American Journal of Medical Genetics Part C (Seminars in Medical Genetics)

A R T I C L E

Agenesis of the Corpus Callosum: A Clinical Approach to Diagnosis ELIZABETH EMMA PALMER*

AND

DAVID MOWAT

This review article aims to guide the clinician in establishing a diagnosis in patients with agenesis of the corpus callosum (ACC), presenting antenatally or postnatally. ACC may be isolated, or occur in association with other neuroanatomical lesions and/or congenital anomalies, and has many different genetic causes. Neuropsychological outcome varies considerably from normal to profound intellectual disability depending on the etiology. Approximately 25% of individuals with antenatally diagnosed apparently isolated ACC have intellectual disability. Subtle neurological, social, and learning deficits may still occur in those with normal intelligence and longitudinal neurocognitive follow‐up is recommended for all children with ACC. The finding of ACC should prompt detailed clinical assessment in order to determine and manage the underlying condition. It is recognized that genetic factors contribute to ACC in the vast majority of cases. Less commonly ACC can result from antenatal infections, vascular or toxic insults, and it is increasingly recognized that ACC, particularly isolated ACC, may be due to an interaction of a number of “modifier” genetic and environmental factors. There are a large number of genetic conditions in which ACC may be a feature. We suggest a diagnostic algorithm to help guide the clinician towards diagnosis, to provide outcome advice and to aid in genetic counseling. © 2014 Wiley Periodicals, Inc. KEY WORDS: agenesis of the corpus callosum; prenatal; postnatal; review; genetics; clinical; genetic counseling

How to cite this article: Palmer EE, Mowat D. 2014. Agenesis of the corpus callosum: A clinical approach to diagnosis. Am J Med Genet Part C Semin Med Genet 9999:1–14.

INTRODUCTION In this review article we have summarized currently known causes of agenesis of the corpus callosum (ACC) using OMIM and PubMed searches. We have included data when ACC has been described in more than one independent case (see Supplementary Table S1). We have highlighted the adjunctive neuroanatomical and other salient clinical features that may provide diagnostic clues to the physician. We hope that this approach will be helpful to clinicians (clinical geneticists, pediatricians, neurologists, fetal‐maternal specialists, and others) who care for individuals and their families when ACC is identified in the antenatal or postnatal setting.

NORMAL ANATOMY AND FUNCTION The corpus callosum (CC) is the largest white matter tract in the human brain, containing about 200 million axons that connect the left and right cerebral hemispheres: consisting of approximately 2–3% of all cortical fibers [Aboitiz and Montiel, 2003]. It is one of the five main cerebral commissures (bundles of nerve fibres that cross the midline of the human brain at the level of their origin), the others being the anterior, posterior, hippocampal, and habenular commissures. The CC is unique to placental mammals, and, in the human, is thought to play a critical role in cognition [Leighton et al., 2012]. Its’ principal function is the coordination and transfer

of information between the two cerebral hemispheres aiding cognition and neurological function. This interhemispheric communication is important for the

The CC is unique to placental mammals, and, in the human, is thought to play a critical role in cognition. Its’ principal function is the coordination and transfer of information between the two cerebral hemispheres aiding cognition and neurological function.

Emma Palmer is a Clinical Geneticist with a specialist interest in the genetics of intellectual disability. She works with the Genetics of Learning Disability (GOLD) service based in Sydney, and is completing a Masters on the application of exome sequencing for patients with epileptic encephalopathy. David Mowat is a Clinical Geneticist with a special interest in Syndrome diagnosis, causes of intellectual disability, Prenatal Genetics, Neuromuscular disorders, and Tuberous Sclerosis. *Correspondence to: Emma Palmer, Department of Medical Genetics, Sydney Children's Hospital, High Street, Randwick, NSW, Australia. E-mail: [email protected] DOI 10.1002/ajmg.c.31405 Article first published online in Wiley Online Library (wileyonlinelibrary.com).

ß2014 Wiley Periodicals, Inc.

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functional integration of sensory, motor, and visuomotor information, as well as higher cognitive functions such as language and abstract reasoning [Paul, 2011; Hinkley et al., 2012]. The imaging features of the normal CC and of ACC are shown in Figure 1 using antenatal ultrasound (US), fetal magnetic resonance imaging (MRI), and postnatal MRI. The CC has traditionally been divided [Witelson, 1989] into four anatomically defined regions: the genum, rostrum, body (divided into anterior, middle, and posterior segments), and the splenium. The CC is topographically organized: for example the anterior sections connect more anterior regions of the cortex (e.g., prefrontal association areas, premotor, supplementary motor areas, and anterior

inferior parietal regions); the more posterior sections connect the more posterior association areas of the parietal and temporal lobes and the occipital lobes [Paul, 2011]. Callosal connections are both inhibitory (allowing the two hemispheres to inhibit each other and function independently) and excitatory (allowing integration of information between the hemispheres). The majority of fibers are excitatory [Bloom and Hynd, 2005].

STRUCTURAL ANOMALIES OF THE CORPUS CALLOSUM Congenital structural abnormalities of the CC include ACC, which may be

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total agenesis (total absence from birth of all the anatomically defined regions of the CC) or partial (absence from birth of at least one, but not all, regions of the CC: PACC) (see Fig. 1). Hypoplasia of the CC refers to a thinner CC that has a normal anterior‐posterior extent, although this may be hard to quantitate. Other abnormalities of the CC have been noted in a variety of neurodevelopmental conditions, for example, hyperplasia of the CC, which may result from reduced postnatal axonal pruning. Dysgenesis of the CC refers to the CC being present but malformed in some way, including partial ACC and hypoplasia of the CC. ACC can be an apparently isolated malformation, or be associated with additional cerebral malformations with

Figure 1. Imaging of corpus callosum (US and MRI) (A) Abdominal ultrasound at 18–20 weeks gestation, axial view showing normal with visible cavum septum pellucidum (box like structure in the midline). (B) Abdominal ultrasound at 26 weeks gestation, axial view showing dilatation occipital ventricular horns (tear‐drop) and lateral displacement of the anterior horns consistent with colpocephaly suggesting ACC. (C) Ultrasound at 26 weeks gestation, transvaginal sagittal view with absent corpus callosum and abnormal radial gyral pattern. (D–F) Fetal MRI third trimester, axial, sagittal, and coronal views showing normal appearance (CSP arrowed). (G–I) Fetal MRI third trimester, showing ACC dilatation occipital ventricular horns (tear‐drop) and lateral displacement of the anterior horns consistent with colpocephaly and abnormal radial gyral pattern consistent with ACC. (J,K) Cerebral MRI at 6 months, axial and coronal views normal. (L) Cerebral MRI at 6 months female, sagittal view showing normal CC structures and cingulate gyrus. (M–O) Cerebral MRI at 2 years male, showing absent CC and laterally displaced frontal horns (steerhorn appearance). 1 ¼ Cavum Septum Pellucidum (CSP), 2 ¼ dilated posterior part of the ventricles, 3 ¼ lateral displacement of the anterior horns, 4 ¼ corpus callosum (CC), 5 ¼ genu, 6 ¼ rostrum, 7 ¼ body, 8 ¼ splenium, 9 ¼ cingulate gyrus, 10 ¼ steerhorn appearance of anterior horns.

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potential detrimental effects on neurological function (“complex ACC”). Insight into the exact function of the CC is emerging from several lines of evidence including neurophysiological and functional neuroanatomical studies of children and adults with congenital abnormalities of the CC; of patients who have had surgical commissure transections; and of patients with developmental disorders such as autism and schizophrenia [Paul et al., 2007; Paul, 2011].

(e.g., epilepsy) and background genetic and environmental factors. There are also limitations in the methodologies described in much of the neuropsychological literature including: small sample sizes, short follow‐up time, lack of consistency in neuropsychological measures, heterogeneity of sampled individuals, and lack of appropriate control groups. A recent integrative review highlighted that in truly isolated ACC (i.e., no additional neuroanatomical abnormalities identified on postnatal MRI) neurodevelopmental outcome for individuals diagnosed antenatally can range from essentially normal development, in about 75% of individuals, to differing levels of intellectual disability. About 12% of individuals in this series had severe intellectual disability [Sotiriadis and Makrydimas, 2012]. More detailed neuropsychological studies have identified a range of subtle behavioral and social differences in individuals with apparently normal intelligence [Siffredi et al., 2013]. Although there is substantial heterogeneity in findings, individuals with ACC have more consistently been reported to have deficits in “higher” language function such as the pragmatics of language, complex information processing abilities such as “cognitive information processing” (the ability to automatically perform previously learnt cognitive tasks), complex attention and memory skills and specific academic skills, especially mathematics. Subtle social differences that resemble difficulties experienced by patients on the autistic spectrum have also been reported [Badaruddin et al., 2007; Lau et al., 2013]. Given the cognitive difficulties reported in patients with ACC, it is perhaps not surprising that social difficulties will ensue, as social situations require rapid processing of very complex information that is typically handled in lateralized brain regions. Subtle differences in callosal neuroanatomy have also been reported in patients with autism [Frazier and Hardan, 2009] and overlap in underlying genetic risks have been demonstrated for patients with ACC and autism [Sajan et al., 2013; Edwards et al., 2014]. Newer functional

CLINICAL CONSEQUENCE OF ACC/PACC Neurodevelopmental outcome for individuals with callosal abnormalities is very varied, even when the neuroanatomy appears relatively similar between patients. There is often significant overlap in neuropsychological outcome between patients with total and partial ACC, in that neuropsychological outcome is not clearly worse for patients with isolated total ACC compared to partial ACC. It is as yet unclear to what

Neurodevelopmental outcome for individuals with callosal abnormalities is very varied, even when the neuroanatomy appears relatively similar between patients. There is often significant overlap in neuropsychological outcome between patients with total and partial ACC, in that neuropsychological outcome is not clearly worse for patients with isolated total ACC compared to partial ACC. degree this variability is affected by differences between patients in their compensatory neuronal plasticity, precise neuroanatomy, clinical co‐morbidities

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imaging tools such as magnetoencephalography (MEG‐I) and tractography are starting to clarify that individuals with ACC have impairments in functional connections between specific regions within the frontal, parietal, and occipital cortices, and that the degree of “under‐ connectedness” correlates with impairments in specific cognitive skills, in particular verbal processing speed and executive function, important for more complex cognitive and social skills [Hinkley et al., 2012]. An insight into the potential role of neuronal plasticity in affecting neuropsychological outcome can be gained by looking at studies of patients who have had therapeutic resection of the commissures. There are two main types of these surgical procedures, traditionally performed for the treatment of intractable epilepsy. Commissurotomy (“classic” “split‐brain” procedure) involves severing all cerebral commissures including the anterior commissure. In callosotomy the anterior commissure is not surgically severed, and therefore this procedure more closely mimics congenital ACC where the anterior commissure is usually intact. In general, patients with commissurotomies and adolescents and adults with callosotomies present with the “disconnection” syndrome, including impairments in the inter‐hemispheric transfer of sensory information and deficits in bimanually coordinated motor activity. In comparison, patients with congenital ACC and patients with early callostomy show little evidence of a disconnection syndrome with simple tactile information, suggesting a degree of compensation at the neuronal level. Indeed, individuals with congenital ACC differ in the extent to which they have developed additional, potentially compensatory, anatomical tracts such as Probst and heterotropic bundles [Tovar‐Moll et al., 2007] and may differ in the degree to which they recruit the anterior commissure [Paul et al., 2012].

PREVALENCE The prevalence of agenesis of ACC as reported in the literature is incredibly

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varied: ranging from 0.5 per 10,000 in the general population [unselected autopsy series, Grogono, 1968] to 230–600 per 10,000 in children with neurodevelopmental disability [Jeret et al.,

The prevalence of agenesis of ACC as reported in the literature is incredibly varied: ranging from 0.5 per 10,000 in the general population [unselected autopsy series, Grogono, 1968] to 230–600 per 10,000 in children with neurodevelopmental disability, which would make it one of the most common brain malformations. 1985–1986; Schaefer and Bodensteiner, 1992], which would make it one of the most common brain malformations. Accurate prevalence estimates are hampered by differences in the definition of the type of callosal abnormalities between studies and their varied ascertainment. The largest birth prevalence study was a review of data from California, pertaining to diagnosis of ACC in the first year of life [Glass et al., 2008]. This gave a prevalence of 1.4 per 10,000 live births when neuroanatomical review differentiated agenesis of the CC from hypoplasia, and cases were excluded when the callosal malformation was thought to be secondary to the embryonic change that generated the principal malformation (e.g., a neural tube defect) or to a destructive lesion (e.g., porencephaly). The authors comment that this is likely to be an underestimate of the true prevalence due to limitations in antenatal and postnatal detection of ACC. Antenatal detection is limited by the sensitivity of antenatal US at different gestations (see postnatal section). Postnatal ascertainment is limited, as asymptomatic or more mildly affected individuals will not necessarily

have neuroimaging, especially not in the first year of life.

ETIOLOGY OF ACC It is recognized that genetic factors contribute to ACC in the vast majority of cases [Dobyns, 1996; Edwards et al., 2014]. Less commonly ACC can result from antenatal infections, vascular or toxic insults (summarized in Table I), and it is increasingly recognized that ACC, particularly isolated ACC, may be polygenic in many cases, due to an interaction of a number of “modifier” genetic and environmental factors. All forms of genetic inheritance have been implicated, including X‐ linked, autosomal recessive, and autosomal dominant. Chromosomal aberrations have been identified as an important cause and advanced maternal age is particularly associated with an increased prevalence of ACC due to chromosomal disorders [Glass et al., 2008]. Callosal abnormalities can be associated with chromosomal trisomies (e.g., 13,18, and mosaic trisomy 8), cytogenetically visible structural chromosomal rearrangements (e.g., 8p rearrangements), and an increasing number of submicroscopic copy number variants (CNV), detectable by chromosomal microarray. In the Californian Birth Prevalence Study [Glass et al., 2008], chromosomal disorders were associated with 17% of ACC detected before the end of the first year of life. In a case series of 255 postnatal patients, 9% of patients with ACC had at least one de novo CNV, and 7% had at least one large (>500 Kb) de novo CNV [Sajan et al., 2013]. Although detection of such CNVs is not necessarily proof that they are wholly causal of the ACC [for discussion of complexity of clinical interpretation of CNV see Palmer et al., 2012 and Palmer et al., 2014], additional supportive evidence such as a lack of an alternative causal diagnosis, overlapping CNV in other patients with shared clinical features, and functional evidence of gene(s) in the CNV being important in CC development will aid in clinical interpretation of chromosomal studies. A recent analysis [O’Driscoll et al., 2010] of chromosomal studies of

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374 patients with ACC identified 12 chromosomal loci where abnormalities are consistently associated with ACC (detected in at least 6 subjects with ACC), and at least 30 other recurrent loci that may contain genes that cause or contribute to ACC. More common chromosomal aberrations associated with a high penetrance for ACC are summarized in Table II. Many cases are apparently sporadic, and it is possible that a majority of individuals have ACC as a consequence of de novo dominant mutations, as has been suggested for intellectual disability in general [de Ligt et al., 2012]. It is hoped that recent advances in animal models and next‐generation sequencing (NGS) will increase our understanding of the genetic cause for a greater proportion of affected individuals.

NEURODEVELOPMENTAL PATHWAYS IN CC FORMATION ACC is one of the most complicated neurological birth defects as the formation of the CC involves multiple

Formation of the corpus callosum involves normal neuronal and glial cell proliferation (neurogenesis), midline patterning, callosal neuron migration and specification, axon guidance, and post‐guidance development. There is therefore no one unifying genetic pathway underlying ACC but rather multiple complex and interacting ones. neurodevelopmental processes, each orchestrated by a large number of interacting genes. Current understanding of CC development is excellently summarized in a recent review article [Edwards

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TABLE I. Causes of Agenesis of the Corpus Callosum Cause Genetic

Subtype

Additional notes

Monogenic autosomal recessive, dominant and X‐linked forms (See Supplementary Table S1 online). Polygenic.

“Syndromic” diagnosis made in 30–45% in two case series of which 20–35% had an identifiable monogenic cause [Bedeschi et al., 2006; Schell‐Apacik et al., 2008]. May be explanation for many cases of unexplained ACC, especially when isolated [Edwards et al., 2014]. Chromosomal disorders associated with 17.8% of ACC detected before the end of the first year of life in Californian birth prevalence study [Glass et al., 2008]. De novo copy number variants detected by chromosomal microarray in 9% of postnatal cases [Sajan et al., 2013]. Callosal abnormalities are often hypoplastic and may be secondary to effects on postnatal CNS development or white matter injury. Often affected individuals have failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. They may have specific dysmorphisms and additional congenital anomalies (see Supplementary Table online) Associated with microcephaly, a general reduction in white matter volume and hypoplasia of the CC (most severe in the splenium) as well as partial and complete ACC. Affected individuals may have distinctive craniofacial features (e.g., smooth philtrum, thin upper lip) and distinctive behavioral differences such as attention deficit disorder. E.g., cytomegalovirus, toxoplasmosis, rubella and influenza. Usually other associated abnormalities. Rare, especially since neonatal screening introduced in many countries since 1960s. Rare.

Chromosomal Including trisomies (18,13, mosaic 8), and karyotypically visible rearrangements and submicroscopic copy number variants. Metabolic

Environmental

E.g., Pyruvate dehydrogenase deficiency, Fumarase deficiency, Smith–Lemli–Opitz syndrome, Glutaric aciduria Type II, Neonatal Adrenoleucodystrophy, Nonketotic hyperglycinemia, Desmosterolosis. Antenatal alcohol exposure.

Antenatal infections Maternal phenylketonuria Vascular/hypoxic insults

ACC, agenesis of corpus callosum; CNS, central nervous system; CC, corpus callosum.

TABLE II. More Common Chromosomal Aberrations Associated with ACC [Adapted from O’Driscoll et al., 2010; Edwards et al., 2014] Chromosome aberration

Candidate gene(s) for ACC

1q42–q44 deletion

AKT3, DISP1, ZBTB18

4p16.3 deletion (Wolf–Hirschhorn syndrome)

WHSC1, LETM1, TACC3, SLBP, HSPX153, WHSC2, YOL027, MSR7, FGFR3, CPLX1, DGKQ, FGFRL1, CTBP1 MARCKS, MAP3K4, NRE1, ARID1B, UST, TIAM2, SYNJ2

6q2 deletion

8p rearrangements including mosaic tetrasomy 8p, 8p inverted duplication/deletions 17q13.3 deletions (Miller–Dieker syndrome) and duplications

ARHGEF10, FZD3, FGFR1, FGF17, FGF20, NRG1 LIS1, YWHAE

Clinical features ACC of variable severity (high penetrance, 80%) and postnatal microcephaly. Growth deficiency, variable DD/ID, craniofacial dysmorphism, seizure disorder, congenital anomalies (e.g., cardiac and renal). Microcephaly, dysgenic corpus callosum (high penetrance, 70%). Periventricular nodular heterotopia, polymicrogyria, cerebellar malformations, hydrocephalus. ACC (medium penetrance 25–45%). Brain malformations including ACC (medium penetrance 25%; high penetrance (80%) for mosaic tetrasomy 8p), speech problems. Lissencephaly  ACC (high penetrance 75%), microcephaly, craniofacial dysmorphism. Duplication associated with autism.

ACC, agenesis of corpus callosum; DD, developmental delay; ID, intellectual disability.

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et al., 2014]. Formation of the CC involves normal neuronal and glial cell proliferation (neurogenesis), midline patterning, callosal neuron migration and specification, axon guidance, and post‐guidance development. There is therefore no one unifying genetic pathway underlying ACC but rather multiple complex and interacting ones. Consequently there are currently over 100 human genes and an additional number of mouse genes implicated in these processes [O’Driscoll et al., 2010; Edwards et al., 2014].

ISOLATED OR SYNDROMIC ACC The task of identifying the underlying genetic condition for patients with ACC is daunting; with over 200 genetic syndromic conditions associated with ACC listed in the Online Mendelian Inheritance in Man (OMIM) database (accessed March 2014). Many of these conditions have very variable phenotypes—and there may be members of the same family with the same genetic mutation who have partial or complete ACC, hypoplasia of the CC, or an apparently normal CC. Additional neuroanatomical and co‐morbid clinical features can also be very variable within and between families. Some disorders, such as Aicardi syndrome, do not yet have an identified genetic cause. Where it is possible, identification of the underlying causal diagnosis is of paramount importance in guiding management (e.g., investigating for co‐ morbid conditions, such as Hirschsprung in patients with Mowat–Wilson syndrome), allowing families to access appropriate support groups, and accurate reproductive counseling. Currently, identification of the underlying diagnosis is achieved less than 50% of the time. It is anticipated that advances in gene identification and genetic diagnostics (including NGS “panels”, exome and whole‐ genome sequencing) will improve the diagnostic yield. Such newer diagnostic techniques are likely to be particularly useful when the patient does not have “typical” features of a known genetic syndromic condition, or indeed where

the range of presentations for a particular genetic cause is currently not clear, and may include “non‐syndromic” intellectual disability. The diagnostic yield for patients with apparently isolated “non‐syndromic” ACC is particularly low at present [Edwards et al., 2014]. An example of the value of genome‐ wide NGS techniques was demonstrated in a recent exome sequencing project on a cohort of consanguineous families who were described as having essentially non‐ syndromic neuropsychiatric conditions and ACC. Recessive mutations in the gene C12orf57 were identified in 4 out of 25 families [Akizu et al., 2013]. Mutations in C12orf47 have also been identified in families with craniofacial, cardiac, neurological, and visual abnormalities including colobomatous microphthalmia [Salih et al., 2013; Zahrani et al., 2013], and it has been suggested that mutations in C12orf57 is the major cause of Temtamy syndrome, a previously described multiple‐congenital anomaly syndrome [Temtamy et al., 1996]. Whole genome approaches (including exome and genome sequencing) may represent the future of genetic investigation for patients with ACC. There are limitations and disadvantages of such approaches, including the identification of variants of unknown significance and “co‐incidental” genetic mutations that predispose to adult‐onset, potentially incurable, conditions. These tests are still not generally first‐line investigations, and clinical acumen and targeted testing is still appropriate.

CLINICAL GUIDE TO PRENATAL DIAGNOSIS OF CC ABNORMALITIES Ideally antenatally detected structural anomalies of the brain are managed by an interdisciplinary team including Maternal Fetal Medicine (MFM) specialists, midwifes, genetic counselors/social workers, clinical geneticists, neuroradiologists, fetal pathologists, pediatric neurologists, and neonatologists/ pediatricians. The CC first appears in the genu region at 13–14 weeks, and follows a cranio‐caudal progression to form the body, the isthmus, and the splenium.

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The anterior part of the rostrum appears last [Volpe et al., 2006]. By 18–22 weeks the final shape of the CC is apparent on imaging although further thickening occurs throughout pregnancy and infancy (see Table III). Antenatal imaging earlier than or at 18–20 weeks (the usual timing of standard US screening) does not reliably detect total agenesis, partial agenesis, or hypoplasia of the CC (see Fig. 1) [Bennett et al., 1996]. Indirect US features that may indicate a CC anomaly include the absence of the cavum septi pellucidi, colpocephaly (dilatation of the atria and occipital horns of the lateral ventricles), abnormal course of the pericallosal artery, widening of the interhemisphere fissure, and radial disposition of the sulci on the internal aspects of the hemispheres [Santo et al., 2012]. Once an abnormality of the CC is suspected distinguishing between an isolated and a complex case is difficult. A detailed morphology US in a specialist center is recommended looking for intra and extracranial abnormalities and an amniocentesis offered for cytogenetics or chromosome microarray (CMA) analysis. Standard cytogenetic karyotype is abnormal in 17.8% of cases and such cases often have associated findings on imaging [Santo et al., 2012]. Prenatal CMA looking for microdeletions/microduplications is becoming increasingly available. Postnatal CMA detects up to 9.4% of pathogenic CNV based on one recent study [Sajan et al., 2013]. Screening for congenital infection is also recommended on maternal blood and amniotic fluid (if available) even though the detection rate is likely to be low. The most common brain anomalies associated with CC include posterior fossa anomalies, interhemispheric cysts, and neuronal migration disorders found in 45.8% of cases on a recent review [Sotiriadis and Makrydimas, 2012]. Fetal MRI is recommended as this allows

The most common brain anomalies associated with CC include posterior fossa anomalies, interhemispheric

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TABLE III. Timeline of Corpus Callosum Development [Adapted from Santo et al., 2012; Edwards et al., 2014] First trimester

Timing

6 weeks gestation

Second Trimester 13–14 weeks 14–15 weeks 18–19 weeks post post post conception conception conception

Developmental Axons destined Pioneering axons to cross the stages of begin to midline can corpus cross the be seen callosum midline growing medially within the hemispheres

cysts, and neuronal migration disorders found in 45.8% of cases on a recent review. Fetal MRI is recommended as this allows direct visualization of the CC and may identify additional brain abnormalities.

direct visualization of the CC and may identify additional brain abnormalities. Ultrasound imaging has a false positive rate of 20% [Santo et al., 2012]. Prenatal MRI is preferable after 22 weeks as it provides improved detection of additional abnormal gyral patterns and heterotopia in up to 22.5% of cases [Santo et al., 2012]. The earlier the prenatal MRI (20 weeks or less) the greater the likelihood that further structural brain anomalies will be missed. Other imaging modalities may become available in clinical practice in the next few years in order to help with prognosis advice (e.g., tractography) [Edwards et al., 2014]. Exome or genome testing may also have a role in the prenatal setting in the future as genetic technology becomes more advanced (Table IV). The Supplementary Table S1 (see supporting information online) describes the large number of syndromes associated with ACC. The exact pro-

Anterior sections begin to grow

Posterior sections being to grow

Postnatal 20 weeks post conception

Third Trimester

0–2 months

2 months‐ adolescence

Ongoing Ongoing Molecular and Shape of activity axonal axonal corpus dependent growth growth callosum axonal complete pruning

portion of genetic syndromes in prenatal ascertained cases is difficult to quantify due to ascertainment bias of the cohorts described in the literature. The presence of additional US/MRI findings suggests a less favorable prognosis but a specific diagnosis is often not possible. Many couples elect to terminate the pregnancy in these circumstances. Many couples choose to interrupt the pregnancy even in the absence of additional abnormal findings because

of their concerns about a poor neurodevelopmental outcome. There is relatively little data looking at outcome in the context of isolated ACC and PACC although the emerging trend suggests a better outcome than previously expected. A recent review looked at the developmental outcome in 132 fetuses with isolated ACC from 16 studies and suggested that 71.2% have intelligence in the normal range, 13.6% have borderline or moderate disability, and

TABLE IV. Summary of Management for Antenatally Diagnosed CC Abnormalities US 18–20 weeks False positive rate 20%. Maternal–fetal medicine including detailed morphology ultrasound. Clinical Genetics assessment. Amniocentesis Chromosome microarray (take parental DNA samples for parental studies if required). Save DNA cell line for potential genetic testing. Screening for congenital infection on maternal blood and amniotic fluid. Fetal MRI 20–22 weeks or later. 22% have additional‐cerebral findings. Diagnosis Complex or isolated. Poor prognosis versus normal or near normal outcome in 75%. Management options. Post delivery examination Stillborn or neonatal. Follow up and genetic counseling. US, ultrasound; MRI, magnetic resonance imaging.

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15.2% have severe disability [Sotiriadis and Makrydimas, 2012]. In many of these cases the neurodevelopmental data, follow‐up period and imaging modality varied widely. When limiting the analysis to isolated ACC, prenatal MRI and standardized neurodevelopmental assessment the rates were 75.4% and 11.6% for normal and severe disability, respectively [Sotiriadis and Makrydimas, 2012]. In a 10‐year follow‐up study of an original cohort of 17 children with antenatally detected isolated ACC, 27% had borderline intelligence and 73% were in the normal range [Moutard et al., 2012]. More subtle learning difficulties however were prevalent in this second group. For an ongoing pregnancy of apparently isolated ACC or PACC with a normal CMA, serial US imaging is recommended to monitor growth and fetal wellbeing. The recent review by Santo et al. [2012] suggests that 15.1% of cases thought to be isolated prenatally were found to have additional abnormalities after birth. Postnatal assessment including MRI of all babies with CC abnormalities (isolated/complex) is very important in order to establish a diagnosis. Learning difficulties appear to be common in cases of isolated ACC [Moutard et al., 2012] so long‐term neurodevelopmental surveillance is recommended.

For stillborn babies with isolated or complex CC anomalies post‐delivery investigations ought to be offered including external examination by a dysmorphologist, and a full autopsy (including brain) in order to obtain information to aid genetic counseling (see Supplementary Table S1 in supporting information online). Where a specific diagnosis is forthcoming the genetic implications to the couple and their reproductive options can be discussed.

CLINICAL GUIDE TO POSTNATAL REVIEW OF PATIENT WITH CC ABNORMALITIES The postnatal diagnosis of CC anomalies usually arises following the birth of a baby with apparently isolated ACC diagnosed in pregnancy or following neuroimaging of a child with developmental delay or epilepsy. The question is whether an etiological diagnosis is possible to aid management, provide prognostic information, and genetic counseling. Key steps in the assessment, investigation, and management of the postnatal patient with ACC are summarized in Table V. Two postnatal case series, where assessment of patients included review by a clinical geneticist and chromosomal

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studies, identified a syndromic or chromosomal cause in 33% [21/62, Bedeschi et al., 2006] and 39% [11/28, Schell‐ Apacik et al., 2008] of cases. Many of the genetic syndromes associated with ACC have highly variable neurological and neuroanatomical features, which may range from essentially “non‐syndromic” borderline intellectual disability to profound developmental delay with additional neuroanatomical abnormalities and congenital anomalies. It is also striking that many genetic syndromes have overlapping associated clinical features. In particular ocular abnormalities and “midline” congenital anomalies including hypertelorism, clefting of the lip/ palate, congenital cardiac anomalies, and urogenital abnormalities feature in many different syndromic conditions associated with ACC. This may reflect commonalities in developmental pathways affecting midline patterning. With these diagnostic difficulties in mind we have suggested key features that physicians should consider in their clinical assessment (Table VI) and diagnostic investigations (Tables VII– IX) of the postnatal patient with ACC. The intention is that these guides should be used with the table of genetic syndromes associated with ACC (Supplementary Table S1 in supporting information online) that

TABLE V. Summary of Management for Postnatally Diagnosed CC Abnormalities Pediatric, Neurology, and Clinical Genetics Review. Family history. Full history and examination (see Table VI and Supplementary Table S1 online for details). Pediatric Neuroradiologist review of MRI brain (see Table VII) Ophthalmology and Audiology review (see Table VIII). Investigations (see Table IX) Chromosome microarray (consider repeating postnatally if low resolution targeted array done prenatally). DNA extraction and storage for targeted genetic testing if clinical diagnosis suspected. Metabolic investigations if metabolic diagnosis suspected, e.g., plasma and csf lactate, urine organic and amino acids, csf and plasma amino acids (? Glycine ratio), VLCFA, 7 dehydrocholesterol. Consider screening for congenital infections if suggestive symptoms or signs. Consider exome/whole genome sequencing or NGS “panel” (e.g., for intellectual disability) if no diagnosis and important remaining management/recurrence questions. Genetic counseling and discussion of support groups 2–3% recurrence risk if isolated and no family history. Neurocognitive/psychological follow‐up, including for adolescence and young adulthood

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TABLE VI. Key Features to Consider on Clinical Assessment of the Postnatal Patient with ACC Family history Three‐generation family pedigree. Male pregnancy loss (suggestive of FLNA mutations). Craniofacial/digital/neurocognitive features in female relatives (e.g., ocular hypertelorism in OG/BBBS, adducted thumbs and borderline intellectual disability in L1, borderline intellectual disability in ARX). History of renal cell cancer and hereditary leiomyomatosis (carriers of Fumarase Deficiency) or cancers suggestive of Lynch syndrome, e.g., Gastrointestinal and endometrial (relatives of patients with CMRDS). Maternal phenylketonuria. Antenatal history Antenatal imaging (US/Prenatal MRI). Any associated congenital anomalies? Antenatal chromosomal testing (pathological or contributory copy number variant identified?). Symptoms suggestive of congenital infection (e.g., CMV, rubella, toxoplasmosis, influenza). Teratogenic exposures including alcohol intake. Polyhydramnios (e.g., PS, FS, Hydrolethalus). Intra‐uterine growth restriction/microcephaly (e.g., MOPD, NLS, SLO, IGF1 deficiency). Medical history Severity and nature of neurological/cognitive/behavioral features. Characteristic personality (e.g., MED12, SLO). Movement disorder (e.g., ARX). Psychiatric features (e.g., FLNA, AS2, MED12). Any suggestion of progressive neurological symptoms (e.g., progressive peripheral neuropathy in AS2) or developmental regression (e.g., metabolic condition). Any visual or hearing impairment? Any unusual symptoms, e.g., episodic hyperventilation (PHS), episodic hypothermia and hyperhidrosis (SS1), stimulus‐induced drop attacks (CLS), mirror movements (Isolated GnRH deficiency). Pattern of postnatal growth, e.g., tall stature (PS, SS2, MSS); short stature (MOPD, SCKS, IGF1 deficiency, NLS, RTS, TCS). Systemic symptoms, e.g., combined immunodeficiency (VS), hypogonadotropic hypogonadism (Isolated GnRH deficiency), primary hypothyroidism (EDHHACC), anemia secondary to alpha‐thalassemia (ATRX). Any non‐cerebral structural anomalies, e.g., congenital diaphragmatic hernia (FS, DBS, PS), omphalocele (DBS) laryngo‐tracheo‐ esophageal defects (OG/BBBS), cardiac (MWS1, TARP, TCS, FLNA, SLO, TS, SS2, RTS, OG/BBBS, MED12, DS, CLS, GS, ciliopathy spectrum), asplenia/internal organ malposition (ciliopathy spectrum, IS), renal (ciliopathy spectrum, SS2, RTS, FS, PS [renal tumours]), anal anomalies/constipation (MWS1, MED12, GPS, PHS), jaw keratocyts (GS). Examination Craniofacial dysmorphism or facial gestalt suggestive of a syndromic diagnosis (see Supplementary Table S1, group A and Fig. 2A–C). In particular: craniosynostosis (Apert, CJS, MCPH/SCKS) or facial asymmetry (CJS), hypertelorism (multiple), hypotelorism (holoprosencephaly), blepharophimosis (MWS2, BPIDS), subtle ocular abnormalities, distinctive nose (e.g., GPS, PHS, MOPD, RTS; nose broad/bifid in CFNS, Pai, and Hydrolethalus syndromes), distinctive ears (e.g., MWS1, NLS, FS, MED12, YVS), orofacial clefting (e.g., ciliopathy spectrum including OFD1, OG/BBBS, PS, TARP, PPS, FS, MWS2, SLO, Hartsfield. Midline cleft lip in Pai, Sakoda, and ALX syndromes), tongue abnormalities (OFD1), teeth abnormalities (e.g., talon cusps RTS, single central incisor Holoprosencephaly), micrognathia/Pierre Robin (e.g., TARP, ACC with mental retardation, ocular coloboma and micrognathia, FS, MED12, MWS2, MSS, MOPD, TCS, NLS, YVS). Skeletal features. In particular: hands and feet: poly/syndactyly (Apert, OFD1, SLO, ciliopathy spectrum, Greig), broad thumbs (RTS), abnormal nails (CFNS), palmar pits (GS), fleshy, hyperextensible tapered fingers (CLS), distal digital hypoplasia (FS), absent/ hypoplastic fifth distal phalanges (CSS), hypoplastic fingers or thumbs (YVS), adducted (clasped) thumbs (L1), ectrodactyly (Hartsfield). Spinal abnormalities causing (kypho) scoliosis (e.g., CLS, MWS2, GPS, SS2, ARX, AS1, AS2, CFNS, GS). Absent/hypoplastic clavicles (YVS). Contractures, e.g., muscular dystrophy‐ dystroglycanopathy type A spectrum conditions, NLS, MWS2, ARX, GPS). Shortened limbs (e.g., SLO, Apert, MOPD, PPS, DS, Hydrolethalus). “Marfanoid” habitus or connective tissue differences (e.g., MED12, FLNA). Absent/hypoplastic patellae (GPS). Skin features, e.g., cutis laxa (PYCR1), severe ichthyosis (NLS), linear skin defects (MLSD), oculocutaneous hypopigmentation (VS), hypohidrotic ectodermal dysplasia (EDHHACC). Abnormalities of external genitalia (e.g., MWS1, ATRX, OG/BBBS, GPS, CFNS, TCS, DS, SLO, NLS, MED12, YVS, SOX2). Neurological findings: e.g., nystagmus (CASK, ciliopathy spectrum, CFEOM3A), hypotonia (multiple), spasticity (ARX, L1), spastic paraplegia (ARSP11), signs peripheral neuropathy/areflexia (AS2), movement disorder/tremor/ataxia (CASK, ARX, L1), muscle weakness (Muscular dystrophy‐dystroglycanopathy type A spectrum conditions). Abbreviated conditions listed in Table X; US, ultrasound; MRI, magnetic resonance imaging; CMV, cytomegalovirus.

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TABLE VII. Neuroradiological Features that May Point to a Particular Syndromic Diagnosis for the Postnatal Patient with ACC Cerebral ectopic calcification (falx‐ GS, NLS), Cerebellar hypoplasia (CASK), Lissencephaly (LISS), Hydrocephalus with or without stenosis of the aqueduct of Sylvius in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia (L1), Molar tooth sign (Joubert Spectrum Disorders), Hypoplasia of the thalamus producing a V‐shaped enlarged third ventricle (C12orf57), Symmetric cystic lesions and gliosis in the cortex, basal ganglia, brain stem, or cerebellum (PDH deficiency), Periventricular nodular heterotopia (FLNA), Sphenoethmoidal meningoencephalocele (Sakoda complex), Severe hydrocephalus/anencephaly, olfactory aplasia, fused thalami, hypothalamic hamartoma (Hydrolethalus), CNS tumors (CMRDS), CC lipoma (ALX), Holoprosencephaly spectrum. Abbreviated conditions listed in Table X; CNS, central nervous system; CC, corpus callosum.

has been subdivided into groups based on clinical “handles” to aid navigation of such a large number of genetic syndromes. These are: group A—recognizable syndromic diagnoses with characteristic craniofacial dysmorphism (e.g., Fig. 2A–C); group B—syndromes with primarily neuroanatomical/neurological features (no striking craniofacial or other clear “handles”); group C—syndromes with prominent ocular phenotype (e.g., Fig. 2D,E); group D—metabolic conditions;

group E—ciliopathy spectrum conditions; group F—“other” syndromes without craniofacial, ocular or neurological handles.

Expert review of the neuroimaging is critical in the ascertainment and classification of CC abnormality and detection of any additional neuroanatomical features that could point to a particular diagnosis or offer prognostic information (see Supplementary Table S1 “neuroanatomical features” and group B). Therefore involvement

of a Pediatric Neuroradiologist and Neurologist is very helpful. Examples of radiological features that might point to a particular diagnosis are listed in Table VII. Abnormalities of the visual system are commonly seen in association with ACC and may point towards a particular syndromic diagnosis. Therefore formal pediatric ophthalmological review is recommended for all postnatal patients with ACC. Syndromes in Group C in the Supplementary Table S1 have prominent and consistent ocular features, but ocular

TABLE VIII. Examples of Ophthalmological Findings in a Number of Syndromic Causes of ACC 1

MWS (microphthalmia and Axenfeld anomaly), AS1 (retinal see Fig. 2D,E), DBS (high myopia, retinal detachment, progressive vision loss, and iris coloboma), Ciliopathy spectrum (e.g., ocular motor apraxia, nystagmus, colobomas, retinal dystrophies), VS (cataracts), Sakoda complex (multiple including “morning glory” abnormality), FS (cloudy corneas, microphthalmia), TS (optic atrophy, coloboma), Muscular dystrophy‐ dystroglycanopathy type A spectrum conditions (microphthalmia, colobomas, anterior chamber abnormalities, retinal dysplasias), RTS (cataract, coloboma), Pai syndrome (anterior segment abnormalities, heterochromia iris, and conjunctival lipoma). Abbreviated conditions listed in Table X.

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TABLE IX. Key Investigations for Postnatal Patients with ACC Chromosomal microarray to detect pathogenic copy number variant(s) with appropriate genetic counseling [e.g., Palmer et al., 2012]. Metabolic testing, e.g., blood lactate and pyruvate, blood pH, plasma amino acids, urine organic and amino acids, 7 dehydrocholesterol (SLO), CSF lactate (PDH deficiency), csf: plasma glycine ratio (NKHG), VLCFA (neonatal adrenoleukodystrophy) if any features to suggest metabolic cause. Screen for congenital infections if there is a prenatal history or associated suggestive symptoms (e.g., IUGR, congenital rash, microcephaly, hepatic involvement). Targeted molecular genetic testing for a particular genetic syndromic diagnosis if clinically suspected. Abbreviated conditions listed in Table X.

defects can be present in many other ACC syndromes (examples listed in Table VIII). A number of blood, urine, and CSF investigations are recommended for patients presenting postnatally with

ACC and developmental delay. These are summarized in Table IX. If the above investigations are not informative, then consideration can be made, after discussion with the patient and family about the possibility of next

generation sequencing (NGS). Options include a NGS “panel” (e.g., ciliopathy panel, intellectual disability panel) or exome/whole genome sequencing. A specific etiological diagnosis for isolated ACC remains elusive in many cases.

Figure 2. Clinical photographs of features in patients with syndromes associated with ACC (A–C) Male with Mowat–Wilson syndrome in infancy and early childhood showing typical facial gestalt and uplifted ear lobe. (D,E) Bilateral retinal lacunae typical of Aicardi syndrome in a female with antenatally detected ACC.

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GENETIC COUNSELING TABLE X. Key to Conditions Abbreviated in Tables VI–IX ALX, ALX related Frontonasal Dysplasia syndromes ARSP11, Autosomal recessive spastic paraplegia 11 ARX, ARX related syndrome AS1, Aicardi syndrome, AS2, Andermann syndrome ATRX, Alpha Thalassemia mental retardation syndrome BPIDS, Blepharophimosis‐ptosis‐intellectual disability syndrome CASK, CASK related disorder CFEOM3A, Congenital fibrosis of ocular muscles 3A CFNS, Craniofrontonasal syndrome CJS, Curry‐Jones syndrome CLS, Coffin–Lowry syndrome CMRDS, Constitutional mismatch repair deficiency syndrome CSS, Coffin–Siris syndrome DBS, Donnai‐Barrow syndrome DS, Desmosterolosis EDHHACC, Ectodermal dysplasia hypohidrotic hypothyroidism agenesis of corpus callosum FLNA, Filamin‐A related Syndromes FS, Fryns Syndrome GPS, Genitopatellar syndrome GS, Gorlin syndrome IS, Ivemark syndrome L1, L1CAM related syndromes LISS, Lissencephaly syndromes MCPH, Primary autosomal recessive microcephalies MED12, MED12 related syndromes MLSD, Microphthalmia linear akin sefects syndrome MOPD, Microcephalic osteodysplasic dwarfism MSS, Marshall–Smith syndrome MWS1, Mowat–Wilson syndrome MWS2, Marden–Walker syndrome NKHG, Non‐ketotic Hyperglycinemia NLS, Neu‐Laxova syndrome OG/BBBS, Opitz G/BBB syndrome OFD1, Oro‐Facial‐Digital syndrome 1 PHS, Pitt–Hopkins syndrome PPS, Peter’s Plus syndrome PS, Perlman syndrome RTS, Rubenstein–Taybi syndrome SCKS, Seckel Spectrum syndrome SLO, Smith–Lemli–Opitz syndrome SS1, Shapiro syndrome SS2, Sotos syndrome TARP, Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of left superior vena cava syndrome TCS, Toriello‐Carey syndrome TS, Temtamy syndrome VLCFA, Very long chain fatty acid VS, Vici syndrome YVS, Yunis–Varon syndrome

When a genetic syndromic diagnosis with an established pattern of inheritance, or a genetic cause on whole genome testing (CMA or exome/ genome sequencing) is reliably made, appropriate reproductive counseling can be made. Unfortunately it is likely that at least 50% of the time, a clear genetic diagnosis will not be made, and therefore advice on the likelihood of recurrence can only be given empirically. A recurrence risk of 2–3% for siblings of probands with apparently isolated sporadic ACC has been quoted in the literature [Young, 1995]. Ongoing clinical genetic review, in view of likely improvements in genetic diagnostics, would be appropriate. Referral to a fetal medicine unit to the parents of an affected child in a subsequent pregnancy, for detailed neuroradiological review, including consideration of US and prenatal MRI, should also be offered. There are a growing number of patient and family support groups for ACC. Many families find contact with such groups helpful and some helpful websites for families are listed in Table XI.

CONCLUSIONS Isolated or syndromic ACC is a relatively rare condition that may be identified antenatally by US and cerebral MRI or postnatally after MRI for investigation of developmental delay. The number of cases that are missed by routine antenatal US surveillance is unclear. The finding of ACC should prompt detailed clinical assessment in order to determine and manage the underlying condition. Despite this many cases remain undiagnosed. There are numerous conditions in which ACC may be a feature, many being recognized by their associated clinical findings. If a diagnosis is made, then specific information can be conveyed to the family and health providers to aid management and determine the chance of recurrence for the couple or relevance to other family members. The rate of intellectual disability for

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TABLE XI. Patient and Family Resources Agenesis of the Corpus Callosum Support Groups National Organization for Disorders of the Corpus Callosum (NODCC) (USA) www.nodcc.org Australian Disorders of the Corpus Callosum (ausDoCC) (Australia) www.ausdocc. org.au Corpal: Support group for ACC and Aicardi Syndrome (UK) www.corpal.org.uk Parent information sheets http://www.umaine.edu/edhd/about/research/acc/what‐is‐agenesis‐of‐the‐ corpus‐callosum‐acc/ http://agenesiscorpuscallosum.com.blogspot.com.au/—(written by a parent) https://sites.google.com/site/accawareness/me‐and‐my‐acc—(written by an adult with ACC) http://www.knowingalex.com/ (eBook written by an adult with ACC and his Mother)

antenatally diagnosed apparently isolated cases of ACC or PACC is approximately 25%. A normal or near normal neurodevelopmental outcome occurs in approximately 75% of cases based on the available literature. Subtle neurological, social, and learning deficits may still occur but have not been studied in detail. Longitudinal neurocognitive follow‐up is recommended for all children with ACC/PACC whether ascertained pre or postnatally.

ACKNOWLEDGMENTS Dr. Jeanette Taylor, Paediatric Radiologist, Prince of Wales Hospital, Sydney, and Dr Glenn McNally, Director of Medical Imaging, Royal Women’s Hospital, Sydney, for their very helpful assistance with compilation of neuroimaging, Dr. Ian Andrews, Consultant Neurologist, Sydney Children’s Hospital, for useful comments on the text, Pamela Dawes in the Medical Imaging Department at Sydney Children’s Hospital for formatting the images and to the patients and their families for allowing inclusion of clinical photographs.

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