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Agenesis of the Corpus Callosum

Published:November 07, 2020DOI:https://doi.org/10.1016/j.ajog.2020.08.179

      Introduction

      The corpus callosum is the major interhemispheric bundle of commissural fibers in the brain that allows the transfer of motor, sensory, and cognitive information between the 2 hemispheres. Several abnormalities may affect the corpus callosum, including complete or partial agenesis, dysgenesis (an abnormal shape), or hypoplasia (decreased thickness).
      • Rüland A.M.
      • Berg C.
      • Gembruch U.
      • Geipel A.
      Prenatal diagnosis of anomalies of the corpus callosum over a 13-year period.
      These malformations can occur in isolation; in association with chromosomal, syndromic, or monogenic disorders; or, rarely, secondary to infectious, ischemic, or teratogenic causes.

      Definition

      Agenesis of the corpus callosum (ACC) refers to the complete or partial absence of the main commissural fiber tracts that connect the cerebral hemispheres. In partial agenesis, the posterior segments of the corpus callosum are usually missing.

      Ultrasound Findings

      Complete ACC is typically suspected in the second-trimester ultrasound examination when the cavum septi pellucidi (CSP) is not visualized in the axial plane (Figure 1, A ). The concurrent absence of the CSP and the corpus callosum is due to their shared embryogenesis. Another finding that raises the suspicion for ACC is the shape and size of the lateral ventricles. The teardrop shape of the ventricles (colpocephaly) reflects the disproportionally enlarged occipital horns relative to the frontal horns (Figure 1, A). Dilation of the occipital horns is caused by reduced white matter formation in the absence of callosal axons, whereas dilation of the frontal horns is limited by the firm caudate nuclei at their lateral borders. Furthermore, the frontal horns are frequently compressed medially by the bundles of Probst, resulting in their pointed and slitlike appearance. Despite this conspicuous change in ventricular configuration, atrial width measurements are usually within the reference range (<10 mm) in most cases of ACC before 24 weeks of gestation. With advancing gestational age, however, ventriculomegaly becomes more common.
      International Society of Ultrasound in Obstetrics & Gynecology Education Committee
      Sonographic examination of the fetal central nervous system: guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’.
      In addition, the medial walls of the teardrop-shaped ventricles are positioned parallel to each other and to the midline (Figure 1). It should be noted that these anatomic findings can be seen to varying degrees in partial ACC as well, but they tend to be more subtle.
      Figure thumbnail gr16
      Figure 1Agenesis of the corpus callosum, axial plane
      A, Absence of the cavum septi pellucidi and an uninterrupted midline separating the frontal lobes. B, Same image as image A with labels highlighting the widened interhemispheric space (small arrows). The posterior horns of the lateral ventricles are disproportionately dilated relative to the anterior horns, resulting in a “teardrop” configuration (colpocephaly). In addition, note that the ventricles are parallel to each other and to the midline (long arrow).
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.
      With partial ACC, the CSP may appear (1) normal, (2) dysmorphic, or (3) unusually short and wide in the axial plane (Figure 2).
      • Youssef A.
      • Ghi T.
      • Pilu G.
      How to image the fetal corpus callosum.
      A CSP length-to-width ratio of <1.5 has indeed been proposed as a screening marker for the detection of partial ACC.
      • Youssef A.
      • Ghi T.
      • Pilu G.
      How to image the fetal corpus callosum.
      Figure thumbnail gr17
      Figure 2Partial agenesis of the corpus callosum, axial plane
      Note the dysmorphic, short, and wide cavum septi pellucidi.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.
      When the above described indirect signs are noted in the axial plane, the next step in the evaluation is the fetal neurosonogram, in which the coronal and sagittal planes are examined as well.
      International Society of Ultrasound in Obstetrics & Gynecology Education Committee
      Sonographic examination of the fetal central nervous system: guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’.
      In the coronal plane, the absence of the CSP and the corpus callosum allows the roof of the third ventricle to expand upward into the interhemispheric space and reach the midline falx, which is most evident in the midcoronal plane (Figure 3). The anterior horns of the lateral ventricles tend to be “comma shaped” and concave toward the midline in this view (Figure 3). Not all of the above indirect signs need to be present simultaneously to suspect the diagnosis of ACC.
      Figure thumbnail gr18
      Figure 3Coronal section of 2 different fetuses with ACC
      A, A fetus at 30 5/7 weeks of gestation with a dilated and abnormally shaped third ventricle. The roof of the diamond-shaped third ventricle is elevated and reaches the midline falx. The frontal horns of the lateral ventricles appear parallel, slitlike, and demonstrate a slight crescent-shaped concavity toward the midline. B, Coronal section of a fetus at 20 1/7 weeks of gestation. The findings are similar to those shown in image A.
      3rd V, third ventricle; Ant horn, anterior horn of the lateral ventricle.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.
      In the median (midsagittal) plane, the corpus callosum is normally visualized as an anechoic C-shaped structure with echogenic boundaries (Figure 4, A and B). The pericallosal artery is seen just above the corpus callosum outlining its shape (Figure 4, C). All anatomic segments of the corpus callosum should be fully developed by 20 weeks of gestation.
      Figure thumbnail gr19
      Figure 4Normal corpus callosum and pericallosal artery at 22 weeks of gestation
      A, Normal corpus callosum with fully developed anatomic segments. B, A zoomed and labeled view of a normal corpus callosum. C, Color Doppler demonstrating the normal pericallosal artery course above and in very close proximity to the corpus callosum.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.
      The definitive diagnosis of complete or partial ACC is made in the directly acquired 2-dimensional median plane
      • Youssef A.
      • Ghi T.
      • Pilu G.
      How to image the fetal corpus callosum.
      or in the median plane of an axially acquired 3-dimensional volume (Figure 5).
      • Bornstein E.
      • Monteagudo A.
      • Santos R.
      • Keeler S.M.
      • Timor-Tritsch I.E.
      A systematic technique using 3-dimensional ultrasound provides a simple and reproducible mode to evaluate the corpus callosum.
      • Monteagudo A.
      • Timor-Tritsch I.E.
      • Mayberry P.
      Three-dimensional transvaginal neurosonography of the fetal brain: ‘navigating’ in the volume scan.
      • Pilu G.
      • Segata M.
      • Ghi T.
      • et al.
      Diagnosis of midline anomalies of the fetal brain with the three-dimensional median view.
      Color Doppler visualization of the pericallosal artery with very low pulse repetition frequency settings can provide further evidence that the corpus callosum is present (Figure 4, C) or absent (Figure 5, B). However, diagnostic conclusions should not be based solely on an abnormal course of the pericallosal artery. Transvaginal scans can be helpful in demonstrating more subtle callosal abnormalities and parenchymal brain abnormalities if the fetus is in a vertex presentation.
      International Society of Ultrasound in Obstetrics & Gynecology Education Committee
      Sonographic examination of the fetal central nervous system: guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’.
      Figure thumbnail gr20
      Figure 5Median or midsagittal view of complete and partial ACC
      A, Complete absence of the corpus callosum and CSP. B, Color Doppler fails to visualize the pericallosal artery in the anatomic location where it would normally be expected to branch off the anterior cerebral artery (oval). C, Partial absence of the corpus callosum. Only the genu and anterior portion of the body of the corpus callosum is present, whereas the posterior body and the splenium are absent. The arrow points toward the sharp demarcation at which the corpus callosum is interrupted.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.

      Associated Abnormalities

      ACC has been described in association with more than 200 genetic syndromes and chromosomal anomalies.
      • Palmer E.E.
      • Mowat D.
      Agenesis of the corpus callosum: a clinical approach to diagnosis.
      Structural anomalies and syndrome-associated findings are common. Extracerebral fetal abnormalities are seen in a wide range of organ systems and are present in approximately 60% of ACC cases, of which cardiac and genitourinary malformations are the most common. Coexisting additional brain abnormalities occur in 46% of ACC cases.
      • Santo S.
      • D’Antonio F.
      • Homfray T.
      • et al.
      Counseling in fetal medicine: agenesis of the corpus callosum.
      Some of these abnormalities are better visualized by magnetic resonance imaging (MRI),
      • Griffiths P.D.
      • Brackley K.
      • Bradburn M.
      • et al.
      Anatomical subgroup analysis of the MERIDIAN cohort: failed commissuration.
      and others manifest only late in gestation or postnatally.
      • D’Antonio F.
      • Pagani G.
      • Familiari A.
      • et al.
      Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis.
      The most commonly diagnosed concurrent brain abnormalities are Dandy-Walker syndrome, vermian dysgenesis, disorders of neuronal migration, polymicrogyria, and gray matter heterotopia.
      Meningeal dysplasia induced by the same abnormal ontogenetic pathways that caused the ACC occasionally results in the development of sonographically echogenic lipomas in the midline (Figure 6) or in interhemispheric cysts. The latter can secondarily compress cerebrospinal fluid circulation and result in worsening ventriculomegaly.
      Figure thumbnail gr21
      Figure 6Axial section showing an echogenic nodular lipoma in a fetus with partial ACC
      The echogenic lipoma (arrow) has largely replaced the CSP and the genu of the corpus callosum.
      SMFM. SMFM Anomalies Consult Series #3. Am J Obstet Gynecol 2020.

      Differential Diagnosis

      A definitive ultrasonographic diagnosis of ACC should be possible in the median plane unless visualization and resolution are impaired. However, the indirect signs in the axial and coronal views require differential diagnostic considerations. If the colpocephalic ventricles are dilated, the broad differential diagnosis of ventriculomegaly should be considered. An enlarged interhemispheric space can occasionally be seen with brain atrophy, usually in the setting of microcephaly. Conversely, the ultrasonographic presence of a CSP can be mimicked by an interhemispheric cyst, by the widened interhemispheric space in conjunction with abnormal medial hemispheric sulcation patterns, or by the inclusion of the columns of the fornices underneath the floor of the CSP in the axial scanning plane.
      • Callen P.W.
      • Callen A.L.
      • Glenn O.A.
      • Toi A.
      Columns of the fornix, not to be mistaken for the cavum septi pellucidi on prenatal sonography.
      Because the etiology of ACC is heterogeneous, genetic testing, family history, and the presence of coexisting major and minor malformations can be helpful in the differential diagnosis.

      Genetic Evaluation

      Chromosomal abnormalities occur in 17% of ACC cases,
      • Palmer E.E.
      • Mowat D.
      Agenesis of the corpus callosum: a clinical approach to diagnosis.
      and even isolated complete or partial ACC carries a 4.8% and 7.5% risk for aneuploidy, respectively,
      • D’Antonio F.
      • Pagani G.
      • Familiari A.
      • et al.
      Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis.
      most commonly trisomies 18 and 13 and mosaic trisomy 8.
      • Palmer E.E.
      • Mowat D.
      Agenesis of the corpus callosum: a clinical approach to diagnosis.
      Significant copy number variants on chromosomal microarray analysis (CMA) occur in 5.7% of cases of complete or partial ACC.
      • D’Antonio F.
      • Pagani G.
      • Familiari A.
      • et al.
      Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis.
      Recent data also suggest that testing for single-gene variants
      • Edwards T.J.
      • Sherr E.H.
      • Barkovich A.J.
      • Richards L.J.
      Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes.
      or exome sequencing
      • de Wit M.C.
      • Boekhorst F.
      • Mancini G.M.
      • et al.
      Advanced genomic testing may aid in counseling of isolated agenesis of the corpus callosum on prenatal ultrasound.
      can identify the cause in some cases. Serologic testing for cytomegalovirus or Zika virus is rarely useful unless suggested by other findings.
      Diagnostic testing with amniocentesis for CMA should be offered when ACC is detected. Subject to institutional resource utilization policies, it is reasonable to initially perform karyotype analysis or fluorescence in situ hybridization, with reflex to CMA if these test results are normal. If there are additional anomalies, consanguinity, or a family history of a specific condition, gene panel testing or exome sequencing is sometimes useful because CMA does not detect single-gene (Mendelian) disorders. If exome sequencing is pursued, appropriate pretest and posttest genetic counseling by a provider experienced in the complexities of genomic sequencing are recommended. After appropriate counseling, cell-free DNA screening is an option for patients who decline a complete diagnostic evaluation, although this screening modality will not identify the underlying genetic cause in most cases other than the common aneuploidies.

      Pregnancy and Delivery Management

      A detailed ultrasound examination and neurosonogram should be performed as part of the initial workup. Fetal echocardiography is suggested because of the association with cardiac malformations. Fetal MRI is particularly useful in the workup of isolated ACC based on the ultrasound examination, because even subtle coexisting brain abnormalities can substantially worsen the prognosis. A third-trimester follow-up ultrasound examination is recommended to detect late-manifesting brain abnormalities. The route and site of delivery should be determined by routine obstetrical indications.

      Prognosis

      Complete and partial ACCs associated with coexisting brain abnormalities or genetic syndromes tend to lead to poor neurodevelopmental outcomes.
      • D’Antonio F.
      • Pagani G.
      • Familiari A.
      • et al.
      Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis.
      In contrast, isolated complete and partial ACCs have a better prognosis and appear to have similar outcomes. Prenatal counseling in isolated cases is challenging because of highly variable neurodevelopmental outcomes that cannot be predicted by the neuroanatomic profile. Borderline-moderate and severe neurodevelopmental delays are observed in 14.9% to 16.0% and 8.2% to 12.5% of isolated cases, respectively.
      • D’Antonio F.
      • Pagani G.
      • Familiari A.
      • et al.
      Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis.
      Epilepsy occurs in 7% to 16% of affected individuals,
      • D’Antonio F.
      • Pagani G.
      • Familiari A.
      • et al.
      Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis.
      and abnormal fine and gross motor controls are evident in approximately 10% of cases.
      • D’Antonio F.
      • Pagani G.
      • Familiari A.
      • et al.
      Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis.
      Deficits in higher language function, complex information processing, social functioning,
      • Palmer E.E.
      • Mowat D.
      Agenesis of the corpus callosum: a clinical approach to diagnosis.
      and learning disabilities
      • des Portes V.
      • Rolland A.
      • Velazquez-Dominguez J.
      • et al.
      Outcome of isolated agenesis of the corpus callosum: a population-based prospective study.
      have also been reported with prolonged follow-up, but these deficits tend to manifest later in life, usually at school age.

      Summary

      Complete and partial ACC are usually suspected when indirect signs are detected on routine axial scanning planes of the fetal brain. Not all signs have to be present simultaneously to suspect this diagnosis and to prompt detailed neuroimaging. Fetal neurosonography, by transvaginal ultrasonography if possible, should be performed to obtain the median and coronal planes. Fetal MRI and amniocentesis with CMA are important components in the prenatal workup. Prognostication in isolated ACC is difficult because of the variation in neurodevelopmental outcomes that cannot be predicted by neuroanatomic findings.

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