, during febrile pneumonia, he had a generalised seizure lasting 5 minutes; EEG showed no discharges and revealed an immature parieto-occipital rhythm, and valproic acid was started, management reported in the case rather than a validated protocol for MWS. The child remained under follow-up for developmental delay and renal and gastrointestinal problems [32].

Figures. The open-access article includes Figure 1 (uplifted earlobes, frontal bossing, short neck; https://pmc.ncbi.nlm.nih.gov/articles/PMC8072816/figure/fig1-2329048X211006511/), Figure 2 (hypertelorism, telecanthus, nasal tip; https://pmc.ncbi.nlm.nih.gov/articles/PMC8072816/figure/fig2-2329048X211006511/), Figure 3 (overlapping toes; https://pmc.ncbi.nlm.nih.gov/articles/PMC8072816/figure/fig3-2329048X211006511/), Figure 4 (complete CC agenesis on sagittal 3D T2 imaging; https://pmc.ncbi.nlm.nih.gov/articles/PMC8072816/figure/fig4-2329048X211006511/), Figure 5 (bilateral incomplete hippocampal inversion on coronal T2 imaging; https://pmc.ncbi.nlm.nih.gov/articles/PMC8072816/figure/fig5-2329048X211006511/) and Figure 6 (enlarged occipital horns on axial T2 imaging; https://pmc.ncbi.nlm.nih.gov/articles/PMC8072816/figure/fig6-2329048X211006511/) [32].

Lessons. This case's prenatal pathway differs from current recommendations: there was no targeted neurosonography, fetal MRI or CMA, which SMFM and the Delphi consensus recommend for ACC [1, 2], and the previous pregnancy with ACC left no sample for investigation. The authors argue that fetal MRI would have shown the hippocampal abnormality, that CMA and, if normal, exome sequencing should be offered in isolated ACC, and that molecular confirmation in the proband is essential for prenatal diagnosis in a future pregnancy [32]. The case reproduces the findings of prospective cohorts: among the few cases of severe ID in prenatally “isolated” ACC in the French and Italian series were children with MWS and Vici syndrome diagnosed only after birth [124, 197]. The truncating variant fits the haploinsufficiency mechanism of MWS. The usual sibling recurrence risk for a proband with a de novo variant is approximately 2% because of possible gonadal mosaicism [22]; in this family, however, the previous fetus with ACC and heart disease raises the possibility of recurrence, discussed by the authors and compatible with parental mosaicism described in MWS, but impossible to confirm without a sample [22, 32].

11. Prognosis and Long-Term Follow-Up

11.1. Isolated ACC: Systematic Reviews

The prognosis of ACC depends predominantly on associated abnormalities and the cause. SMFM summarises that complete and partial agenesis with coexisting brain abnormalities or genetic syndromes tend to have a poor outcome, whereas isolated forms have a better prognosis and similar outcomes to one another, which cannot be predicted from the neuroanatomical profile; in isolated cases, borderline to moderate delay affects 14.9–16.0% and severe delay 8.2–12.5% [1].

Table 11.1 — Systematic reviews of neurodevelopment in isolated ACC

11.2. Follow-Up Cohorts

Table 11.2 — Follow-up cohorts of prenatal or isolated ACC

The Chinese cohorts have short follow-up and high termination rates, limiting interpretation; European series with follow-up to school age (France and Italy) show the most informative distribution for counselling. Overall, the sources suggest approximately two-thirds to three-quarters of children have normal development, 6–15% have severe impairment, and an intermediate group has learning difficulties or borderline functioning, becoming more apparent at school age and in the second decade [14, 124, 197, 201]. Absence of impairment at 2–3 years does not exclude later difficulties, and absence of severe events in small series does not equate to zero risk.

11.3. Complete Versus Partial Agenesis

Isolated complete and partial forms have similar overall outcomes [1], but epilepsy and impaired cognition were numerically more frequent in isolated pACC in the 2016 meta-analysis, with very wide intervals [121]. pACC more frequently reveals additional abnormalities only after birth (16.2%) than cACC (4.3%) [151]. In the North American cohort of 161 children, cACC was more frequently diagnosed prenatally and was associated with less cerebral palsy [125].

11.4. Prediction Using Fetal MRI

An anatomical fetal MRI score developed in Vienna assesses seven categories (gyration, opercularisation, temporal lobe symmetry, lamination, hippocampal position, basal ganglia and ventricular size), totalling 0 to 11 points. In 21 children with isolated ACC (37 MRI examinations, mean gestational age 28.3 weeks), the score correlated negatively with cognitive (ρ=−0.559), motor (ρ=−0.414) and language (ρ=−0.565) development, assessed at a mean age of 2.6 years; a cut-off of ≤3 (good prognosis) versus ≥4 (high risk) correctly predicted prognosis in 20/21 (95.2%; 95% CI 77.3–99.2), with interobserver agreement of 0.959 [147]. In validation involving 137 consecutive cases (74 isolated), the score was higher in associated forms and did not differ between complete and partial agenesis, and correctly predicted outcome in 90.7% of isolated cases with follow-up (42 isolated cases, mean age 3.1 years) [202]. These are single-centre data with small samples and short follow-up.

11.5. Prognosis of the Entities Covered in Boxes

In Aicardi syndrome, a 2007 survey found a mean age at death of 8.3 years and a median age of 18.5 years (from under 1 year to over 23 years; the oldest survivor was 32 years old) [20]. In the study of 408 cases, 45 patients had died (between 1 month and 33 years), mortality risk peaked at 16 years and the probability of survival to 27 years was 0.62 (95% CI 0.47–0.77) [30]. The course in adulthood is poorly known: paediatric series include a few patients aged 27 to 33 years and, in France, the fewer than five adult patients recorded showed no psychomotor regression. About ten published cases correspond to “moderate forms”, with walking, short sentences and controlled epilepsy; in adolescence, severe orthopaedic complications (hip dislocation, scoliosis) and loss of sitting or walking may occur. Regarding scoliosis, a curve greater than 25° before 10 years without independent walking predicts severe scoliosis (more than 60° after 16 years), whereas independent walking at 10 years with minimal or no scoliosis predicts low risk [35]. In HMSN/ACC, walking is lost at a mean age of 13.8 years and death occurs at a mean age of 33 years, usually from respiratory failure [21]. In DCC carriers, developmental prognosis is favourable, with normal to borderline intelligence and mainstream schooling in most [31, 135], and in the French cohort, DCC aetiology was associated with a favourable neurodevelopmental prognosis [5]. In MWS, severity depends on the type of ZEB2 alteration (section 2.6), seizures become easier to control in adolescence and adulthood, and patients have no known offspring [22, 71].

11.6. Surveillance

Table 11.3 — Recommended surveillance

12. Summary and Final Considerations

Agenesis of the corpus callosum is a frequent anatomical finding in imaging series and relatively rare in the general population, where population-based registries suggest approximately 2 cases per 10,000 live births when agenesis and hypoplasia diagnosed in the first year are included. The much higher figures from imaging series reflect selected populations, and Orphanet values for the isolated form do not match the studies cited; each estimate should be presented with the population and definition it measures.

Aetiology is heterogeneous: more than 200 chromosomal and monogenic syndromes, inborn errors of metabolism, teratogens and infections can produce the same callosal phenotype, which serves as a common final pathway for defects in axon guidance, neuronal migration, transcriptional regulation, the primary cilium, cellular trafficking and energy metabolism. DCC has become the paradigm of monogenic isolated agenesis, with dominant inheritance, incomplete penetrance, sex-related modification and a favourable prognosis, and with a biallelic form, developmental split-brain syndrome, which suppresses all commissures. Aicardi syndrome still has no identified gene and is diagnosed by the triad of callosal agenesis, chorioretinal lacunae and infantile spasms. Motor and sensory neuropathy with agenesis of the corpus callosum illustrates the founder effect in Quebec and the existence of a dominant allelic disorder without agenesis. Mowat–Wilson syndrome reminds us that apparently isolated prenatal agenesis may represent a syndrome with Hirschsprung disease, heart disease and severe ID.

Prenatally, the current approach combines targeted neurosonography with a median plane, fetal MRI and amniocentesis with microarray, and trio exome sequencing after a normal microarray has yields of 23–43%, with approximately one-third even in the isolated form. Guidelines differ regarding the sagittal screening plane, callosal biometry, infectious investigation and the place of exome sequencing, and the 2025 Delphi consensus acknowledges that its recommendations are based on expert opinion. After birth, MRI, dysmorphology and ophthalmological examinations, microarray, exome or genome sequencing and targeted metabolic and endocrine investigations complete the assessment, remembering that every test has limitations and a negative result does not exclude a genetic cause.

The isolated form has a favourable prognosis in most children, with approximately two-thirds to three-quarters having normal development, but a minority have severe impairment, often due to a syndrome recognised only after birth, and an intermediate group develops language, executive function, learning and social cognition difficulties that become apparent at school age. There is no targeted treatment; early intervention from the first year, longitudinal neurocognitive follow-up, treatment of epilepsy and endocrine deficiencies, and syndrome-specific management form the basis of care. Cannabidiol in Aicardi syndrome remains an off-label use supported only by an uncontrolled open-label study. Counselling depends on a specific diagnosis and, without one, storing DNA and performing autopsy following termination are the investment that allows the family's questions to be answered in a future pregnancy.

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